Littérature scientifique sur le sujet « 305.5/69092 b »

In the United States, the Clean Water Act (CWA) is the primary legislation driving surface water quality management. Its goal is to “restore and maintain the chemical, physical, and biological integrity of the Nation’s waters.” Section 305(b) of the CWA requires states to document CWA progress by reporting whether applicable water quality standards are achieved for all state waters every two years. Developing strategies for increasing the proportion of waters achieving standards requires diagnosing factors driving 305(b) data temporal trends. This analysis demonstrates how systematically analyzing 305(b) data in new ways can help document CWA progress (or lack thereof) and associated drivers. Idaho 305(b) data were used to evaluate the relative contribution of assessment progress and restoration to 2002–2022 Idaho 305(b) temporal trends. Assessment progress was defined as assessing unassessed waters and correcting assessment errors. Restoration was defined as changes from not achieving one or more standards to achieving all assessed standards because water quality improved. From 2002–2022, the percentage of Idaho stream kilometers achieving all assessed standards increased from 24% to 32%. Systematically evaluating reasons for stream status changes revealed this trend was driven primarily by assessment progress, specifically progress monitoring previously unassessed waters in good condition and correcting prior assessment errors. More stream km changed from impaired to unimpaired because prior assessment errors were corrected than because water quality improved. In each biennial 305(b) report ≤ 5% of all stream km changing status resulted from water quality improvement. As of 2022, more state stream km were impaired (39%) than unassessed (29%) and restoration success rates will likely become the primary driver of 305(b) temporal trends in the future. Systematically analyzing 305(b) data in new ways may help develop new empirically driven strategies for accelerating CWA progress and merits further investigation.

The title compound was prepared according to the literature in order to determine whether it has a bicyclic cage structure resulting from intramolecular O → B coordination or a monocyclic boronate structure incorporating a trigonal planar boron atom. Crystals of 5-methyl-5-nitro-2-phenyl-1,3-dioxa-2-boracyclohexane are orthorhombic, a = 17.2358(4), b = 6.5007(2), c = 9.9225(3) Å, Z = 4, space group Pnam. The structure was solved by direct methods and was refined by full-matrix least-squares procedures to R = 0.064 and Rw = 0.070 for 798 reflections with I ≥ 3σ(I). The molecule actually has C1symmetry but, in the solid state, is located at a site of crystallographic Cs symmetry. In order to maintain the apparent mirror symmetry the nitro oxygen atoms are disordered over two mirror-related rotational positions around the C(2)—N bond. The molecule was found to have a monocyclic boronate structure, in agreement with earlier predictions. The six-membered heterocyclic ring has a "semi-planar" conformation. Bond distances and angles are normal.

In this study, the contemporary comparison method (CC) of half-sibs relation was used to estimate the breeding values of Holstein-Friesian sires for 305 -day milk yield (305-DMY) and basic components of milk traits, 409 records of cows that are daughters of ten sires in eight Syrian dairy farms where used. Result of the study showed differences in the estimated breeding values(ccEBVs), where the E Sire achieved the highest value of 305-DMY trait (254.47 kg), while the B Sire achieved the highest value of milk protein percentage (MPP), milk fat percentage (MFP)and milk lactose percentage (MLP) traits (0.822 %, 0.857 %and 1.09% respectively). According to their sires, daughters of E Sire outperformed the counterparts in the 305-DMY (p = 0.001), MPP (p = 0.001) and MFP (p = 0.04) traits (5701.44 kg, 3.55%, and 3.88% respectively). According to source of farm, daughters in Farm 5 achieved the highest value of 305-DMY trait (p=0.04) and daughters in the seventh farm achieved the highest value of MPP trait (p=0.007), the values were 5403.48 kg and 3.54 % respectively. Values of heritability (h2) for the traits of 305-DMY, MPP, MFP and MLP were 0.33,0.54,0.43 and 0.47 respectively. Most of genetic and phenotypic correlations coefficients were approaching to zero except the genetic relation between MLP and MPP and phenotypic relation between MFP and MPP (0.88 and 0.84 respectively).

Abstract Emerging therapies including chimeric antigen receptor (CAR) T therapy targeting B cell maturation antigen (BCMA) have shown promising clinical outcomes in relapsed and refractory multiple myeloma (RRMM). However, majority of patients eventually develop progressive disease due to heterogeneity in BCMA expression or loss of antigen during treatment. Therefore, new targets are required to overcome the problem of resistance encountered with these agents. The expression of GPRC5D (G-protein-coupled receptor class 5 member D) is high on MM cells and low in normal tissues. Although high levels of GPRC5D and BCMA were found in similar proportions of MM patients, they are independently expressed by MM cells. GPRC5DxCD3 bispecific T-cell-redirecting antibody is currently under clinical investigation. Preliminary results have shown early evidence in efficacy with tolerable safety profile. These findings identified GPRC5D as an ideal therapeutic antibody drug conjugate (ADC) target for the treatment of patients with RRMM. Therefore, the present study was aimed at developing a novel anti-GPRC5D ADC drug LM-305 and evaluating its preliminary efficacy by performing preclinical activity using in vitro and in vivo mouse models. The binding affinity of LM-305 was evaluated by flow cytometry in engineered GPRC5D over-expressing MM tumor cells and endogenous GPRC5D-expressing MM tumor cells. The internalization of LM-305 was assessed with pH-dependent dye in NCI-H929 and MM.1R cell lines. The cytotoxicity of LM-305 was assessed by cell viability assay in MM tumor cell lines. In vivo anti-tumor activity of multiple doses of LM-305 (1mg/kg, 3mg/kg, 10mg/kg) was evaluated in NCI-H929 and MM.1R tumor cell line derived xenograft (CDX) models. In vitro studies revealed that LM-305 binds with high affinity to GPRC5D over-expressing cell lines and GPRC5D endogenously expressing MM cells in a dose-dependent manner. It can be efficiently internalized by GPRC5D expressing cells and further lysosomal lysis was detected by pHrodo dye. LM-305 displayed potent cytotoxicity when co-cultured with MM tumor cells (NCI-H929 and MM.1R) with IC50 values ranging from 0.1 to 0.3 nM. In vivo tumor xenograft models suggested that treatment with LM-305 resulted in dose-dependent inhibition of tumor growth in tumor bearing mice. Additionally, LM-305 exhibited complete response (CR) in the GPRC5D high-expressing MM CDX models at a dose of 3mg/kg. Moreover, LM-305 showed good safety profile in the animal studies. In conclusion, this preclinical data suggested that LM-305 is a novel GPRC5D targeting ADC with best-in-class potential, and therefore it can be a promising therapeutic candidate for the treatment of RRMM patients expressing GPRC5D. Citation Format: Wentao Huang, Jie Luo, Yifan Li, Da Fei, Xia Qin, Runsheng Li. Preclinical activity of LM-305 targeting G-protein-coupled receptor class 5 member D (GPRC5D) antibody drug conjugate for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6020.

Introduction: Bruton's Tyrosine Kinase (BTK) is an essential component of normal and malignant B-cell receptor signaling. Covalent BTK inhibitors have transformed the treatment of B-cell malignancies but are limited by off-target toxicity and acquired resistance, leading to eventual treatment discontinuation and disease progression. Emerging evidence suggests that acquired resistance is mediated predominantly by BTK C481 substitution mutations at the covalent BTK inhibitors' binding site. There is significant unmet clinical need for new treatment approaches that overcome acquired resistance and minimize toxicity. LOXO-305 is a highly selective, non-covalent, next generation BTK inhibitor. We previously showed that LOXO-305 potently inhibited both wild-type (WT) BTK and BTK C481S -mediated kinase activity in enzyme and cell-based assays with nanomolar potency, caused regression of BTK-dependent lymphoma mouse xenograft models, and was more than 300-fold selective for BTK over 98% of 370 other kinases tested and showed no significant inhibition of non-kinase off targets at 1 mM (Brandhuber et al. SOHO 2018). In addition, ADME and pharmacokinetic experiments in two preclinical species predicted that LOXO-305 will have high human exposure and sustained BTK C481S target coverage in patients at clinically achievable doses. Here we describe the activity of LOXO-305 against additional BTK C481 substitution mutations, including mutations identified in patients with acquired resistance to covalent BTK inhibitors. We further determine equilibrium-binding affinities for LOXO-305 for diverse mutant BTK enzymes in comparison to other clinically available BTK inhibitors. Methods: To assess cellular BTK inhibitor potency, HEK293T cell lines transiently expressing wild-type BTK and BTK C481 substitution mutations were serum starved and incubated with LOXO-305 overnight. Cells were next incubated with serum and orthovanadate for 5 min and the phosphorylated Y223 BTK was analyzed by immunoblot. Bands were quantified and the IC50 values calculated with GraphPad Prism. The equilibrium-binding affinities for targeted BTK inhibitors to BTK enzyme variants were determined by surface plasmon resonance (SPR) using the Biacore T200. Biotinylated BTK variants were immobilized on a docked streptavidin coated sensor chip. Five concentrations of each inhibitor plus blank controls were analyzed. Association/dissociation rate constants were calculated by global fitting of the data to a 1:1 binding interaction model. Results: While BTK C481S possessed similar levels of basal Y223 autophosphorylation as wild-type BTK in cells, BTK C481T autophosphorylation was reduced by ~50%, C481R by ~90%, and mutants C481F, and C481Y were inactive in HEK293T cells. LOXO-305 inhibited Y223 phosphorylation of all active mutants with similar nanomolar potency. In contrast, autophosphorylation of all BTK C481 mutants were resistant to both Ibrutinib and acalabrutinib. Equilibrium-binding affinities of LOXO-305 for select BTK C481 substitution mutations confirmed LOXO-305's superior potency versus commercially available BTK inhibitors (ibrutinib and acalabrutinib). Conclusions: The next generation, non-covalent, highly selective BTK inhibitor LOXO-305 potently inhibited the cellular activity of BTK C481S, T and R mutations and displayed strong equilibrium binding to WT BTK and several BTK C481 substitution mutations. Together with high selectivity and significant BTK target coverage in vivo, these results indicate that LOXO-305 may overcome acquired resistance to covalent BTK inhibitors in patients without significant off-target toxicity. A phase 1 clinical trial of LOXO-305 is currently underway. Disclosures Gomez: LOXO Oncology Inc.: Employment, Equity Ownership. Isabel:Loxo Oncology: Employment. Rosendahal:Loxo Oncology: Employment. Rothenberg:LOXO Oncology Inc.: Employment. Andrews:Loxo Oncology: Employment. Brandhuber:LOXO Oncology Inc.: Employment, Equity Ownership.

e12586 Background: Breast cancer (BC) is the most common malignancy among the women in Armenia (AM). Currently there is a knowledge gap regarding the morphology distribution of the BC in AM. Methods: The data on patients with BC diagnosed in 2015-2016 in the pathology lab “Davidyants Labs” in AM were retrospectively reviewed. Pts with Her2+ results by IHC were excluded from the study, due to unavailability to perform FISH or CISH analyses. Overall 361 pathology reports were evaluated. Results: The median age was 54 years; range [19-82]. Histopathological subtypes were defined for 305 pts, from which lobular carcinoma 57.4% of cases (175/305), ductal carcinoma 26.9% (82/305), mucinous carcinoma 2.6% (8/305), mixed type carcinoma (lobular and ductal) 2.6% (8/305), DCIS 2% (n = 6/305), non specified carcinoma 2% (6/305), medullary carcinoma 1% (n = 3/305) and others 5.6% (17/305). Within the cohort 8.5% (23/270) were grade 1, 65.9% grade 2 (178/270); 25.6% grade 3 (n = 69/270). Vascular or lymphatic invasion was present in 59.5% (50/84) and 64.7% (55/85), respectively. Staging distribution, based on pT pN data for 92 pts who went to primary surgery, was: 0 stage 7.6% (7/92), I stage 22.8% (21/92), II stage 41.3% (38/92), III stage 28.3% (26/92). Staging distribution based on ypT ypN data for 27 pts who went to surgery after neoadjuvant chemo was 0 stage 25.9% (7/27), I stage 18.5% (5/27), II stage 29.6% (8/27), III stage 25.9% (7/27). ER and PR were defined for 244 patients. ER positive 89.8% (219/244) of cases, PR pos. 73% (178/244), ER/PR pos. 72.5% (177/244) cases. Her receptor was defined for 237 patients. Her3+ 16.9% (40/237); Her2+ 12.7% (30/237); Her1+ 38% (90/237); Her0 32.5% (n = 77/237). We could not evaluate Her2+ status by FISH or CISH, so these results were excluded from the analysis. Ki67 was low (≤20) in 42.1% (101/240) of cases and high ( > 20) in 57.9% (139/240). Within the group Luminal A type was 41.4% (84/203); Luminal B 32.5% (66/203); Her positive 19.7% (40/203) and triple negative 6.4% (13/203). p53 and perineural invasion (Pn) was present in 32% (16/50) and 52% (26/50), respectively. Tumor leukocyte infiltration was determined for 16 patients. Leukocyte infiltration was positive in 43.7% (7/16) cases, negative in 25% (4/16) cases, minimal in 31.3% cases (5/16). Conclusions: BC in Armenian women presents with different epidemiological characteristics in comparison with other ethnicities. Lobular type BC is the most frequent type among Armenian women, however, differential diagnosis between lobular/ductal carcinomas was done without IHC (E-Cadherin), which rises the need for further studies on that regard.

Additive Main Effect and Multiplicative Interaction (AMMI) is a method that is used in research to study interaction between genotype and location. The aim of this research is to apply fixed AMMI in examining the production of corn genotype data and to explore yield stability of its based on biplot picture and AMMI Stability Value (ASV). This research uses six corn genotypes, eight trial locations, and three repetitions. The Interaction Principal Component Analysis (IPCA) that are significant to entered in the model based on analysis of variance fixed AMMI are IPCA1, IPCA2, and IPCA3 with total diversity interaction as much as 92,16%. The biplot picture and ASV should the stable genotype in all location are genotype KUI Carotenoid Syn FS. 17-3-2-B-B T01 and genotype CML 305-B-B T01. In addition, corns that are able to adapt only in certain location is: genotype KUI Carotenoid Syn FS. 5-1-5-B-B T01, genotype KUI Carotenoid Syn FS. 25-3-2-B-B T01, genotype KUI Carotenoid Syn FS. 17-3-1-B T01, and genotype CML 130-B-B T01.

Abstract Abstract 2341 Poster Board II-318 Background. The clinical heterogeneity of chronic lymphocytic leukemia (CLL) requires parameters to stratify patients into prognostic subgroups to adapt treatment ranging from ‘watch and wait’ to allogeneic stem cell transplantation. To this end, several parameters such as lymphocyte doubling time, β-2 microglobulin, CD38 and ZAP-70 expression, immunoglobulin variable heavy chain (IgVH) mutation status and genetic abnormalities, as assessed by fluorescence in situ hybridization (FISH), have been integrated in clinical practice. Aims. In the present study, we investigated by FISH the incidence of the known major cytogenetic alterations (+12 and 13q14, 17p13, 11q23 deletions) in a series of Binet A B-CLL patients included in the prospective O-CLL1 GISL study started in April 2007. Methods. Molecular markers characterization and FISH analyses were performed as previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. GCC, 2008). A cut-off value of 2% was used to distinguish mutated and unmutated patients. CD38 and ZAP-70 were determined by flow-cytometry and a 30% cut-off was used to distinguish between positive or negative cases. Results. Up to date, 326 patients have been enrolled in the trial and FISH data concerning trisomy 12 and 13q14, 17p13, 11q23 deletions were available in 305 patients. At least one abnormality was found in 197 (64%) cases. The most frequent was del(13)(q14) (150/305, 49%), followed by +12 (40/303, 13%) (in one and three cases accompanied by 17p13 and 13q14 deletions, respectively), del(17)(p13) (7/305, 2%) and del(11)(q23) (17/305, 5%). 13q14 deletion was found as a sole abnormality in 134 patients; in the remaining cases, it was combined with +12 (3 pts) and 17p13 (3 pts) or 11q23 (10 pts) deletions. Among patients with 13q14 deletions, 99 were monoallelic, 12 biallelic and 39 showed a combination of the two patterns. Biomarkers data were available in all of the patients: 95/305 (31%) cases had unmutated IgVH genes; ZAP-70 and CD38 were positive in 117/305 (38%) and 72/305 (23%) cases, respectively. Concerning the distribution of cytogenetic aberrations, the unmutated IgVH group included 29/150 (19%) 13q14 deleted cases, 23/40 (57%) cases with trisomy 12 and 4/7 (57%) and 16/17 (94%) with 17p13 and 11q23 deletions, respectively. ZAP-70-positive groups included 43/150 (28%) 13q14 deleted cases, 26/40 (65%) cases showing trisomy 12 and 5/7 (71%) and 12/17 (70%) with 17p13 and 11q23 deletions, respectively. Finally, CD38-positive cases included 18/150 (12%) 13q14 deleted cases, 26/40 (65%) cases carrying trisomy 12 and 5/7 (71%) and 7/17 (41%) with 17p13 and 11q23 deletions, respectively. The percentages of IgVH mutations significantly correlated with cytogenetic alterations; namely, 5.8±0.3 for cases with del(13)(q14), 4.6±0.4 for normal karyotype, 2.6±0.5 in +12, 0.3±0.2 in del(11)(q23), and 1.7±0.9 in del(17)(p13) cases (p for trend <0.0001). A significant correlation was also found for ZAP-70 expression: namely 32±1.8 for cases with del(13)(q14), 38.6±2.2 for normal karyotype, 47.6±3.7 for +12, 55.8±7.0 for del(11)(q22) and 42.4±11.7 for del(17)(p13) (p<0.0001). Similarly, CD38 percentages were (mean value ± sem) 9.3±1.7, 16.9±2.1, 52.9±5.7, 26.8±6.2, 37.0±12.7 for del(13)(q14), normal karyotype, +12, del(11)(q23) and del(17)(p13) alterations, respectively (p for trend <0.0001). Finally, cytogenetic abnormalities were clustered in 3 risk groups [i.e. low del(13)(q14) and normal; intermediate (+12); and high risk del(11)(q23) and del(17)(p13)] and significantly correlated (p<0.0001) with a scoring system in which cases were stratified in 4 different groups according to the absence (group 0) or presence of 1 (group 1), 2 (group 2) or 3 (group 3) biomarkers (Morabito et al., BJH, 2009, voce). Interestingly, 147/154 cases scoring 0, gathered in the low FISH group, whereas 17/22 high FISH risk cases clustered in scoring 2-3. Conclusions. Our preliminary results indicate that in Binet stage A B-CLL patients at diagnosis cytogenetic abnormalities with an expected negative clinical impact are relatively few (7.2%) but significantly associated with prognostic biomarkers which negatively predict the clinical outcome in B-CLL. Disclosures: No relevant conflicts of interest to declare.

305 Background: SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report planned interim analysis for our first-line cohort. Methods: Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, response by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Planned interim efficacy and safety analysis approved by DSMB is reported here. Results: For cohort 1, n = 19. Median age 63.5 (51-80). 80% Male; 65% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 32%. Etiology of cirrhosis: HCV 84%, ETOH 26%, NASH 5%. BCLC B 21%, C 70%. AFP > 400: 47%, PVT: 32%, metastases: 64%, post-transplant: 21%. Reason off study: PD (n = 10), toxicity (n = 2), lost to f/u (n = 1), withdrew (n = 1). N = 16 completed C1, n = 2 remain on study. mTTP is 4.2 months (95% CI: 3.7-NA). mOS 13.8 months (95% CI: 13.8-NA). Response Rate (CR+PR): 25%. Best response: CR n = 1 (6%), PR n = 3 (19%), SD n = 7 (44%). 4+ cycles: n = 9 (56%). % alive. Median duration of response 7.6 months (3.67-20). Gr 1/2 AEs as expected from SOR. Gr 3: AST elevated (n = 1), diarrhea (n = 1) due to SOR. Gr 2 rash (n = 1) due to HCQ. No Gr 4/5. Dose reduction: 70% for SOR, 0% for HCQ. PD analysis on the 3 responders show favorable immune profile changes (increase in cytotoxic T cells and decrease T Regs). Conclusions: SOR/HCQ had a better response rate (25%) than historically SOR alone (2%) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may have a role in patients with CP B cirrhosis, transplant or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing. Clinical trial information: NCT03037437.

The results of a single crystal X-ray structure determination of monoclinic (MeNH3)2SiF6 are reported: a = 962.3(5), b = 964.4(1), c = 966.4(5) pm, " = 100.03(3)°; V = 883.2(7) Å3, Z = 4, space group C2/c; wR2 = 0.0999 based on F02 of 1291 independent reflections (including H refinement without restrictions). The structure is related to that of (NH4)2SiF6, but contains the dumb-bells of the cations well oriented along the greater cell diagonals and fixed by one nearly linear and two bi-furcated hydrogen bonds (N...F: 281 and 293 - 305 pm, resp.). The [SiF6]2- octahedron is nearly undistorted with average bond length Si-F: 167.7 pm (169.9 pm corrected for thermal motion)

Abstract The ASME Boiler and Pressure Vessel Code (ASME BPVC) Section III, Division 5, Subsection HB, Subpart B provided only one design fatigue curve for Grade 91 steel (Gr.91) at 540 °C (or 1000 °F) in 2019 and earlier versions. To overcome this disadvantage, The ASME Section III Working Group on Creep-Fatigue and Negligible Creep (WG-CFNC) had taken an action to incorporate the temperature-dependent design fatigue curves for Gr. 91 developed by Japan Society of Mechanical Engineers (JSME) into ASME BPVC Section III Division 5. As a result, the temperature dependent design fatigue curves are provided in the 2021 edition of the ASME BPVC. To clear the features of the best-fit fatigue curve equation developed by the JSME, 305 data stored in the database were analyzed. Details of the database and relationship between the best-fit fatigue curve equation and the data including the statistic values and the values of 95% and 99% lower confidence bound calculated by failure probability assessment were clarified through analysis. In addition to the best-fit fatigue curve equation, an equation for dynamic stress-strain response showing the behavior of Gr.91 steel under cyclic loading of is also provided based on the same database. Moreover, some additional available data of fatigue and creep-fatigue tests obtained in Japan are also provided for considering the creep-fatigue damage evaluation under elevated temperature condition.