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Kepert, Cameron J., Lu Wei-Min, Peter C. Junk, Brian W. Skelton e Allan H. White. "Structural Systematics of Rare Earth Complexes. XI (‘Maximally’) Hydrated Rare Earth(III) Trifluoro- and Trichloro-acetates". Australian Journal of Chemistry 52, n.º 6 (1999): 459. http://dx.doi.org/10.1071/ch98042.
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Room-temperature single-crystal X-ray structure determinations carried out on ‘maximally’ hydrated rare earth(III) trifluoroacetates, Ln(tfa)3.x H2O, crystallized at room temperature, show the Ln = La, Ce adducts to be isomorphous and monoclinic, P 21/c, a ≈ 11·9, b ≈ 12·8, c ≈ 9·8 8 Å, β ≈ 103·7°, Z = 4; they are trihydrates. The Ln = Pr, Lu (and, implicitly, intermediate Ln) adducts are also monoclinic, P 21/c, Z = 4, and trihydrates, but of a different polymorph, with a ≈ 9·2, b 18·8, c ≈ 9·8 Å, β ≈ 114°. For the four determinations, conventional R values on |F| were 0·038, 0·032, 0·036, and 0·034 for No 2952, 4821, 4544, and 4092 independent ‘observed’ (I > 3σ(I)) diffractometer reflections respectively. The Ln = La, Ce adducts are two-dimensional polymers, the sheets parallel to the bc plane; the other systems are binuclear, the two metal atoms being linked by four bridging carboxylate O-tfa-O′ ligands. In both structural types, the metal atoms are eight-coordinate, but differ in the number of water molecules (2 cf. 3) in the O8 array. Extension of previous studies by single-crystal X-ray methods on the structural characterization of trivalent rare earth trichloroacetates, ‘maximally’ hydrated at local ambience, Ln(tca)3.x H2O, suggests the following arrays to be prevalent. The Ln = La adduct is a pentahydrate, monoclinic, P21/c, a 5·636(7), b 22·454(4), c 16·58(1) Å, β 90·52(8)°, Z = 4 f.u., R 0·035 for No 4154. The compound is a linear polymer along a, successive nine-coordinate La (separated by a) being linked by three O-tca-O′ bridging ligands at the opposite faces of a tricapped trigonal prismatic array, the equatorial sites being filled by water molecules. The Ln = Ce adduct is a trihydrate, monoclinic, P 21/c, a 10·071(2), b 22·973(2), c 20·222(5) Å, b 119·48(2)°, Z= 8 f.u., R 0·050 for No 5019. The array is also linear polymeric, but with successive Ce being linked alternately now by sets of two and then four O-tca-O′ bridging carboxylates along b, the Ln = Ce coordination number being diminished (relative to La) to eight with the coordination of two water molecules to each metal. Ln = Pr, Lu (and, presumptively, intermediate Ln) are dihydrates, triclinic, P 1, a ≈ 11·70, b ≈ 12·8, c ≈ 15·3 Å, α ≈ 71, β ≈ 77·85, γ ≈ 65·5°, Z = 4 f.u., R 0·056, 0·059 for No 5650, 5398. The array is a linear polymer, similar to that of the Ln = Ce adduct but alongside the bridging acetate pair one of the water molecules now bridges, resulting in a stepped Ln 1 array (along c) rather than a quasi-straight one as is found for the Ln = Ce (and La) adduct. Structure determinations are also recorded for rare earth(III) trichloroacetate ethanol trisolvates, Ln(tca)3.3EtOH. Adducts of Ln = La, Yb (and, implicitly, intermediate Ln) are isomorphous, triclinic, P 1, a ≈ 12, b ≈ 11·8, c ≈ 11·4 Å, α ≈ 114, β ≈ 100, γ ≈ 104°, Z = 2 f.u., R 0·056, 0·050 for No 3843, 4171. The complexes are centrosymmetric dimers [(EtOH)3(tca-O)Ln(O-tca-O′)4Ln(O-tca)(HOEt)3], the two metal atoms being linked by four O-tca-O′ bridging carboxylate groups; the metal atoms are eight-coordinate, the other four sites being occupied by four oxygen atoms from unidentate ethanol and carboxylate moieties. Bis(bis(2-pyridyl)aminium) bis(diaquatetrakis(trichloroacetato)lanthanate(III)), 2(dpaH+) [(H2O)2-(tca-O)(tca-O,O′)2La(O-tca-O′)2La(O,O′-tca)2(O-tca)(OH2)2]2-, is triclinic, P 1, a, 13·901(2), b 13·764(3), c 10·073(2) Å, α 104·04(2), β 108·93(2), γ 101·50(2)°, Z = 1 binuclear f.u., R 0·045 for No 4999. The anion is binuclear, the two nine-coordinate lanthanum atoms being linked by a pair of bridging O-carboxylate-O′ groups. The other seven sites of the LaO9 array are occupied by a pair of O,O′ -chelating and one O-unidentate carboxylate groups and a pair of water molecules.
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FU, CHIH-CHIANG, JASON SHIAN-CHING JANG, I.-SUI LEE e HUEI-SEN WANG. "STRAIN RATE DEPENDENCE ON THE HIGH TEMPERATURE MECHANICAL BEHAVIOR OF THE NI-18SI-3.0NB-1.0CR-0.2B INTERMETALLIC ALLOY". International Journal of Modern Physics B 23, n.º 06n07 (20 de março de 2009): 1040–46. http://dx.doi.org/10.1142/s0217979209060439.
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The effect of strain rate and temperature on the mechanical behavior of the Ni -18 Si -3.0 Nb -1.0 Cr -0.2 B alloy was investigated by atmosphere-controlled tensile testing in vacuum and air atmosphere at different strain rates and different temperatures. The results reveal that the Ni -18 Si -3.0 Nb -1.0 Cr -0.2 B alloy exhibits ductile mechanical behavior (UTS > 1200 MPa, ε > 8%) at room temperature under different atmosphere conditions. In addition, both of the ultimate tensile strength and elongation exhibit quite insensitive response with respect to the loading strain rate when tests are held at temperatures below 973K. The elongation of the samples tested in vacuum and air for the Ni -18 Si -3 Nb -1 Cr -0.2 B alloy exhibits a significantly increase with temperature from 973K to 1073K. In addition, all fracture surfaces tested at 1073K in vacuum and air atmosphere presents a typical ductile fracture surface, a fully dimpled fracture pattern. The fact of increasing in elongation at high temperature (1073K) is suggested to be attributed by the dynamic recrystallization that occurs preferentially around the dispersion phase or grain boundaries and so as to enhance the ductility by reducing the stress concentration at or near grain boundaries.
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Harb, Wael, Mansoor N. Saleh, Kyriakos P. Papadopoulos, Feng Chai, Maria Larmar, Giovanni Abbadessa, Brian Schwartz e Anthony Tolcher. "Clinical Trial Results from the Subgroup of Lymphoma/CLL in a Phase 1 Study of ARQ 092, a Novel Pan AKT-Inhibitor". Blood 126, n.º 23 (3 de dezembro de 2015): 5116. http://dx.doi.org/10.1182/blood.v126.23.5116.5116.
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Abstract Background: ARQ 092 is an oral allosteric, potent and selective AKT inhibitor with in vitro and in vivo activity in solid and hematological tumors. ARQ 092-101, the first clinical trial of ARQ 092, has enrolled more than 100 subjects with advanced solid tumors or recurrent malignant lymphoma. As reported previously, the dose escalation portion of the study has been completed and two dosing schedules (intermittent and weekly), are recommended for phase 2 studies. The recommended phase 2 dose (RP2D) for the intermittent dosing schedule is 200 mg once daily (QD) (one week on, one week off) and for the weekly dosing schedule is 300 mg twice daily (BID) (one day on, six days off). [1, 2] Enrollment in an expansion cohort at RP2Ds is ongoing. Here we report the results from 11 subjects with lymphoma/CLL. Material and Methods: Subjects with lymphoma/CLL have been enrolled and treated in the dose escalation and expansion cohorts with intermittent or weekly dosing schedule at the RP2Ds. Tumor responses for subjects with lymphoma were evaluated based on the Revised Response Criteria for Malignant Lymphoma. Adverse events were evaluated based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Blood samples were collected for PK analysis. Archival or biopsy tumor tissue samples were collected for genetic analysis. Results: As of 15 Jun 2015, 11 subjects with lymphoma/CLL (73% male; median age 78 years; 5 follicular, 3 mantle cell, 2 diffuse large B cell, 1 CLL; 4 in dose escalation cohorts, 7 in expansion cohort) have been enrolled and treated at initial doses of 120 to 270 mg QD intermittently (n=7) or 300 mg BID weekly (n=4). All subjects have received at least one prior systemic therapy (median 2, range 1-6). Median duration on study treatment for all 11 subjects was 8 weeks (range 1 to 30 weeks). One subject with CLL and two with follicular lymphoma experienced durable partial responses, respectively with times to response of 8, 8 and 24 weeks and response durations of 16, 8+, and 2+ weeks. The two follicular PR subjects, one of whom had an AKT1 (E17K) mutation, remain on study treatment. In addition, one subject with follicular and one with mantle cell lymphoma experienced stable diseases. Four subjects experienced progressive diseases and two were not evaluable for tumor responses due to early consent withdrawal and clinical disease progression. Table 1. Common drug-related adverse events (≥10%) included macula-papular rash 45%, hyperglycemia 36%, mucosal inflammation 18% and stomatitis 18%. Response Follicular N=5 CLL N=1 Mantle cell N=3 Diffuse large B cell N=2 Total N=11 PR 2 1 3 SD 1 1 2 PD 1 2 1 4 NE 1 1 2 ORR 40% 100% 0% 0% 27% DCR 60% 100% 33% 0% 45% Conclusions: The safety profile of lymphoma subjects is consistent with subjects with solid tumors enrolled in this study. Preliminary signs of single agent activity have been documented with 3 PRs in heavily pretreated lymphoma/CLL including one with AKT1 (E17K) mutation. [1] First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. M. Saleh et al., Abstract LB-197, AACR 104th Annual Meeting, 6-10 Apr 2013. Washington, D.C. U.S. [2] First-in-human study with ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma. M. Saleh et al., Abstract 320, EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics , 18-21 Nov 2014, Barcelona, Spain Disclosures Harb: Onyx Pharmaceuticals: Consultancy. Chai:ArQule, Inc.: Employment. Larmar:ArQule, Inc.: Employment. Abbadessa:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment.
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Hönle, Wolfgang, Sigrid Furuseth e Hans Georg von Schnering. "Synthesis and Crystal Structure of Ordered, Orthorhombic α-NbBr5". Zeitschrift für Naturforschung B 45, n.º 7 (1 de julho de 1990): 952–56. http://dx.doi.org/10.1515/znb-1990-0706.
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Niobium pentabromide, NbBr5, is prepared in the orthorhombic ordered (α)-form from the elements in sealed quartz ampoules (Nb powder, Br2, l) at 973 K. The structure has been determined from single crystal data (a = 1288.8(2), b = 1869.0(3), c = 614.9(1) pm; Pnma (No. 62); Z = 8; R = 0.055). α-NbBr5_ forms dimeric Nb2Br10 molecules with d̄(Nb–Brb) = 271.5 pm, d̄(Nb–Bre) = 240.8 pm and d̄(Nb– Bra) = 246.1 pm. α-NbBr5 is a diamagnetic semiconductor with cgsχmoldia(300 K) = –72 × 10-6 cm3/mol. The band gaps of NbCl5, α-NbBr5 and NbI5 have been determined by diffuse reflection to be Eg(NbCl5) = 2.74 eV, Eg(α-NbBr5) = 1.99 eV, and Eg(NbI5) = 0.99 eV.
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Whittall, Ian R., Mark G. Humphrey e David C. R. Hockless. "Structural Systematics of Metal Acetylide Complexes. II. X-Ray Studies of Some Nickel σ-Acetylide Complexes". Australian Journal of Chemistry 51, n.º 3 (1998): 219. http://dx.doi.org/10.1071/c97082.
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The structures of Ni(C≡CR)(PPh3)(η-C5H5) (R = Ph (1), C6H4-4-NO2 (2), 4-C6H4C6H4-4′-NO2 (3), (E)-4-C6H4CH=CHC6H4-4′-NO2 (4), 4-C6H4C≡CC6H4-4′-NO2 (5), 4-C6H4N=CHC6H4-4′-NO2 (6)) have been determined by single-crystal X-ray diffraction studies, refining by full-matrix least-squares analysis. For (1), crystals are triclinic, space group P-1, with a 10·094(2), b13·429(3), c 18·835(5) Å,α 103·24(2), β 91·50(2), γ 90·10(2)°, Z 4, 5844 unique reflections (595 parameters), converging at R 0·033 and Rw 0·024. For (2), crystals are orthorhombic, space group Pna21, with a 16·799(2), b 8·681(2), c 17·485(2) Å, Z 4, 1774 unique reflections (325 parameters), converging at R 0·031 and Rw 0·029. For (3), crystals are monoclinic, space group P 21/c, with a 11·140(3), b 18·282(4), c 15·296(2) Å, β 105·18(2)°, Z 4, 3132 unique reflections (397 parameters), converging at R 0·039 and Rw 0·024. For (4), crystals are monoclinic, space group P 21/n, with a 12·929(7), b 16·953(8), c 15·601(7) Å, β 112·55(3), Z 4, 3023 unique reflections (397 parameters), converging at R 0·039 and Rw 0·025. For (5), crystals are monoclinic, space group P 21/n, with a 12·710(5), b 16·882(3), c 15·693(4) Å, β 111·37(3)°, Z 4, 3216 unique reflections (397 parameters), converging at R 0·035 and Rw 0·030. For (6), crystals are monoclinic, space group P 21/n, with a 12·594(1), b 16·936(2), c 15·611(1) Å, β 112·476(5)°, Z 4, 3564 unique reflections (397 parameters), converging at R 0·038 and Rw 0·041. For structurally characterized 18-electron (cyclopentadienyl)nickel(II) acetylide complexes, statistically insignificant decreases in the average Ni-C(1) distance and trans influence and an increase in the average C(1)-C(2) parameter are observed on introduction of an acceptor substituent at the alkynyl ligand.
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McDonagh, Andrew M., Mark G. Humphrey e David C. R. Hockless. "Preparation of cis- and trans-[OsCl2(Me2SO)4], and X-Ray Crystal Structures of the All-S-Bound Isomers". Australian Journal of Chemistry 51, n.º 9 (1998): 807. http://dx.doi.org/10.1071/c98017.
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Efficient syntheses of the cis and trans isomers of [OsCl2(Me2SO)4] are reported. While a structural study of thetrans isomer confirms the spectroscopically assigned all-S-bound Me2SO configuration, a crystallographic determination of the cis isomer reveals a previously unheralded all-S-bound Me2SO geometry, in contrast to the spectroscopically inferred configuration predominant in solution which has one O-bound ligand. Fortrans-[OsCl2(Me2SO)4], crystals are tetragonal, space group I 4/m, with a 9·092(2), c 11·212(3) Å, Z 2, 566 unique reflections (34 parameters), converging at R 0·026 and Rw 0·032. For cis-[OsCl2(Me2SO)4], crystals are triclinic, space group P-1, with a 8·193(2), b 8·941(3), c 13·837(3) Å, α 79·77(2), β 79·91(2), γ 65·03(2)°, Z 2, 4152 unique reflections (173 parameters), converging at R 0·021 and Rw 0·018.
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Dasari, Arvind, Joleen M. Hubbard, Cathy Eng, Heather Yeckes-Rodin, Stacey M. Ukrainskyj, Zhao Yang, William R. Schelman, Marek K. Kania e Tanios S. Bekaii-Saab. "Phase 1/1b trial of fruquintinib in patients with advanced solid tumors: Preliminary results of the dose expansion cohorts in refractory metastatic colorectal cancer." Journal of Clinical Oncology 40, n.º 4_suppl (1 de fevereiro de 2022): 93. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.093.
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93 Background: Fruquintinib (F) is a highly selective, novel, oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3. The phase (Ph) 3 FRESCO study (NCT02314819) that investigated F (5mg daily, 3 weeks (wks) on 1 wk off) showed improved median overall survival in patients (pts) with metastatic colorectal cancer (mCRC) in third line and beyond when compared to placebo (9.3 vs. 6.6 months); hazard ratio 0.65 (P < 0.001) and led to its approval in China. Methods: This is an ongoing Ph 1/1b open-label, dose escalation/expansion study conducted in the US. Here we present the preliminary safety and antitumor efficacy data from pts with refractory mCRC in Cohort (Coh) B (progressed on all standard therapies including TAS-102 [TAS] and/or regorafenib [R]) and in Coh C (did not receive TAS or R). Results: As of data cutoff on 27 July 2021, 81 mCRC pts had been treated (41 in Coh B and 40 in Coh C); median age of 57 years (range: 34─77), Caucasian (81.5%), female (44.4%), and ECOG PS 1 (59.3%). In Coh B, the median number of prior therapies was 5 (range: 3-9), 8 pts (19.5%) received R, 19 (46.3%) received TAS and 14 (34.1%) received both R and TAS. In Coh C, the median number of prior therapies was 4 (range: 1-10). Five pts remain on treatment; reasons for treatment discontinuation included: 56 pts (69.1%) due to progressive disease or death, 8 pts (9.9%) due to adverse events (AE), and 12 pts (14.8%) due to withdrawal of consent or physician decision. The median duration of F treatment was 4.4 months (range: 0.7– 20.0) in Coh B and 3.7 months (range: 0.02-14.3) in Coh C. The most frequently reported AEs of any grade in Coh B were fatigue (53.7%), proteinuria (51.2%), and hypertension (HTN; 48.8%). In Coh C the most frequently reported AEs of any grade were HTN (75.0%), proteinuria (40.0%), and myalgia (32.5%). Hand-foot syndrome (HFS) was reported in 29.3% of Coh B pts and 22.5% of Coh C pts. The disease control rate [DCR] was 68.3% in Coh B (1 partial response [PR] and 27 stable disease [SD]) and 59.5% for the 37 patients with at least one post-baseline tumor assessment in Coh C (2 PRs and 20 SDs). Conclusions: F is generally well-tolerated in heavily-pretreated pts with refractory mCRC. Evidence of antitumor activity was observed in cohorts B and C. The multi-cohort dose expansion is ongoing. F is being further investigated in refractory mCRC in a global Ph 3 study (NCT04322539). Clinical trial information: NCT03251378.
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Chow, WS, AB Hope e JM Anderson. "Further Studies on Quantifying Photosystem II in vivo by Flash-Induced Oxygen Yield From Leaf Discs". Functional Plant Biology 18, n.º 4 (1991): 397. http://dx.doi.org/10.1071/pp9910397.
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It was shown briefly [W. S. Chow, A. B. Hope and J. M. Anderson (1989), Biochirnica et Biophysics Acta, 973, 105-8] that the oxygen evolved per flash from leaf discs, under steady-state flashing conditions and in the presence of background far-red light, gave a valid measure of the number of functional photosystem II (PS II) reaction centres. Further work on this direct and convenient method has been done to optimise conditions for making reliable measurements. It is found that, to obtain the higher estimates of [PS II], corresponding to functionality of practically all PS II reaction centres that bind herbicides, a form of 'light activation' is necessary after a prolonged dark pre-incubation. Without a sufficient number of flashes being given following a long dark incubation, the number of functional PS II reaction centres was underestimated. Provided light activation had occurred, the measured number of functional PS II reaction centres was independent of flash frequencies up to at least 40 Hz. The results strongly suggest that, in steady-state, light-limited photosynthesis, there does not exist any sub- stantial fraction of non-functional or 'slow' PS II reaction centres.
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Mendis, Shanthi, U. Samarajeewa e R. O. Thattil. "Coconut fat and serum lipoproteins: effects of partial replacement with unsaturated fats". British Journal of Nutrition 85, n.º 5 (maio de 2001): 583–89. http://dx.doi.org/10.1079/bjn2001331.
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The aim of the present study was to examine the effect of reducing saturated fat in the diet, or partly replacing it with unsaturated fat, on the serum lipoprotein profile of human subjects. The study had two intervention periods, 8 weeks (phase 1) and 52 weeks (phase 2). In phase 1, total fat was reduced from 31 to 25 % energy (polyunsaturated fatty acids (PUFA):saturated fatty acids (SFA) ratio increased from 0.2 to 0.4) by reducing the quantity of coconut fat (CF) in the diet from 17.8 to 9.3 % energy intake. In phase 2, subjects were randomised to groups A and B. In group A total fat was reduced from 25 to 20 % energy (PUFA:SFA ratio increased from 0.4 to 0.7) by reducing the quantity of CF in the diet from 9.3 to 4.7 % total energy intake. In group B, the saturated fat content in the diet was similar to group A. In addition a test fat (a mixture of soyabean oil and sesame oil, PUFA:monosaturated fatty acids ratio 2) contributed 3.3 % total energy intake and total fat contributed 24 % energy intake (PUFA:SFA ratio increased from 0.7 to 1.1). At the end of phase 1, there was a 7.7 % reduction in cholesterol (95 % CI -3.6, -12.2) and 10.8 % reduction in LDL (95 % CI -4.9, -16.5) and no significant change in HDL and triacylglycerol. At the end of phase 2, the reduction in cholesterol in both groups was only about 4 % (95 % CI -12, 3.2) partly due the concomitant rise in HDL. The reduction in LDL at 52 weeks was significantly higher in group B (group A mean reduction 11 %, 95 % CI -20.1, -2.0 and group B mean reduction 16.2 % 95 % CI -23.5, -8.9). In phase 2, triacylglycerol levels showed a mean reduction of 6.5 % in group 2A and a mean increase of 8.2 % in group 2B. The reduction of saturated fat in the diet is associated with a lipoprotein profile that would be expected to reduce cardiovascular risk. The reduction of dietary saturated fat with partial replacement of unsaturated fat brings about changes in total cholesterol, HDL- and LDL-cholesterol that are associated with a lower cardiovascular risk.
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Torgashina, A., E. Sokol, J. Khvan, B. Chalcev, D. Tabakov, S. Glukhova e O. Golovina. "OP0320 CHARACTERISTICS OF PERIPHERAL BLOOD B-CELL SUBSETS IN PATIENTS WITH SJOGREN SYNDROME". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de maio de 2021): 196.1–196. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2982.
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Background:B-cells play a pivotal role in primary Sjogren’s syndrome (SS) pathogenesis. Recent studies have shown disturbances in the peripheral B cell populations in primary SS.Objectives:To examine В-cell subsets in peripheral blood of SS patients (pts) and to analyze the association between B-cell subsets and SS activity.Methods:Twenty active SS pts (19F/1M): median age 42 years (range) (32-54); disease duration 3 (2-10) years; ESSDAI score ≥5 in 6 pts, <5 in 14 pts), were included. SS was diagnosed based on the ACR-EULAR 2016 criteria. Twenty healthy donors composed the control group. CD19+B cells, memory B-cells (CD19+CD27+), non-switched memory B-cells (CD19+IgD+CD27+), switched memory B-cells (CD19+IgD-CD27+), naïve (CD19+IgD+CD27-), double negative (CD19+IgD-CD27-), transitional (CD19+IgD+CD10+CD38+) B-cells, plasmablasts (CD19+СD38+++IgD-CD27+), and plasma cells (CD19+СD38+) were analyzed by multicolor flow cytometry using cytometer Navios (Beckman Coulter, USA).The nonparametric Mann-Whitney test, the unpaired Student’s t test for group comparison, and the Pearson`s x2 criterion were used for statistical analysis. Data were shown as median (Me) with an interquartile range of 25 - 75 percentile. The differences were considered statistically significant when p <0.05. Statistica 10 for Windows (StatSoft Inc., USA) package was used for statistical data processing.Results:The percentages/absolute numbers of plasmablasts, plasma cells and transitional B-cells in SS were significantly higher than in healthy donors, р<0.01 for all cases (Table 1).Table 1.B-cell subsets in patients with SS, SS and MALT lymphoma and healthy donors.B-cell subsetsSSHDPt 1FN%Abs. cells/μl%Abs. cells/μl%Abs. cells/μlB lymphocyte12,8 (7,9 – 19,7)151 (95-112)8,5 (7,2-11,0)200 (100-200)4,531**plasma cells6,9 (4,2-10)12 (6-22)0,1 (0,05-0,1)0,1 (0-0,2)5,713*plasmablasts0,88 (0.37-1.8)2 (1-3)0,1 (0,1-0,2)0,2 (0,1-0,4)26,612*/**transitional B-cells5.7 (0.9-17)8 (4-32)0,1 (0-0,1)0,1 (0-0,3)00*switched cells9.1 (5.9-20.7)18 (11-29)12,8 (9,3-17,0)20 (10-40)5216**non-switched memory B-cells4.13 (2.7-5.4)7 (3-15)7,4 (3,7-11,1)10 (5-20)165**SS Sjogren’s patients; HD healthy donors, Pt 1 patient with SS and MALT lymphoma* SS and HD groups compared, р<0.01** Pt 1 and SS group comparedOne of the patients (Pt 1) was diagnosed with MALT lymphoma of the parotid salivary gland; she had a distinct B-lymphocyte subpopulations distribution, which was different from the rest of the SS group. She had the lowest percentage / absolute B lymphocyte count of all patients with SS, the highest percentage of switched cells and non-switched memory B-cells, and the highest percentages/absolute numbers of plasmablasts. For this reason, the patient was excluded from the subsequent analysis (Table 1).Patients with activity of SS by ESSDAI ≥ 5 had a significantly higher percentage of B cells (p=0.007), and significantly higher absolute B lymphocyte count of naïve cells (p=0.04) and plasmablasts (p=0.048).Conclusion:Immunophenotyping showed disturbed homeostasis of the B-cells subpopulations in our SS cohort. A significant increase in plasmablasts in SS, as well as a positive correlation of the level of plasmablasts with the SS activity and presence of lymphoma could suggest the important role of these cells in the pathogenesis of SS.Disclosure of Interests:None declared.
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Goel, Deepak, Aayushi Bansal e Anant Gopal Nigam. "Effect of Achyranthes aspera, 0.2% Aqueous Chlorhexidine Gluconate and Punica granatum Oral Rinse on the Levels of Salivary Streptococcus mutans in 8 to 12 Years Old Children". Journal of Contemporary Dental Practice 16, n.º 11 (2015): 903–9. http://dx.doi.org/10.5005/jp-journals-10024-1779.
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ABSTRACT Background and objectives To study the effect Achyranthes aspera, 0.2% aqueous chlorhexidine gluconate and Punica granatum oral rinse on salivary Streptococcus mutans count in children. Materials and methods A total of 60 children of 8 to 12 years of age were randomly allocated into 3 groups. Group A was given 0.2% chlorhexidine mouthwash, group B was given 10% A. aspera mouthwash and group C was given 15% P. granatum mouthwash. The day 1 saliva samples were collected from the subjects and innoculated onto mitis salivarius bacitracin (MSB) agar. The colony counts were obtained by a clinical microbiologist who was blinded to the subject allocation. Plaque scores were then recorded by the investigator with the help of a volunteer. Following this, they received a thorough scaling and polishing. Subjects in each group were then provided with 140 ml of the respective mouthwash, as a daily supervised rinse after breakfast and before sleeping as per instructions. Following mouth rinsing, the children were instructed not to eat or drink for 15 minutes. At the 7th day, unstimulated saliva was again collected from the subjects of all 3 groups, inoculated onto MSB agar and colony count was obtained. Modified Quigley- Hein plaque index was also evaluated for the refreshed score at this stage. Colony counting was done using loop method and statistical analysis was done using Statistical Package for the Social Science (SPSS) software version 21. Results All the three mouthwashes showed statistically significant reduction of S. mutans count and plaque index after 7 days, i.e. chlorhexidine (p < 0.001 for reduction in S. mutans count and p < 0.05 for plaque score reduction), A. aspera (p < 0.01 for reduction in S. mutans count and p < 0.05 for plaque score reduction) and P. granatum (p < 0.01 for reduction in S. mutans count and p < 0.05 for plaque score reduction). Chlorhexidine had marginally better results in reducing S. mutans count. Conclusion • Efficacy of chlorhexidine, A. aspera and P. granatum was statistically significant with respect to reduction of S. mutans count with chlorhexidine being marginally better than the other two, • All the three mouthwashes were found to be at par when plaque index values from baseline and after interception of 7 days was calculated, • Punica granatum has better antimicrobial effect than A. aspera. How to cite this article Bansal A, Marwah N, Nigam AG, Goenka P, Goel D. Effect of Achyranthes aspera, 0.2% Aqueous Chlorhexidine Gluconate and Punica granatum Oral Rinse on the Levels of Salivary Streptococcus mutans in 8 to 12 Years Old Children. J Contemp Dent Pract 2015;16(11):903-909.
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Chahinian, A. P., K. J. Propert, J. H. Ware, B. Zimmer, M. C. Perry, V. Hirsh, A. Skarin, S. Kopel, J. F. Holland e R. L. Comis. "A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B." Journal of Clinical Oncology 7, n.º 8 (agosto de 1989): 993–1002. http://dx.doi.org/10.1200/jco.1989.7.8.993.
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The Cancer and Leukemia Group B (CALGB) conducted a prospective randomized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer (SCCL). After stratification for sex and performance status, patients were randomly assigned to receive chemotherapy with methotrexate, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (CCNU) (MACC), or MACC plus warfarin (MACC + W), or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC (MEPH/MACC). Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values. A total of 328 patients were enrolled, and 294 were evaluable. There was a statistically significant advantage in objective response rates (complete [CR] and partial responses [PR], respectively) for MACC + W (17% and 50%) as compared with MACC alone (8% and 43%) or MEPH/MACC (10% and 38%) (P = .012). Both failure-free survival (P = .054 Wilcoxon test) and overall survival (P = .098 Wilcoxon test) were higher on MACC + W (median, 6.6 months and 9.3 months, respectively), as compared with MACC (5.0 months and 7.9 months) and MEPH/MACC (5.0 months and 7.9 months). Toxicity was comparable among the three arms, except for increased hemorrhagic events on MACC + W, which were life-threatening in four patients (4%), and lethal in two others (2%). These data support the role of warfarin in the treatment of SCCL, but do not establish its mechanism of action. Warfarin deserves further studies in SCCL, particularly in patients with limited disease.
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Oranchuk, Dustin J., André R. Nelson, Adam G. Storey e John B. Cronin. "Variability of Regional Quadriceps Architecture in Trained Men Assessed by B-Mode and Extended-Field-of-View Ultrasonography". International Journal of Sports Physiology and Performance 15, n.º 3 (1 de março de 2020): 430–36. http://dx.doi.org/10.1123/ijspp.2019-0050.
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Purpose: Regional muscle-architecture measures are reported widely; however, little is known about the variability of these measurements in the rectus femoris, vastus lateralis, and anterior and lateral vastus intermedius. The aim of this study was to quantify this variability. Methods: Regional muscle thickness, pennation angle (PA), and calculated and extended-field-of-view–derived fascicle length (FL) were quantified in 26 participants using ultrasonography across 51 limbs on 3 occasions. To quantify variability, the typical error of measurement (TEM) was multiplied by 2, and thresholds of 0.2–0.6 (small), 0.6–1.2 (moderate), 1.2–2.0 (large), 2.0–4.0 (very large), and >4.0 (extremely large) were applied. In addition, variability was deemed large when the intraclass correlation coefficient (ICC) was <.67 and coefficient of variation (CV) >10%, moderate when ICC > .67 or CV < 10% (but not both), and small when both ICC > .67 and CV < 10%. Results: Muscle thickness of all muscles and regions had low to moderate variability (ICC = .88–.98, CV = 2.4–9.3%, TEM = 0.15–0.47). PA of the proximal and distal vastus lateralis had low variability (ICC = .85–.96, CV = 3.8–8%) and moderate to large TEM (TEM = 0.42–0.83). PA of the rectus femoris was found to have moderate to very large variability (ICC = .38–.74, CV = 11.4–18.5%, TEM = 0.61–1.29) regardless of region. Extended-field-of-view–derived FL (ICC = .57–.94, CV = 4.1–11.5%, TEM = 0.26–0.88) was superior to calculated FL (ICC = .37–.84, CV = 7.4–17.9%, TEM = 0.44–1.33). Conclusions: Variability of muscle thickness was low in all quadriceps muscles and regions. Only rectus femoris PA and FL measurements were highly variable. The extended-field-of-view technique should be used to assess FL where possible. Inferences based on rectus femoris architecture should be interpreted with caution.
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Tangduangdee, Chairath, Suvaluk Asavasanti e Kanruethai Taichan. "Browning kinetics of egg white during high-temperature process". วารสารวิทยาศาสตร์ประยุกต์ กรมวิทยาศาสตร์บริการ 12, n.º 2 (24 de novembro de 2023): 23–34. http://dx.doi.org/10.60136/bas.v12.2023.647.
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Egg white product is commonly produced by pasteurization to avoid brown color development and needs to be kept in a refrigerator. To explore the opportunity of producing shelf-stable egg white products, this research aimed to develop the browning kinetic model of egg white undergoing a high-temperature treatment and to minimize the browning reaction by desugaring with glucose oxidase. Egg white (8 mL) was filled in sample holders equipped with a thermocouple. The sample holders were preheated in a water bath at 70°C for 30 minutes to solidify the sample and then heated in an oil bath at 100, 110, and 130°C for 30 minutes. The color of the sample surface was measured using a spectrophotometer. The yellowness index (YI) was calculated to identify the degree of brown color development. It was found that the L* value of egg white declined, while a* and b* values increased with increasing heating time. The first-order kinetic model was applicable for predicting the change of YI-ratio (R2 = 092-0.95, RMSE = 0.11-029). In addition, the samples pre-treated with glucose oxidase of 30 units/mL-egg white and 30°C-incubation for 6.5 hours had a significant reduction of the YI-ratio from 5.9 to 2.6. This research indicates the potential for egg-white production at a high temperature with lighter color by adding glucose oxidase.
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Bindi, L., F. Nestola, E. Makovicky, A. Guastoni e L. De Battisti. "Tl-bearing sulfosalt from the Lengenbach quarry, Binn Valley, Switzerland: Philrothite, TlAs3S5". Mineralogical Magazine 78, n.º 1 (fevereiro de 2014): 1–9. http://dx.doi.org/10.1180/minmag.2014.078.1.01.
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AbstractPhilrothite, ideally TlAs3S5, is a new mineral from the Lengenbach quarry in the Binn Valley, Valais, Switzerland. It occurs as very rare crystals up to 200 mm across on realgar associated with smithite, rutile and sartorite. Philrothite is opaque with a metallic lustre and shows a dark brown streak. It is brittle; the Vickers hardness (VHN25) is 128 kg/mm2 (range: 120–137) (Mohs hardness of 3–3½). In reflected light philrothite is moderately bireflectant and weakly pleochroic from dark grey to light grey. Under crossed polars it is anisotropic with grey to bluish rotation tints. Internal reflections are absent. Reflectance percentages for the four COM wavelengths (Rmin and Rmax) are: 26.5, 28.8 (471.1 nm), 25.4, 27.2 (548.3 nm), 24.6, 26.3 (586.6 nm) and 24.0, 25.1 (652.3 nm), respectively.Philrothite is monoclinic, space group P21/c, with a = 8.013(2), b = 24.829(4), c = 11.762(3) Å, β = 132.84(2)°, V = 1715.9(7) Å3, Z = 8. It represents the N = 4 homologue of the sartorite homologous series. In the crystal structure [R1 = 0.098 for 1217 reflections with I > 2σ(I)], Tl assumes tricapped prismatic sites alternating to form columns perpendicular to the b axis. Between the zigzag walls of Tl coordination prisms, coordination pyramids of As(Sb) form diagonally-oriented double layers separated by broader interspaces which house the lone electron pairs of these elements.The eight strongest calculated powder-diffraction lines [d in Å(I/I0) (hkl)] are: 12.4145 (52) (020); 3.6768 (100) (61); 3.4535 (45) (131); 3.0150 (46) (53); 2.8941 (52) (81); 2.7685 (76) (230); 2.7642 (77) (34); 2.3239 (52) (092). A mean of five electron microprobe analyses gave Tl 26.28(12), Pb 6.69(8), Ag 2.50(4), Cu 0.04(2), Hg 0.07(2), As 32.50(13), Sb 3.15(3), S 26.35(10), total 97.58 wt.%, corresponding, on the basis of a total of nine atoms, to (Tl0.789Pb0.198)∑=0.987 (As2.662Sb0.159Ag0.142Cu0.004Hg0.002)∑=2.969S5.044. The new mineral has been approved by the Commission on New Minerals, Nomenclature and Classification (CNMNC) of the International Mineralogical Association (2013-066) and named for Philippe Roth (b. 1963), geophysicist and well known mineral expert on the Lengenbach minerals for more than 25 years.
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Yuan, Yuan, Irene Kang, Jin Sun Bitar, Andrew A. Davis, Christie Hilton, Minxuan Huang, Michael A. Thompson, Jacob Mercer, Stephen Lawrence Shiao e Eric Vail. "Comparison of tumor immune microenvironments (TIMEs) between primary and metastatic sites (Mets) in triple-negative breast cancer (TNBC)." Journal of Clinical Oncology 42, n.º 16_suppl (1 de junho de 2024): 1097. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.1097.
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1097 Background: The TIME is critical in determining response to immune checkpoint inhibitors (ICIs), but TIME differences across primary and mets in TNBC are not well understood. Since ICIs are standard of care for patients with TNBC, we studied the TIMEs of primary TNBC and mets to investigate how immune composition may affect ICI efficacy. Secondary analysis stratified cohorts by race and disease sites to compare TIMEs in Black or African American (B/AA) with White patients, since TNBC has a high prevalence of B/AA women who are underrepresented in studies and have a worse prognosis. Methods: We retrospectively analyzed de-identified next-generation sequencing data from TNBC patients (n=1,044) in the Tempus Database. Tumors from primary breast (PB, n=553), liver (n=153), lymph node (LN, n=174), lung (n=111), and bone (n=53) sites were sequenced with the Tempus xT DNA (648-gene panel) and xR RNA assays. Histologies included invasive ductal carcinoma (82%), lobular carcinoma (2.2%), mixed ductal and lobular carcinoma (1.7%), and other (14%). Demographics, TMB, MSI, PD-L1, and proportions of B, T (CD4+, CD8+), NK cells, and macrophages were compared across sites. LN were used as a positive control. Chi-squared/Fisher’s exact or Kruskal-Wallis tests were used to assess statistical significance (two-sided, evaluated at the 0.05 alpha level). Results: The cohort (median age=57 years, IQR 46-66) comprised a diverse population (65% White, 23% B/AA, 2.8% Asian, and 9.3% other). Liver exhibited a lower percentage of B cells and higher percentage of macrophages compared to PB (p<0.0001 for both), lung (p<0.0001 for both), and bone (B cells p<0.0001, macrophages p<0.05). Liver also exhibited lower percentages of CD8+ T cells compared to PB (p<0.05) and CD4+ and NK cells compared to lung (CD4+ cells p<0.01, NK cells p<0.0001). Bone had lower percentages of CD8+ cells compared to PB (p<0.0001), lung (p<0.001), and liver (p<0.01). Compared to lung, bone had a lower percentage of CD4+ cells (p<0.0001) and higher percentage of macrophages (p<0.01). PD-L1 positivity, TMB, and MSI exhibited no differences across sites. Secondary analysis compared the TIME between B/AA and White cohorts in PB (B/AA n=85 vs White n=204: %B cells, 15 vs 11, p=0.017; %CD8 cells, 4.9 vs 7.3, p=0.025), liver (B/AA n=15 vs White n=48: %B cells, 8 vs 4, p=0.2; %CD4, 23 vs 14, p=0.2; %CD8, 7.2 vs 4.6, p=0.07), and lung (B/AA n=9 vs White n=33: %B cells, 22 vs 11, p=0.021; %CD8, 7.9 vs 5.2, p=0.5). Conclusions: Compared to PB and lung, liver and bone had immune cell infiltrates indicating a less immunogenic TIME in the overall TNBC population. Although limited by sample size, this is one of the first studies to assess the TIME across race and sites of disease. These findings are hypothesis generating and provide further rationale to better understand how the TIME across disease sites and race may alter the efficacy of ICIs in TNBC.
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Norikawa, Yutaro, Kouji Yasuda e Toshiyuki Nohira. "Effect of Temperature on Grain Growth during Ti Electrodeposition in Lif–LiCl Eutectic Melt". ECS Meeting Abstracts MA2022-01, n.º 23 (7 de julho de 2022): 1197. http://dx.doi.org/10.1149/ma2022-01231197mtgabs.
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1. Introduction Ti has superior properties, such as high specific strength, corrosion resistance, biocompatibility, and is used for many fields such as airplane, chemical plant, consumer products. However, its high manufacturing cost and poor processability have hindered its further spread. Thus, a number of smelting processes and processing methods have been investigated to reduce the cost and spread the use of Ti. Among them, plating Ti metal on inexpensive substrates is one of the methods that can utilize the surface properties of Ti. Electrodeposition is a promising plating method from the viewpoints of the cost and the flexibility in shape of substrate. Therefore, electrodeposition of Ti metal in high-temperature molten salts has been investigated for a long time [1–3]. Our group has reported the electrodeposition of Ti films with compact and smooth surfaces in molten KF–KCl and LiF–LiCl containing Ti(III) ions at 923 K [4–7]. We also reported that the Ti films obtained in LiF–LiCl at 823 K had smoother surfaces [8]. In the present study, we investigated the effect of temperature on the grain growth and smoothness of Ti films electrodeposited in LiF–LiCl eutectic melt at 823–973 K. 2. Experimental The experiments were carried out in eutectic LiF–LiCl melt (30:70 mol%, melting point 774 K) at 823–973 K. The melt was placed in a nickel crucible and the experiments were conducted in an airtight Kanthal container in an argon glove box. As Ti(III) ion sources, Li2TiF6 (2.00 mol%) and Ti sponge (1.33 mol%) were added to the melt. The added amounts of Ti sponge were twice the amounts necessary to generate Ti(III) ions by comproportionation reaction between Ti(IV) ions and Ti(0) according to Eq. 1. Ti(0) + 3Ti(IV) → 4Ti(III) (1) Ni plates were used as working electrodes, and Ti rods was used as counter and reference electrodes. The samples prepared by galvanostatic electrolysis were analyzed by XRD and SEM/EDX after washing with distilled water to remove adhered salts. 3. Results and Discussion Fig. 1 shows the optical and surface SEM images of the samples obtained by galvanostatic electrolysis at 823, 873, 923, and 973 K. The cathodic current density was 50 mA cm−2 and electrolysis time was 20 min. All the samples have a metallic luster and are confirmed to be Ti metal by XRD analysis. However, the brightness differs between samples, with the Ti film at 823 K showing the highest brightness. From the surface SEM images, the crystal grain size of Ti increases as the temperature rises. This tendency is reasonably explained by previous work on the temperature dependence on grain growth of Ti [9]. Also, the value of surface roughness (Sa) measured by SEM increases as the temperature increases. The smoothest Ti film with Sa = 2.05 ± 0.22 μm was obtained at 823 K. These results show that Ti film with smoother surface can be electrodeposited by suppressing the grain growth of Ti at lower temperatures. To obtain thicker films, electrolysis was conducted for longer time at 823 K, where grain growth is suppressed. Fig. 2 shows the optical and SEM images of the samples obtained by galvanostatic electrolysis at a cathodic current density of 50 mA cm−2 and charge densities of 60, 150, and 450 C cm−2. As shown in the SEM images, the thickness of the Ti film increases with the increase in charge density. Although some deposition onto the edge was observed at 450 C cm−2, the thickness of the Ti film reaches 100 μm. Acknowledgement A part of this work was supported by JSPS Fellows grant number 19J15015. A part of this study was conducted as a collaboration with Sumitomo Electric Industries, Ltd. The present address of Kouji Yasuda is Graduate School of Engineering, Kyoto Univ. References [1] D. Wei, M. Okido, and T. Oki, J. Appl. Electrochem., 24, 923 (1994). [2] A. Robin and R. B. Ribeiro, J. Appl. Electrochem., 30, 239 (2000). [3] V. V. Malyshev and D. B. Shakhnin, Mater. Sci., 50, 80 (2014) [4] Y. Norikawa, K. Yasuda, and T. Nohira, Mater. Trans., 58, 390 (2017). [5] Y. Norikawa, K. Yasuda, and T. Nohira, Electrochemistry, 86, 99 (2018). [6] Y. Norikawa, K. Yasuda, and T. Nohira, J. Electrochem. Soc., 166, D755 (2019). [7] Y. Norikawa, K. Yasuda, and T. Nohira, J. Electrochem. Soc., 167, 082502 (2020). [8] M. Unoki, Y. Norikawa, K. Yasuda, and T. Nohira, ECS Trans., 98, 393 (2020) [9] K. Okazaki and H. Conrad, Metall. Trans., 3, 2411 (1972). Figure 1
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McNevin, Ciara S., Mutaz Mohammed Nur, Cathal O'Brien, Brianan McGovern, Julia McFadden, Anne-Marie Baird, Karen Anne Cadoo et al. "Prevalence of mismatch repair deficiency in a large prospective prostate cancer cohort." Journal of Clinical Oncology 41, n.º 16_suppl (1 de junho de 2023): 5031. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.5031.
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5031 Background: Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are predictive biomarkers for immunotherapy response. The best approach to identify patients with such tumors is unclear in prostate cancer. Methods: This study included men diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). The highest-grade/index lesions of tumor tissue from radical prostatectomy (95%) or transurethral resections of the prostate were mounted in triplicate on tissue microarrays. Immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2 was performed, with scoring as MMR-deficient requiring a visible staining in a non-tumor internal positive control of the same case. For validation, a polymerase chain reaction-based MSI assay (Idylla MSI Test, Biocartis) was performed on tumor DNA of MMR-deficient cases and a selection of MMR-intact cases. Results: The study included 1016 men with prostate cancer. Tumor stage was predominantly pathologically localized (71% stage pT1/2, 18% T3a/b) with a full distribution of Gleason scores, including 20% Gleason score 6 (grade group 1), 36% 3+4 (grade group 2), 23% 4+3 (grade group 3), 8% 8 (grade group 4) and 13% 9-10 (grade group 5). MMR tumor scoring could be performed for MLH1 in 747 cases (75% of those with tumor tissue), for MSH2 in 903 cases (90%), for MSH6 in 708 cases (74%), and for PMS2 in 703 cases (72%). The remaining tumors were unevaluable due to lack of non-tumor tissue necessary as an internal positive control. Of the 903 tumors evaluable for MSH2 protein loss, 4 tumors had loss of MSH2 (prevalence 0.4%, 95% confidence interval [CI] 0.2–1.1%), and 3 of 708 evaluable tumors had concomitant loss of MSH6 (prevalence 0.4%, 95% CI 0.1–1.2%). No tumor had loss of MLH1 or PMS2. The MMR-deficient tumors had Gleason scores of 3+4, 8 (two cases), and 9–10. Tumor DNA of 1 of the 4 MMR-deficient tumors met the manufacturer’s cut-off for MSI-high; two additional MMR-deficient cases had non-zero repeats, with good reproducibility between tumor cores and technical replicates. One MSH2-deficient tumor and 6 DNA samples from 3 MMR-intact cases had repeat scores of zero. Conclusions: In this nationwide prospective study, MMR deficiency was rare in primary, surgically treated prostate cancer. This low prevalence contrasts with hospital-based studies of MMR deficiency and MSI that may have represented tumors with certain clinical features. The low prevalence and the need for an internal positive control for reliable scoring calls into question to what extent immunohistochemistry-based screening for MMR deficiency on limited tissue specimens, such as prostate biopsies, is routinely feasible.
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Mervaala, Eero Ma, Zhong Jiang Cheng, Timo Vaskonen, Ilkka Tikkanen, Heikki Karppanen, Dominik N. Muller, Joon-Keun Park, Friedrich C. Luft e Heikki Vapaatalo. "Endothelial Dysfunction and Salt-Sensitive Hypertension in Spontaneously Diabetic Goto-Kakizaki Rats". Hypertension 36, suppl_1 (outubro de 2000): 726. http://dx.doi.org/10.1161/hyp.36.suppl_1.726-a.
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P182 Dysfunction of vascular endothelium has been associated with several cardiovascular risk factors including hypertension, hypercholesterolemia, and congestive heart failure. We tested the hypothesis whether or not endothelial dysfunction also participates in the pathogenesis of spontaneously diabetic Goto-Kakizaki (GK) rats, an animal model for type 2 diabetes. Furthermore we evaluated the influence of high sodium diet (6 % NaCl w/w) and chronic AT1 receptor blockade (valsartan 10 mg/kg p.o. for 8 weeks starting at age 8 weeks). Compared to age-matched non-diabetic Wistar controls, GK rats had higher b-glucose levels (9.3±0.5 vs 6.9±0.2 mmol/l), 2.7-fold higher s-insulin levels, impaired glucose tolerance in oral glucose tolerance test, and moderately increased s-cholesterol and s-triglyserides levels (all variables p<0.05). Mean arterial blood pressure, measured by radiotelemetry, was 15 mm Hg higher in GK rats (p<0.01), whereas no difference in heart rate was observed. Heart weight- and kidney weight -to-body weight ratios were higher in GK rats (p<0.05), and 24-hour albuminuria was 1.5-fold. Endothelium-mediated vascular relaxation of noradrenaline-precontracted mesenteric arterial rings to acetylcholine was markedly impaired in GK rats compared to Wistar rats (p<0.05), whereas the endothelium-independent relaxations to sodium nitroprusside were similar in both strains. Semiquantitative scoring of ED-1 positive cells showed perivascular monocyte/macrophage infiltration in kidneys of GK rats. High sodium diet increased blood pressure in GK rats by 24 mm Hg, 24-hour albuminuria by 350 %, induced cardiac hypertrophy, and further impaired endothelium-dependent vascular relaxation (all variables p<0.05). Inflammatory cell response was also aggravated by high sodium diet. Chronic AT1 receptor blockade did not decrease blood pressure, but partially protected against albuminuria, inflammatory cell response, and endothelial dysfunction in salt-loaded GK rats. Our findings indicate that hypertension in diabetic GK rats is salt-sensitive and associated with endothelial dysfunction and perivascular inflammation.
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Kivi, Indrek, Priit Moeller, Jaan Aruväli e Gunnar Nurk. "Influence of A-site Deficiency and Ni/Co Ratio in B-site on Electrochemical Performance of (La0.25Sr0,25Ca0.45)yTi0.95Ni0.05-xCoxO3- d Anode". ECS Meeting Abstracts MA2023-01, n.º 54 (28 de agosto de 2023): 80. http://dx.doi.org/10.1149/ma2023-015480mtgabs.
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La0.25Sr0.25Ca0.45TiO3 -d (LSCT) is a perovskite (ABO3) type mixed ionic-electronic conductive (MIEC) oxide and has been proposed as an electrode material for high temperature fuel cell [1]. This material owing high conductivity, robustness in hydrocarbon fuels and significant amount of attention has been paid to improve the electrochemical activity [1, 2]. Doping of B-site with some d-metal cation (Ni, Co, Mn, V, Mo) has been demonstrated to improve the catalytic activity. One of the advantages of the MIEC conducting scaffold based electrodes is that the catalyst phase on the electrode surface can be kept to a minimum, usually less than 5 wt%, which minimizes any risks of physical damage during redox cycling [2]. In this work, Ni/Co ratio and deficiency of A-site, of (La0.25Sr0.25Ca0.45)xTi0.95Ni0.05-yCoyO3 -d were varied. Electrical as well as electrochemical performance and chemical composition of LSCTNC surface was monitored. The electrochemical measurements of symmetric cells during 100 h tests show that small stochiometric changes in A-site significantly influence the activity and initial degradation rate of the electrode. The chemical and structural changes of the material surface have a key role on the electrochemical performance of the electrode [3]. The electrode materials were analysed using XRD, TOF SIMS and electrochemical methods. XRD and TOF SIMS results for studied electrode powders showed significant dependence of the lattice parameters and electrode surface composition on the perovskite elemental composition. The results from impedance spectroscopy (measured at temperatures from 973 to 1123 K in H2 environment, at OCV) demonstrate a significant influence of the A-site deficiency and B-site composition on the electrochemical properties of studied electrodes. Robert Price, Mark Cassidy, Jan G. Grolig, Gino Longo, Ueli Weissen, Andreas Mai, John T. S. Irvine, Advanced Energy Materials, 11, 1 (2021). Paul A. Connor, Xiangling Yue, Cristian D. Savaniu, Robert Price, Georgios Triantafyllou, Mark Cassidy, Gwilherm Kerherve, David J. Payne, Robert C. Maher, Lesley F. Cohen, Rumen I. Tomov, Bartek A. Glowacki, Ramachandran Vasant Kumar, John T. S. Irvine, Advanced Energy Materials, 8, 1 (2018). Ove Korjus, Priit Möller, Kuno Kooser, Tanel Käämbre, Olga Volobujeva, Jaak Nerut, Sander Kotkas, Enn Lust, Gunnar Nurk, Journal of Power Sources, 494, 1 (2021).
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Guo, Jhe-Cyuan, Ta-Chen Huang, Chia-Chi Lin, Min-Shu Hsieh, Chin-Hao Chang, Jang-Ming Lee, Jason C. Cheng et al. "Postchemoradiotherapy (CRT) pathologic stage classified by American Joint Committee on Cancer (AJCC) staging system to predict prognosis of patients with locally advanced esophageal squamous cell carcinoma (ESCC)." Journal of Clinical Oncology 33, n.º 3_suppl (20 de janeiro de 2015): 158. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.158.
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158 Background: Preoperative CRT followed by surgery is a curative treatment option for patients with locally advanced ESCC. Whether post-CRT pathologic staging can predict the outcomes of these patients is uncertain. Methods: Among 194 patients enrolled in three phase II clinical trials of preoperative CRT for patients with locally advanced ESCC (clinical T3N0-1M0 or T1-3N1M0 or M1a according to AJCC 6th edition), 140 patients were included. All patients received preoperative CRT comprised with twice weekly paclitaxel/cisplatin-based regimens and radiotherapy 40Gy given in 20 fractions, and esophagectomy. Post-CRT pathologic staging was classified according to AJCC 7thedition. Clinicopathologic factors were analyzed for their impacts on patients' overall survival (OS) and progression-free survival (PFS). Results: One hundred and thirty two men and 8 women were enrolled. The distribution of the post-CRT pathologic stages according to AJCC 7thedition and their median survival times were listed in Table 1. In univariate analysis, gender, performance status (PS), tumor location, pathologic N, pathologic stage, extranodal extension (ENE), and pathologic complete response (pCR) were statistically significant factors associated with PFS; PS, tumor location, pathologic N, pathologic stage, ENE, and pCR were statistically significant factors associated with OS. In multivariate analysis, PS (P < 0.001), tumor location (P = 0.016), and ENE (P = 0.024) were independent prognostic factors for PFS; PS (P < 0.001) and post-CRT pathologic stage (P = 0.027) were independent prognostic factors for OS. Conclusions: Post-CRT pathologic staging classified by AJCC 7thedition could predict the survivals of patients with locally advanced ESCC who underwent preoperative paclitaxel/cisplatin-based CRT followed by esophagectomy. (The work was supported by the Grant of MOST 103-2314-B-002-092.) [Table: see text]
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Terada, Yoshiki, Hirohisa Nakamae, Ran Moriguchi, Hiroshi Kanashima, Erina Sakamoto, Dai Momose, Mizuki Aimoto et al. "The Impact of Relative Dose Intensity of Rituximab-CHOP on Survival in Diffuse Large B-Cell Lymphoma Patients". Blood 112, n.º 11 (16 de novembro de 2008): 4931. http://dx.doi.org/10.1182/blood.v112.11.4931.4931.
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Abstract Background. Recently several retrospective studies showed that relative dose intensity (RDI) in combination chemotherapy including CHOP significantly influences survival in aggressive lymphoma. Based on these data, maintaining high RDI in chemotherapy by, for example, prophylactic granulocyte colony-stimulating factor (G-CSF) administration has been attempted to obtain better outcome. Moreover, rituximab, a chimeric monoclonal anti CD20 antibody combined with CHOP chemotherapy (R-CHOP) has significantly ameliorated the outcome in patients with diffuse large B-cell lymphoma (DLBL). However, it is unclear if higher RDI even in combination with rituximab will improve outcome in B cell type aggressive lymphoma. Hence, in the current study, we retrospectively analyzed the impact of RDI in R-CHOP as an initial treatment on survival of patients with DLBL. Furthermore, we determined the factors influencing RDI. Patients and Methods. We studied 100 previously untreated DLBL patients who underwent more than 3 courses of R-CHOP chemotherapies at 5 institutions from December 2003 to February 2008. The median age of the patients was 60 years old (range 19–79). The median number of R-CHOP course was 6 (range, 3–8). In the current study, the RDI was calculated by averaging the delivered RDIs of cyclophosphamide (CY) and adriamycin (ADR) for all chemotherapy courses. Results. The median average RDI of CY and ADR (CY/ADR-RDI) in all patients was 87.9%. Twenty three of 100 patients were treated with RDI less than 75 %. With a median follow-up of 21.2 months, the probability of 4-year overall survival (OS) was significantly higher in patients with higher RDI (>=75%) than that in patients with lower RDI (<75%) (78.6 % vs. 60%; P = 0.01). In univariate Cox regression model to identify prognostic factors for OS, RDI [hazard ratio (HR) = 0.7 per 0.1 of RDI; 95% CI 0.6– 0.9; P = 0.02] and high/high-intermediate International Prognostic Index (IPI) (HR = 4.7; 95% CI 1.3–17; P = 0.04) were significant factors influencing OS. In multivariate model, RDI was only a significant factor influencing OS (HR = 0.8 per 0.1 of RDI; 95% CI 0.6–1.0; P = 0.04). In multivariate logistic analysis to determine factors influencing RDI, elderly patients (>=51 ) [odds ratio (OR) = 0.2; 95% CI 0.1–0.7; P = 0.01] and high/high-intermediate IPI (OR = 0.3; 95% CI 0.1–1.0; P = 0.04) were significant factors for reduced RDI, whereas prophylactic G-CSF (OR = 3.2; 95% CI 1.1–9.3; P = 0.04) was found to be a significant factor for increased RDI. Conclusion. In newly diagnosed DLBL patients, the current results demonstrated that high RDI in CHOP even when combined with rituximab was significantly associated with better survival and higher RDI could be effectively maintained by G-CSF.
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Sarkozy, Clementine, Thierry Jo Molina, Roch Houot, Sydney Dubois, Gian Matteo Pica, Philippe Ruminy, Charles Herbaux et al. "Results of the Phase II of Epirchop Study, Evaluating the Efficacy of Tazemetostat in Combination with R-CHOP in Elderly Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL): A Lysa Study". Blood 142, Supplement 1 (28 de novembro de 2023): 853. http://dx.doi.org/10.1182/blood-2023-174607.
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Introduction: Tazemetostat (TAZ) is a selective oral EZH2 inhibitor with a favorable safety profile and activity in pts with either EZH2wild type or mutant B-cell NHL. In the phase I part of Epi-RCHOP study, we reported that R-CHOP plus TAZ (Taz-RCHOP) was well tolerated with safety and PK results comparable to R-CHOP alone, and the RP2D of TAZ in combination with RCHOP was consistent with TAZ monotherapy (800mg BID). We report here the efficacy results of the phase II TAZ R-CHOP study (Epi-RCHOP, NCT02889523), in pts 60-80y with newly diagnosed DLBCL. Methods: Pts received 6 R-CHOP every 21 days in combination with continuous TAZ at 800 mg BID, plus 2 cycles of TAZ and R (cycle 7 and 8). Prophylaxis with G-CSF, valaciclovir and trimethoprim sulfamethoxazole were strongly recommended. Primary endpoint was PET-based complete metabolic response rate (CR, Lugano 2014) at end of study treatment (EOT, i.e 8 cycles or at time of permanent treatment discontinuation) (data cut-off was January 30, 2023). Sample size calculation was made with the expectation of an increase of 10% in CR, with an H0 hypothesis of 70% and an H1 assumption of 80%, leading to a theorical sample size of 122 pts, assuming a drop out of 5%. The efficacy set correspond to pts who signed an informed consent and received at least one dose of TAZ. Pts without response assessment (no matter the reason) were considered non-responders. Key secondary objectives were progression free and overall survival. A sensitivity analysis was performed excluding pts who withdrawn their consent (N=112). Analyses were conducted using SAS® version 9.3. Results: From July 31, 2020 to July 18, 2022, 122 pts were enrolled in 27 LYSA centers. Median age was 70 years (60-80), 57% were female, 12% had an ECOG-PS2+, 70.5% a stage IV disease and 19.7% stage III, 66% elevated LDH, 73.8% an IPI of 3-5. Mutational profile was available for 76 pts, of whom 10 (13%) had an EZH2 mutations and 26 (34%) and EZB profile as assessed with LymphGen classifier. One hundred pts (82%) received 8 cycles and 22 had a premature treatment discontinuation (PTD), 12 (9.8%) during the first 2 cycles and 10 (8.2%) between cycle 3 and 8. Reasons for PTD were: consent withdrawal (N=10, including 7 during cycle 1 & 2), adverse events (AE, N=6, including 2 treatment related), death (N=2, both due to septic shock), protocol deviation (N=2), progressive disease (N=1) or physician decision (N=1). Overall, the median percentage of TAZ dose received was 98.4% (mean 77.2%, Q1: 61%; Q3: 100%), and AE led to TAZ interruption in 4.1%, discontinuation in 2.8% and dose reduction in 2.4% of the cases. Mean time between cycles was 21.5 days. In oct 2020, after the inclusion of 22 pts, recommendation to cap vincristine at 1mg was done, due to an excess of constipation. At end of treatment or PTD, 92/122 pts (75.4%, IC95: 66.8-82.8%) achieved CR, 8 (6.6%) PR, 5 (4.1%) had a PD, 2 (1.6%) had died (septic shock) and 15 (12.3%) were not evaluated and considered as non-responders. The primary objective was not met in this efficacy set, with a CR of 75.4% (lower than the H1 at 80%). The sensitivity analysis, excluding the 10 pts that withdrawn their consent (all non-evaluated), showed a CR rate of 82.1% (92/112, IC95: 73.8-88.7%) and PR rate of 7.1%. After a median follow-up of 18.5 months (Range = [0.2; 28.1]), 17/122 pts had a relapse/progression (13.9%) and 12 had died: 4 due to lymphoma, 3 to COVID-19, 4 to AE (2 septic shock, 1 acute myeloid leukemia and 1 heart failure), 1 unknown cause (in CMR). The estimated 18m PFS and OS were 77.7% (IC95: 67.5-85.1%) and 88.8% (IC95: 79.9-93.9%) respectively. Most frequent AE were: neutropenia (53%), anemia (51%), nausea (47%), asthenia (42%), peripheral neuropathy (37%), gastro-intestinal hypomotility (35%), weight loss (28%), vomiting (24%), thrombocytopenia (24%). AE of grade 3 or more occurred in 73% of the pts and were mainly hematological AE with neutropenia (48%, including 6% of febrile neutropenia), anemia (23%), thrombocytopenia (17%) and gastro-intestinal disorder (overall 10.7%). Red blood cell and platelets transfusions were administered in 31% and 11.5% of the pts respectively. Conclusion: R-CHOP plus TAZ is doable. Efficacy results in this trial conducted during the COVID pandemic in a particularly challenging population, suggest that the combination warrant further investigation including correlative studies with molecular subclassification that will be presented.
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Anderson, David, Matthew Garlinghouse, Arica Hauger, Alison Moody, Ann M. Berger e Jean L. Grem. "Neural mechanisms of impaired executive function in untreated colorectal cancer patients." Journal of Clinical Oncology 38, n.º 15_suppl (20 de maio de 2020): e24170-e24170. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e24170.
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e24170 Background: Cancer-related cognitive impairment (CRCI) affects 45% of colorectal cancer (CRC) patients prior to treatment. This study aimed to explore the neural mechanisms of CRCI in this severely understudied population by using a combination of neuropsychological and cognitive neurophysiology assessments. Methods: Newly diagnosed Stage I-IV CRC patients were recruited at a Midwestern tertiary medical center. Enrollment criteria included normal or corrected to normal vision and no prior cancer within 3 years. Healthy comparisons were recruited and demographically-matched to Stage III/IV patients scheduled to receive chemotherapy. Participants completed neuropsychological measures of processing speed, psychomotor speed, executive function, and verbal memory at study baseline. We recorded scalp electroencephalography while participants performed a computer-based cognitive task designed to measure control over spatial attention. Two event-related potentials were measured following presentation of a task-irrelevant spatial cue: (1) N2, a neural correlate of stimulus selection emerging approximately 160 milliseconds after stimulus presentation; and (2) N2pc, a neural correlate of spatial attention allocation emerging approximately 200 milliseconds after stimulus presentation. Results: CRC patients were enrolled within 4-8 weeks following surgery for Stage I (11%), II (31%), and III (35%) CRC; Stage IV patients (23%) started chemotherapy without surgery. Patients (n = 26) and controls (n = 14) were matched on age and gender; patients were trending toward lower education than controls (p = .06). Patients performed worse than controls on executive function assessments (Trials B: p = .049; Stroop: p = .025). N2 amplitudes were smaller in patients than controls (p = 0.032. N2pc amplitudes were larger in patients than controls (p = .092). N2 amplitudes were associated with Stroop interference scores (r = 0.50, p = .068). Conclusions: CRC patients demonstrated impaired executive function performance at baseline. Neurophysiological data suggest impairments may emerge from limited neural resources available for stimulus selection and poor control over spatial attention. Correlations between neurophysiological data and executive function performance suggest participants better able to overcome task-irrelevant interference had relatively more neural resources available for stimulus selection. Overall, these results suggest patients may be limited in their ability to focus their attention on caregiver and health care team instructions. Clinical trial information: NCT03683004 .
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Mehta, Parinda A., Stella M. Davies, Ashish Kumar, Meenakshi Devidas, Susan Lee, Tiffany Wilke, James Elliott et al. "Perforin Polymorphism A91V and Susceptibility to Childhood Acute Lymphoblastic Leukemia (ALL)." Blood 106, n.º 11 (16 de novembro de 2005): 1453. http://dx.doi.org/10.1182/blood.v106.11.1453.1453.
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Abstract Perforin plays a key role in the cytotoxicity of NK cells and cytotoxic T lymphocytes. Genetic mutations in perforin gene (PRF1) give rise to 30–40% of cases of familial hemophagocytic lymphohistiocytosis. We recently studied two boys who had been treated for PreB ALL and subsequently developed HLH. Both showed decreased perforin expression in NK cells and were found to be heterozygous for PRF1 A91V. The functional consequences of the PRF1 A91V (resulting from C272T transition) are controversial; between 3 and 17% of apparently normal people are heterozygous for this polymorphism depending on the population studied. Recent data suggest that A91V results in conformational change that may impair processing of perforin protein to the active form, and that the polymorphism may increase susceptibility to ALL in children (Trambas et al, Blood2005; 106:932; Santoro et al, Haematologica2005;90:697). We have genotyped 655 normal blood donors and 2,272 children with ALL treated on Pediatric Oncology Group 9900 clinical trials. Genotyping was performed using a specific PCR assay (Taqman). Genotypes in the normal US blood donors showed significant variation in allele frequency by race, with a very low frequency of the variant allele in black controls (0.7% compared with 4% in white controls). Allele frequencies did not vary by gender and genotype frequencies were in Hardy Weinberg equilibrium (whites C/C 92%; C/T 8%; T/T 0.2%). In light of the low frequency of the variant allele in blacks, analysis of leukemia cases was restricted to a comparison of white cases and white controls. Analyses were performed for all B-lineage ALL cases combined, and were also further stratified for known genetic subtypes of ALL. Perforin genotype CC Perforin genotype CT or TT p-value (cases versus controls Controls (n=507) 464 (91.5%) 43 (8.5%) - Cases (all; n= 1321) 1198 (90.7%) 123 (9.3%) 0.58 BCR-ABL 22 (76%) 7 (24%) 0.0048 Trisomy 4,10 238 (93.7%) 16 (6.3%) 0.29 TEL-AML1 250 (90.6%) 26 (9.4%) 0.66 E2A-PBX 24 (92.3%) 2 (7.7%) 0.89 MLL abn. 40 (87%) 6 (13%) 0.29 Hyperdiploid 244 (92.4%) 20 (7.6%) 0.66 Hypodiploid 8 (100%) 0 (0%) 0.40 Taken together, these data indicate that the A91V polymorphism is not associated with an overall increased risk of childhood ALL, in contrast to the previous report. PRF1 A91V was identified with significantly increased frequency in children with BCR-ABL positive ALL. However, this observation includes a relatively small number of cases and the potential association should be explored further, perhaps in adult ALL series in which the frequency of BCR-ABL positivity is likely to be high.
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Redeker, I., S. Moustakis, S. Tsiami, X. Baraliakos, I. Andreica, B. Buehring, J. Braun e U. Kiltz. "AB0823 TREATMENT WITH ADALIMUMAB IN PATIENTS WITH CHRONIC INFLAMMATORY RHEUMATIC DISEASES: A STUDY OF TREATMENT TRAJECTORIES ON A PATIENT LEVEL IN CLINICAL PRACTICE". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de maio de 2021): 1435.2–1436. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1838.
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Background:There is evidence that drug retention rates to adalimumab (ADA) in patients (pts.) with chronic inflammatory rheumatic diseases (CIRD) are impaired by loss of efficacy and adverse events, and that about 50% of users had discontinued ADA within 5 years (1). With the introduction of ADA biosimilars in October 2018, non-medical switching from originator to ADA biosimilars is now increasingly part of daily practice in rheumatologic care.Objectives:The aim was to study treatment trajectories over two years in pts. with CIRD receiving originator ADA.Methods:Pts. with CIRD on originator ADA who switched to ADA biosimilar from October 2018 onwards were identified and followed until 2020. Disease activity (ASDAS), physical function (HAQ, BASFI), and changes in treatment were documented every 3 months. The four predefined treatment trajectories “continued ADA biosimilar therapy”, “back-switch to originator ADA therapy”, “switch to other biological (b) disease modifying anti-rheumatic drug (DMARD) therapy”, and “stopped bDMARD therapy /death /drop out” were used to compare characteristics of pts. with different trajectories.Results:A total of 111 CIRD pts. on treatment with originator ADA were switched to ADA biosimilar (Table 1). The majority of pts. 75 continued therapy with ADA biosimilar (Figure 1 next page) while 16% switched back to originator ADA, 7% switched to a different bDMARD, and 9% either stopped treatment (n=9) or died (n=1). Pts. who continued ADA biosimilar were more frequently male, older or with a longer disease duration than those who switched therapy back to originator ADA and those who switched to a different bDMARD (Table 1). The previous duration on originator ADA treatment was increased in patients who continued ADA biosimilar compared to those who switched therapy back to originator ADA and those who switched to a different bDMARD. There was more functional impairment (HAQ, BASFI) and higher disease activity (ASDAS) in pts. who switched compared to those who continued ADA biosimilar therapy (Table 1). Treatment with csDMARDs and glucocorticoids was increased in pts. who continued ADA biosimilar therapy, while pts. who switched therapy had more previous bDMARD therapies (Table 1).Table 1.Characteristics of patients at baseline for the entire group and stratified by treatment trajectoryTotal groupN=111 (100%)Treatment trajectorycontinued ADA biosimilar therapyN=75 (67.6%)back-switch to originator ADA therapyN=18 (16.2%)switch to different bDMARD therapyN=8 (7.2%)no bDMARD therapy /death /drop outN=10 (9.0%)Age, y51.2 (14.5)51.5 (13.6)50.6 (16.8)43.5 (9.5)56.4 (19.0)Women, No. (%)46 (41.4)27 (36.0)9 (50.0)6 (75.0)4 (40.0)RA23 (20.7)17 (22.7)2 (11.1)1 (12.5)3 (30.0)axSpA68 (61.3)47 (62.7)11 (61.1)6 (75.0)4 (40.0)PsA15 (13.5)7 (9.3)4 (22.2)1 (12.5)3 (30.0)Other diagnoses5 (4.5)4 (5.3)1 (5.6)0 (0.0)0 (0.0)Disease duration, median (IQR), y5.0 (2.0-8.0)5.0 (2.0-9.0)3.5 (2.0-6.0)2.0 (1.0-5.5)4.5 (2.0-8.0)Duration previous originator ADA therapy40.7 (27.7)45.3 (27.8)35.0 (25.2)20.3 (24.7)32.3 (25.1)DAS283.0 (1.0)2.9 (1.0)3.4 (1.0)-3.3 (1.2)CRP, median (IQR), mg/L0.2 (0.1-0.3)0.1 (0.1-0.2)0.2 (0.0-0.5)0.2 (0.2-1.3)0.3 (0.2-0.4)HAQ score1.3 (0.8)1.1 (0.7)1.7 (0.8)-1.8 (1.0)ASDAS2.2 (1.1)2.0 (1.0)3.0 (1.2)2.7 (0.9)2.3 (0.2)BASFI3.5 (2.6)3.0 (2.5)5.4 (2.4)3.4 (1.6)5.4 (1.6)+values are given as mean (SD)Conclusion:Two thirds of pts. who switched to ADA biosimilar remained on this therapy for 2 years. As many as 16% of pts. switched back to ADA originator. Whether or to what degree this was influenced by nocebo effects needs further study. The same is true for the effect of functional impairment – it would be interesting to know whether this was due to inflammation or structural damage.References:[1]Neovius M et al. Ann Rheum Dis 2015; 74:354-360[2]The study was funded by Hexal Germany.Figure 1.Treatment trajectories of ADA therapy in patients with CIRD during two years ADA: adalimumab; bDMARD: biological disease modifying anti-rheumatic drug.Disclosure of Interests:None declared
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Strand, V., P. Patel, N. Chen e E. Lesser. "AB0835 THE IMPACT OF ADALIMUMAB VS PLACEBO ON PATIENT-REPORTED OUTCOMES AND UTILITY MEASURES AMONG PATIENTS WITH MODERATELY TO SEVERELY ACTIVE PSORIATIC ARTHRITIS". Annals of the Rheumatic Diseases 79, Suppl 1 (junho de 2020): 1722–23. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1254.
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Background:Physical function and health-related quality of life(HRQoL) are negatively impacted in patients(pts) with PsA. Treatment with conventional and biological (b) DMARDs improved patient-reported outcomes(PROs).Objectives:To assess impact of adalimumab(ADA) vs placebo(PBO) on PROs following 12-week (wk) treatment.Methods:Pts(n=315) with moderately to severely active PsA and bDMARD naive were randomized to ADA 40mg or PBO every other wk. We assessed PROs at baseline(BL) and wk 12 using the 36-item Short-Form(SF-36) Health Survey physical(PCS) and mental component summary(MCS) scores, 8 domain scores ranging from 0(worst) to 100(best), and SF-6D utility measure derived from all 8 SF-36 domains with scores ranging from 0.296(worst) to 1.00(full health) and minimally important difference(MID) of 0.041. Patient Global Assessment of disease activity(PtGA) and pain(both utilizing 100 mm visual analog scale[VAS]) and HAQ disability index(DI) were assessed. Mean changes from BL, percentages of pts with improvements ≥minimum clinically important differences(MCID), and scores ≥US age-and gender-matched normative values(A/G norms) were analyzed, based on as observed data.Pvalues were assessed by analysis of variance model for continuous variables andCochran–Mantel–Haenszeltest for binary outcomes, adjusting by baseline MTX use and extent of psoriasis. Numbers needed to treat(NNTs) are reported using proportions of pts reporting improvements ≥MCID in SF-36, PtGA, pain, and HAQ-DI.Results:BL PRO scores were similar between ADA(n=151) and PBO(n=162;Table 1). Improvements from BL at wk 12 with ADA vs PBO were significant in PtGA, pain, HAQ-DI, and SF-36 PCS(change: 9.3 vs 1.4;P<0.001) but not in SF-36 MCS(1.6 vs 1.2;Table 1). Six of 8 SF-36 domains significantly improved from BL to wk 12 with ADA vs PBO(allP≤0.05;Table 1andFigure 1). SF-6D improvements exceeded MID with ADA(change: 0.071) vs PBO(0.018). Proportions of pts reporting improvements ≥MCID at wk 12 were significantly greater with ADA vs PBO in all PROs, except SF-36 role emotional and mental health domains, with corresponding NNTs ≤6.4(Figure 2). Proportions of pts who reported scores ≥A/G norms in HAQ-DI, SF-36 PCS, and 6 of 8 SF-36 domains were significantly greater with ADA vs PBO(Figure 2).Table 1.Mean Disease Characteristics and SF-36 Domain Scores by Treatment Group at Baseline and Wk 12 Compared With Age-and Gender-Matched Normative ValuesADA 40 mg eowPBOA/G normsBaselineWeek 12[change from baseline to week 12]BaselineWeek 12[change from baseline to week 12]SF-36 PCS33.242.5[9.3**]33.334.7[1.4]≥50SF-36 MCS48.149.8[1.6]46.648.4[1.2]≥50SF-6D0.6530.724[0.071]0.6410.659[0.018]—PtGA47.125.9[–21.7**]48.147.5[0.2]—Pt pain51.126.8[–24.1**]48.849.1[1.3]—HAQ-DI1.00.6[–0.4**]1.00.9[–0.1]≤0.25Baseline(vs A/G norms)Week 12(vs A/G norms)Baseline(vs A/G norms)Week 12(vs A/G norms)Physical Functioning50.8(−31.5)65.9***(−16.4)48.2(−34.1)52.0(−30.3)82.3Role Physical37.1(−45.9)65.9***(−17.1)32.6(−50.4)40.6(−42.4)83.0Bodily Pain41.3(−31.6)61.0***(−11.9)40.2(−32.7)43.7(−29.2)72.9General Health49.5(−20.8)62.1***(−8.2)52.1(−18.2)53.0(−17.3)70.3Vitality41.4(−17.8)55.1***(−4.1)41.6(−17.6)45.0(−14.2)59.2Social Functioning66.3(−19.0)77.8†(−7.5)61.7(−23.6)66.7(−18.6)85.3Role Emotional65.1(−23.4)70.4(−18.1)59.1(−29.4)66.0(−22.5)88.5Mental Health67.6(−8.5)72.9(−3.2)64.9(−11.2)67.3(−8.8)76.1ADA, adalimumab; A/G norm, age-and gender-matched normative value; eow, every other week; DI, disability index; MCS, mental component summary; MID, minimally important difference; PBO, placebo; PCS, physical component summary; PtGA, Patient Global Assessment of disease activity; SF-36, 36-item Short-Form Health Survey; SF-6D, Short-Form 6D.SF-6D MID=0.041.Statistical analysis ADA vs PBO:†P<0.05; *P<0.01; **P<0.001; ***P<0.0001.Conclusion:Statistically significant and clinically meaningful improvements and scores ≥A/G norms(higher definition of response) at week 12 were reported with ADA vs PBO in pts with moderately to severely active PsA.Disclosure of Interests:Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB, Pankaj Patel Shareholder of: AbbVie, Employee of: AbbVie, Naijun Chen Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, Elizabeth Lesser Shareholder of: AbbVie Inc, Employee of: AbbVie Inc
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Kim, Hawk, Jae-Hoo Park, Je-Hwan Lee, Young Don Joo, Won-Sik Lee, Sung-Hwa Bae, Hun-Mo Ryoo et al. "Prospective Randomized Comparison of Cyclophosphamide Versus Cyclophosphamide Plus Fludarabine In Addition to Anti-Thymocyte Globulin for the Conditioning Therapy In Allogeneic Hematopoietic Cell Transplantation for Bone Marrow Failure Syndrome". Blood 116, n.º 21 (19 de novembro de 2010): 34. http://dx.doi.org/10.1182/blood.v116.21.34.34.
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Abstract Abstract 34 We performed randomized phase III study to compare the regimen related toxicities (RRT) of two different conditioning regimens, cyclophosphamide (CyATG) vs. cyclophosphamide plus fludarabine (CyFluATG) given in addition to anti-thymocyte globulin (ATG) for allogeneic hematopoietic cell transplantation (alloHSCT) for bone marrow failure syndrome including severe aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (MDS). CyATG consisted of Cyclophosphamide (Cy) 50 mg/kg (D –5 to –2). CyFluATG arm received fludarabine (Flu) 30 mg/m2 (D –6 to –2) and Cy 50 mg/kg (D –3 to –2). Thymoglobuline 3 mg/kg, lymphoglobulin 15 mg/kg on days -4 to -2 or alemtuzumab 20mg on day -4 were infused in both arms. Patients were stratified by stem cell donor (related vs. unrelated). Total 83 patients (40 patients to Cy-ATG and 43 patients to Cy-Flu-ATG) were enrolled from February 2003. All patients except for one patient, who had assigned to Cy-Flu-ATG arm and died during conditioning, received full planed regimen and all planned patients were included in this analysis. Median age was 34 (15-60) years and male patients were 42/83 (50.6%). AA patients were 79 and MDS were 4. Matched sibling donors were 53 (63.9%). ATG was used in form of thymoglobulin (n=75, 90.4%), and some patients had received ALG (n=5, 6.0%) or alemtuzumab (n=3, 3.6%). Median duration from diagnosis to transplantation was 4.7 (0.2-177.7) months. Age, gender, donor type were not different in both arms (Table 1). Various TRT were similar between Cy-ATG and Cy-Flu-ATG (Table 2); granulocyte graft failure rate (p=0.959), platelet graft failure rate (p=0.625), acute GvHD (p=0.388), chronic GvHD (p=0.991), CMV antigenemia (p=0.550), hematuria (p=0.480). However, pulmonary complications (p=0.005) was significantly lower in CyFluATG arm. Infection rate (p=0.130) and sinusoidal obstruction syndrome (SOS, p=0.101) seemed lower in CyFluATG arm but were not statistically significant. Any RRTs were significantly higher in CyATG arm (80.0% vs. 39.5%; p<0.001) but any treatment-related toxicities were similar in both arms (85% vs. 79.1%; p=0.483). Figure 1 shows that 4-year survival rates (77.7% vs. 87.6%) were higher in CyFluATG arm without any statistical significance (p=0.265) and this trend was similar in MRD (81.9 vs. 92.1%; p=0.354) and AD (69.3 vs. 80.2%; p=0.442). In conclusion, overall treatment-related complications and survival were similar between CyATG CyFluATG, however, CyFluATG seemed superior over CyATG in terms of pulmonary complications and RRT.Table 1.Characteristics of patients between Cy-ATG and Cy-Flu-ATGCharacteristicsCy-ATGCy-Flu-ATGp-valueGender, n (%)0.586Male19 (47.5)23 (53.5)Female21 (52.5)20 (46.5)Age, median (range)34.5 (15±59)34.0 (18±60)0.365Months from diagnosis to SCT, median (range)4.8 (0.2–147.2)4.6 (0.9–177.7)0.982Diagnosis, n (%)0.617AA39 (97.5)40 (93.0)MDS1 (1.9)3 (7.0)Infused CD34+ cell dose (?106/kg), mean±SD5.76±4.895.25±5.300.449ATG, n (%)0.360Thymoglobulin38 (95.0)37 (86.0)ALG1 (2.5)4 (9.3)Alemtuzumab1 (2.5)2 (4.7)HLA-A, B, C and DR molecular matching, n (%)0.699Full matched30 (75.0)30 (69.8)1 locus mismatched3 (7.5)3 (7.0)2 loci mismatched3 (7.5)2 (4.7)Not determined4 (10.0)8 (18.6)Donor, n (%)0.834MSD26 (65.0)27 (62.8)AD14 (35.0)16 (37.2)Table 2.The comparison of treatment-related toxicities between Cy-ATG and Cy-Flu-ATGFactorsCy-ATGCy-Flu-ATGp-valueGraft failure, n (%)5 (12.5)7 (16.3)0.625Granulocyte1 (2.5)1 (2.3)0.959Platelet5 (12.6)7 (16.3)0.625Acute GvHD, n (%)Any grades6 (15.0)10 (23.3)0.388Grade 3/42 (5.0)1 (2.3)0.514Chronic GvHD, n (%)Any5 (12.5)5 (11.6)0.991Extensive4 (10.0)3 (7.0)0.369CMV antigenemia, n (%)24 (60.0)23 (53.5)0.550Infection, n (%)32 (80.0)28 (65.1)0.130Interstitial pneumonitis, n (%)0 (0.0)0 (0.0)–Pulmonary complications, n (%)14 (35.0)4 (9.3)0.005SOS, n (%)5 (12.5)1 (2.3)0.101Hematuria, n (%)10 (8.7)8 (29.6)0.480Any regimen-related toxicities, n (%)32 (80.0)17 (39.5)<0.001Any treatment-related toxicities, n (%)34 (85.0)34 (79.1)0.483Figure 1.Overall survivalFigure 1. Overall survival Disclosures: Off Label Use: Cyclophosphamide, Fludarabine and thymoglobulin were used in conditioning regimens of this phase III clinical trial.
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Yoshino, Takayuki, Maria Di Bartolomeo, Kanwal Pratap Singh Raghav, Toshiki Masuishi, Fotios Loupakis, Hisato Kawakami, Kensei Yamaguchi et al. "Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01)." Journal of Clinical Oncology 39, n.º 15_suppl (20 de maio de 2021): 3505. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3505.
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3505 Background: T-DXd is an antibody–drug conjugate of a humanized anti-HER2 antibody bound to a topoisomerase I inhibitor by a cleavable linker. The primary analysis of DESTINY-CRC01 (DS8201-A-J203; NCT03384940), a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC showed promising antitumor activity and a manageable safety profile (cohort A median follow-up [FU], 27.1 weeks; Siena S, ASCO 2020). We present updated longer-term efficacy and safety data. Methods: Pts had centrally confirmed HER2-expressing, RAS wild-type mCRC that progressed after ≥2 prior regimens. 6.4 mg/kg of T-DXd was administered every 3 weeks (Q3W) in 3 cohorts (A: HER2 IHC3+ or IHC2+/ISH+; B: IHC2+/ISH−; C: IHC1+). The primary end point was confirmed objective response rate (ORR) by independent central review in cohort A. Secondary end points were disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: At data cutoff (Dec 28, 2020), 86 pts (A, 53; B, 15; C, 18) received T-DXd. Median age was 58.5 y (range, 27-79), 53.5% were male, and 90.7% had left colon or rectum cancer. Median prior regimens for metastatic disease was 4 (range, 2-11). All pts had prior irinotecan; 30.2% in cohort A had prior anti-HER2 therapy. Median (m) treatment duration (all pts) was 3.0 mo (95% CI, 2.1-4.1; cohort A, 5.1 mo [95% CI, 3.9-7.6]). In cohort A (median FU, 62.4 weeks), confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6-59.6), DCR was 83.0% (44/53 pts; 95% CI, 70.2-91.9), mDOR was 7.0 mo (95% CI, 5.8-9.5), mPFS was 6.9 mo (95% CI, 4.1-8.7) with 37 (69.8%) PFS events, and mOS was 15.5 mo (95% CI, 8.8-20.8) with 36 (67.9%) OS events. These results are consistent with the primary analysis. Confirmed ORR was 43.8% (7/16 pts; 95% CI, 19.8-70.1) in pts with prior anti-HER2 therapy, 57.5% (23/40 pts; 95% CI, 40.9-73.0) in pts with IHC3+ status, and 7.7% (1/13 pts; 95% CI, 0.2-36.0) in pts with IHC2+/ISH+ status. In cohorts B and C, mPFS was 2.1 mo (95% CI, 1.4-4.1) and 1.4 mo (95% CI, 1.3-2.1); mOS was 7.3 mo (95% CI, 3.0-NE) and 7.7 mo (95% CI, 2.2-13.9), respectively. Treatment-emergent adverse events (TEAEs) of grade (G) ≥3 occurred in 65.1% of pts (56/86); the most common TEAEs were hematologic and gastrointestinal. TEAEs leading to drug discontinuation occurred in 13 pts (15.1%). 8 pts (9.3%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (4 G2; 1 G3; 3 G5). Conclusions: T-DXd at 6.4 mg/kg Q3W showed promising activity and durability with longer-term FU in this pt population. The safety profile was consistent with prior results; ILD continues to be recognized as an important identified risk that requires careful monitoring and intervention as needed. These results support continued exploration of T-DXd in pts with HER2-overexpressing mCRC. Clinical trial information: NCT03384940.
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Yoshino, Takayuki, Maria Di Bartolomeo, Kanwal Pratap Singh Raghav, Toshiki Masuishi, Hisato Kawakami, Kensei Yamaguchi, Tomohiro Nishina et al. "Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01)." Journal of Clinical Oncology 40, n.º 4_suppl (1 de fevereiro de 2022): 119. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.119.
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119 Background: T-DXd is an antibody-drug conjugate of a humanized anti-HER2 antibody bound to a topoisomerase I inhibitor by a cleavable linker. The primary analysis of DESTINY-CRC01 (DS8201-A-J203; NCT03384940), a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC showed promising antitumor activity and a manageable safety profile (cohort A median follow-up [FU], 27.1 weeks; Siena S, ASCO 2020). We present updated longer-term efficacy and safety data. Methods: Pts had centrally confirmed HER2-expressing, RAS wild-type mCRC that progressed after ≥2 prior regimens. 6.4 mg/kg of T-DXd was administered every 3 weeks (Q3W) in 3 cohorts (A: HER2 IHC3+ or IHC2+/ISH+; B: IHC2+/ISH−; C: IHC1+). The primary endpoint was confirmed objective response rate (ORR) by independent central review in cohort A. Secondary endpoints were disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: At data cutoff (Dec 28, 2020), 86 pts (A, 53; B, 15; C, 18) received T-DXd. Median age was 58.5 y (range, 27-79), 53.5% were male, and 90.7% had left colon or rectum cancer. Median prior regimens for metastatic disease was 4 (range, 2-11). All pts had prior irinotecan; 30.2% in cohort A had prior anti-HER2 therapy. Median (m) treatment duration (all pts) was 3.0 mo (95% CI, 2.1-4.1; cohort A, 5.1 mo [95% CI, 3.9-7.6]). In cohort A (median FU, 62.4 weeks), confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6-59.6), DCR was 83.0% (44/53 pts; 95% CI, 70.2-91.9), mDOR was 7.0 mo (95% CI, 5.8-9.5), mPFS was 6.9 mo (95% CI, 4.1-8.7) with 37 (69.8%) PFS events, and mOS was 15.5 mo (95% CI, 8.8-20.8) with 36 (67.9%) OS events. These results are consistent with the primary analysis. Confirmed ORR was 43.8% (7/53 pts; 95% CI, 19.8-70.1) for pts with prior anti-HER2 therapy, 57.5% (23/53 pts; 95% CI, 40.9-73.0) for pts with IHC3+ status, and 7.7% (1/53 pts; 95% CI, 0.2-36.0) for pts with IHC2+/ISH+ status. In cohorts B and C, mPFS was 2.1 mo (95% CI, 1.4-4.1) and 1.4 mo (95% CI, 1.3-2.1); mOS was 7.3 mo (95% CI, 3.0-NE) and 7.7 mo (95% CI, 2.2-13.9), respectively. Treatment-emergent adverse events (TEAEs) of grade (G) ≥3 occurred in 65.1% of pts (56/86); the most common TEAEs were hematologic and gastrointestinal. TEAEs leading to drug discontinuation occurred in 13 pts (15.1%). 8 pts (9.3%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (4 G2; 1 G3; 3 G5). Conclusions: T-DXd at 6.4 mg/kg Q3W showed promising activity and durability with longer-term FU in pts with HER2-expressing mCRC. The safety profile was consistent with prior results; ILD continues to be an important identified risk that requires careful monitoring and intervention as needed. These results support continued exploration of T-DXd in this patient population. Clinical trial information: NCT03384940.
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Dunleavy, Kieron, Richard Little, Alan S. Wayne, Nicole Grant, Stefania Pittaluga, Elaine S. Jaffe, Seth Steinberg et al. "Long-Term Outcome of AIDS-Related Lymphoma Treated with Abbreviated Cycles of EPOCH-RR: A Prospective Study of 40 Patients". Blood 112, n.º 11 (16 de novembro de 2008): 3606. http://dx.doi.org/10.1182/blood.v112.11.3606.3606.
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Abstract We hypothesized that the addition of rituximab to EPOCH chemotherapy could improve tumor kill, allowing delivery of fewer cycles of treatment and therefore reducing toxicity. Patients received EPOCH-RR (in mg/m2/d – etoposide 50, vincristine 0.4 and doxorubicin 10 all CIV d 1–5; cyclophosphamide 750 mg IV d 5; prednisone 60 po days 1–5 and rituximab 375 IV d 1,5 and G-CSF sc d 6–15) every 21 days. Prophylactic IT methotrexate was administered and HAART was suspended during therapy. Cyclophosphamide was adjusted based on absolute neutrophil count (ANC) nadir. Response was assessed by CT and FDG-PET scan and patients received 1 cycle beyond CR for a minimum of 3 cycles. Characteristics of 40 enrolled patients are: median (range) age 42 (9–60) years; IPI 3 (0–4); ECOG PS 1 (1–4), CD4 count 222 (0–835) cells/mm3; HIV viral load 34,766 (0–6,080000) RNA copies/mL; male sex 35 (88%); LDH > N 27 (68%); stage IV 27 (68%) and histology diffuse large B-cell lymphoma (DLBCL) 32 (80%) and Burkitt lymphoma (BL) 8 (20%). Of 38 evaluable patients (2NE), median (range) number of cycles given is 3 (3–5) with CR/CRu in 35 (92%) and PR in 1 (3%) patients. At 4 years median follow-up, PFS and OS are 86% and 70%, respectively. Eight patients with BL are in continuous CR. For patients with CD4 > and < 100 cells/mm3, PFS is 96% and 69%, respectively. IPI did not impact OS and PFS. Early PET scanning (after cycle 2) had a high negative predictive value (100%) but low positive predictive value (20%). Fever/neutropenia occurred on 30%, ANC < 500/mm3 on 40%, and platelets < 50,000/mm3 on 23% of cycles. EPOCH-RR was associated with less CD4 loss - median 128 cells/mm3 (range +154 to −639) compared to historical data with EPOCH alone (median 189 cells/mm3 (range +19 to −973). Patients with CD4 < 100/mm3 had good tumor control, but OS was only 31% due to late deaths from advanced AIDS. Patients with CD4 counts > 100/mm3 had an extremely good PFS and OS. The addition of rituximab did not appear to cause serious infection related complications or deaths. However, one treatment-related death occurred from complications of mycobacterium avium intercellulare. Abbreviated EPOCH-RR is highly effective and tolerable in ARL and enables the administration of fewer treatment cycles (median 3 versus 6). PET scanning has a very high negative but low positive predictive value for subsequent relapse, possibly due to HIV associated PET changes. Accrual continues.
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Bertrand, Yves, Stefan Suciu, Nathalie Grardel, Marleen Bakkus, Francoise Mazingue, Karima Yacouben, Anne Uyttebroeck et al. "The Prognosis of Children Acute Lymphoblastic Leukemia (ALL) with Minimal Residual Disease (MRD) ≥10-2 After Induction (TP1) Depends on the Prephase Response and on the Level of the MRD After Consolidation (TP2): Results of the 58951EORTC Trial". Blood 118, n.º 21 (18 de novembro de 2011): 2571. http://dx.doi.org/10.1182/blood.v118.21.2571.2571.
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Abstract Abstract 2571 Background: In our previous EORTC 58881 trial in childhood ALL, we have shown the prognostic impact of the MRD, quantitated by polymerase chain reaction assay. Patients with TP1 MRD ≥10–2 (D35), had a higher risk of relapse than those with TP1 MRD<10-2 (Cavé et al, NEJM, 1998). For these patients hematopoietic stem cell transplantation (HSCT) with an HLA matched donor was recommended in our subsequent EORTC 58951 trial. Here we report on the patients with MRD ≥10-2 (TP1) in the 58951 trial. Methods: Between December 1998 and July 2008, 1955 children (1y-18y) with ALL were enrolled in the 58951 trial, 1459 being evaluable for the MRD (TP1) by PCR (rearrangements of the T-cell receptor and immunoglobulin heavy chain genes). Seventy-nine patients with Phi-negative ALL had a TP1 MRD ≥10-2, and 69 of them achieved a complete hematological remission after induction. Here we report on the outcome of these 69 patients. Results: At a median follow-up of 7.6 years, the overall 5-years EFS and OS rates for the 69 patients were 56.1% (SE 6.0%) and 62.0% (SE 5.9%) respectively. Prephase good responders (PGR) (<1000 blasts/mm3 D8) (N=40) had a better OS rate as compared to prephase poor responders (PPR) (N=29): 72.2% (SE 7.1%) vs 48.0% (SE 9.3%) (hazard ratio=0.43, p = 0. 002). In B-lineage ALL patients the OS was similar between PGR (N=32) and PPR (N=6) subgroups, whereas in T-ALL patients there was a better OS for PGR (N=8) than for PPR (N=23) subgroup. Of note, all the patients with hyperdiploidy > 51 chromosomes were PGR. TP2 MRD (after consolidation) was assessed in 59 pts. All patients but one (1/13) with TP2 MRD ≥10-2 died. In PGR patients, those with TP2 MRD < 10-3 (N=18) had a significant better OS rate at 5 years than those with TP2 MRD ≥10-3 (N=17): 88.9% (SE 7.4%) vs 52.3 % (SE 12.3%), hazard ratio=0.17, p=0.009. We observed no relapses among patients with hyperdiploidy > 51 chromosomes and TP2 <10-3. PPR patients had a poor 5-year OS, independent of TP2 level (MRD <10-3 (N=8) or MRD ≥10-3 (N=16)). Conclusions: The prognosis of children ALL with TP1 MRD ≥10-2 has improved with early intensification of the treatment as compared to the one observed in our previous 58881 study. However the outcome of these patients was still heterogeneous and the prephase response was still of prognostic importance. Patients with GPR and TP2 <10-3 had a favourable prognosis and for those patients HSCT is not mandatory. For other patients with PPR and/or TP2 ≥10-3 the prognosis was worse and these patients may benefit from alternative therapy and/or intensification with HSCT. Disclosures: No relevant conflicts of interest to declare.
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Levavi, Hannah, Daiva Ahire, Yosef Joseph Rene Amel Riazat-Kesh, Tianxiang Sheng, Dahniel L. Sastow, Jonathan Feld, Douglas Tremblay et al. "Array CGH + SNP in ALL Enhances Detection of Complex Cytogenetic Profiles and Suggests That PRSS1 Loss May Play a Role in Leukemogenesis". Blood 142, Supplement 1 (28 de novembro de 2023): 6062. http://dx.doi.org/10.1182/blood-2023-185332.
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Introduction Cytogenetic alterations are essential prognostic biomarkers in patients (pts) with acute lymphoblastic leukemia/lymphoma (ALL), but are limited by the propensity of leukemic blasts to undergo apoptosis in culture, poor-quality chromosomes, and overgrowth by normal cells. Array CGH + SNP has 10,000-fold higher resolution than conventional cytogenetics and can identify submicroscopic gains, losses and copy number neutral loss of heterozygosity (cnLOH) irrespective of mitotic rate. Few studies outside of clinical trials have investigated microarray findings in adults with ALL or correlated microarray findings with clinical outcomes. Methods We retrospectively reviewed pts with ALL and mixed phenotype acute leukemia (MPAL) aged ≥18 years at diagnosis at our institution between 2017 and 2022. Array analysis was performed on diagnostic bone marrow or peripheral blood samples using high resolution CGH + SNP Genetisure cancer array platform (Agilent). Statistical analysis was done using R software (R core team, 2022). Results Baseline characteristics of included pts (n = 60) are shown in Table 1. CGH + SNP analysis identified 93.3% (56/60) of pts with genomic changes with a mean of 7 (range 0 - 28) aberrations per pt. Among pts with a normal karyotype, 81.8% (9/11) had new genomic abnormalities revealed by CGH + SNP, but significantly fewer aberrations were detected per pt compared to those with abnormal karyotypes (mean 3.09 v. 7.67, p = .008). Pts with Ph-like B-ALL/MPAL had significantly more aberrations on array than pts without Ph-like phenotype (mean 12.0 v. 5.85, p.= .002). Among the 78.3% of pts without complex cytogenetics on chromosome analysis, 44.7% (21/47) were found to have a complex genomic profile (≥5 aberrations) with the addition of CGH + SNP. However, there was no difference in CR rates or OS in pts with <5 or ≥5 microarray aberrations (p = .515 and p = .970, respectively). Quantity of copy number alterations (CNAs) as detected on array was not predictive of achieving end of induction CR/CRi/CRh (mean 6.08 in pts who achieved CR/CRi/CRh v. 7.02 in pts with primary refractory disease, p = .310). Hispanic pts had the same number of CNAs as non-Hispanic pts (mean 6.69 v. 6.94, p = .435). On linear regression analysis, there was no correlation between number of CNAs and age (r 2 = -.01, F = 0.1941, p = .661) or BMI (r 2 = 5.21 x10 -5, F = 0.0029, p = .957). The most frequent focal aberrations were detected in CDKN2A/B (n = 19), IKZF1 (n = 17), PRSS1 (n = 11), PAX5 (n = 8), BTG1 (n = 8) and RB1 (n = 8) (Figure 1). RB1 loss was enriched in pts with T-ALL (45.5% v. 6%, p = .003),and occurred at significantly higher rates than previously reported in T-ALL (Schraders, 2009). Loss of PRSS1 was detected in 18.3% (11/60) of the cohort. Homozygous PRSS1 deletions were identified in 3/11 (27.3%) pts. We identified the minimal overlapping deleted region on 7q34 in all 11 pts, which included the PRSS1 gene within the 124 kb region. Five of 6 pts who had repeat arrays performed at the end of induction had resolution of this aberration. The one pt who retained PRSS1 loss after induction had primary refractory disease, but after further treatment and attainment of CR1, this pt cleared the PRSS1 loss. Asparaginase associated pancreatitis, which has been linked to PRSS1 variations, occurred in only 1 pt with PRSS1 loss. Pts harboring PRSS1 loss were significantly less likely to achieve MRD negativity after induction (50% vs. 82%, P = .041) and had numerically more relapses (37.5% vs. 19%, p = .300), but no OS difference was observed (p = .290). Conclusions In our institutional cohort, the addition of CGH + SNP array reclassified almost half (44.7%) of pts without complex cytogenetics to harbor complex genomic changes (≥5 aberrations). Pts with Ph-like ALL had significantly more aberrations on array than those with Ph-positive or -negative B-ALL. Focal PRSS1 loss was associated with reduced rates of MRD clearance at the end of induction. This aberration resolved upon disease remission, raising the possibility that both homozygous and/or heterozygous deletions of 124 kb from the 7q34 chromosomal region of the PRSS1 gene may potentially have a role in ALL pathogenesis. Further studies with larger cohorts utilizing CGH + SNP analyses at additional time points during treatment are needed to explore the potential integration of microarray data for refined ALL risk stratification as well as to elucidate the functional role of PRSS1 in leukemogenesis.
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Talati, Chetasi, Aaron D. Goldberg, Amanda Przespolewski, Onyee Chan, Najla Al Ali, Christopher Famulare, David A. Sallman et al. "Comparison of Induction Strategies and Responses for Acute Myeloid Leukemia Patients after Resistance to Hypomethylating Agents for Antecedent Myeloid Malignancy". Blood 132, Supplement 1 (29 de novembro de 2018): 665. http://dx.doi.org/10.1182/blood-2018-99-119879.
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Abstract Background Outcomes in patients (pts) with secondary acute myeloid leukemia (sAML) (therapy related myeloid neoplasms and AML with myelodysplasia related changes (MRC) per WHO 2016 classification (Arber et al, Blood 2016)) are poor. Pts treated with hypomethylating agents (HMAs) have suboptimal responses to induction chemotherapy (IC) upon transformation to AML. Previously, it was retrospectively demonstrated that the IC with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) yields significantly higher response rates (64%) than 7+3 (cytarabine and anthracycline) (29%) in pts with prior HMA exposure (Jaglal et al, Leukemia Research 2014). Following the recent approval of CPX-351 for induction in sAML subgroup, we investigated outcomes after CPX-351 to cladribine based regimens and 7+3 in pts with sAML with prior HMA exposure. Methods We identified pts with sAML who had prior HMA treatment for an antecedent hematologic malignancy (AHM) and later received induction chemotherapy upon AML transformation from Moffitt Cancer Center (MCC) (n=229), Memorial Sloan Kettering Cancer Center (n=11) and Roswell Park Comprehensive Cancer Center (n=2). Patients were divided into 3 cohorts based on induction regimen: (A) cladribine based (CLA+/-G+/-M) (B) standard 7+3 and (C) CPX-351. Demographics, disease-specific variables, and outcomes were collected in accordance with the institutional review board approved protocol. Responders (R) were defined as pts achieving CR or CRi as defined by the 2003 International Working Group (IWG) criteria after 1 or 2 cycles of the either induction regimen whereas non-responders (NR) were defined as responses other than CR/CRi. Pts receiving a second induction with a different regimen were considered NR. Fisher's exact test and the ANOVA test were used to determine significance for continuous and categorical variables. Kaplan-Meier analysis with log-rank test was performed to estimate overall survival (OS). Results Among 242 pts who received IC for AML after HMA failure for prior AHM, 114 were treated with (A) cladribine based regimen (B) 94 pts with standard 3+7 and (C) 34 pts with CPX-351 (Cohort C). Baseline characteristics for all 3 cohorts are outlined in Table 1A. Median age for cohort A, B, and C were 65 (33-82), 66 (26-81), and 69 (36-82), respectively. Males comprised of 68.4%, 63% and 52.9% of the cohorts A, B and C, respectively. No pts had favorable-risk karyotype as defined by European LeukemiaNet (ELN) 2017 criteria. Adverse risk karyotype was noted in 42.1% of cohort A, 34.6% of cohort B and 22.7% of cohort C (p=.337). The majority of pts received azacitidine as their HMA for their AHM (88.7%, 84.9% and 82.4% in cohorts A, B, C, respectively) and median number of cycles administered prior to transformation to AML were 6, 4 and 5 for cohorts A, B, and C, respectively. Response rates in each cohort are summarized in Table 1B. The CR/CRi rate was 53% in cohort A, 32% in cohort B and 41.1% in cohort C (p=.005 between cohort A and B) (p=.329 between cohorts A and C) (p=.526 between cohorts B and C). The early death rates (<60 days of induction) were not significantly different among the 3 cohorts, at 12%, 8% and 2.9% in cohorts A, B and C respectively (p=.200). In pts who received ≤ 4 cycles of HMAs prior to AML transformation, response rates to CPX-351 were higher (64.3%) than in pts who received >4 cycles of HMAs (25.0%) (p=.0397). Cohort A (56.5% vs. 50.0%, p=.288) and B (39.1% vs. 25.5%, p=.175) did not demonstrate such a difference (Table 1C and 1D). There was a trend towards better OS (19.9 vs. 5.5mo) with CPX-351 treated pts with ≤ 4 cycles of HMAs compared to >4 cycles (p=.092) (Figure 1). To date, 70.0% of responding pts in cohort A have undergone an allogeneic stem cell transplant compared to 31.0% in cohort B and 28.6% in cohort C (p=.15). There was no significant difference in median OS among the 3 groups, cohort A (7.27 months), cohort B (7.63 months) and cohort C (7.07 months) (p=.887). Among responders, the mOS did not differ (12.93, 21.7, and 19.9 months for cohorts A, B, and C respectively, p=.635). Conclusions We demonstrate that cladribine-based induction regimens and CPX-351 yield higher CR/CRi rates compared to 7+3 in pts with sAML after HMA failure. Prolonged duration of HMA exposure may lower response potential with CPX-351 upon AML transformation. Median OS remains poor and did not differ among the 3 groups illustrating the unmet need for therapy for sAML pts after HMA failure. Disclosures Goldberg: AROG: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau. List:Celgene: Research Funding. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau. Tallman:AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sweet:Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy; Astellas: Consultancy; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria.
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Elitzur, Sarah, Ruth Shiloh, Jan Loeffen, Agata Pastorczak, Masatoshi Takagi, Simon Bomken, Andre Baruchel et al. "ATM Germline Pathogenic Variants Affect Treatment Outcomes in Children with Acute Lymphoblastic Leukemia/Lymphoma and Ataxia Telangiectasia". Blood 142, Supplement 1 (28 de novembro de 2023): 520. http://dx.doi.org/10.1182/blood-2023-179333.
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Introduction Ataxia telangiectasia (A-T) is a multisystem disorder caused by biallelic germline pathogenic variants (PV) in the ATM gene. An important feature of A-T is an increased predisposition to cancer with a reported incidence of 25%, primarily attributed to hematological malignancies. Patients with A-T and cancer are usually excluded from therapeutic clinical trials, limited information thus exists concerning their treatment outcomes and toxicity profiles and consequently, optimal management strategies are unclear and an unmet need. In this multinational study, we aimed to investigate the characteristics and outcomes of leukemia and lymphoma in a large cohort of children with A-T and to determine risk factors which impact treatment outcome in order to generate consensus and data-based prospective treatment recommendations. Methods This study of patients aged ≤25 years with A-T and hematological malignancies was conducted through the International BFM Study Group. Patient data were collected from medical records, including specific patient comorbidities. Each reported ATM PV identified in the cohort was classified as null (resulting in complete loss of ATM activity) or hypomorphic (allowing residual ATM activity) according to the expected functional activity of the ATM protein and published functional studies. Patients with reported ATM PV were then classified as Group A (two null PV) or Group B (at least one hypomorphic PV). Results We report 202 pediatric and adolescent/young adult patients with A-T and hematological malignancies from 25 countries. The cohort included 82 patients with ALL/LBL (41%), predominantly (85%) of T-cell lineage, 91 with mature B-cell lymphomas (45%), 21 with Hodgkin lymphoma (10%) and 8 with other hematological malignancies (4%) (Fig 1). Of 111 patients with classifiable germline ATM variants, 82 (74%) were classified as Group A and 29 as Group B (26%). The distribution of patients with Group A and Group B germline ATM PV differed considerably between tumor types with 44% of the patients with lymphoblastic leukemia/lymphoma classified as Group B vs. 5% of those with mature B cell lymphomas ( p<.001). In total, 185 patients (92%) treated with curative intent were included in the outcome analyses, 135 (73%) of whom were treated with attenuated therapy regimens. Four-year OS and EFS for the entire cohort were 50.8% (95% CI 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Surprisingly, cure rates of patients with A-T and malignancy did not appear to improve significantly with therapy modernization over the last four decades with 4-year EFS rates of 41.6% (95% CI 26.6-65), 49.6% (95% CI 38.8-63.4) and 48.0% (95% CI 37.4-61.7) for those treated before 2000, between 2000-2009 and since 2010, respectively ( p=.54). The major cause of treatment failure for the entire cohort was treatment-related mortality (TRM) with a 4-year cumulative incidence of 32.8% (95% CI 19.5-32.4), followed by progressive cancer in 14.5% (95% CI 10-19.8) and second malignancy in 4.9% (95% CI 13.1-85.8) (Fig 2). We identified factors that were significantly associated with survival for this unique patient population. Older age had a significantly deleterious effect upon survival with 4-year EFS rates of 69.1% (95%CI 55.9-85.4), 45.3% (95% CI 34.5-59.4), 39.8% (95% CI 25-63.2), and 33.7% (95% CI 20.8-54.6) for children aged ≤5 years, 5-10 years, 10-15 years and ≥15 years, respectively ( p=.003). The type of germline ATM PV also had a significant impact: 4-year EFS for patients with Group B ATM PV was 78.7% (95% CI 63.7-97.2) vs. 39.4% (95% CI 29-53.3) for Group A ( p<.001). Group A PV were associated with an increased TRM (OR 9.3; 95% CI 1.6-180.1; p=.042) and decreased EFS (HR .371 95% CI 16.6-82.6; p=.009). Conclusions We demonstrate in this first comprehensive international study that leukemia and lymphoma in children with A-T are curable. While the standard treatment stratification system for patients with hematological malignancies without A-T focuses upon cancer relapse/progression as the main cause of treatment failure, TRM was the main cause of therapy failure in patients with A-T and was strongly associated with the underlying germline ATM variant type. This study further fulfills an unmet need for international collaboration and provides a platform for data-based guidelines for a novel risk stratification system and optimal therapy selection for this unique patient population.
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Perlman, Jordan, e Jennifer Mammen. "PSUN223 The Three Different Clinical Phenotypes of Checkpoint Inhibitor-Induced Diabetes Mellitus". Journal of the Endocrine Society 6, Supplement_1 (1 de novembro de 2022): A443—A444. http://dx.doi.org/10.1210/jendso/bvac150.923.
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Abstract Checkpoint inhibitor-induced diabetes mellitus (CIADM) is a rare but morbid complication of cancer immunotherapies. The most common presentation is acute hyperglycemia and severe insulin deficiency. Our experience managing 25 patients in our new Immune-Related Adverse Events (IRAE) clinic indicates that there are three distinct CIADM phenotypes. Many of our patients required admission for diabetic ketoacidosis (15/25), amongst whom we can distinguish fulminant type 1 diabetes mellitus (9/15) from ketosis-prone type 2 diabetes mellitus (T2a-CIADM) (6/15) using serum c-peptide levels. The T1-CIADM patients have decreased serum c-peptide levels that did not improve on recheck obtained 12-28 weeks following insulin initiation (mean c-peptide = 0.2 ng/mL [NR = 1.1-4.4 ng/mL], range = 0-0.5 ng/mL). In contrast, serum c-peptide levels recovered into the reference range in T2a-CIADM patients within 12 weeks of hospital discharge (mean c-peptide = 2.9 ng/mL, range 2.1-9.3 ng/mL). It does not appear sufficient to identify T1-CIADM using traditional islet cell autoantibodies (GAD-65, IA-2A, IAA and ZnT8A) as 54% of our patients (6/11) were negative. This is consistent with other published reports. None of the T2a-CIADM patients were autoantibody-positive. Three of our GAD-65-positive T1-CIADM had preexisting islet cell autoantibodies in pretreatment serum obtained through involvement in clinical trials. None of the controls for these index cases had islet cell autoantibodies and only 2/156 developed GAD-65 autoantibodies during ICI treatment. These patients had no evidence of impaired glucose tolerance or a concerning family history. This suggests that latent autoimmune diabetes in adults (LADA) is accelerated with ICI-exposure resulting in the autoantibody-positive T1-CIADM subgroup. Interestingly (but perhaps expected), there was more reported family history of diabetes in our T2a-CIADM (6/9) than T1-CIADM patients (1/11). Our third observed phenotype (T2b-CIADM) consists of five additional patients referred for significant progression of known T2DM. These patients were prescribed oral medications and had reasonable blood glucose control (HbA1c < 8%) before starting immunotherapy. Three patients experienced rapid deterioration in blood glucose control (manifesting as polyuria/polydipsia) and were hospitalized for severe hyperglycemia. None had laboratory evidence of DKA/HHS. All three patients were discharged on multiple daily insulin injections (MDI). The differences in total daily insulin requirements (TDD) between clinical phenotypes highlight possible dissimilarities in underlying physiology. Those patients designated T2b-CIADM have a mean TDD of 1.2 units/kg/day (range = 0.8-2.3 units/kg/day) indicating the presence of insulin resistance. The patients who have new disease (T1-CIADM and T2a-CIADM) seem to need doses more reminiscent of B-cell dysfunction (mean = 0.5 units/kg/day, range 0.2-1.3 units/kg/day). We have not observed any return of insulin secretion in four patients who discontinued ICI treatment after three years of follow-up. It is important that we continue to investigate the mechanisms contributing to CIADM as uncontrolled hyperglycemia can impact the immune system and alter the antineoplastic effects of ICIs. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
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Wang, Han, Tong Zhou, Yong Wang, Wei Zhang e Linsen Li. "Stabilizing Lattice Oxygen in Slightly Li-Enriched Nickel Oxide Cathodes Toward High-Energy Batteries". ECS Meeting Abstracts MA2022-02, n.º 7 (9 de outubro de 2022): 2559. http://dx.doi.org/10.1149/ma2022-0272559mtgabs.
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LiNiO2 (LNO, 100% Ni) is an old material first identified in the early 1990s (as a higher-capacity and lower-cost alternative to LiCoO2) but has yet to fulfill its potential. Despite intense research efforts for more than two decades, LNO still exhibits rapid capacity loss during cycling and poor thermal stability (1-3). The traditional LNO is generally prepared by solid-state reactions and recognized as Li-deficient Li1-yNi1+yO2 (4). Ex situ characterizations indicated that the performance degradation originates from the detrimental phase transition (layered to rock-salt structure) during electrochemical cycling (5-7), which is closely related to the lattice-oxygen release during charge (8, 9). To improve the performance of LNO, the structure is commonly modified by lattice doping or surface coating, which have led to improved cycle stability but at the cost of capacity loss (10). Meanwhile, these modification approaches failed to address the lattice oxygen instability, as the O2 release was still detected for the doped or surface-coated layered cathodes (11, 12). Here, we demonstrate an Li-enrichment strategy to produce a trigonal-structured layered Li-enriched LNO (Li1.04Ni0.96O2, LR-LNO) with a slight excess of Li to occupy the Ni sites, which is a possible phase according to the Li-Ni-O phase diagram but has never been experimentally synthesized (Figure 1). LR-LNO (Figure 1) enables a combination of a high specific energy density of 904 Wh kg-1, outstanding cyclability (~80% capacity retention after 400 cycles in full cells versus 35 cycles for LNO), and significantly enhanced thermal stability (>70 °C increase in thermal-runaway temperature over LNO). We further designed a double-tilt electrochemical liquid cell inside a transmission electron microscope (TEM) to track the local structural changes at the surface of individual particles during galvanostatic cycling (Figure 2), revealing the performance-enhancing mechanism behind the slight change in the material composition. Excess Li ions in the Ni layer promoted intralayer migration of Ni ions during delithiation in LR-LNO, generating vacancy clusters to trap the electrochemically oxidized molecular O2 in the near-surface lattice. Consequently, the oxygen redox reaction became highly reversible, and the detrimental layered-to-rock-salt phase transition are effectively inhibited, thus improving the structural reversibility of LR-LNO during cycling and the thermal stability.Our results provide a composition fine-tuning strategy to produce highly-reversible cathodes for high energy-density, low-cost and safe batteries. Beyond batteries, the double-tilt operando TEM technique will facilitate studies into complex phase transitions in a wide range of materials. Figure 1 Pristine structure and outstanding performance of LR-LNO References M. M. Thackeray, K. Amine, Layered Li–Ni–Mn–Co oxide cathodes. Nature Energy 6, 933-933 (2021). A. Manthiram, J. B. Goodenough, Layered lithium cobalt oxide cathodes. Nature Energy 6, 323-323 (2021). K. Turcheniuk, D. Bondarev, V. Singhal, G. Yushin, Ten years left to redesign lithium-ion batteries. Nature 559, 467-470 (2018). J.-H. Kim, K.-J. Park, S. J. Kim, C. S. Yoon, Y.-K. Sun, A method of increasing the energy density of layered Ni-rich Li[Ni1−2xCoxMnx]O2 cathodes (x = 0.05, 0.1, 0.2). Journal of Materials Chemistry A 7, 2694-2701 (2019). C. S. Yoon, D.-W. Jun, S.-T. Myung, Y.-K. Sun, Structural stability of LiNiO2 cycled above 4.2 V. ACS Energy Lett. 2, 1150-1155 (2017). D.-W. Jun, C. S. Yoon, U.-H. Kim, Y.-K. Sun, High-energy density core-shell structured Li[Ni0.95Co0.025Mn0.025]O2 cathode for lithium-ion batteries. Chem. Mater. 29, 5048-5052 (2017). C. S. Yoon, M. H. Choi, B. B. Lim, E. J. Lee, Y.-K. Sun, Review—high-capacity Li[Ni1-xCox/2Mnx/2]O2 (x = 0.1, 0.05, 0) cathodes for next-generation Li-ion battery. J. Electrochem. Soc. 162, A2483-A2489 (2015). N. Li et al., Unraveling the cationic and anionic redox reactions in a conventional layered oxide cathode. ACS Energy Lett. 4, 2836-2842 (2019). S. S. Zhang, Problems and their origins of Ni-rich layered oxide cathode materials. Energy Storage Materials 24, 247-254 (2020). M. Bianchini, M. Roca-Ayats, P. Hartmann, T. Brezesinski, J. Janek, There and back again-the journey of LiNiO2 as a cathode active material. Angew. Chem., Int. Ed. 58, 10434-10458 (2019). N. Li et al., Correlating the phase evolution and anionic redox in Co-Free Ni-Rich layered oxide cathodes. Nano Energy 78, (2020). F. Strauss et al., Li2ZrO3-Coated NCM622 for Application in Inorganic Solid-State Batteries: Role of Surface Carbonates in the Cycling Performance. ACS applied materials & interfaces 12, 57146-57154 (2020). Figure 1
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Andreica, I., I. Roman, X. Baraliakos, U. Kiltz e J. Braun. "AB1188 SARS-CoV-2 VACCINATION WILLINGNESS AND PREDICTORS IN PATIENTS WITH CHRONIC INFLAMMATORY RHEUMATIC DISEASES (CIRD) AND WITHOUT CIRD". Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 1709.1–1709. http://dx.doi.org/10.1136/annrheumdis-2022-eular.5261.
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BackgroundRecent surveys in chronic inflammatory rheumatic diseases (CIRD) showed a high degree of vaccine hesitancy. Current knowledge about patients’ attitudes towards vaccination against SARS-CoV-2 is limited.ObjectivesTo assess the willingness of CIRD patients to be vaccinated against SARS-CoV-2 and to identify influencing factors compared to non-CIRD patients.MethodsIn this cross-sectional study, two cohorts of consecutively in parallel recruited patients with and without CIRD presenting to our tertiary hospital answered questions of a structured interview to assess vaccination willingness to SARS-CoV-2, experience with SARS-CoV2 in their environment and their personal history of infections and vaccinations. Vaccination willingness was assessed by a numerical rating scale (0: fully disagree; 10: fully agree). Arbitrarily defined cut-offs were used to define definite (score ≥7) and probable willingness (scores of 5 or 6) to be vaccinated. Statistical analyses were performed with appropriate tests such as Kendall-tau b.ResultsA total of 514 CIRD and 100 non-CIRD patients, mean age 54.7±12.8 and 55.6±9.8 years, were included. Definite and probable willingness to be vaccinated against SARS-CoV-2 was declared by 79.6% and 90.7% vs. 76.0% and 85.0% of CIRD and non-CIRD patients, respectively. Only 60% of CIRD patients believed that the vaccines against SARS-CoV-2 were safe, and 42% indicated to be afraid of side effects. Vaccination willingness correlated significantly with the degree of education, age, identification with a risk group for COVID-19 disease, hypertension, and the degree of information about preventable diseases. There was no correlation with the history of infections or with immunosuppressive therapy.ConclusionAlthough our results show a high willingness for vaccination against SARS-CoV-2 in both groups, there was quite some uncertainty regarding the safety and efficacy of the vaccines. Since major influencing factors were education and information about SARS-CoV-2 and COVID-19, patient education should be immediately improved.Table 1.Patient demographics, disease characteristics and infection historyCIRD patientsNon-CIRD patientsMissing values of CIRD and non-CIRD patients No. (%)Group differences p-valueAge (years), mean (SD)54.7 ± 12.855.6 ± 9.800Women, No. (%)315 (61.3)83 (83)00Body mass index (BMI, kg/m2), mean (SD)27.9 ± 5.930.4 ± 7.800CIRD, No. (%)192 (37.3)0Rheumatoid arthritis134 (26)Axial spondyloarthritis72 (14)Psoriatic arthritis116 (22.6) Connective tissue disease/vasculitisDisease duration (years), mean (SD)9.8 ± 8.94.0 ± 6.500Therapy, No. (%)316 (61.5)0 bDMARDs147 (28.6) csDMARDs33 (6.4) tsDMARDs18 (3.5) no DMARDsHistory of a positive SARS-CoV-2 PCR test No. (%)22 (4.3)5 (5.0)3 (0,6)5 (5)0.79History of recurrent infection No. (%)54 (10.5)16 (16.0)1 (0.2)00.12History of severe infection No. (%)23 (4.5)13 (13.0)3 (0.6)00.004Educational level, No. (%)9 (9.3)35 (6.8)3 (3)0.13 low (< 8 years)50 (10.4)67 (69.1) moderate (8 to 12 years)275 (57.4)21 (21.6) high (> 12 years)154 (32.2)BMI body mass index, SD standard deviation, no number, DMRD Disease Modifying Anti-Rheumatic Drugs, b biological, ts targeted synthetic, cs conventional syntheticFigure 1.Vaccination willingness of CIRD patientsAcknowledgementsWe wish to thank all persons who participated in the current study.Furthermore, we thank Dr. Styliani Tsiami, Tanja Kobylinski and the clinical departments for assisting with recruitment of participants.Disclosure of InterestsNone declared
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Issa, Ghayas C., Hagop M. Kantarjian, C. Cameron Yin, Koji Sasaki, Guillermo Garcia-Manero, Courtney DiNardo, Koichi Takahashi et al. "Prognostic Implications of Pre-Treatment Hypodiploidy and Complex Cytogenetics in Adult Patients with Acute Lymphocytic Leukemia (ALL) Treated with Hyper-CVAD". Blood 126, n.º 23 (3 de dezembro de 2015): 4874. http://dx.doi.org/10.1182/blood.v126.23.4874.4874.
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Abstract Background Pretreatment cytogenetic analysis is frequently used to predict response and outcome in hematologic malignancies. Hypodiploidy is associated with a poor prognosis in childhood ALL. Similarly, complex cytogenetics is a known adverse prognostic factor in myeloid malignancies. The impact of hypodiploidy and complex cytogenetics has not been extensively assessed in adult patients with ALL. To address this issue, we have conducted a retrospective analysis of all adult patients with ALL treated with frontline Hyper-CVAD based regimens at our institution. Methods We reviewed 332 adult patients treated between May 2000 and March 2015. Patients with Philadelphia-positive ALL and those with t(4;11) were excluded. Hyodiploidy was defined as 45 or less chromosomes. Hyperdiploidy was defined as 47 and more chromosomes. Complex karyotype was defined as having 5 or more chromosomal abnormalities (Moorman et al., Blood 2007). We analyzed the clinical outcomes based on the cytogenetic risk groups. Chi-square test was performed to evaluate differences in response rates. Survival was calculated using Kaplan-Meier estimates and compared using the log-rank test. Results Patient characteristics, responses to therapy, and outcomes are summarized in Table 1. Thirty-five patients (10%) were hypodiploid, 67 (20%) were hyperdiploid, and 71 (21%) had a complex karyotype. With a median follow-up of 28 months (range 0.5 - 176 months), the median survival was 61, 69, and 45 months for patients with diploid, hypodiploid, and hyperdiploid cytogenetics respectively. The 3-year survival rates were 63%, 59% and 53%, respectively (p=0.18). Similarly, having a complex karyotype did not affect survival when compared to diploid cytogenetics with a median survival of 58 and 61 months respectively. The 3-year survival rates were 63% and 59%, respectively (p=0.27). Conclusion Unlike what has been described in childhood ALL, the prognosis of adult ALL patients with a hypodiploid or complex karyotype treated with Hyper-CVAD based regimens is similar to patients with a diploid karyotype. This could be attributed to a different biology of the disease or could be related to the treatment given in this population. The use of genomics combined with cytogenetic analysis could perhaps constitute a better predictive biomarker. Table 1. Characteristics (n total=332) Diploid (n=147) Hypodiploid(n=35) Hyperdiploid(n=67) Complex (n=71) Median age, y (range) 44 (16-83) 58 (20-80) 54 (18-85) 58 (18-85) Sex no. (M/F) (182/150) 95/52 14/21 34/33 39/32 WBC, median x 109/L(range) 3.85 (0.4-216) 3.6 (0.7-420) 3.9 (0.6 -134) 3 (0.5-87) Hg, median g/L (range) 9.3 (3.5-16) 8.9 (4-11.9) 9.2 (4.5-14) 9.2 (5-14) Platelets, median x 109/L (range) 64 (1-626) 32 (7-233) 36 (7-271) 32 (7-233) Creatinine, median mg/dL (range) 0.9 (0.3-4) 0.8 (0.45-1.5) 0.8 (0.5-2.3) 0.8 (0.4-2.3) Bilirubin, median mg/dL (range) 0.5 (0-8) 0.6 (0.2-5.6) 0.5 (0.2-11) 0.5 (0.2-5.4) LDH, median IU/L (range) 839 (268-32029) 1460 (172-6408) 1177 (345-8953) 1241 (172-8953) Blasts in BM, median % (range) 78 (0-99) 88 (60-98) 83 (26-100) 84(26-97) Blasts in PB, median % (range) 12 (0-99) 36 (0-92) 26 (0-96) 26(0-100) B-ALL (n=282) n 120 33 63 65 T-ALL (n=50) n 27 2 4 6 Complete response (%) 92 88 88 88 3-year survival rate (%) 63 59 53 56 Disclosures DiNardo: Novartis: Research Funding. Cortes:Teva: Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.
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Lemes, K. M., L. A. Silva, E. C. C. Celeghini, M. A. Alonso, G. Pugliesi, H. F. Carvalho, F. J. Affonso, D. F. Silva, T. G. Leite e R. P. Arruda. "175 FOLLICULAR DEVELOPMENT AND OVARIAN BLOOD FLOW IN MARES WITH EARLY OR LATE OVULATION POSTPARTUM". Reproduction, Fertility and Development 27, n.º 1 (2015): 178. http://dx.doi.org/10.1071/rdv27n1ab175.
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The postpartum period is characterised by the rapid uterine involution process and return of ovarian activity (foal heat), resulting in a fertile oestrus in most of the mares. However, the follicular development and selection processes during this period are not completely known in horses. We aimed to study the characteristics of follicular growth and vascular perfusion in the ovary during the early postpartum period in mares that demonstrated oestrous behaviour and had early (<10 days) or late (≥10 days) ovulation. Ten mares were scanned daily from the first day postpartum (Day 1) until the day of the first postpartum ovulation (Day 0). The animals were split in the early (n = 3) and late (n = 7) ovulation groups (averaged interval between parturition and ovulation: 8.0 ± 0.0 and 14.7 ± 1.2 days, respectively). For ultrasound exams a Duplex B-mode and colour Doppler instrument (M5VET®, Mindray, Shenzhen, China) was used with a multifrequency linear probe. Data were analysed for the main effects of group, day, and their interaction using the PROC MIXED procedure of SAS software (version 9.3, SAS Institute Inc., Cary, NC, USA). For the follicular growth, no difference (P > 0.05) was detected between the groups when the data were analysed for the days relative to ovulation (from Day 7 to Day 1). However, the dominant follicle was larger (P < 0.05) in the early-ovulated group (37.2 ± 1.6 v. 21.9 ± 1.1) in all days during early postpartum (Day 1 to Day 7). The number of follicles with >25 mm diameter was also greater (P < 0.05) in the early-ovulated group (1.1 ± 0.1 v. 0.1 ± 0.1) during the first 3 days postpartum. In addition, the late-ovulated mares showed greater number of follicles with 20–25 mm during Day 4 to Day 7 (2.0 ± 0.2 v. 0.7 ± 0.1). For the blood flow characteristics, no difference (P > 0.05) was detected in the coloured signals of blood flows in the follicular wall of the dominant follicle or in the ovarian pedicle ipsilateral to the largest follicle. Therefore, the characteristics of the follicle growth on the preceding days of ovulation were similar between the early- and late-ovulated mares and consistent with the follicular dynamics expected in non-pregnant and non-lactating mares. However, when the data were analysed for the days relative to parturition, a greater follicle development was present in mares that ovulate earlier during the postpartum period (<10 days). In conclusion, the results suggest that important events may occur previous to the parturition, resulting in an early follicle development, mainly in those mares that show heat signs and ovulate within 10 days postpartum. Research was supported by FAPESP process number 2010/10692-9 and CNPq process number 135954/2011-8.
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Broussard, Emilee A., Jhones O. Sarturi, Kaliu G. Silva, Bradley J. Johnson, Barbara Rodrigues e Beatriz Dos Reis. "PSVI-29 Using Feeding Behavior Assessment to Evaluate the Effects of Beef Cattle Dietary Type Or the Presence of Saccharomyces Cerevisiae". Journal of Animal Science 101, Supplement_3 (6 de novembro de 2023): 622–23. http://dx.doi.org/10.1093/jas/skad281.726.
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Abstract The effects of live yeast and diet type (grower or finisher) offered to beef steers on feeding behavior were evaluated. Eight ruminally cannulated yearling beef steers (BW = 550 ± 20 kg) were used in a duplicated 4 × 4 Latin Square design and offered four dietary treatments to ad libitum intake, following a 2 × 2 factorial treatment arrangement: A) presence or not of live-yeast Saccharomyces cerevisiae [2 × 1010 CFU/g (CNCM I-1077)]; and B) diet type. Diets (DM basis) contained 3% yellow-grease and mineral/vitamin supplement-adjusted. The grower [40% low-quality alfalfa-hay (LQ-hay), 35% steam-flaked corn (SFC), 20% wet corn gluten feed (WCGF)] and finisher (65% SFC, 20% WCGF, 8% LQ-hay) diets were offered once daily at 0700 h. Live-yeast cells or placebo (soybean meal) were delivered with gel capsules (0.25 g, as is) twice daily directly into the rumen via ruminal cannula. Four, 35 d periods were used, in which feeding behavior assessment was conducted by trained personnel on d 31 (continuous 24 h, every 5 min) while no other major management was performed during the evaluation. The time spent eating, ruminating (standing/laying), resting (stating/laying), active, and drinking were recorded, while chewing was estimated by adding rumination and eating time. The number of meals and time spent on each meal were also assessed. Data were analyzed using the GLIMMIX procedures of SAS, with animal considered as the experimental unit. The statistical model used the fixed effects of diet type, live-yeast presence, and the diet × live-yeast interaction, while square, period, and animal(square) were used as random effects. No diet × live-yeast interactions (P ≥ 0.17) or main effects of live-yeast (P ≥ 0.23) were observed for the variables measured. Feeding behavior was affected by diet type, in which steers offered a grower diet had greater time spent ruminating (341 vs. 231 min/d; P < 0.01), eating (154 vs. 105 min/d; P < 0.01), chewing (494 vs. 336 min/d; P < 0.01), and meal length (13 vs. 10 min/meal; P < 0.01), while less time resting (838 vs. 973 min/d; P < 0.01) compared with those offered the finisher diet. The time spent drinking (15 min/d; P = 0.29) and the number of daily meals (13 meals/d; P = 0.66) were not affected by treatments, while steers offered the finisher diet tended (P = 0.12) to be more active than those offered the grower diet (116 vs. 95 min/d). As expected, grower diets were more prone than finisher diets to stimulate feeding behavior variables of beef steers. Moreover, when directly introduced inside the rumen via ruminal cannula, the live yeast used seemed to not affect the feeding behavior of beef steers consuming a steam-flaked corn-based grower or finisher diet.
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Van der Heijde, D., X. Baraliakos, M. Dougados, M. Brown, D. Poddubnyy, F. Van den Bosch, N. Haroon et al. "OP0019 BIMEKIZUMAB IN PATIENTS WITH ACTIVE ANKYLOSING SPONDYLITIS: 24-WEEK EFFICACY & SAFETY FROM BE MOBILE 2, A PHASE 3, MULTICENTRE, RANDOMISED, PLACEBO-CONTROLLED STUDY". Annals of the Rheumatic Diseases 81, Suppl 1 (23 de maio de 2022): 12–13. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2441.
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BackgroundBimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A. In a phase 2b study, BKZ showed rapid and sustained efficacy and was well tolerated up to 156 weeks (wks) in patients (pts) with active ankylosing spondylitis (AS).1,2ObjectivesTo assess efficacy and safety of BKZ vs placebo (PBO) in pts with active AS up to Wk 24 in the ongoing pivotal phase 3 study, BE MOBILE 2.MethodsBE MOBILE 2 (NCT03928743) comprises a 16-wk double-blind, PBO-controlled period and 36-wk maintenance period. Pts were aged ≥18 yrs, met modified New York criteria and had active AS (BASDAI ≥4, spinal pain ≥4) at BL. Pts were randomised 2:1, BKZ 160 mg Q4W:PBO. From Wk 16, all pts received BKZ 160 mg Q4W. Primary and secondary efficacy endpoints were assessed at Wk 16.ResultsOf 332 randomised pts (BKZ: 221; PBO: 111), 322 (97.0%) completed Wk 16 and 313 (94.3%) Wk 24. BL characteristics were comparable between groups: mean age 40.4 yrs, symptom duration 13.5 yrs; 72.3% pts male, 85.5% HLA-B27+, 16.3% TNFi-experienced. At Wk 16, the primary (ASAS40: 44.8% BKZ vs 22.5% PBO; p<0.001) and all ranked secondary endpoints were met (Table 1). Responses with BKZ were rapid, including in PBO pts who switched to BKZ at Wk 16, and increased to Wk 24 (Figure 1; Table 1). Substantial reductions of hs-CRP by Wk 2 and MRI SIJ and spine inflammation by Wk 16 were achieved with BKZ vs PBO (Table 1). At Wk 24, ≥50% pts had achieved ASDAS <2.1 (Figure 1).Table 1.Efficacy at Wks 16 and 24BLWk 16Wk 24PBO N=111BKZ 160 mg Q4W N=221PBO N=111BKZ 160 mg Q4W N=221p valuePBO→BKZ 160 mg Q4W N=111BKZ 160 mg Q4W N=221Ranked endpoints in hierarchical orderASAS40* [NRI] n (%)--25 (22.5)99 (44.8)<0.00163 (56.8)119 (53.8)ASAS40 in TNFi-naïve† [NRI] n (%)--22 (23.4)a84 (45.7)b<0.00156 (59.6)a100 (54.3)bASAS20† [NRI]n (%)--48 (43.2)146 (66.1)<0.00185 (76.6)159 (71.9)BASDAI CfB† [MI] mean (SE)6.5 (0.1)6.5 (0.1)–1.9 (0.2)–2.9 (0.1)<0.001–3.3 (0.2)–3.3 (0.1)ASAS PR† [NRI]n (%)--8 (7.2)53 (24.0)<0.00128 (25.2)56 (25.3)ASDAS-MI† [NRI] n (%)--6 (5.4)57 (25.8)<0.00143 (38.7)67 (30.3)ASAS 5/6† [NRI]n (%)--16 (14.4)94 (42.5)<0.00157 (51.4)107 (48.4)BASFI CfB† [MI] mean (SE)5.2 (0.2)5.3 (0.2)–1.1 (0.2)–2.2 (0.1)<0.001–2.2 (0.2)–2.4 (0.2)Nocturnal spinal pain CfB† [MI]mean (SE)6.8 (0.2)6.6 (0.1)–1.9 (0.2)–3.3 (0.2)<0.001–3.7 (0.3)–3.8 (0.2)ASQoL CfB† [MI] mean (SE)8.5 (0.4)9.0 (0.3)–3.2 (0.3)–4.9 (0.3)<0.001–4.9 (0.4)–5.4 (0.3)SF-36 PCS CfB† [MI] mean (SE)34.6 (0.8)34.4 (0.6)5.9 (0.8)9.3 (0.6)<0.00110.6 (0.8)10.8 (0.6)BASMI CfB† [MI] mean (SE)3.8 (0.2)3.9 (0.1)–0.2 (0.1)–0.5 (0.1)0.005–0.5 (0.1)–0.6 (0.1)Other endpointsnEnthesitis-free state†c [NRI]n (%)--22 (32.8)d68 (51.5)e-33 (49.3)d70 (53.0)eASAS40 in TNFi-experienced [NRI]n (%)--3 (17.6)f15 (40.5)g---ASDAS-CRP CfB [MI]mean (SE)3.7 (0.1)3.7 (0.1)–0.7 (0.1)–1.4 (0.1)-–1.7 (0.1)–1.6 (0.1)hs-CRP (mg/L) [MI] geometric mean (median)6.7 (6.3)6.5 (8.2)6.0 (6.3)2.4 (2.4)-1.9 (2.2)2.1 (2.3)MRI spine Berlin CfBh [OC] mean (SD)3.3 (4.9)i3.8 (5.3)j0.0 (1.4)k–2.3 (3.9)l---SPARCC MRI SIJ score CfBh [OC] mean (SD)5.8 (7.7)i7.4 (10.7)m1.1 (6.9)k–5.6 (9.9)l---Randomised set. *Primary endpoint; †Secondary endpoint; an=94; bn=184; cMASES=0 in pts with BL MASES >0; dn=67; en=132; fn=17; gn=37; hIn pts in MRI sub-study; in=45; jn=82; kn=43; ln=79; mn=83; nNominal p values not shown.Over 16 wks, 120/221 (54.3%) BKZ pts had ≥1 TEAE vs 48/111 (43.2%) PBO; three most frequent on BKZ were nasopharyngitis (BKZ: 7.7%; PBO: 3.6%), headache (4.1%; 4.5%) and oral candidiasis (4.1%; 0%). No systemic candidiasis was observed. Up to 16 wks, incidence of SAEs was low (1.8%; 0.9%); no MACE or deaths were reported; 2 (0.9%) IBD cases occurred in pts on BKZ.ConclusionDual inhibition of IL-17A and IL-17F with BKZ in pts with active AS resulted in rapid, clinically relevant improvements in efficacy outcomes vs PBO. No new safety signals were observed.1,2References[1]van der Heijde D. Ann Rheum Dis 2020;79:595–604; 2. Gensler L. Arthritis Rheumatol 2021;73(suppl 10):0491.AcknowledgementsThis study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of InterestsDésirée van der Heijde Consultant of: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Novartis, Pfizer, UCB Pharma, Employee of: Imaging Rheumatology BV (Director), Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB Pharma, Paid instructor for: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB Pharma, Consultant of: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB Pharma, Maxime Dougados Consultant of: AbbVie, Eli Lilly, Novartis, Merck, Pfizer, and UCB Pharma, Grant/research support from: AbbVie, Eli Lilly, Novartis, Pfizer, and UCB Pharma, Matt Brown Speakers bureau: Novartis, Consultant of: Pfizer, Clementia, Ipsen, Regeneron, Grey Wolf Therapeutics, Grant/research support from: UCB Pharma, Denis Poddubnyy Speakers bureau: AbbVie, BMS, Eli Lilly, MSD, Novartis, Pfizer, and UCB Pharma, Consultant of: AbbVie, Biocad, Eli Lilly, Gilead, GSK, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB Pharma, Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Filip van den Bosch Speakers bureau: AbbVie, Bristol Myers-Squibb, Celgene, Janssen, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Amgen, Eli Lilly, Galapagos, Janssen, Merck, Novartis, Pfizer and UCB Pharma, Nigil Haroon Consultant of: AbbVie, Amgen, Janssen, Merck, Novartis and UCB Pharma, Huji Xu: None declared, Tetsuya Tomita Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Eli Lilly, Janssen, Kyowa Kirin, Mitsubishi-Tanabe, Novartis, and Pfizer, Consultant of: AbbVie, Eli Lilly, Gilead, Novartis, and Pfizer, Lianne S. Gensler Consultant of: AbbVie, Eli Lilly, Gilead, GSK, Novartis, Pfizer, and UCB Pharma, Grant/research support from: Novartis, Pfizer, and UCB Pharma; paid to institution, Marga Oortgiesen Employee of: UCB Pharma, Carmen Fleurinck Employee of: UCB Pharma, Thomas Vaux Employee of: UCB Pharma, Alexander Marten Employee of: UCB Pharma, Atul Deodhar Speakers bureau: Janssen, Novartis, and Pfizer; consultant of AbbVie, Amgen, Aurinia, BMS, Celgene, Eli Lilly, GSK, Janssen, MoonLake, Novartis, Pfizer, and UCB Pharma, Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, and UCB Pharma.
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Casu, Carla, Pedro Ramos, Luca Melchiori, Ella Guy, Eliezer A. Rachmilewitz, Patricia Giardina, Robert W. Grady, Maria de Sousa e Stefano Rivella. "Potential Therapeutic Applications of Jak2 Inhibitors in Beta-Thalassemia and Sickle Cell Disease",. Blood 118, n.º 21 (18 de novembro de 2011): 3187. http://dx.doi.org/10.1182/blood.v118.21.3187.3187.
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Abstract Abstract 3187 ß-Thalassemia and sickle cell disease (SCD) are the most common genetic red blood cell (RBC) disorders characterized respectively by limited production of aberrant ß-globin chains. In both cases, chronic transfusions and iron chelation are required to treat the anemia and/or formation of abnormal RBC. In ß-thalassemia, anemia stimulates erythropoietin (Epo) synthesis, which in turn leads to increased erythropoiesis and development of hepatosplenomegaly, often resulting in the need for splenectomy. Recently, we demonstrated that erythroid cells from ß-thalassemic mice have a hyper-activation of Jak2, a kinase that mediates the signaling triggered by the binding of Epo to the Epo receptor. This led us to hypothesize that Jak2 inhibitors could be utilized to minimize erythroid expansion in this disorder, limiting splenomegaly. A Jak2 inhibitor (Tg101209 or Tg) was first tested in mice affected by ß-thalassemia intermedia (th3/+). Two doses of Tg (150 and 100 mg/Kg/day) were given orally for 10 days. Tg administration induced a mild decrease of hemoglobin levels (8.8±0.2, 8±0.2 and 7.8±0.2g/dL for placebo, Tg 100 mg/Kg and Tg 150 mg/Kg treated mice, respectively. p<0.05) and in the number of reticulocytes (approximately 75% of the levels seen in controls, p<0.05). Splenomegaly was also reduced in Tg-treated mice (up to 60%; p<0.05), the extent of this effect correlating with the dosage used. Reduction of splenomegaly was associated with a decrease in the number of erythroid progenitors in this organ (p<0.05) and trend toward normalization of the splenic architecture. These data support our hypothesis that, in ß-thalassemia, splenomegaly is associated with increased erythroid proliferation and it can be alleviated by administration of Jak2 inhibitors, with only a mild increase in anemia. We further tested the effect of Tg in other anemias associated with extramedulary hematopoiesis (EMH) and splenomegaly, including SCD. Administration of the drug to mice affected by SCD led to a significant worsening of anemia (more pronounced than that seen in th3/+ mice) and a proportional reduction of splenomegaly and EMH. We then evaluated the outcome of combining Tg with blood transfusion, a common therapy in b-thalassemia and SCD. In b-thalassemia, massively enlarged spleens are believed to sequester a significant proportion of circulating RBC, thereby limiting their lifespan and the efficacy of transfusion regimens. We hypothesize that decreasing splenomegaly by administration of Jak2 inhibitors could increase the efficacy of transfusion. This was first tested in th3/+ animals. In this case, transfusion alone was sufficient to increase the hemoglobin (Hb) levels approximately 3 g/dL and reduce the spleen size to 65% of that seen in non-transfused controls. In this model, the combined effect of transfusion and administration of Tg was more effective, the spleen size been 50% of non-transfused controls (p<0.05). We further tested this approach in mice affected by ß-thalassemia-major (th3/th3), for which transfusion is required for survival and massive splenomegaly develops rapidly. Administration of Tg together with transfusion led to a greater increase in Hb levels compared to transfusion alone (9.3±0.4 vs 7.3±0.5g/dL, p<0.05). This was likely a consequence of reduced splenomegaly and decreased sequestration of RBCs in Tg/transfused mice. Lastly, we tested combination therapy in a mouse model of SCD. Mice treated with Tg and transfusion exhibited slightly lower levels of Hb than transfused controls (Hb=9.7±0.2g/dL versus Hb=10.9±0.2g/dL). However, compared to the control, mice receiving combination therapy exhibited a larger percentage of donor RBCs, while endogenous erythropoiesis was markedly suppressed along with the production of sickle RBCs (1.3±0.3×106 RBC/ul compared to transfused-controls exhibiting 2.7±0.3×106 RBC/ul). In summary, administration of Jak2 inhibitors might reduce the production of pathological cells that, together with preservation of the splenic architecture, could minimize the propensity of patients to thrombotic events. Furthermore, suppression of endogenous erythropoiesis and reduction of the transfusion regimen would be expected to also reduce iron accumulation, making it easier to prevent its toxic effects through chelation therapy. Disclosures: No relevant conflicts of interest to declare.
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Elbeialy, A., H. El Abd, A. Shahin e R. Ibrahim. "AB1090 BIOMARKERS TO DIFFERENTIATE EARLY INDISTINGUISHABLE CASES OF OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (junho de 2020): 1834.1–1834. http://dx.doi.org/10.1136/annrheumdis-2020-eular.358.
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Background:Osteoarthritis (OA) and rheumatoid arthritis (RA) are the most frequent inflammatory diseases of the musculoskeletal system, which could not be differentiated in their early stages, and characterized by degradation of articular cartilage and impairment of joint function. Sometimes, criteria and radiography are not insufficient to distinguish early-stages of RA and OA and predict disease course, and therefor biomarkers that help clinicians to early diagnose disease are essential.Objectives:The aim of this study is to estimate serum level of Matrix metalloproteinase 3 (MMP3) and hrdroxyproline (HP) in early RA and OA patients to see if they can be used to differentiate both diseases at their early stagesMethods:The aim of this study is to estimate serum level of Matrix metalloproteinase 3 (MMP3) and hrdroxyproline (HP) in early RA and OA patients to see if they can be used to differentiate both diseases at their early stagesResults:We found a highly significant elevation of serum MMP3 in OA patients group compared to RA patients and control groups. We also found a highly significant elevation of MMP3 in RA patients than control group,(P < 0.001). Meanwhile, we found a highly significant elevation of HP in OA patients than in RA patients and control groups, (P < 0.001), whereas there was no significant difference between HP in RA patients and control groups (P > 0.05).Table 1.Demonstration of serum levels of MMP3 and HP in all groups.“Enzyme”OA(n=40)RA(n=40)Control(n=40)p-valueMMP3 pg/mL559.92±1112.84153.25±162.0559.79±63.54<0.001HPµg/mL12.87±18.754.81±6.894.52±1.55<0.001HPµg/mL4.81±6.894.52±1.55> 0.05Conclusion:Our results suggest that serum levels of Hydroxyproline (HP) rather than MMP3 could be used as a potential biomarker for early differentiation between osteoarthritis (OA) and rheumatoid arthritis (RA) when diagnostic criteria failed to be fulfilled.References:[1]Benedetti S, Canino C, Tonti G, Medda V, Calcaterra P, Nappi G, Salaffi F, Canestrari F. (2010): Biomarkers of oxidation, inflammation and cartilage degradation in osteoarthritis patients undergoing sulfur-based spatherapies. ClinBiochem.; 43: 973-8.[2]Fenton, S. A. M., Veldhuijzen van Zanten, J. J. C. S., Duda, J. L., Metsios, G. S., and Kitas, G. D. (2018). Sedentary behaviour in rheumatoid arthritis: definition, measurement and implications for health. Rheumatology. (Oxford) 57(2), 213-226.[3]Murphy, G., and Nagase, H. (2008). Progress in matrix metalloproteinase research. Mol. Aspects Med. 29(5), 290-308.[4]Bonnans, C., Chou, J., and Werb, Z. (2014). Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15(12), 786-801.[5]Hofman, K., Hall, B., Cleaver, H., & Marshall, S. (2011): High-throughput quantification of hydroxyproline for determination of collagen. Analytical biochemistry, 417(2), 289-291.[6]Barranco, C. (2015): Osteoarthritis: activate autophagy to prevent cartilage degeneration? Nat. Rev. Rheumatol. 11, 127.[7]M.S. Radha and Dr. M.R. Gangadhar (2015), Serum enzyme of matrix metalloproteinase-3 in patients with knee osteoarthritis, International Journal of Recent Scientific Research Vol. 6, Issue, 6, pp.4457-4460, June, 2015.[8]Bassiouni, H. M., El-Deeb, M., Kenawy, N., Abdul-Azim, E., & Khairy, M. (2011). Phonoarthrography, musculoskeletal ultrasonography, and biochemical biomarkers for the evaluation of knee cartilage in osteoarthritis. Modern rheumatology, 21(5), 500-508.[9]Ahmed, U., Anwar, A., Savage, R. S., Costa, M. L., Mackay, N., Filer, A., Raza, K., Watts, R. A., Winyard, P. G., Tarr, J., Haigh, R. C., Thornalley, P. J., and Rabbani, N. (2015). Biomarkers of early stage osteoarthritis, rheumatoid arthritis and musculoskeletal health. Sci. Rep. 5, 9259.Acknowledgments:We are indebted to Dr El Shaimaa Abdel Hakim, and Dr Asmaa Fouaad for their great help in this studyDisclosure of Interests:None declared
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Cimek, Jarosław, Xavier Forestier, Ryszard Stepien, Mariusz Klimczak e Ryszard Buczynski. "Synthesis conditions of ZBLAN glass for mid-infrared optical components". Photonics Letters of Poland 10, n.º 1 (31 de março de 2018): 8. http://dx.doi.org/10.4302/plp.v10i1.804.
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We report on successful synthesis of ZBLAN glass. Different purity of zirconium tetrafluoride used for synthesis and fluorinating agents were analyzed to obtain high optical quality glass. Among fluorinating agents we used ammonium bifluoride, xenon difluoride and sulfur hexafluoride. The best results in form of synthetized glasses have transmission window extending from 0.2 to 8.0 um, which allows to fabricate fibers for mid-infrared applications. Full Text: PDF ReferencesR. Stępień, J. Cimek, D. Pysz, I. Kujawa, M. Klimczak, and R. Buczyński, Soft glasses for photonic crystal fibers and microstructured optical components, Opt. Eng. 53, 071815 (2014). CrossRef D. Pysz, I. Kujawa, R. Stępień, M. Klimczak, A. Filipkowski, M. Franczyk, L. Kociszewski, J. Buźniak, K. Haraśny, R. Buczyński, Stack and draw fabrication of soft glass microstructured fiber optics, Bull. Pol. Acad. Sci.-Tech. Sci., 62(4), 667-683 (2014). CrossRef R. Kasztelanic, I. Kujawa, R. Stępień, K. Haraśny, D. Pysz and R. Buczyński, Molding of soft glass refraction mini lens with hot embossing process for broadband infrared transmission systems, Infrared Phys. Technol. 61, 299-305 (2013). CrossRef Moynihan C.T. (1987) Crystallization Behavior of Fluorozirconate Glasses. In: Almeida R.M. (eds) Halide Glasses for Infrared Fiberoptics. NATO ASI Series (Series E: Applied Sciences), 123, Springer, Dordrecht. CrossRef M. R. Majewski, R. I. Woodward, S. D. Jackson, Dysprosium-doped ZBLAN fiber laser tunable from 2.8?m to 3.4?m, pumped at 1.7?m, Opt. Lett. 43, 971-974 (2018). CrossRef G Bharathan, R. I. Woodward, M. Ams, D. D. Hudson, S. D. Jackson, A. Fuerbach, Direct inscription of Bragg gratings into coated fluoride fibers for widely tunable and robust mid-infrared lasers, Opt. Express 25, 30013-30019 (2017). CrossRef Y. Shen, Y. Wang, H. Chen, K. Luan, M. Tao, J. Si, Wavelength-tunable passively mode-locked mid-infrared Er3+-doped ZBLAN fiber laser, Sci. Rep. 7, 14913 (2017). CrossRef J. Méndez-Ramos, P. Acosta-Mora, J. C. Ruiz-Morales, T. Hernández, M. E. Borges, P. Esparza, Heavy rare-earth-doped ZBLAN glasses for UV?blue up-conversion and white light generation, J. Lumin. 143, 479-483 (2013). CrossRef X. Jiang, N. Y. Joly, M. A. Finger, F. Babic, G. K. L. Wong, J. C. Travers, P. St. J. Russell, Deep-ultraviolet to mid-infrared supercontinuum generated in solid-core ZBLAN photonic crystal fibre, Nat. Photonics 9, 133?139 (2015). CrossRef X. Jiang, N. Y. Joly, M. A. Finger, F. Babic, M. Pang, R. Sopalla, M. H. Frosz, S. Poulain, M. Poulain, V. Cardin, J. C. Travers, P. St. J. Russell, Supercontinuum generation in ZBLAN glass photonic crystal fiber with six nanobore cores, Opt. Lett. 41, 4245-4248 (2016). CrossRef A. Medjouri, E. B. Meraghni, H. Hathroubi, D. Abed, L. M. Simohamed, O. Ziane, Design of ZBLAN photonic crystal fiber with nearly zero ultra-flattened chromatic dispersion for supercontinuum generation, Optik 135, 417?425 (2017). CrossRef D. C. Tee, N. Tamchek, C. H. Raymond Ooi, Numerical Modeling of the Fundamental Characteristics of ZBLAN Photonic Crystal Fiber for Communication in 2?3 ?m Midinfrared Region, IEEE Photon. J. 8, 4500713 (2016) . CrossRef Y. Dai, K. Takahashi, I. Yamaguchi, Thermal oxidation of fluorozirconate glass and fibres, J. Mater. Sci. Lett. 12, 1648?1651 (1993). CrossRef P. Hlubina, White-light spectral interferometry with the uncompensated Michelson interferometer and the group refractive index dispersion in fused silica, Opt. Commun. 193, 1-7 (2001). CrossRef F. Gan, Optical properties of fluoride glasses: a review, J. Non Cryst. Sol. 184, 9-20 (1995). CrossRef A. Filipkowski, B. Piechal, D. Pysz, R. Stepien, A. Waddie, M. R. Taghizadeh, and R. Buczynski, Nanostructured gradient index micro axicons made by a modified stack and draw method, Opt. Lett. 40, 5200-5203 (2015). CrossRef R. Kasztelanic, A. Filipkowski, D. Pysz, R. Stepień, A. J. Waddie, M. R. Taghizadeh, and R. Buczynski, High resolution Shack-Hartmann sensor based on array of nanostructured GRIN lenses, Opt. Express 25, 1680-1691 (2017). CrossRef
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Nagler, Adi, Shelly Kalaora, Deborah Gitta Rosenberg, Michal Alon, Eilon Barnea, Ronen Levy, Kevin Vervier et al. "672 Identification of microbial-derived HLA-bound peptides in melanoma". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (novembro de 2020): A710. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0672.
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BackgroundThe query for tumor shared and neo-antigens as a therapeutic approach has been the focus of cancer immunology for the past two decades. Notably, these peptide sequences can bind to HLA molecules and present on the cell surface, subsequently to be recognized by T-cell receptors (TCRs), activating the immune system and so facilitating in tumor rejection.1–3 The search for new origins of targetable types of HLA peptides is consistently growing, and new studies show peptides that are derived from non-canonical open reading frames (ORFs), altered translation, proteasome splicing, viral proteins and more.4–6 In light of the new findings, showing the important role of intra-tumor and gut bacteria in tumor-genesis and their effect on the immune response,7–10 we went on a quest for discovering whether intracellular bacteria antigens can be presented by tumor cells, and whether these antigens may elicit an immune response.MethodsCombination of HLA peptidomics with 16S rDNA sequencing.ResultsCombination of HLA peptidomics with 16S rDNA sequencing of 17 melanoma metastasis derived from 9 different patients, lead us to the unbiased identification of an intracellular bacterial peptide repertoire presented on HLA-I and HLA-II molecules. We were able to validate these results by co-culturing the bacterial species identified by 16S sequencing with the patient derived melanoma cells, further validating the peptide’s presentation by preforming HLA peptidomics on the infected cells. Importantly, we were able to identify common bacterial peptides from different metastases of the same patient as well as from different patients. Some of the common bacterial peptides, as well as others, were able to elicit an immune response by the autologous tumor infiltrating lymphocytes (TILs), suggesting potential therapeutic implications of these peptides.ConclusionsThe insights gathered through this study elucidate the effect of intra-tumor bacteria on the immune response and so, may lead to the development of novel clinical applications.ReferencesNeefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 2011;11: 823–836.Stronen E, Toebes M, Kelderman S, et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science 2016; 352: 1337–1341.Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348: 62–68.Chen J, Brunner AD, Cogan JZ, et al. Pervasive functional translation of noncanonical human open reading frames. Science 2020; 367: 1140–1146.Starck SR, Shastri N. Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance. Immunol Rev 2016;272:8–16.Croft NP, Smith SA, Pickering J, et al. Most viral peptides displayed by class I MHC on infected cells are immunogenic. Proc Natl Acad Sci U S A 2019; 116: 3112–3117.Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359:97–103.Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91–97.Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359:104–108.10. Nejman D, Livyatan I, Fuks G et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 2020;368:973–980.
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Arnet, Ursina, Franziska Bossuyt, Benjamin Beirens e Wiebe De Vries. "Shoulder pain in persons with tetraplegia and the association with force application during manual wheelchair propulsion". Current Issues in Sport Science (CISS) 8, n.º 2 (14 de fevereiro de 2023): 091. http://dx.doi.org/10.36950/2023.2ciss091.
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Introduction
Shoulder pain is highly prevalent in persons with spinal cord injury (Liampas et al., 2021) and restricts daily mobility and thus participation and quality of life. Shoulder loading activities, such as manual wheelchair propulsion or transfers, are seen as risk factors for shoulder pain. To minimize the risk for shoulder pain, clinical guidelines instruct persons with spinal cord injury to “use long, smooth strokes that limit high impacts on the pushrim”. Findings supporting this recommendation have been found for persons with paraplegia (Beirens et al., 2021). However, dependent on their lesion level, persons with tetraplegia do not have, full triceps function and are not able to grasp the hand rim properly, which will alter force application and may further impact shoulder pain. The aim of this study was to investigate the association between wheelchair propulsion biomechanics, including force application and spatio-temporal characteristics, and shoulder pain in persons with tetraplegia.
Methods
Sixteen community-dwelling, wheelchair dependent participants with tetraplegia (C7-C5, age 49.1 ±2.9 years, 23.4 ±2.4 years since injury, 94% male) were measured during wheelchair propulsion on a treadmill at two speed / power output conditions: 0.56 ms-1/10W and 0.83 ms-1/15W. A Smartwheel was fitted to the personal wheelchair to measure force application. The applied forces, their effectiveness (fraction of effective force) and smoothness (rate of rise of force, jerk), as well as push frequency, push angle and timing of the push cycles were analyzed. Based on the Wheelchair User Shoulder Pain Index (0-150), participants were stratified in groups with low (≤ 7), moderate (8-35) and high (≥ 36) shoulder pain. A mixed-effect multilevel analysis was used to identify the association between the dependent variables (propulsion biomechanics) and group of shoulder pain when controlling for sex, age, time since injury, lesion level, body weight and height.
Results and Discussion
The analysis showed that persons with high shoulder pain applied the force over a longer push angle (85.6°) and had a shorter recovery time (0.4s) and applied the force more effective (FEF = 40.7%) than persons with low pain (push angle = 81.2°, recovery time = 0.5s, FEF = 35.2%). In addition, persons with high shoulder pain applied less medial directed force (6.4 N) compared to persons with moderate pain (14.9 N). The results of this cross-sectional study on wheelchair propulsion in persons with tetraplegia are in contradiction to previously reported results in person with paraplegia (Beirens et al., 2021). Interestingly, tetraplegic persons with high shoulder pain are following clinical recommendation on how to propel the wheelchair optimally. These results support the importance of differentiating between lesions levels when further investigating force application as a risk factor for shoulder pain. In addition, the results ask for a close examination and possible adaptation of the clinical guidelines for persons with tetraplegia.
References
Beirens, B. J. H., Bossuyt, F. M., Arnet, U., van der Woude, L. H. V., & de Vries, W. H. K. (2021). Shoulder pain is associated with rate of rise and jerk of the applied forces during wheelchair propulsion in individuals with paraplegic spinal cord injury. Archives of Physical Medicine and Rehabilitation, 102(5), 856-864. https://doi.org/10.1016/j.apmr.2020.10.114
Liampas, A., Neophytou, P., Sokratous, M., Varrassi, G., Ioannou, C., Hadjigeorgiou, G. M., & Zis, P. (2021). Musculoskeletal pain due to wheelchair use: A systematic review and meta-analysis. Pain and Therapy, 10, 973-984. https://doi.org/10.1007/s40122-021-00294-5
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Kumar, Priya, Todd E. Defor, Claudio Brunstein, Juliet Barker, John E. Wagner, Daniel J. Weisdorf, Jeffrey S. Miller et al. "Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Treatment of Acute Lymphocytic Leukemia (ALL) in 126 Adults: Impact of Donor Source on Leukemia Free Survival (LFS)." Blood 106, n.º 11 (16 de novembro de 2005): 2064. http://dx.doi.org/10.1182/blood.v106.11.2064.2064.
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Abstract White blood cell (WBC) count and specific cytogenetic abnormalities at diagnosis, patient age and disease status at HSCT have previously been identified as risk factors associated with LFS in patients with ALL. As the use of umbilical cord blood (UCB) is relatively new, particularly for adults, we sought to evaluate the relative impact of donor source. In this single center study, 126 adults aged 18–61 (median 31) years (yrs) underwent myeloablative conditioning (cyclophosphamide 120 mg/kg and total body irradiation 1320–1375 cGy based regimen in 92%) followed by allogeneic HSCT. Stem cell source was an HLA matched related donor (MRD) in 85, HLA matched unrelated donor (URD:M) in 15, HLA mismatched unrelated donor (URD:MM) in 14 and HLA 0–2 (A, B, DRB1) mismatched UCB in 12. At the time of HSCT, 64 patients were in CR1, 51 in CR2, and 11 patients in ≥ CR3; 20 pts had T-lineage disease; 38 pts (30%) had either t(9;22)(n=28), t(4;11) or t(1,19) (n=10) with the remainder (70%) having normal cytogenetics. WBC ≥ 30 x 109/l at diagnosis was documented in 50%. Demographics, disease characteristics at initial diagnosis and transplant variables were similar in all 4 groups except: year of transplant after 1996 and use of growth factor for all UCB recipients. Outcomes by donor source: MRD URD:M URD:MM UCB P N 85 15 14 12 Median follow up in yrs 9.3 3.5 7.2 1.2 OS 1 yr % (95% CI) 41 (31–52) 33 (9–57) 14 (0–33) 75 (51–100) 0.02 LFS 1 yr % (95% CI) 35 (25–45) 27 (4–49) 14 (0–33) 67 (40–93) 0.03 Relapse 1 yr % (95% CI) 21 (12–30) 20 (0–40) 0 8 (0–23) 0.22 TRM 1 yr % (95% CI) 44 (33–55) 53 (27–79) 86 (57–100) 25 (1–49) <0.01 As a consequence of low TRM, OS and LFS were superior after UCB transplants. In multiple regression analysis, 5 independent risk factors were significantly associated with poorer OS: use of URD:M (RR 3.8, 95% CI 1.1–13.8, p= 0.04) and URD:MM (RR 4.9, 95% CI, 1.3–19.1, p= 0.02), ≥ CR3 at HSCT (RR 3.0, 95% CI, 1.1–8.8, p= 0.04), WBC >30 x 109/l (RR 2.4, 95% CI, 1.4–4.1, p<0.01), cytomegalovirus (CMV) seropositive recipient and donor (RR 4.0, 95% CI, 2.0–7.9, p<0.01), and ≥ 2 induction regimens to achieve initial CR (RR 2.7, 95% CI, 1.2–5.9, p= 0.01). Patients who developed grade II–IV acute graft versus host disease (GVHD) had significantly lower mortality rates (RR 0.4, 95% CI, 0.2–0.7, p<0.01). There was no impact on OS by year of transplant or use of growth factor. Variables associated with poor LFS were identical to those for OS, and GVHD was again associated with improved LFS. These results support the use of UCB as an alternative stem cell source for adults with ALL with results comparable to outcomes observed with MRDs. In addition, GVHD is associated with improved LFS suggesting a significant graft versus leukemia effect with all donor graft sources.
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Dewi, Melina Surya, e Yufiarti. "Play-based Learning Activities for Creativity in Children's Dance Movements". JPUD - Jurnal Pendidikan Usia Dini 15, n.º 1 (30 de abril de 2021): 101–20. http://dx.doi.org/10.21009/jpud.151.06.
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Play-based learning activities are important programs throughout the world of children's education. Through play, children learn creatively and constructively. This study aims to solve the problem of creativity in early-childhood dance movements with the hope that there will be an increase in aspects of fluency, flexibility and elaboration through play activities related to educational dance. This action research uses an action research method which is carried out in three cycles. The subjects in this study were 19 children aged 5-6 years in Kindergarten in Central Jakarta. Data collection was carried out through observation, interviews, field notes, video documentation and photos. The findings show every child's creativity in dance movements can be improved through playing activities. Increased creativity in dance movements occurs in the aspects of fluency, flexibility, and elaboration. Another important finding, there is an increase in the optimal ability of dance creativity in the third cycle of this action research. The implication from this research is that play activities suitable for learning creative dance in early childhood must be designed as a program that emphasizes aspects of fluency, flexibility, and elaboration.
Keywords: Early Childhood, Creativity in dance movements, Play based learning activities
References:
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Brehm, M. A., & McNett, L. (2007). Creative dance for learning: The kinesthetic link. McGraw-Hill.
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Cleland, F. E., & Gallahue, D. L. (1993). Young Children’s Divergent Movement Ability. Perceptual and Motor Skills, 77(2), 535–544. https://doi.org/10.2466/pms.1993.77.2.535
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Craft, A. (2000). Creativity across the primary curriculum: Framing and developing practice. Routledge.
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Cropley, A. (2001). Creativity in education & learning: A guide for teachers and educators. Kogan Page.
Doherty, J., & Bailey, R. (2002). Supporting Physical Development and Physical Education in the Early Years (1st edition). Open University Press.
Eckhoff, A. (2011). Creativity in the Early Childhood Classroom: Perspectives of Preservice Teachers. Journal of Early Childhood Teacher Education, 32(3), 240–255. https://doi.org/10.1080/10901027.2011.594486
Garaigordobil, M., & Berrueco, L. (2011). Effects of a Play Program on Creative Thinking of Preschool Children. The Spanish Journal of Psychology, 14(2), 608–618. https://doi.org/10.5209/rev_SJOP.2011.v14.n2.9
Gilbert, A. G. (2019). Brain-compatible dance education (Second Edition). Human Kinetics, Inc.
Hoffmann, J. D., & Russ, S. W. (2016). Fostering pretend play skills and creativity in elementary school girls: A group play intervention. Psychology of Aesthetics, Creativity, and the Arts, 10(1), 114–125. https://doi.org/10.1037/aca0000039
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Hui, A. N. N., Chow, B. W. Y., Chan, A. Y. T., Chui, B. H. T., & Sam, C. T. (2015). Creativity in Hong Kong classrooms: Transition from a seriously formal pedagogy to informally playful learning. Education 3-13, 43(4), 393–403. https://doi.org/10.1080/03004279.2015.1020652
Jeffrey, B. (2006). Creative teaching and learning: Towards a common discourse and practice. Cambridge Journal of Education, 36(3), 399–414. https://doi.org/10.1080/03057640600866015
Karaca, N. H., Uzun, H., & Metin, Ş. (2020). The relationship between the motor creativity and peer play behaviors of preschool children and the factors affecting this relationship. Thinking Skills and Creativity, 38, 100716. https://doi.org/10.1016/j.tsc.2020.100716
Karpati, F. J., Giacosa, C., Foster, N. E. V., Penhune, V. B., & Hyde, K. L. (2016). Sensorimotor integration is enhanced in dancers and musicians. Experimental Brain Research, 234(3), 893–903. https://doi.org/10.1007/s00221-015-4524-1
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Davis, Craig C., Melissa Mazur e Paul Szabolcs. "IL-7 along with Optimized CD3/CD28 Artificial APC Beads Promotes Ex Vivo Expansion of Cord Blood T Cells towards Adoptive Immunotherapy." Blood 110, n.º 11 (16 de novembro de 2007): 2992. http://dx.doi.org/10.1182/blood.v110.11.2992.2992.
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Abstract Background: Viral infections are the leading cause of non-relapse mortality after unrelated umbilical cord blood transplants (UCBT). Post-transplant lymphopenia, lack of established antiviral memory, and lack of cytotoxic function among infused UCB lymphocytes are jointly responsible for ineffective immunity. We have previously demonstrated ex vivo T cell expansion and maturation starting from a very small fraction (<5%) of the graft that could be employed post transplant as donor leukocyte infusion (DLI). Naïve UCB T cells proliferate when stimulated with IL-2 + CD3/CD28 co-stimulatory beads that function as artificial antigen presenting cells (APCs). However, high rate of apoptosis (>10%) has hindered T cell expansion. We hypothesized that the presence of cytokines essential for T cell homeostasis, in particular IL-7 may aid expansion and survival, beads with different densities of CD3/CD28 antibodies may impact UCB T cell expansion. Research Design: From frozen/thawed specimens we tested 2 different sources of CD3/CD28 artificial beads (historical control beads vs ClinExVivo®, (Invitrogen Corporation), ± IL-7. Methods: Thawed UCB samples were centrifuged over Ficoll gradient. T cells were positively selected with EasySep®, (StemCell Technologies) and were incubated in gas permeable bags with CD3/CD28 beads in 5% serum replete media + 100u/ml IL-2 ± 10ng/ml of IL7. Media & cytokines were replenished to maintain a concentration of ∼0.75 ×106 cells/ ml. Automated cell count, trypan blue viability assessed overall cell growth and viability at each feeding . ‘Lyse no wash’ FACS staining with Trucount® beads quantified viable CD3+ T cells. 4-color FACS was employed to characterize the evolution of surface and intracellular immunophenotype. Cytotoxicity profile of the day 0 and D12-14 progeny was tested by Europium release assay (Delfia® assay) against a Burkitt’s lymphoma cell line (IM9). Two-tailed paired Student t-tests analyzed the impact of the experimental variables. Results: At the end of 12–14 day expansion periods, analyzing all cytokine conditions, we could demonstrate an average of 43-fold viable CD3+ T cell expansion using control APC beads (n=8), while T cells on ClinExVivo® beads expanded on average 94-fold (p=0.11, n=11). Addition of IL7 to the culture media afforded significantly better expansion with the control bead condition (mean 43 vs 26 fold, p=0.02). IL7 also enhanced T cell expansion with ClinExVivo® beads (mean 147 fold vs 49 fold, though statistically NS). There were significantly more viable T cells generated with ClinExVivo® beads when all timepoints were analyzed, irrespective of the absence (p=0.017) or presence (p=0.05) of IL7. We also analyzed the mechanism how IL7 may potentiate overall T cell expansion. T cells entering cell cycle was enhanced (though not significantly) as demonstrated with intracellular Ki-67 staining (65% T cells in cycle with IL7 versus 52% without, p=0.2). IL7’s overall salutary effect on total expansion may be best explained by simultaneously reduced T cell apoptosis as quantified by activated ic Caspase-3 detection (9.3% versus 7.6% without vs with IL7, respectively, p=0.08) regardless of the source of beads. Granzyme A, B, perforin expression was enhanced comparably, while cytotoxicity was absent against IM9 cells regardless of ± IL-7. Conclusions: These results demonstrate significant expansion of UCB T cell that is further improved by utilizing ClinExVivo® clinical grade APC beads and IL7. These results pave the way to donor-derived UCB T cell expansion suitable for DLI to boost immunity.