Articoli di riviste: "309.1/8"

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Boland, Rochelle E., Laura Nardo e Stuart B. Hooper. "Cortisol pretreatment enhances the lung growth response to tracheal obstruction in fetal sheep". American Journal of Physiology-Lung Cellular and Molecular Physiology 273, n. 6 (1 dicembre 1997): L1126—L1131. http://dx.doi.org/10.1152/ajplung.1997.273.6.l1126.

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We have investigated whether cortisol pretreatment of sheep fetuses will result in a greater liquid accumulation within the lung and a greater lung growth response to obstruction of the fetal trachea. Chronically catheterized fetal sheep received either 1) a cortisol infusion at an increasing dose (1.5–4.0 mg/day) from days 118 to 127 of gestation; the fetal trachea was then obstructed from days 128 to 131 of gestation ( n = 4); 2) a saline infusion from days 118 to 127 of gestation; the fetal trachea was then obstructed from days 128 to 131 of gestation ( n = 4); or 3) a saline infusion from days 118 to 127 of gestation with no period of tracheal obstruction (control; n = 4). Fetal tracheal pressures were measured from days 128 to 131 of gestation, whereas lung liquid secretion rates and volumes were measured on days 118, 128, and 131 of gestation. On day 131 of gestation, all fetuses were given an intravenous injection of [3H]thymidine and were killed 8 h later. Cortisol pretreatment increased the volume of liquid that accumulated within the fetal lung from 69.5 ± 4.1 to 96.1 ± 14.1 ml/kg after 3 days of tracheal obstruction. Similarly, cortisol pretreatment significantly enhanced the increase in lung DNA content from 257.4 ± 11.0 to 309.1 ± 16.3 mg/kg after 3 days of tracheal obstruction. We conclude that pretreatment of fetuses with cortisol increases the volume of liquid that accumulates after tracheal obstruction and, as a result, increases the fetal lung growth response to tracheal obstruction.

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Doyizode, Ashwini, Kausar Mundargi e Savitri Siddanagoudra. "Auditory and visual reaction times among children of chronic smokers and non-smokers: A comparative study". National Journal of Physiology, Pharmacy and Pharmacology 12, n. 9 (2023): 1. http://dx.doi.org/10.5455/njppp.2023.13.07354202201082022.

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Background: Tobacco consumption is the primary cause for cancers in men and women in India. Second hand smoking also has toxins in the similar concentration affecting children in particular leading to many health-related conditions including neurological disorders. The present study was done with the hypothesis that passive smoking in children causes delay in their reaction time when compared to the children of non-smokers which indicates cognition deficit. Aims and Objectives: The objectives of the study are as follows: (1) Comparison of the visual simple reaction time (VSRT) and visual choice reaction time (VCRT) among the children of chronic smokers and non-smokers and (2) to compare the auditory simple reaction time (ASRT) and auditory choice reaction time (ACRT) among the children of chronic smokers and non-smokers. Materials and Methods: This was a cross-sectional study. After obtaining necessary permission and consents, 30 children aged between 8 and 14 years with exposure to passive smoking as cases and 30 children of non-smoking parents as controls were included in the study. Audio-visual reaction timer was used. Results: Student’s “t” test was used for analysis. Mean value of VSRT showed 248.3 ms among controls and 277.7 ms in cases; VCRT among controls was 277.4 ms and 309.1 ms in cases (P < 0.05). Means of ASRT in controls was 213 ms and 250.4 in cases; ACRT in controls was 244 ms and among cases was 272.4 ms (P < 0.05). Conclusion: Significant delay in VSRT, VCRT, and ASRT was seen among the children exposed to tobacco smoke. ACRT also showed delayed response but not statistically significant.

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Нerasymenko, Y. S. "The Main Tendencies in the Development of Ecologically Oriented Business in Ukraine and Worldwide". Business Inform 11, n. 514 (2020): 83–88. http://dx.doi.org/10.32983/2222-4459-2020-11-83-88.

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The article is aimed at assessing the main tendencies in the development of ecologically oriented business in Ukraine and in certain regions of the world. The major tendencies in the development of ecologically oriented business both in Ukraine and worldwide are researched. The production of organic products in the world for 1999–2018 was analyzed in terms of acreage, production volumes and structure. It is emphasized that the growth rate of this market is very high in all analyzed indicators. Global organic products market volumes in 2017 amounted to USD 97 billion, compared to USD 15.2 billion in 1999. In view of the volume of consumption per inhabitant, the leaders were Switzerland (USD 325), Denmark (USD 315) and Sweden (USD 268). In Ukraine, the amount of consumption per capita was less than 1 US dollar. The largest markets in absolute terms were the USA and the EU countries. The structure of the organic market of different countries was studied, as well as the leaders in the consumption of organic products were identified. It is specified that the structure of the organic products market in each country has significant features. Thus, in Norway, a significant proportion belongs to baby food products (33.1%), while Germany has the widespread consumption of organic bread and bakery products (8%), and eggs (21.0%). It is underlined that the vast majority of organic products produced in Ukraine are exported (EUR 104 million in 2018). In Ukraine during 2002–2017, acreages under organic crops grew at a high rate (from 164.4 thousand hectares to 420 thousand hectares). However, in 2018 there was a decrease in these areas to the level of 309.1 thousand hectares, although the number of enterprises engaged in production increased from 375 to 501. It is concluded that further development of the organic products market is possible only if the level of incomes together with the State support of producers increase.

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Нerasymenko, Y. S. "The Main Tendencies in the Development of Ecologically Oriented Business in Ukraine and Worldwide". Business Inform 11, n. 514 (2020): 83–88. http://dx.doi.org/10.32983/2222-4459-2020-11-83-88.

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Abstract (sommario):

The article is aimed at assessing the main tendencies in the development of ecologically oriented business in Ukraine and in certain regions of the world. The major tendencies in the development of ecologically oriented business both in Ukraine and worldwide are researched. The production of organic products in the world for 1999–2018 was analyzed in terms of acreage, production volumes and structure. It is emphasized that the growth rate of this market is very high in all analyzed indicators. Global organic products market volumes in 2017 amounted to USD 97 billion, compared to USD 15.2 billion in 1999. In view of the volume of consumption per inhabitant, the leaders were Switzerland (USD 325), Denmark (USD 315) and Sweden (USD 268). In Ukraine, the amount of consumption per capita was less than 1 US dollar. The largest markets in absolute terms were the USA and the EU countries. The structure of the organic market of different countries was studied, as well as the leaders in the consumption of organic products were identified. It is specified that the structure of the organic products market in each country has significant features. Thus, in Norway, a significant proportion belongs to baby food products (33.1%), while Germany has the widespread consumption of organic bread and bakery products (8%), and eggs (21.0%). It is underlined that the vast majority of organic products produced in Ukraine are exported (EUR 104 million in 2018). In Ukraine during 2002–2017, acreages under organic crops grew at a high rate (from 164.4 thousand hectares to 420 thousand hectares). However, in 2018 there was a decrease in these areas to the level of 309.1 thousand hectares, although the number of enterprises engaged in production increased from 375 to 501. It is concluded that further development of the organic products market is possible only if the level of incomes together with the State support of producers increase.

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Kurashina, Toshiaki, Kent A. Kirchner, Joey P. Granger e Ami R. Patel. "Chronic Sodium-Potassium-ATPase Inhibition with Ouabain Impairs Renal Haemodynamics and Pressure Natriuresis in the Rat". Clinical Science 91, n. 4 (1 ottobre 1996): 497–502. http://dx.doi.org/10.1042/cs0910497.

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1. Chronic Na+,K+-ATPase inhibition with ouabain induces hypertension in the rat. To examine the role of the kidney in this process, the effect of changes in renal perfusion pressure on glomerular filtration rate, renal blood flow and urinary sodium excretion were determined in rats treated intraperitoneally with ouabain (27.8 μg day−1 kg−1 body weight) or vehicle for 6 weeks. 2. After ouabain administration, baseline mean arterial pressure was significantly higher (P < 0.05) in ouabain-treated rats (151 ± 2 mmHg; n = 9) than in control rats (116 ± 4 mmHg; n = 8). 3. At equivalent renal perfusion pressures, glomerular filtration rate was significantly lower (P < 0.05) in ouabain-treated rats compared with control rats. Glomerular filtration rate was 721 ± 73μl/min at 150 mmHg, and fell significantly to 322 ± 64 μl/min at 100 mmHg. In the control group, glomerular filtration rate was well autoregulated. The glomerular filtration rate autoregulatory index was calculated to determine the ability to maintain glomerular filtration rate during changes in renal perfusion pressure (0 reflects perfect autoregulation; >1 reflects the absence of autoregulation). This index was greater in the ouabain group than in the control group (1.54 ± 0.2 compared with 0.29 ± 0.2; P < 0.05). Renal blood flow showed a similar pattern. 4. Absolute urinary sodium excretion rate was less in ouabain-treated rats than in control rats at equivalent renal perfusion pressures. The slope of the relationship between absolute urinary sodium excretion rate and renal perfusion pressure was greater (P < 0.05) in the control group than in the ouabain group (309.1 ± 57.1 compared with 82.1 ± 14.8 μmol min−1 mmHg−1). 5. Thus, chronic inhibition of Na+,K+-ATPase induces less efficient autoregulation of glomerular filtration rate and renal blood flow as well as a rightward shift in the pressure natriuresis relationship, such that a 25–30 mmHg higher renal perfusion pressure is necessary to excrete any given sodium load. These abnormalities may contribute to the development and maintenance of hypertension in this model.

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Lahoz, B., J. L. Alabart, M. J. Cocero, D. Monniaux, S. Fabre e J. Folch. "352 THE USE OF PLASMA ANTI-MÜLLERIAN HORMONE IN SHEEP AS AN ENDOCRINE MARKER OF THE OVARIAN RESPONSE TO FOLLICLE-STIMULATING HORMONE IN MULTIPLE-OVULATION EMBRYO TRANSFER PROGRAMS". Reproduction, Fertility and Development 27, n. 1 (2015): 264. http://dx.doi.org/10.1071/rdv27n1ab352.

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The performance of MOET (multiple-ovulation embryo transfer) programs in sheep is limited, mainly due to variable ovarian responses to FSH superovulation treatments. In several mammalian species, anti-Müllerian hormone (AMH) has been demonstrated to be a good predictor of the ovarian follicle population able to respond to gonadotropins. Therefore, we aimed to evaluate its usefulness in ovine MOET programs. With this goal, two MOET trials involving 24 adult ewes in total were performed. Each ewe received a fluorogestone acetate sponge (Sincropart 30 mg, CEVA Animal Health SA, Barcelona, Spain) which was replaced by a new one after 6 days (T–4). Four days later (T0), the first FSH injection (Folltropin-V, Minitub Ibérica SL, Tarragona, Spain) of a superovulation treatment consisting in 280 IU of FSH administered in 8 decreasing doses was applied. Blood samples were taken at T–4 and T0 using lithium heparin tubes for AMH measurement. Ewes were inseminated 51 h after sponge removal. Eight days after sponge removal, ovulation rate was recorded and embryo recovery was carried out under general anaesthesia. After morphological evaluation, 2 embryos were transferred to each recipient previously synchronized. The plasma concentrations of AMH were determined using the AMH equine ELISA kit (AnshLab, Webster, TX, USA). The sensibility of the assay was 27.8 pg mL–1, and the intra-assay coefficient of variation was 4.8%. Relationships between the AMH concentration of each animal and the number of corpora lutea (CL), embryo recovered and lambs born per donor ewe were tested using the Pearson correlation coefficient. Normality of the variables was assessed by Kolmogorov–Smirnov test. The plasma AMH concentrations at T–4 were highly correlated with those at T0 (r = 0.95; P < 0.01), so both sampling times could be used indistinctly. The plasma AMH concentration at T0 was highly variable between animals, ranging from 0 to 309.1 pg mL–1 (mean ± s.e.m.: 98.4 ± 18.4 pg mL–1). Similarly, the number of CL ranged from 2 to 29 (12.2 ± 1.5), recovered embryos from 0 to 17 (7.6 ± 1.2), and lambs born per donor and session from 0 to 13 (4.5 ± 0.9). The AMH concentration at the beginning of the FSH treatment (T0) was highly correlated with the total number of CL (r = 0.70; P < 0.01), but significance was not attained for AMH with the other variables. The number of CL was also correlated with the number of recovered embryos (r = 0.69; P < 0.01) and lambs born (r = 0.58; P < 0.01). In conclusion, AMH concentrations measured in blood plasma before the FSH treatment could be used to predict the number of CL per donor ewe, and so to improve the efficiency of MOET programs. Further studies are necessary to assess the individual repeatability of a given ewe from session to session as well as the relationship of AMH with other embryo-related variables.

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Akazawa, Toshiyuki, Masaru Murata, Junichi Tazaki, Katsuo Nakamura, Tohru Kanno, Masayoshi Kobayashi, Kohji Itabashi e Makoto Arisue. "Surface Structure Design and Characterization of Bioabsorbable and Functionally Graded Apatites Originated from Bovine Bone". Key Engineering Materials 309-311 (maggio 2006): 1051–54. http://dx.doi.org/10.4028/www.scientific.net/kem.309-311.1051.

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Abstract. Bioabsorbable and functionally graded apatites (fg-HAp) ceramics were designed using calcined bovine bone (b-HAp) by the partial dissolution-precipitation methods. The fg-HAp ceramics with micro-pores of 10-160 nm had larger specific surface areas (30-40 m2･g-1) than the b-HAp ceramics, although the two HAp ceramics exhibited same macro-pore sizes of 100-600 µm and porosities of 60-80 %. Surface structure of these ceramics was modified by soaking at 309.5 K for 1-90 days in a simulated body fluid (SBF). At 8 days after the soaking, microstructure of the fg-HAp changed from small grains to dense cocoon-like ones by rapid precipitation of HAp microcrystals, while at 14 days, that of the b-HAp was porous urchin-like grains, suggesting that the fg-HAp had higher bone-bonding ability than the b-HAp.

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Briand, Richard, Nobuharu Yamaguchi, Jacques Gagne, Tomohiko Kimura, Lisa Farley, Sylvain Foucart, Reginald Nadeau e Jacques de Champlain. "Corelease of neuropeptide Y like immunoreactivity with catecholamines from the adrenal gland during splanchnic nerve stimulation in anesthetized dogs". Canadian Journal of Physiology and Pharmacology 68, n. 3 (1 marzo 1990): 363–69. http://dx.doi.org/10.1139/y90-050.

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The release of neuropeptide Y like immunoreactivity (NPY-li) from the adrenal gland was studied in relation to the secretion of catecholamines (CA:NE, norepinephrine; E, epinephrine) during the left splanchnic nerve stimulation in thiopental–chloralose anesthetized dogs (n = 16). Plasma concentrations of NE, E, and NPY-li were determined in the left adrenal venous and aortic blood. Adrenal outputs of NPY-li, NE, and E were 2.4 ± 0.4, 1.4 ± 0.2, and 7.3 ± 1.7 ng/min, under basal conditions, respectively. These values increased significantly (p < 0.05; n = 8) in response to a continuous stepwise stimulation at frequencies of 1, 3, and 10 Hz given at 3-min intervals during 9 min, reaching a maximum output of 4.6 ± 0.9 (NPY-li), 240.2 ± 50.2 (NE), and 1412.5 ± 309.7 ng/min (E) at a frequency of 10 Hz. Burst electrical stimulation at 40 Hz for 1 s at 10-s intervals for a period of 10 min produced similar increases (p < 0.05) in the release of NPY-li (4.8 ± 1.0 ng/min, n = 8), NE (283.5 ± 144.3 ng/min, n = 8), and E (1133.5 ± 430.6 ng/min, n = 8). Adrenal NPY-li output was significantly correlated with adrenal NE output (r = 0.606; n = 24; p < 0.05) and adrenal E output (r = 0.640; n = 24; p < 0.05) in dogs receiving the burst stimulation. The present findings demonstrate that NPY-li is coreleased with NE and E from the adrenal gland in response to direct splanchnic nerve stepwise or burst stimulation at high frequencies in anesthetized dogs. It is thus possible that the adrenal medullary NPY-li contributes to the modulation of circulating NPY-li levels under various physiopathological conditions.Key words: adrenal medulla, burst stimulation, catecholamines, corelease, neuropeptide Y, splanchnic nerves.

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Pershakova, A. E., I. S. Kazakov, M. A. Artemov, A. V. Zolotarev, O. V. Zhukova, E. V. Karlova, E. B. Eroshevskaya e V. M. Malov. "Suprachoroidal administration of triamcinolone acetonide in patients with macular edema after vitrectomy: Technique and results". Aspirantskiy Vestnik Povolzhiya 23, n. 4 (9 dicembre 2023): 44–50. http://dx.doi.org/10.55531/2072-2354.2023.23.4.44-50.

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Aim – to study the effectiveness of triamcinolone acetonide (TA) injection into the suprachoroidal space using a microneedle for the treatment of macular edema after vitrectomy. Material and methods. During the study, the results of suprachoroidal administration of triamcinolone acetonide were analyzed in 8 patients (8 eyes) who were observed with macular edema as a complication of vitrectomy. Ophthalmological examination included visometry, non-contact tonometry, indirect ophthalmoscopy with lens 78 D, and optical coherence tomography (OCT) of the macular area. Best corrected visual acuity (BCVA) before the operation ranged from 0.1 to 0.8 (0.25 (0.10; 0.50), retinal thickness in the foveolar area varied from 342 to 728 µm (513.0 (443.0; 585.5) according to OCT data. During the operation, all patients underwent the injection of 0.1 ml of triamcinolone acetonide using a microneedle into the suprachoroidal space 3.5-4.0 mm posterior to the limbus. Results. One month after suprachoroidal injection of TA, the thickness of macular edema statistically significantly decreased to 327.5 (309.0; 380.5) μm (p = 0.011719) and BCVA increased to 0.45 (0.25; 0.80) (p = 0.027709). Three months after surgery, the retinal thickness in the macular area was 333.5 (311.5; 503.0) (p = 0.068704). The lack of statistical significance in the reduction of macular edema 3 months after suprachoroidal TA injection is explained by the fact that 3 out of 8 patients (37.5%) experienced a recurrence of macular edema after 3 months. However, BCVA has significantly increased to 0.6 (0.25; 0.90) (p = 0.043115). In 5 out of 8 patients (62.5%) a stable positive result was achieved within 3 months in the form of relief of macular edema. In the postoperative period, an increase in intraocular pressure was noted only in 2 cases of measurements, in patients observed for secondary glaucoma as a concomitant diagnosis. Intraocular pressure was compensated in both cases after correction of the treatment regimen. Conclusion. The presented technique is effective in treatment of macular edema associated with vitrectomy, as well as safe, which may be the reason for its further study.

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Chekaev, N. P., e A. A. Galiullin. "The effect and aftereffect of bird manure on the agrochemical properties of leached chernozem and productivity of agricultural crops". Agrarian science, n. 1 (2 marzo 2022): 102–5. http://dx.doi.org/10.32634/0869-8155-2022-355-1-102-105.

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The article presents the results of field studies of the effect of different doses of chicken manure on the agrochemical properties of leached chernozem and crop yields of the crop rotation link, carried out in the training and production center of the Penza State Agrarian University in 2017–2019. Studies have shown that the use of different doses of manure in direct action led to an increase in the content of mobile forms of nitrogen, phosphorus and potassium in the soil. In the aftereffect, in the second and third years, there is a decrease in their content to the level of the initial values. The pHsol indicator in direct action increased by 0.06–0.16 units. In the second and third years, a decrease in the pHsol was observed up to the level of the original values. The total increase in grain yield of cultivated crops in experiments from the direct action and aftereffect of the introduced doses of manure from 2 to 10 t/ha was 0.46–2.76 t/ha of grain units compared to control. The highest total productivity was at a manuredose of 10 t/ha. The payback of 1 ton of manure for three years of operation was 229.5– 309.5 kg/t. The highest payback was noted at doses from 4 to 8 t/ha.

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Du, Y., J. Gu, Y. Yang, Y. Chen, Y. Wang, Z. Mei, Y. Li et al. "Efficacy and safety of bicyclol for treating patients with antituberculosis drug-induced liver injury". International Journal of Tuberculosis and Lung Disease 28, n. 1 (1 gennaio 2024): 6–12. http://dx.doi.org/10.5588/ijtld.23.0038.

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BACKGROUND: Bicyclol was used for treating idiosyncratic acute drug-induced liver injury (DILI) in a phase II trial. This study was aimed at evaluating the efficacy and safety of bicyclol 25 and 50 mg thrice a day (TID) for treating acute DILI caused by anti-TB drugs in the light of the trial results.METHODS: We analysed clinical data of patients with TB drug-induced DILI in the trial database. The primary endpoint was reduction in serum alanine aminotransferase (ALT) levels after 4 weeks of treatment compared to baseline.RESULTS: Overall, 148 patients were included, with respectively 48, 52 and 48 patients included in the control (456 mg polyene phosphatidylcholine TID), high-dose (50 mg bicyclol TID) and low-dose (25 mg bicyclol TID) groups. ALT levels decreased by respectively â–“149.0 (IQR â–“299.3 to â–“98.3 (), â–“225.5 (IQR â–“309.3 to â–“181.8 ) and â–“242.5 (IQR â–“364.8 to â–“153.8) U/L in the control, high-dose and low-dose groups (P < 0.001). The ALT normalisation rates at weeks 1, 2, 4, 6 and 8 were higher in the high- and low-dose groups, while adverse events and serious adverse events were similar across groups.CONCLUSIONS: Bicyclol (25 and 50 mg TID) is effective and safe in treating anti-TB DILI, and bicyclol 50 mg TID showed higher efficacy.

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Sone, M., A. Ohno, G. J. Albrecht, K. Thurau e F. X. Beck. "Restoration of urine concentrating ability and accumulation of medullary osmolytes after chronic diuresis". American Journal of Physiology-Renal Physiology 269, n. 4 (1 ottobre 1995): F480—F490. http://dx.doi.org/10.1152/ajprenal.1995.269.4.f480.

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Restoration of urine osmolality (Uosm) and medullary osmolyte contents after chronic diuresis was studied in rats infused for 6 days with furosemide and subsequently given the vasopressin analogue, 1-desamino-8-D-arginine vasopressin (DDAVP). Papillary tip intra- and extracellular electrolyte concentrations were measured by electron microprobe analysis, tissue contents of methylamines (glycerophosphorylcholine, betaine), polyols (myo-inositol, sorbitol), and several amino acids in different kidney zones by high-performance liquid chromatography. Administering DDAVP continuously after diuresis increased Uosm from (means +/- SE) 348 +/- 8 to 1,265 +/- 127 after 1 day and 2,485 +/- 186 mosmol/kgH2O after 3 days. The sum of all osmolytes at the papillary tip rose from 309.2 +/- 28.9 to 690.9 +/- 105.8 and 1,282.8 +/- 21.0 mmol/kg protein after days 1 and 3, respectively. Although interstitial tonicity (sum of Na, Cl, and K concentrations) was increased by 116 and 223% after 1 and 3 days DDAVP, intracellular tonicity was similar in chronic diuresis and following 1 or 3 days DDAVP. Coadministration of DDAVP with betaine, myo-inositol, and choline (“osmolyte treatment”) did not accelerate the restoration of Uosm but caused significantly higher contents of osmolytes (except myo-inositol) in inner medulla and/or papilla after 3 days. In a minority of animals, restoration of Uosm and reaccumulation of medullary osmolytes were impeded in both DDAVP- and DDAVP/osmolyte-treated rats. These data indicate that, after chronic diuresis, accumulation of organic osmolytes and restoration of Uosm proceed in parallel. Capacity for transport and/or synthesis of organic osmolytes, rather than their availability, appear to limit reaccumulation on the first day of recovery. By the third day, delivery of some osmolytes or their precursors may limit the restoration of medullary osmolyte content. The failure of some rats to attain sufficient concentrating ability within this time period may be related to deficient reaccumulation of medullary osmolytes.

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Ota, Yumiko, Takeru Wakatsuki, Tetsuo Mashima, Daisuke Takahari, Keisho Chin, Takashi Ichimura, Mariko Ogura et al. "Plasma biomarker dynamics following ramucirumab treatment and survival analysis after ramucirumab treatment failure in patients with advanced gastric cancer." Journal of Clinical Oncology 36, n. 4_suppl (1 febbraio 2018): 79. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.79.

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79 Background: Ramucirumab (RAM) showed significantly improved survivals of gastric cancer in the second line with paclitaxel or single use. It is known that RAM causes pharmacodynamic changes of plasma VEGF-A family levels during treatment. However, its clinical significance is still unclear. The aim of this study is to reveal the changes of plasma biomarker levels until disease progression, and to examine associations between plasma biomarker levels at disease progression and survival after RAM treatment failure. Methods: Plasma samples were collected at three points: base line, day 8, and disease progression. Nine kinds of plasma biomarker related to angiogenesis: VEGF-A, C, D, PlGF, sVEGFR-1, 2, Neuropilin-1 (NRP1), Angiopietin-1, and SDF-1α, were measured by means of ELISA. The dynamics of plasma biomarkers were compared using the ANOVA. Patients were dichotomized by optimal cut-off value in each biomarker. Survival after RAM treatment failure was estimated by Kaplan-Maier methods and compared by log-rank test. Results: Plasma samples were collected from 21 patients. Median age was 67 y.o and female was dominant (57%). Plasma VEGF-A and PlGF levels sharply increased at day 8 and these higher plasma levels were sustained until disease progression: the median VEGF-A and PlGF levels at baseline, day 8, and disease progression were 20.2, 350.2, and 596.7 pg/ml for VEGF-A (p<0.001) and 10.5, 223.4, and 261.1 pg/ml for PlGF (p<0.001), respectively. Conversely, plasma NRP1 levels consistently decreased during treatment course: the median NRP1 levels at baseline, day 8, and disease progression were 444.3, 309.2, and 230.9 mg/ml (p=0.001). The median survival after disease progression was 3.1 months (95%CI 2.5-3.7). Patients with higher VEGF-A and NRP1 levels showed shorter survival with 4.5 vs. 0.9 months (HR 3.15 95%CI 1.6-6.4 p<0.001) for VEGF-A and 8.8 vs. 2.6 months (HR 2.92 95% CI 1.4-6.3 p=0.002) for NRP1. Conclusions: Our data suggest that not only a clue of mechanism of acquired resistance of RAM but necessity of new treatment strategy after RAM treatment failure. Further understanding of molecular correlates and clinical validation are warranted.

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Lenz, Jiří, Dominika Macháčová, Petra Konečná, Luděk Fiala, Michal Kyllar e František Tichý. "Effects of different fixatives over different fixation times, including Antigenfix, on immunohistochemical studies". Acta Veterinaria Brno 91, n. 2 (2022): 179–88. http://dx.doi.org/10.2754/avb202291020179.

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Tissue fixation is an essential step in the performance of ancillary studies, including immunohistochemistry. The aim of this study was to compare the effect of various fixatives and fixative times on immunohistochemistry (IHC) in bovine and porcine endometrium using progesterone receptors and SOX2 antibodies. Immunohistochemical staining with progesterone receptors and SOX2 was performed on tissue samples fixed in formalin, Antigenfix, Greenfix, Bouin’s solution and methacarn at 1.5, 8.5, 15.5, 29.5, 64.5, 189.5, 249.5, 309.5 and 369.5 days of fixation. Formalin and Antigenfix proved to be the best fixative for both short-term and long-term fixation for IHC. Bouin’s solution was partially applicable for short-term (24 h) fixation. Greenfix and methacarn were absolutely inappropriate fixatives for IHC (completely negative staining using methacarn). These results were obtained on an automated immunostainer using EDTA buffer pH 8.4 as the antigen retrieval solution. When the staining procedure was performed manually and citrate buffer with different pH values was used, weakly positive results were obtained with both progesterone receptors (pH 8 and 9) and SOX2 (pH 7.2); however, significantly lower staining quality was obtained using the methacarn fixative compared to aldehyde fixatives. The reported findings demonstrated the superiority of aldehyde fixatives (formalin and Antigenfix) over alcohol fixatives (methacarn) and fixatives combining both denaturing and cross-linking proteins (Greenfix and Bouin’s solution) for IHC. Antigen retrieval-IHC using EDTA buffer was found to be excellent for aldehyde fixatives, but proved to be completely unsuitable for methacarn, Greenfix, and Bouin’s solution.

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Ge, Yucheng, Yukun Liu, Ruichao Zhan, Zhenqiang Zhao, Jun Li, Wenying Wang e Ye Tian. "Genotype and Phenotype Characteristics of Chinese Pediatric Patients with Primary Hyperoxaluria". Human Mutation 2023 (14 settembre 2023): 1–11. http://dx.doi.org/10.1155/2023/4875680.

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Primary hyperoxaluria (PH) is a rare monogenic disorder characterized by recurrent kidney stones, nephrocalcinosis, and renal impairment. To study the genotype and phenotype characteristics, we evaluated the clinical data of 42 Chinese pediatric PH patients who were diagnosed from May 2016 to April 2022. We found that patients with the PH3 type showed an earlier age of onset than those with the PH1 and PH2 types (1 versus 5 and 8 years, respectively, P < 0.001 ). Urine citrate was significantly lower in PH1 and PH2 patients than that in PH3 patients (91.81 and 85.56 versus 163.9 μg/mg, respectively, P = 0.044 ). Spot urine oxalate levels were slightly higher in PH1 than that in PH2 and PH3 patients (457.9 versus 182.38 and 309.14 μg/mg, respectively, P = 0.189 ). A significant negative correlation between the urine calcium/creatinine ratio and the oxalate/creatinine ratio was observed in the entire PH cohort ( r = − 0.360 , P = 0.04 ) and the PH3 cohort ( r = − 0.674 , P = 0.003 ). PH-causative genes showed hotspot mutations or regions, including c.815_816insGA and c.33dup in AGXT, 864_865del in GRHPR, and exon 6 skipping and c.769T>G in HOGA1. In the PH1 cohort, the estimated glomerular filtration rate (eGFR) was lowest in patients with heterozygous c.33dup. In the PH3 cohort, patients with heterozygous exon 6 skipping presented the lowest eGFR and a significant decrease in the renal survival advantage. In summary, PH1 patients exhibit much more severe phenotypes than those with other types. Hotspot mutations or regions exist in patients with all types of PH and show differences among ethnicities. Genotype-phenotype correlations are observed in PH1 and PH3.

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Li, Xiaoyu, Yuefeng Du, Jinglin Guo e Enrong Mao. "Design, Simulation, and Test of a New Threshing Cylinder for High Moisture Content Corn". Applied Sciences 10, n. 14 (17 luglio 2020): 4925. http://dx.doi.org/10.3390/app10144925.

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Corn harvesting mode has gradually changed from ear harvesting to direct grain harvesting. In view of the problems of high moisture content in corn harvesting in China, such as the rates of broken grains (BGR) and uncleared grains (UGR) being too high, a new single longitudinal axial threshing cylinder was designed, which mainly included a cylinder spindle, a spiral feeding inlet, a T-type rasp bar, a separating straight rod, and a spiral extracting rod. Firstly, the three states of grain during the threshing process and the key influence factors of threshing and force analysis of corn ears in the threshing device were analyzed, then the structure of the threshing cylinder was designed, and its parameters were determined by theoretical analysis results. The arrangement mode of threshing elements adopted a combination of a T-type rasp bar, a separating straight rod, and a spiral extracting rod with a 6-head spiral pattern and an arrangement step of 250 mm. Secondly, the arrangement step of threshing elements was determined by discrete element method solution (DEM) simulation; the result showed that the average movement velocity was 55.04 m/s and the threshing time was 6–8 s. Finally, a multiple factors experiment of the threshing device was carried out, and the result showed that the order of the effect factors of the BGR and UGR was cylinder rotational speed > concave clearance > feed amount. When cylinder rotational speed was 309.17 r/min, concave clearance was 35.48 mm, and the feed amount was 6.13 kg/s. The verification experiment result showed that the BGR and UGR were 1.24% and 1.33%, respectively, which meet standard requirements. The research results could provide a reference for the design of a high moisture content grain threshing device and combine harvester.

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Liu, Man-Hai, Yi-Fen Li e Bing-Huei Chen. "Inhibition of Melanoma Cells A375 by Carotenoid Extract and Nanoemulsion Prepared from Pomelo Leaves". Plants 10, n. 10 (7 ottobre 2021): 2129. http://dx.doi.org/10.3390/plants10102129.

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This study aims to determine carotenoids in pomelo leaves (Citrus grandis Osbeck), a rich source of nutrients and phytochemicals, by high-performance liquid chromatography-mass spectrometry and prepare carotenoid nanoemulsions for the study of its inhibitory mechanism on melanoma cells A375. Fourteen carotenoids were separated within 27 min by using a YMC-C30 column and a gradient mobile phase of methanol-acetonitrile-water (84:14:2, v/v/v) and methylene chloride with a flow rate of 1 mL/min and detection wavelength of 450 nm. All-trans-lutein plus its cis-isomers were present in the largest amount (3012.97 μg/g), followed by all-trans-neoxanthin (309.2 μg/g), all-trans-violaxanthin (208.5 μg/g), all-trans-β-carotene plus its cis-isomers (203.17 μg/g), all-trans-α-carotene plus its cis-isomers (152.5 μg/g), all-trans-zeaxanthin (54.67 μg/g), and all-trans-β-cryptoxanthin plus its cis-isomers (24.56 μg/g). A stable carotenoid nanoemulsion was prepared with a mean particle size of 13.3 nm, zeta-potential of −66.6 mV, a polydispersity index of 0.132 and an encapsulation efficiency of 99%. Both the carotenoid extract and nanoemulsion could upregulate p53, p21, cyclin B and cyclin A expressions in melanoma A375 cells and downregulate CDK1 and CDK2 in a concentration-dependent manner. Also, they could upregulate Bax and cytochrome-C and downregulate Bcl-2, leading to cell apoptosis through activation of caspase-9, caspase-8 and caspase-3. Compared to extract, carotenoid nanoemulsion was shown to be more effective in inhibiting the growth of melanoma cells A375. This finding further demonstrated that a carotenoid nanoemulsion prepared from pomelo leaves possessed a great potential to be developed into functional foods or even botanic drugs.

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Ríos-Elósegui, Daniela, e Michel E. Hendrickx. "Abundance, relative growth and fecundity of Emerita rathbunae Schmitt, 1935 (Decapoda, Anomura, Hippidae) in the S.E. Gulf of California, Mexico". Crustaceana 88, n. 2 (2015): 127–43. http://dx.doi.org/10.1163/15685403-00003400.

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Specimens of the mole crabEmerita rathbunaeSchmitt, 1935, were collected during a one-year period along two sandy beaches in the S.E. Gulf of California, Mexico. A total of 2171 specimens were examined. Only 8% of the collected females were ovigerous. The large majority of males (95%) were collected in the sand as “free living” males, while the rest (39 individuals) were “dwarf males”, with developed genital papilla, 95% of which were found attached to females. Density for pooled samples reached an overall maximum of 309.8 orgs/m2in February and a minimum in April (65.0 orgs/m2). Females always outnumbered males, except in February. Ovigerous females were observed in the first half of the study period (February to September). Proportions of males were very similar throughout the study period, while indeterminate specimens were proportionally more abundant in its second half. Relationships between CW and CL for both males and females were highly correlated and isometric. Relationships between size and weight were highly correlated in both males and non-ovigerous females for pooled samples or for each sampling zone, and in each case growth was isometric. The number of eggs per ovigerous female varied considerably, from 910 to 22 866, and the relationship between number of eggs per batch and body size was poorly correlated. In the study area,E. rathbunaeappears to have a rather restricted reproduction period. A larger series of data combined with the analysis of other environmental factors, such as beach profiles, current patterns and primary productivity, might bring some additional information on this species biology and ecology. Due to the key role that mole crabs play in the food web of sandy beaches, special attention should be provided to this particular habitat.

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Yu, Hsin-Rong, e Bing-Huei Chen. "Analysis of Phenolic Acids and Flavonoids in Rabbiteye Blueberry Leaves by UPLC-MS/MS and Preparation of Nanoemulsions and Extracts for Improving Antiaging Effects in Mice". Foods 12, n. 10 (10 maggio 2023): 1942. http://dx.doi.org/10.3390/foods12101942.

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Rabbiteye blueberry leaves, a waste produced after harvest of blueberry, are rich in polyphenols. This study aims to analyze phenolic acids and flavonoids in blueberry leaves by UPLC-MS/MS and prepare nanoemulsions for determining anti-aging activity in mice. Overall, 30% ethanol was the most suitable extraction solvent for total phenolic acids and total flavonoids. A total of four phenolic acids and four flavonoids were separated within seven minutes for further identification and quantitation by UPLC-MS/MS in selective reaction monitoring (SRM) mode, with 3-O-caffeoylquinic acid being present in the highest amount (6474.2 μg/g), followed by quercetin-3-O-galactoside (1943.9 μg/g), quercetin-3-O-rutinoside (1036.6 μg/g), quercetin-3-O-glucoside (867.2 μg/g), 5-O-caffeoylquinic acid (815.8 μg/g), kaempferol-3-O-glucoside (309.7 μg/g), 3,5-dicaffeoylquinic acid (195.3 μg/g), and 4,5-dicaffeoylquinic acid (60.8 μg/g). The blueberry nanoemulsion was prepared by using an appropriate ratio of soybean oil, Tween 80, glycerol, ethanol, and water at 1.2%, 8%, 2%, 2%, and 86.8%, respectively, and mixing with dried blueberry extract, with the mean particle size and zeta potential being 16 nm and −54 mV, respectively. A high stability was observed during storage of nanoemulsion for 90 days at 4 °C and heated at 100 °C for 2 h. An animal study revealed that this nanoemulsion could elevate dopamine content in mice brain as well as superoxide dismutase, glutathione peroxidase, and catalase activities in mice liver while reducing the contents of malondialdehyde and protein carbonyl in mice brains. Collectively, the high-dose nanoemulsion possessed the highest efficiency in improving mice aging with a promising potential for development into a health food.

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Alhetheel, Abdulkarim, Ahmed Albarrag, Zahid Shakoor, Ali Somily, Mazin Barry, Haifa Altalhi, Muhammed Bakhrebah et al. "Chemokine Levels among Patients with Middle East Respiratory Syndrome Coronavirus Infection". Vaccines 11, n. 6 (31 maggio 2023): 1048. http://dx.doi.org/10.3390/vaccines11061048.

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Middle East respiratory syndrome coronavirus (MERS-CoV) is associated with significant morbidity and mortality due to intense pulmonary inflammation. Enhanced chemokine-mediated leukocyte infiltration in lungs has been linked with unfavorable outcomes with respect to the disease. This cross-sectional study assessed the levels of chemokines among 46 MERS-CoV-infected patients (19 asymptomatic and 27 symptomatic) and 52 healthy controls using a customized Luminex human chemokine magnetic multiplex panel. The plasma levels of interferon-inducible protein (IP)-10 (568.5 ± 114.7 vs. 55.19 ± 5.85 pg/mL; p < 0.0001), macrophage inflammatory protein (MIP)-1 alpha (MIP-1A) (30.78 ± 2.81 vs. 18.16 ± 0.91 pg/mL; p < 0.0001), MIP-1B (36.63 ± 4.25 vs. 25.26 ± 1.51 pg/mL; p < 0.003), monocyte chemoattractant protein (MCP)-1 (1267 ± 309.5 vs. 390.0 ± 35.51 pg/mL; p < 0.0002), and monokine-induced gamma interferon (MIG) (28.96 ± 3.93 vs. 16.29 ± 1.69 pg/mL; p < 0.001), interleukin (IL)-8 (147.9 ± 21.57 vs. 84.63 ± 10.62 pg/mL; p < 0.004) were significantly higher in symptomatic patients than healthy controls. Likewise, the levels of IP-10 (247.6 ± 80.09 vs. 55.19 ± 5.85 pg/mL; p < 0.0002) and MCP-1 (650.7 ± 149 pg/mL vs. 390 ± 35.51 pg/mL; p < 0.02) were also significantly higher in asymptomatic patients compared to healthy controls. However, no differences were observed in the plasma levels of MIP-1A, MIP-1B, MIG, and IL-8 between asymptomatic patients and uninfected controls. Conversely, the mean plasma levels of regulated on activation normal T cell expressed and secreted (RANTES) (3039 ± 301.0 vs. 4390 ± 223 pg/mL; p < 0.001) and eotaxin (176.9 ± 30.20 vs. 296.2 ± 28.11 pg/mL; p < 0.01) were significantly lower in symptomatic MERS-CoV-infected patients compared to healthy controls. Likewise, the levels of eotaxin (162.7 ± 21.60 vs. 296.2 ± 28.11 pg/mL; p < 0.01) were also significantly lower in asymptomatic patients. Interestingly, the level of MCP-1 (2139 ± 548.2 vs. 776.5 ± 165.3 pg/mL; p < 0.004) was significantly higher in deceased symptomatic patients compared to recovered symptomatic patients. MCP-1 was the only chemokine associated with a higher risk of mortality. Symptomatic MERS-CoV-infected patients had a significant elevation of plasma chemokines and elevated MCP-1 levels were found to be associated with fatal outcomes.

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Obaid Al-Shahbani, Ismail Razak, e Muhammad Tarkhan Abu Al-Mikh Al-Mamouri. "Effect of Adding Bio-Fertilizer and Spraying Nano - and Chelated Iron Fertilizer on the Nutrient Content of Orange Seedling Leaves". IOP Conference Series: Earth and Environmental Science 1060, n. 1 (1 luglio 2022): 012012. http://dx.doi.org/10.1088/1755-1315/1060/1/012012.

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Abstract The study was carried out in the certified citrus propagation nursery of the Horticultural and Forestry Company in Al-Hindiya District / Holy Karbala Governorate during the period 20/4/ up to 20/8/2021, in order to study the effect of adding bio-fertilizer and spraying nano and chelated iron fertilizers on the content of orange seedlings leaves of the elements food. The experiment included three factors, the first biological fertilizing factor, adding ground at four levels, which are (the comparison treatment, azotobacter, mycorrhizal fungi, mycorrhizal fungi + azotobacter). It is the spraying of chelated iron in three levels (zero, 3, and 6 g / liter). A factorial experiment was carried out with a Randomized Complete Block Design, and the averages of traits were compared with the L.S.D. test at the 5% probability level. The results indicated: The biofertilization treatment (Mycorrhizal fungus+ Azotobacter bacteria). And the spraying treatment with nano iron fertilizer (3 g. L-1) was significantly superior in the content of orange seedlings leaves of nutrients (Zn,Fe,K,P,N) and the spraying treatment was The chelated iron fertilizer (6g.l-1) showed the same behavior and showed significant differences in the content of nutrients in the leaves. It gave the highest concentrations of the studied elements. The dual interactions between the study factors gave significant differences in the school characteristics, as it gave the treatment (Azotobacter + Mycorrhizae) + spraying of nano iron (3 g. L-1), and biological fertilization (Azotobacter + Mycorrhizae) + spraying of chelated iron (6 g. L-1), And (nano iron spray (3 g.l-1) + chelated iron spray (6g.l-1) the highest values are superior to the rest of the treatments and reached (2.58%, 0.68%, 2.81%, 300.79 mg. kg-1. dry weight, 42.80 mg. kg-1.d.w.) (2.55%, 0.64%, 2.97%, 297.79 mg. kg-1. d.w., 42.19 mg. kg-1. d.w.) (2.49%, 0.62%, 2.74%, 256.17 mg kg-1 dry weight, 39.66 mg kg-1 dry weight, respectively, gave the triple interaction treatment (Azotobacter + Mycorrhizae) + spray of nano iron (3 g. L-1) + spray of chelated iron (6 g). L-1) was significantly superior in leaf content of the studied elements, and it reached (2.77%, 0.75%, 3.20%, 309.17 mg. kg-1. dry weight, 49.40 mg. kg-1. dry weight), respectively.

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Al Harthy, Munjid, Ravi Amrit Madan, Fatima Karzai, Daniel Peter Petrylak, Joseph W. Kim, Philip M. Arlen, Marc Robert Theoret et al. "A phase I and randomized phase II study of cabozantinib plus docetaxel and prednisone (C+DP) versus docetaxel and prednisone (DP) alone in metastatic castrate-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 37, n. 7_suppl (1 marzo 2019): 173. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.173.

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173 Background: A phase I study of Cabozantinib (C) in combination with docetaxel (D) and prednisone (P) in patients (pts) with mCRPC determined that 40 mg daily was the maximum tolerated dose of C in combination with D and P (C+DP). We report a pooled analysis of the phase I and randomized phase II study comparing C+DP to DP alone. Methods: Eligible pts had mCRPC without prior chemotherapy in the castrate setting. All pts received a fixed dose of D (75 mg/m2IV day one of each 21 day cycle) and P (5 mg PO twice daily), and in the C+DP group, C at three escalating dose levels: 20 mg, 40 mg, or 60 mg in the phase I cohort (all PO daily) and 40 mg daily in the phase II cohort. Results: A total of 32 pts received C+DP (19 pts in phase I and 13 pts in the phase II cohort). 12 pts received DP alone. Baseline characteristics for C+DP vs DP included median age 69 (45 – 84) vs 69 (50-83) and median PSA 74.8 ng/ml (0.01-4093.7) vs 309.5 ng/ml (94.6 – 2649) respectively. Clinical trial information: NCT01683994. 18/32 C+DP pts had previous enzalutamide or abiraterone, with a median PFS of 13.6 months (95% CI: 5.2 – 21.0). 23/32 pts (72%) treated with C+DP required dose reduction or discontinuation of C, and 10/32 (31%) required C discontinuation. 2/32 patients (6%) in the C+DP group died on protocol, possibly related to study drug (sudden death NOS/venous thromboembolism). Grade 4 adverse events (AEs) in the C+DP group included: neutropenia (28%), leukopenia (6%), pulmonary embolism (3%), and mucositis (3%) and in DP: hyperglycemia (8%). Grade 3 AEs (>10%) in C+DP included: neutropenia (31%), febrile neutropenia (16%), leukopenia (13%), hypophosphatemia (13%) and in DP: anemia (17%). Conclusions: In pts with mCRPC, C+DP is associated with a greater PFS and PSA responses compared to DP alone. Toxicities with the combination were manageable. Further study is required to better define the potential benefits of C+DP in mCRPC.[Table: see text]

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Kennedy, Victoria C., James J. Gaspers, Bethany R. Mordhorst, Gerald L. Stokka, Kendall C. Swanson, Marc L. Bauer e Kimberly A. Vonnahme. "Late gestation supplementation of corn dried distiller’s grains plus solubles to beef cows fed a low-quality forage: III. effects on mammary gland blood flow, colostrum and milk production, and calf body weights". Journal of Animal Science 97, n. 8 (10 giugno 2019): 3337–47. http://dx.doi.org/10.1093/jas/skz201.

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Abstract Objectives were to investigate the effects of supplementation with corn dried distiller’s grains plus solubles (DDGS) to late gestating beef cows on arterial blood flow to the mammary glands during late gestation and early lactation; colostrum and milk production; dystocia and immunity; and calf BW. Cows were fed a control (CON; n = 15; 5.1% CP; 36.2% ADF) diet consisting of 90% corn stover and 10% corn silage on a dry basis offered ad libitum or CON diet with supplementation of DDGS (0.30% of BW; SUP n = 12). Mammary gland blood flow was assessed on day 245 of gestation. At parturition, maternal and calving parameters were assessed; colostrum and jugular blood was sampled; and dams were weighed. Mammary gland blood flow and milk production was measured on day 44 of lactation. Calves were weighed fortnightly for 8 wk and at weaning. Colostrum production tended to be greater in SUP dams than in CON dams (837 vs. 614 ± 95 g, P = 0.10). Calves of SUP dams were heavier at birth and 24 h (0 h, 43.2 vs. 39.8 ± 1.0 kg, P = 0.02; 24 h, 44.0 vs. 40.4 ± 1.1 kg, P = 0.02). At birth and 24 h, blood pCO2 was greater in calves born to SUP dams (6.82 vs. 6.00 ± 0.41 kPa, P = 0.04). Serum IgG did not differ (P = 0.21) at 24 h. Ipsilateral mammary gland blood flow of SUP cows was greater than CON cows (2.76 vs. 1.76 ± 0.30 L/min; P = 0.03); however, when summed with contralateral, total blood flow was similar (P = 0.33). Hemodynamic measures on day 44 of lactation were similar (P ≥ 0.32). Milk production tended to be increased (13.5 vs. 10.2 ± 1.2 kg/d, P = 0.07) in SUP vs. CON cows. Despite similar BW through 56 d, calves from SUP cows were heavier (P = 0.04) at weaning (309.7 vs. 292.0 ± 6.0 kg). In conclusion, we accept our hypothesis that DDGS supplementation during gestation influenced mammary blood flow, milk production and calf weights. These findings implicate maternal nutrition’s leverage on both nutrient and passive immunity delivery to the calf early in life as well as potential advantages on long-term performance.

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Dubinsky, M. C., G. D’Haens, R. Atreya, B. Abraham, A. Armuzzi, F. Arguelles-Arias, J. O. Lindsay et al. "OP36 Risankizumab Versus Ustekinumab for the Achievement of Clinical Outcomes and Symptom Improvement in Patients With Moderate To Severe Crohn’s Disease: Results From the Phase 3b SEQUENCE Trial". Journal of Crohn's and Colitis 18, Supplement_1 (1 gennaio 2024): i65—i66. http://dx.doi.org/10.1093/ecco-jcc/jjad212.0036.

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Abstract Background The efficacy and safety of risankizumab (RZB) and ustekinumab (UST) in patients (pts) with moderate to severe Crohn's disease (CD) refractory to prior anti-tumour necrosis factor (TNF)α therapy were compared in the SEQUENCE head-to-head study. Previously, wk24 CD activity index (CDAI) clinical remission rates (CDAI<150) were reported for 50% of pts (first primary endpoint);1 here, the efficacy of RZB versus (vs) UST for achieving wk24 clinical remission and other symptomatic improvements in the full pt population was assessed. Methods SEQUENCE (NCT04524611) was an open-label, multicenter, randomised, efficacy assessment-blinded study in pts with moderate to severe CD (defined in Figure footnote) refractory to TNFα therapy. Pts in the primary efficacy analysis set were randomised 1:1 to receive RZB (intravenous [IV] 600mg induction at BL, week (wk)4 and wk8, then 360mg subcutaneous [SC] maintenance every 8 wks [Q8w], starting at wk12) or UST (single weight-based IV induction followed by a 90mg Q8w SC maintenance starting at wk8) up to wk48. A mandatory steroid taper began at wk2. Randomisation was stratified by BL steroid use and number of failed anti-TNFs. Prespecified non-ranked endpoints included CDAI clinical response and stool frequency (SF)/abdominal pain score (APS) clinical remission (definitions in Figure footnote). CDAI clinical remission at wk48 was a ranked secondary endpoint. CDAI clinical remission at wks 8 and 24, and changes from BL in avg daily APS, SF, and CDAI, were evaluated post-hoc. Binary endpoints were analysed using non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict. Continuous endpoints were analysed using a mixed-effect model with repeated measures. All P values are nominal, except for wk48 CDAI clinical remission (ranked secondary endpoint). Results With RZB vs UST, respectively, greater rates of CDAI clinical remission (59.6% [152/255] vs 42.6% [113/265]; P=0.0001), SF/APS clinical remission (55.7% vs 41.1%; P<0.001) and CDAI clinical response (69.8% vs 54.3%; P<0.001) were observed at wk24; similar results were observed at wk48 (Figure). Mean BL APS in the RZB and UST groups was 1.9 (both groups), SF was 5.5 and 5.6, and CDAI was 309.4 and 310.1, respectively. Least square (LS) mean changes from BL in APS, SF, and CDAI were greater with RZB vs UST and observed early as wk8 (APS: -0.9 vs -0.8; SF: -3.0 vs -2.3; P<0.001; CDAI: -136.3 vs -117.1; P<0.05) (Figure). The safety profiles of RZB and UST were consistent with published results.1 Conclusion In this head-to-head study, improvements in symptomatic outcomes in pts with CD were greater with RZB than UST over 48 wks of treatment. 1doi.org/10.1002/ueg2.12474

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Wetzler, Meir, Wendy Stock, Kathleen A. Donohue, Kouros Owzar, Dorie A. Sher, Eva E. Hoke, John M. McCarty et al. "Autologous Stem Cell Transplantation (SCT) Following Sequential Chemotherapy and Imatinib for Adults with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) — CALGB Study 10001." Blood 110, n. 11 (16 novembre 2007): 2869. http://dx.doi.org/10.1182/blood.v110.11.2869.2869.

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Abstract Imatinib, given sequentially or concomitantly with chemotherapy, now plays an important role in the frontline treatment of Ph+ ALL. Once in morphologic and cytogenetic remission, most patients are recommended to undergo allogeneic SCT. However, many patients lack an HLA-matched donor. No data have yet shown a benefit from autologous SCT in this disease. We hypothesized that sequential chemotherapy and imatinib would result in greater leukemia cell cytoreduction than previously achieved with chemotherapy alone, thereby allowing collection of large numbers of normal hematopoietic stem cells from the blood uncontaminated by residual Ph+ lymphoblasts. Thus, patients without matched sibling donors could undergo autologous SCT with a lower likelihood of relapse. Patients 15–59 years old with Ph+ ALL who had a CR or PR after one cycle of a 4 or 5-drug induction regimen were eligible. Imatinib 400 mg BID was then given for 4 weeks. Central nervous system prophylaxis was given with 3 weekly doses of high-dose systemic and intrathecal methotrexate, followed by another 4 weeks of imatinib. Patients with donors then received allogeneic SCT after 13.2 Gy fractionated total body irradiation (FTBI) and etoposide (60 mg/kg × 1). Those without donors received high-dose cytarabine (2 gm/m2 every 12 hours × 8), etoposide (10 mg/kg/day × 4), and G-CSF (10 mcg/kg) for stem cell mobilization and leukapheresis, followed by autologous SCT after 13.2 Gy FTBI, etoposide (60 mg/kg × 1) and cyclophosphamide (100 mg/kg × 1). Imatinib was held during the transplant period but resumed for maintenance until patients were RT-PCR negative for 12 months. To date, 35 patients have enrolled; 31 were in complete and 4 in partial morphologic remission following induction. Data are available on 16 patients who have completed their SCT so far. The median age at study entry was 41 years for the 8 allogeneic SCT patients (range, 27–54) and 47 years (range, 24–56) for the 8 autologous SCT patients. The time interval between achievement of remission and initiation of either an allogeneic SCT (109 days, range 99–132) or stem cell collection (119 days, range 98–158) was similar between the two groups. The median autologous CD34+ cell yield by leukapheresis was 67.1 × 106/kg (range, 34.8 – 309.8). Peripheral blood stem cells have been assayed from 5 patients by RT-PCR with a sensitivity of 1:105-106; 4 were negative for BCR-ABL. Median time to autologous engraftment was 29 days (range, 28–35). Two patients have relapsed at 334 and 475 days, and 6 are in continuous major molecular remission (≥3 log reduction from pretreatment level) at a median of 487 days (range, 197 – 923). Sequential chemotherapy and imatinib yields RT-PCR negative CD34+ leukapheresis products, allowing autologous SCT for patients without donors. Engraftment is not compromised. Post-transplant imatinib is tolerable. Molecular data on minimal residual disease following induction and pre- and post-autologous SCT will be presented. As patients continue to be accrued, longer follow-up will allow comparison of outcomes between patients who underwent autologous versus allogeneic SCT for Ph+ ALL in first CR.

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Tosta, R., R. Sala, D. Pereira, D. Kendall, F. Elliff, J. Ziemer, E. Adelsberger, J. Moreno, B. Catussi e P. Baruselli. "109 Effect of ruminal infusion with propylene glycol on the invitro embryo production of Holstein (Bos taurus) prepubertal heifers and pregnancy rate of the embryo transfer". Reproduction, Fertility and Development 32, n. 2 (2020): 181. http://dx.doi.org/10.1071/rdv32n2ab109.

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The aim of this study was to evaluate the effect of ruminal infusion with propylene glycol (PG) on the invitro embryo production (IVEP) of Holstein (Bos taurus) prepubertal heifers (7 to 8 months). For this study, 16 prepubertal heifers were distributed into two groups: Propylene Glycol Group (PGG; n=8) and Control Group (CG; n=7). Additionally, 8 pubertal heifers were used for the positive control group (PUB). All animals (n=23) underwent an ovum pickup (OPU) for follicular ablation on Day 0, followed by an FSH protocol treatment (160mg performed in 4 injections twice a day in decreasing doses, designated as D2PM, D3AM, D3PM, and D4AM). Animals from PGG received a ruminal infusion with 250mL of PG twice a day on Days 0, 1, 2, 3, and 4, using a drench. Animals from CG and PUB did not receive any additional treatment. On Day 5 all animals underwent another OPU, and oocytes were used for the IVEP (Sexing Technologies commercial laboratory). The produced embryos were transferred fresh to Holstein heifer recipients. Additionally, blood sampling was performed on D4PM (M1) and on the day of OPU (D5AM, M2) for insulin-like growth factor (IGF-1, via radioimmunoassay) and glucose (hexokinase) analysis. Data were analysed using the GLIMMIX procedure of SAS. No difference was observed between groups for number of recovered oocytes (CG: 14.28±1.9; PGG: 14.87±3.9; PUB: 10.50±2.2; P=0.24), number of viable oocytes (CG: 10.71±2.5; PGG: 10.75±2.7; PUB: 9.50±2.0; P=0.80), cleaved oocytes (CG: 7.71±1.5; PGG: 9.50±2.1; PUB: 6.25±1.4; P=0.14), cleavage rate (CG: 54.2% (7.7 out of 14.2); PGG: 64.1% (9.5 of 14.8); PUB: 59.0% (6.2 of 10.5); P=0.35) and number of blastocysts (CG: 1.71±0.5; PGG: 2.00±0.6; PUB: 3.12±1.0; P=0.71). Pubertal heifers had higher blastocyst rates compared with prepubertal heifers, regardless of PG treatment (CG: 11.9% (1.7 of 14.2); PGG: 13.5% (2 of 14.8); PUB: 29.5% (3.1 of 10.5); P=0.01). No difference was observed between groups for 30-day (CG: 41.7% (5 of 12); PGG: 46.7% (7 of 15); PUB: 42.9% (6 of 14); P=0.96) or 60-day pregnancy rates (CG: 41.7% (5 of 12); PGG: 33.3% (5 of 15); PUB: 42.9% (6 of 14); P=0.86). In addition, no difference was observed for pregnancy loss between 30 and 60 days (CG: 0.0% (0 of 12); PGG: 13.3% (2 of 15); PUB: 0.0% (0 of 14); P=0.99). Regarding metabolic blood analysis, no difference was observed for IGF-1 (ngmL−1) between groups (P=0.38), moment of sample collection (P=0.06), and interaction of group×moment (P=0.87; CG/M1: 263.36±15.2; CG/M2: 297.71±18.7; PGG/M1: 304.25±26.9; PGG/M2: 332.61±31.6; PUB/M1: 309.16±19.9; PUB/M2: 311.07±18.8). Glucose (mg dL−1) was higher (P=0.0001) for pubertal heifers (91.63±1.4) compared with the other groups (CG: 102.25±1.1; PGG: 107.71±3.5); however, no difference was observed for moment of sample collection (P=0.35) or interaction of group×moment (P=0.36). These data show that treatment with PG was not efficient to improve the IVEP of prepubertal Holstein heifers, embryos from prepubertal heifers treated with PG did not have increased pregnancy rate, and treatment did not increase IGF-1 or glucose blood levels.

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Ota, Kazuo, Takashi Akiba, Toshiaki Nakao, Masaaki Nakayama, Teruhiko Maeba, Min Sun Park, Anders Tranaeus e Noriaki Yorioka. "Peritoneal Ultrafiltration and Serum Icodextrin Concentration during Dialysis with 7.5% Icodextrin Solution in Japanese Patients". Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 23, n. 4 (luglio 2003): 356–61. http://dx.doi.org/10.1177/089686080302300408.

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♦ Objectives To assess the efficacy and safety of icodextrin in Japanese patients and to investigate the relationship between net ultrafiltration (UF) during the long dwell and plasma oligosaccharides. ♦ Design Open-labeled clinical trial involving patients on continuous ambulatory peritoneal dialysis (CAPD) receiving icodextrin during the 12-hour long dwell for 6 weeks, preceded by and followed by a 2-week baseline period and a follow-up period during which 1.36% glucose was used for the 8-hour long dwell. ♦ Setting A prospective, randomized multicenter study done in tertiary medical centers. ♦ Patients 18 stable patients on CAPD for 3 months or longer. ♦ Main Outcomes Measures Net UF (in milliliters), UF rate (in milliliters per hour), plasma oligosaccharides, serum osmolarity (in milliosmoles per liter), peritoneal absorption of icodextrin, and peritoneal clearances of icodextrin, creatinine, and urea were assessed. Adverse events, laboratory findings, and vital signs were also monitored. ♦ Results Long-dwell net UF (544.4 ± 96.7 mL at day 3, p < 0.001; 309.4 ± 60.7 mL at week 4, p < 0.001; and 391.7 ± 61.1 mL at week 6, p< 0.001) and UF rate (48.2 ± 38.8 mL/hour at day 3, p < 0.001; 26.9 ± 22.1 mL/hr at week 4, p < 0.002; and 35.3 ± 22.9 mL/hr at week 6, p = 0.0002) were significantly greater during the icodextrin period than at baseline (-25.9 ± 46.0 mL and -2.2 ± 22.1 mL/hr, respectively). Plasma oligosaccharides reached steady state within 2 weeks, remained stable during the treatment period, and returned to baseline level 2 weeks after discontinuation of icodextrin. Serum osmolarity increased during the use of icodextrin by approximately 5 mOsm/L. No statistically significant relationship was found between plasma oligosaccharides and net UF. Peritoneal absorption of icodextrin (36.3% ± 5.1% at day 3,42.2% ± 5.9% at week 4, and 38.0% ± 6.3% at week 6) and peritoneal clearance of icodextrin (10.1 mL/minute at day 3,10.1 mL/min at week 4, and 10.3 mL/min at week 6) showed no major change over time. Serum sodium and serum chloride both decreased by 5 mEq/L with icodextrin but remained within the normal range during the treatment period and returned to baseline levels immediately after discontinuation. No serious adverse events were observed during the study. ♦ Conclusion The results of this study do not support the hypothesis that an increased blood oligosaccharide level and the concomitant elevation in serum osmolarity have a negative impact on peritoneal UF. Therefore, the increase in plasma oligosaccharides appears to be too small to be of clinical significance.

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28

Ota, Kazuo, Takashi Akiba, Toshiaki Nakao, Masaaki Nakayama, Teruhiko Maeba, Min Sun Park, Anders Tranaeus e Noriaki Yorioka. "Peritoneal Ultrafiltration and Serum Icodextrin Concentration during Dialysis with 7.5% Icodextrin Solution in Japanese Patients". Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 23, n. 4 (luglio 2003): 356–61. http://dx.doi.org/10.1177/089686080302300408.

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Abstract (sommario):

♦ Objectives To assess the efficacy and safety of icodextrin in Japanese patients and to investigate the relationship between net ultrafiltration (UF) during the long dwell and plasma oligosaccharides. ♦ Design Open-labeled clinical trial involving patients on continuous ambulatory peritoneal dialysis (CAPD) receiving icodextrin during the 12-hour long dwell for 6 weeks, preceded by and followed by a 2-week baseline period and a follow-up period during which 1.36% glucose was used for the 8-hour long dwell. ♦ Setting A prospective, randomized multicenter study done in tertiary medical centers. ♦ Patients 18 stable patients on CAPD for 3 months or longer. ♦ Main Outcomes Measures Net UF (in milliliters), UF rate (in milliliters per hour), plasma oligosaccharides, serum osmolarity (in milliosmoles per liter), peritoneal absorption of icodextrin, and peritoneal clearances of icodextrin, creatinine, and urea were assessed. Adverse events, laboratory findings, and vital signs were also monitored. ♦ Results Long-dwell net UF (544.4 ± 96.7 mL at day 3, p < 0.001; 309.4 ± 60.7 mL at week 4, p < 0.001; and 391.7 ± 61.1 mL at week 6, p< 0.001) and UF rate (48.2 ± 38.8 mL/hour at day 3, p < 0.001; 26.9 ± 22.1 mL/hr at week 4, p < 0.002; and 35.3 ± 22.9 mL/hr at week 6, p = 0.0002) were significantly greater during the icodextrin period than at baseline (-25.9 ± 46.0 mL and -2.2 ± 22.1 mL/hr, respectively). Plasma oligosaccharides reached steady state within 2 weeks, remained stable during the treatment period, and returned to baseline level 2 weeks after discontinuation of icodextrin. Serum osmolarity increased during the use of icodextrin by approximately 5 mOsm/L. No statistically significant relationship was found between plasma oligosaccharides and net UF. Peritoneal absorption of icodextrin (36.3% ± 5.1% at day 3,42.2% ± 5.9% at week 4, and 38.0% ± 6.3% at week 6) and peritoneal clearance of icodextrin (10.1 mL/minute at day 3,10.1 mL/min at week 4, and 10.3 mL/min at week 6) showed no major change over time. Serum sodium and serum chloride both decreased by 5 mEq/L with icodextrin but remained within the normal range during the treatment period and returned to baseline levels immediately after discontinuation. No serious adverse events were observed during the study. ♦ Conclusion The results of this study do not support the hypothesis that an increased blood oligosaccharide level and the concomitant elevation in serum osmolarity have a negative impact on peritoneal UF. Therefore, the increase in plasma oligosaccharides appears to be too small to be of clinical significance.

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29

Kiptach, Fedir, e Nataliya Blazhko. "Natural and artificial surface water bodies owned and used by forestry enterprises of Lviv region". Visnyk of the Lviv University. Series Geography 53 (18 dicembre 2019): 177–85. http://dx.doi.org/10.30970/vgg.2019.53.10665.

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Abstract (sommario):

The areas of land with natural and artificial surface water bodies owned and used by forestry enterprises of administrative and territorial units of Lviv region are analyzed. Their classification according to the rating values of the described indicators is made, and schematic charts are drawn. The interval for determining the number of classification groups was calculated geometrically as the amplitude between the maximum and minimum values of the areas is too large. Forestry enterprises using water from natural and artificial surface water objects covering an area of 1,963.3 ha (including 1.5 % (642.1 ha) from natural streams (rivers and springs) and lakes and 3.1 % (1,321.2 ha) of artificial surface water bodies (canals, reservoirs and trenches, ponds and artificial water bodies) account for 12.9 % of the total area (42,781.6 ha) of lands of this category in the region. The largest areas of land with natural and artificial surface water bodies owned and used by forestry enterprises are recorded in Sokal (315 ha), Zhovkva (262.8), Busk (235.1), Skole (196.6), Brody (162.9), Mykolaiv (153), Drohobych (125.1), Radekhiv (120), Turka (118.7), and Kamyanka-Buzka (92.8 ha) districts, medium and moderate ones – in Staryi Sambir (68.3 ha) and Yavoriv (27 ha) districts, and the smallest ones – in Stryi (18 ha), Horodok (15), Zolochiv (15), Pustomyty (13), Sambir (7), Zhydachiv (6), Peremyshliany (4), and Mostyska (2.7 ha) districts and in Lviv (5.3 ha). The largest areas of land with natural surface water bodies owned and used by forestry enterprises are recorded in Skole (196.1 hа), Drohobych (124.6), Turka (118.7) and Staryi Sambir (65.8 hа) districts, considerable, medium and moderate ones – in Brody (29.8 hа), Zhovkva (25.5), Yavoriv (21), Zolochiv (13), Kamyanka-Buzka (11.7), Stryi (17) and Sambir (17 hа) districts, small, very small and too small – in Sokal (6.0 hа), Mostyska (2.7), Mykolaiv (2), Busk (1.9) and Zhydachiv (1 hа) districts and in Lviv (5.3 hа), in Horodok, Peremyshliany, Pustomyty and Radekhiv districts no such land has been recorded. The largest and considerable areas of land with artificial surface water bodies owned and used by forestry enterprises are recorded in Sokal (309.0 hа), Zhovkva (237.3), Busk (233.2), Mykolaiv (151), Brody (133.1), Radekhiv (120) and Kamyanka-Buzka (81.1 hа) districts, medium and moderate ones – in Horodok (15 hа), Pustomyty (13), Stryi (8), Yavoriv (6) and Zhydachiv (5 hа) districts, small, very small and too small – in Peremyshliany (4 hа), Staryi Sambir (2.5), Zolochiv (2), Skole (0.5) and Drohobych (0.5 hа) districts, in Mostyska, Sambir and Turka districts no such land has been recorded. Key words: surface water, streams, water reservoirs, forestry enterprises.

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30

Liao, Jianyun, Chaoke Bu, Lan He, Yuelin He, Jujian He, Dan Chen, Bo Lyu et al. "A Novel Protocol Improves Engraftment in Tαβ + Cell Depleted Haplo-HSCT for Patients with Thalassemia Major". Blood 142, Supplement 1 (28 novembre 2023): 4953. http://dx.doi.org/10.1182/blood-2023-185575.

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Abstract (sommario):

Background: Hematopoietic stem cell transplantation (HSCT) remains a proven curative approach for patients with thalassemia major (TM) over long-term practice. However, achieving successful engraftment and managing graft-versus-host disease (GVHD) continue to pose significant challenges. While low incidence of GVHD has been observed in Tαβ + cell-depleted HSCT (TDH) from haploidentical donors, graft failure (GF) remains a considerable concern, particularly in patients with TM. To enhance the engraftment in TM-TDH, we conducted this prospective/retrospective single-center clinical study. Method: A total of 137 patients diagnosed with TM received TDH at the BMT-center, Taixin Hospital, between March 2021 and April 2023. The median age of the patients was 7 years (ranging from 2 to 19 years), with 89 males and 48 females. The median follow-up time was 408 days (ranging from 99 to 857 days). The conditioning regimen consisted of Thymoglobulin on -day 21, followed by 3-Gy total body irradiation on -day 11. On -day 10, the patients received an infusion of donor lymphocytes (2*10 8/kg), followed by cyclophosphamide (Cy) at a dose of 50mg/kg on days -8, -7, and -2, and 25mg/kg on day -1. Additionally, blood-concentration adjusted busulfan was administered on days -6 to -4, fludarabine at a dose of 40mg/kg on days -6 to -2, and thiotepa at 10mg/kg on day -3. For GVHD prophylaxis, short-term (< 6 months) low-dose tacrolimus or sirolimus with or without mycophenolate mofetil was used. The mean infused CD34+ cells were 31.09 (ranging from 14.25 to 61.12) *10 6/kg, TCRγδ+ cells were 39.49 (ranging from 5.18 to 140.39) *10 6/kg, and NK cells were 109.18 (ranging from 27.52 to 309.41) *10 6/kg, respectively. The targeted infusion of TCRαβ+ cells was aimed at 1.5-2.0*10 5/kg. Results: Out of the 137 patients, 133 achieved successful engraftment (97.1%) with median engraftment times of 16 days (ranging from 9 to 48 days) for ANC to reach 0.5x10 9/L, 11 days (ranging from 1 to 23 days) for HB to reach 80g/L, and 10 days (ranging from 5 to 22 days) for platelets to reach 20x10 9/L, respectively. GF was observed in four patients. Among them, two patients with GF underwent salvage alternative donor second HSCT on +day 19 and +day 32, respectively, and are currently thalassemia-free. One patient received infusion of cryopreserved auto-peripheral blood stem cell and continues to live with TM. Unfortunately, four patients passed away, with one GF patient dying from suspected virus myocarditis on +day 11, one potentially due to virus hepatitis or hepatic GVHD on day +188, and the remaining two from virus bronchiolitis obliterans on +day 211 and +day 254, respectively. The overall survival (OS) and thalassemia-free survival (TFS) rates were 96.5% and 94.3%, respectively. The incidence of GF and transplant-related mortality (TRM) were 2.9% and 3.5%, respectively (Fig.). Acute GVHD of grade I-II and grade III-IV was observed in 10.53% and 9.02% of patients, respectively, while mild and moderate chronic GVHD occurred in 7(5.1%) and 1(0.7%) patient(s), respectively. The incidence of veno-occlusive disease was mild and limited. C onc lusion: The current study demonstrates the efficacy of a novel protocol in enhancing engraftment in TDH for patients with TM and with low incidence of both acute GvHD and chronic GvHD. This approach represents a significant advancement in the field of TM-TDH. Fig.1 Curve of OS, TFS, TRM and Rejection in TM-TDH

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31

Lee, Choon Kee, Shuiliang Wang, Xiaoping Huang, John Ryder, Peter Ordentlich e Bolin Liu. "Alkylator-Induced DNA Damage Response in Multiple Myeloma (MM) Cells Is Amplified by Histone Deacetylase (HDAC) Inhibition, Resulting in Significant Synergism in Cell Death". Blood 112, n. 11 (16 novembre 2008): 5157. http://dx.doi.org/10.1182/blood.v112.11.5157.5157.

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Abstract One of the main mechanisms of action of HDAC inhibitors is the transcriptional reactivation of dormant tumor-suppressor genes through acetylation of histones, thereby inducing apoptosis. Treatment with HDACI has also been shown to induce chromatin destabilization in a transcription independent way. In the current study, we sought to determine whether HDAC inhibition induces DNA damage and amplifies alkylator-induced mitotic cell death in both melphalan sensitive- and resistant-MM cell lines (RPMI8226, 8226/LR5). The IC50 values of SNDX275, a class I HDACI agent, and melphalan on the 72-hour MTT assay were 268.05 nM and 245.94 nM in the RPMI8226, and 309.91 nM and 8657.46 nM in the 8226/LR5, respectively. When combined together at clinically attainable concentrations, the combination index by the Chou-Talalay method ranged from 0.27 to 0.75 for the RPMI8226 and from 0.33 to 0.7 for the 8226/LR5, indicating a powerful synergism. For elucidation of molecular mechanisms, MM1S and RPMI8226 cell lines were investigated for apoptosis, histone acetylation, cell cycle analysis, DNA double strand break and DNA damage response serially in 48-hour culture with SNDX-275 at 500 nM and melphalan at 10 μM, alone and in combination. Cleavage of PARP was seen following treatment with each SNDX275 and melphalan, but was highest at 48 hours with the combination of both. Apoptosis was associated with cleavage of caspases of 8, 3 and 9, which was most intense on combination. Melphalan amplified SNDX275-induced acetylation of H3. In cell cycle analysis by flow cytometry, SNDX275 caused an increase in G0-G1 and a decrease in S and G2-M. Cyclin D1, E2F-1 and p53 on western blot were not affected but expression of p21 increased. Melphalan arrested the cell cycle at G2, increased expression of p53 in the RPMI8226 and of p21 in the MM1S. The combination intensified the increase in p21 in both cell lines and in p53 only in the RPMI8226. Phosphorylation of H2AX, a marker of DNA double strand break, increased in a time dependent manner following each drug, along with an increase in phosphorylation of CHK1 and CHK2, indicative of initiation of DNA damage response. The increase in γH2AX and pCHK1 & 2, however, was considerably higher on combination than each drug alone. Furthermore, morphologic assessment of dead cells by the 48 hours of culture revealed a significant increase in mitotic catastrophe on combination in the MM1S: 0% on SNDX275 alone; 10% on melphalan alone; 43.4% on combination. The current study suggests that HDAC inhibition synergizes with melphalan in MM cells and that intensification of DNA damage is one of the mechanisms. Further studies are necessary to understand the role of HDAC inhibition for induction of mitotic catastrophe.

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32

Abaza, Yasmin, Hagop M. Kantarjian, Elias J. Jabbour, Deborah A. Thomas, Tapan M. Kadia, Gautam Borthakur, Jan Burger et al. "Phase II Study of Hyper-CVAD Plus Nelarabine in Previously Untreated Adult T-Cell Acute Lymphoblastic Leukemia and T-Lymphoblastic Lymphoma". Blood 128, n. 22 (2 dicembre 2016): 177. http://dx.doi.org/10.1182/blood.v128.22.177.177.

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Abstract Background: Despite the high complete remission (CR) rates, a significant proportion of adult patients (pts) with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) treated with standard combination cytotoxic regimens will relapse underscoring the need for better therapeutic strategies. Nelarabine combined with intensive chemotherapy has been shown to be safe and effective in the frontline treatment of pediatric T-ALL. There is limited data on the use of nelarabine in the frontline setting in adult T-ALL and T-LL. Methods: This single-arm phase 2 study was designed to determine the CR rate, overall survival (OS), and safety of adding nelarabine cycles to the standard hyper-CVAD regimen in previously untreated or minimally pretreated (failure to 1 induction course or CR after ≤ 2 cycles) pts with T-ALL and T-LL. Treatment consisted of 8 induction/consolidation cycles of hyper-CVAD (odd courses 1, 3, 5, 7) alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C; even courses 2, 4, 6, 8) followed by 30 months of POMP (monthly vincristine, prednisone, 6-mercaptopurine, and MTX) maintenance therapy. Pts received nelarabine at a dose of 650 mg/m2 IV daily over 2 hrs for 5 days after the 8 cycles of induction/consolidation (Regimen 1). After 30 pts, the protocol was amended to deliver nelarabine after cycles 4 and 5 of induction/consolidation (Regimen 2). All patients also receive nelarabine instead of cycles 6 and 7 of POMP maintenance as early intensification. Late intensification consisted of MTX (100 mg/m2 IV on day 1) plus PEG-asparaginase (2000 IU/m2 IV on day 2) and hyper-CVAD given instead of cycles 18 and 19 of POMP maintenance. CNS prophylaxis consisted of 8 intrathecal treatments of MTX alternating with Ara-C. Pts with initial bulky mediastinal disease or with residual disease after induction were considered for local radiation therapy prior to the start of POMP maintenance. Results: To date, sixty-seven pts have been enrolled; 40 pts (60%) had T-ALL, 26 pts (39%) had T-LL, and 1 pt (1%) had biphenotypic disease. Median age was 37 years (range, 18-78) with 76% (N=51) of the pts males. Performance status was 2 in 9 pts (13%). Four pts (6%) had CNS involvement and 31 pts (46%) had mediastinal disease at diagnosis. Median WBC count at presentation was 8.1 x109/L (range, 0.8-309.2) and 11 pts (16%) had a WBC count > 100 x109/L. Based on immunophenotype, pts were categorized as thymic (N=24), mature (N=8), early T-cell precursor ALL (ETP; N=24), early non-ETP (N=2), and not otherwise specified (N=9). At diagnosis, 41 pts (61%) had diploid cytogenetics, 19 pts (28%) had miscellaneous karyotypic abnormalities, and 7 pts (10%) had indeterminate karyotype due to lack of testing and insufficient metaphases. Eleven pts were in CR at the time of initial presentation after having received 1-2 prior courses of therapy. Overall response rate was 96% (54/56 pts); with 52 pts (93%) achieving CR, 2 pts (4%) PR, and 2 pts (4%) no response. CR rates were similar for T-ALL and T-LL, 87% and 100%, respectively. There were no early deaths within the first month of treatment. With a median follow-up of 35 months (range, 2-98), 44 pts (66%) remain alive of which 41 pts (93%) are in remission. Ten pts (15%) received SCT after achieving CR and remain alive post-SCT; 8 remained in CR and 2 relapsed post-SCT. Nineteen pts relapsed with a median time to relapse of 6.5 months (range, 1.4-62). The site of relapses were: 10 hematologic (BM + blood), 5 extramedullary (EM), 3 BM + EM, and 1 BM + CNS. Twenty-three pts (34%) died including 17 pts with CR dying after relapse. Probability of CR duration at 3 years was 68% (95% CI 54-79 %). The 3-year probability of OS was 65% (95% CI 50-76 %) with a median OS of 82 months. There was no statistically significant difference in OS among the two different nelarabine regimens (Figure 1; p-value=0.93). Grade 3-4 nonhematological toxicity was reported in 60 (90%) pts, most frequent toxicities being infection (82%), elevated alanine aminotransferase (ALT) (16%), and thrombotic events (12%). Conclusion: Hyper-CVAD plus nelarabine is safe and effective in the frontline treatmentof adult T-ALL/T-LL and induces durable remissions. Administration of nelarabine earlier during the course of therapy does not appear to influence the outcome. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses; Portola: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding. Wierda:Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding. Jain:Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria; Infinity: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Honoraria; Incyte: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Daver:Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding. Thompson:Pharmacyclics: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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33

Astier, Clémence, Jean-Yves Scoazec, Virginie Marty, Olivia Bawa, Nicolas Signolle, Carine Ngo, Francesco Facchinetti, Antoine Hollebecque e Sophie Postel-Vinay. "Abstract 5714: Characterization of SWI/SNF complex gene mutations, protein expression and tumor immune microenvironment in cholangiocarcinoma". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 5714. http://dx.doi.org/10.1158/1538-7445.am2022-5714.

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Abstract Introduction: Cholangiocarcinoma (CCA) is a rare tumor accounting for less than 2% of all human malignancies. Mutations in the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex have been identified in approximately 20% of all human cancers and more than 40% of CCA. If the role of SWI/SNF on the tumor biology and microenvironment is being uncovered in other tumor types, it remains vastly unknown in CCA. Here, we wanted to investigate, using clinical samples, the association between SWI/SNF defects, the molecular landscape and tumor immune microenvironment in CCA. Material and Methods: Mutation profiling of 103 patients with CCA from Gustave Roussy (GR) was assessed with FoundationOne® CDx 324-gene NGS panel. Formalin-fixed paraffin-embedded tumor tissues from 11 patients with CCA were analyzed for SWI/SNF (PBRM1, ARID1A, SMARCB1 and SMARCA4) and Polycomb-DUB (BAP1) subunits, as well as lymphocytic markers (CD4 and CD8). Stainings were performed using a VENTANA BenchMark ULTRA. Absolute count of positive cells per mm2 was determined by digital image analysis with the Definiens Developer XD™ by selecting at least 5 independent tumoral zones. Pairwise comparisons were performed using the Mann-Whitney test. Results: Among the patients for whom NGS data was available, the most frequently altered genes were TP53 (27%), CDKN2A (17%), KRAS (16%), ARID1A (12%), FGFR2 (12%) and PBRM1 (10%). Subunits of the SWI/SNF complex and BAP1 were mutated in 25% and 10% of cases, respectively. Tumor samples with ARID1A mutations (n=5) showed strongly decreased ARID1A expression compared to WT tumor samples (n=2) (mean = 308.03 positive nuclei (p.n)/mm2 versus 6096.82 p.n/mm2 respectively; P<0.0001) but unchanged PBRM1, SMARCB1 and SMARCA4 expression. PBRM1 mutations (n=4) were associated with decreased expression of PBRM1 (mean = 309.6 p.n/mm2 versus 4980.2 p.n/mm2 in WT samples; P<0.0001) and ARID1A (mean=1196.15 p.n/mm2; P<0.001), but unchanged SMARCB1 and SMARCA4 expression. BAP1 mutations (n=3) were also associated with decreased BAP1 and ARID1A expression (ARID1A mean = 457.70 p.n/mm2; P<0.001). ARID1A and PBRM1-altered tumor samples showed a poorly infiltrated microenvironment, with decreased CD4+ T cell (159.48 positive cells (p.c)/mm2 and 188.66 p.c/mm2 respectively versus 1126.52 p.c/mm2 for WT; P<0.0001) and CD8+ T cell density (72.38 and 76.54 p.c/mm2 versus 548.58 p.c/mm2 for WT; P<0.0001). Conclusion: Mutations in the ARID1A and PBRM1 subunits of the SWI/SNF complex are associated with a loss of protein expression. In contrast to what reported in other tumor types, ARID1A and PBRM1 mutations correlated with poorly lymphocytic TIME in CCA. Decreased PBRM1 expression is further associated with decreased ARID1A expression. Independent revalidation and further study in larger tumor series are warranted. Citation Format: Clémence Astier, Jean-Yves Scoazec, Virginie Marty, Olivia Bawa, Nicolas Signolle, Carine Ngo, Francesco Facchinetti, Antoine Hollebecque, Sophie Postel-Vinay. Characterization of SWI/SNF complex gene mutations, protein expression and tumor immune microenvironment in cholangiocarcinoma [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 5714.

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Athiyarath, Rekha, Kalaiselvi Sakthivel, Vinod J. Abraham, Daisy Singh, Alok Srivastava e Eunice Sindhuvi Edison. "Erythroid Growth Differentiation Factor 15 and Ferroportin Expression During Gestational Iron Deficiency Anemia". Blood 118, n. 21 (18 novembre 2011): 5286. http://dx.doi.org/10.1182/blood.v118.21.5286.5286.

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Abstract Abstract 5286 Iron homeostasis during pregnancy is modulated to meet the increased iron needs but how this is achieved is not very clear. Growth Differentiation Factor (GDF15) produced by the expanded erythroid compartment in β thalassemia has been shown to increase iron absorption by suppressing hepcidin. GDF15 is also highly expressed in the placenta and increasing levels of GDF15 are seen with advancing gestational age of pregnancy. But the role of GDF15 in iron homeostasis in pregnancy has not been elucidated till date. Ferroportin (FPN) is the only known protein involved in iron export and it is the target of hepcidin, the central regulator of iron homeostasis. In this study we analyzed the expression of GDF15 and FPN in pregnant women with iron deficiency anemia. Fourteen pregnant women with proven iron deficiency anemia (IDAP) [Hb<11g/dL and Ferritin <12ng/ul] and thirteen healthy subjects as controls (NC) were enrolled as part of an ongoing study. Serum GDF15 and hepcidin levels were measured by ELISA kits from R&D systems and Bachem, UK respectively. Reticulocytes were isolated and total RNA was purified using Trizol. GDF15 and FPN transcripts were quantified using Taqman Gene expression assays using GAPDH as an internal control. Gene expression values were calculated on the basis of the 2-ΔΔCt method. The mean age of the pregnant women was 22.5±2.5 years. The median ferritin in IDAP was 1.4 and ranged from 0.2 to 8.3 ng/ml. The hepcidin levels were very low [<2ng/ml] in IDAP. Serum GDF15 levels in IDAP was significantly higher as compared to controls [IDAP-3333.71±409 pg/ml vs. NC-309.7±127.0 pg/ml; p=0.000]. Reticulocyte GDF15 mRNA expression was significantly lower [IDAP-25.09 (1.28–239.8) vs. NC-910.4 (0.28–1962); p=0.004] and FPN expression was significantly higher in pregnancy [IDAP-209.8 (48.33–1201) vs. NC-77.96(17.21–281.3); p=0.001] than in the controls. GDF15 mRNA as well as serum GDF15 levels significantly correlated with FPN expression in IDAP [RNA r=0.895; p=0.000; Protein r=0.555, p=0.049] Eight patients were followed up after 8 weeks of supplementation and there was no significant change in the serum GDF15 concentration (3235±468.26pg/ml; p=1.000). However their serum ferritin and hepcidin levels were significantly higher [Ferritin-11.60 (9.80–21.30), p=0.0021; Hepcidin-17.86(0.29–38.50), p=0.015]. There was no significant correlation between GDF15 protein levels and hepcidin (r=0.429, p=0.354). Molecular mechanisms of iron homeostasis in pregnancy are poorly understood. IDAP had very low hepcidin levels which normalized after iron stores were replenished. Elevated GDF15 protein levels in IDAP inspite of low reticulocyte expression indicate that erythroid contribution is minimal and placenta is the main source of GDF15. The significant correlation between GDF15 (mRNA and protein) with FPN expression and absence of correlation with hepcidin levels indicate a possible role for GDF15 in iron homeostasis in pregnancy. These findings has to be validated and the role of GDF15 in modulating FPN and there by iron absorption has to be further elucidated. Disclosures: No relevant conflicts of interest to declare.

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Gai, Y., Q. Deng, R. Pan, X. Chen e M. Deng. "First Report of Cylindrocladium Black Rot of Peanut Caused by Cylindrocladium parasiticum (Teleomorph Calonectria ilicicola) in Jiangxi Province, China". Plant Disease 96, n. 4 (aprile 2012): 586. http://dx.doi.org/10.1094/pdis-11-11-1010.

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In July 2010, a serious disease of peanut (Arachis hypogaea) resembling Cylindrocladium black rot (CBR) was found in Longnan County, Jiangxi Province, China. Symptoms included chlorotic, yellowish and blighted leaves, and wilting of the plants. Taproots and hypocotyls were blackened and rotted. Clusters of reddish orange spherical fruiting bodies appeared in the lesions present on basal stems, pegs, pods, and roots of peanut. Disease incidence reached as much as 50% in some patches of the field. Plants with symptoms were sampled from fields. Microscopic examination revealed that the reddish orange, spherical fruiting bodies were the perithecia and measured 461.6 (337.5 to 609.4) × 395.5 (309.4 to 496.9) μm. With gentle pressure, asci and ascospores were exuded from perithecia. The asci were hyaline, thin walled, and long stalked. Ascospores were hyaline, falcate with one septum, and measured 43.5 (27.3 to 54.5) × 5.6 (4.1 to 6.8) μm with a length/width (L/W) ratio of 7.8 ± 1.3. A fungus with white-to-pale buff border mycelia and yellowish brown pigment was consistently isolated from the edge of basal stem lesions on potato dextrose agar at 25°C. Mycelia grew at temperatures ranging from 8 to 32°C and the optimum was 25 to 26°C. To determine the species, single-conidial isolates of the fungus were cultured on carnation leaf agar for 7 days at 25°C and 12 h of light/dark conditions. Conidia were hyaline, cylindrical with one to three septa (mostly three septa), and measured 49.3 (27.3 to 70.9) × 5.9 (4.1 to 6.8) μm with L/W ratio of 8.4 ± 1.6. Vesicles were globose and measured 5.5 to 10.9 μm in diameter. The fungus was identified as Cylindrocladium parasiticum (teleomorph Calonectria ilicicola) (1,2). A PCR assay was conducted on one representative isolate (JXLN32) by analyzing multilocus sequences of the TUB2 (coding β-tubulin protein), ACT (coding actin), and CaM gene (coding calmodulin protein) and were amplified and sequenced using the primers reported by Crous et al. (3). Sequences of the studied DNA regions were submitted to GenBank (Accession Nos. TUB2: JF429649; ACT: JQ070809; and CaM: JQ070808). BLAST searches with the existing sequences in GenBank showed that there was 99 to 100% identity with the existing sequences of C. ilicicola (GenBank Accession Nos. TUB2: AY725643; ACT: GQ280446; and CaM: GQ267402). To complete Koch's postulates, inoculum was prepared by mixing the microsclerotia (MS) suspension of the isolate (JXLN32) with soil at a proportion of 10 MS per g of soil. Ten replicate plastic pots containing five peanut seeds (cv. Yueyou 7) each were planted and placed in a glasshouse at 25 ± 2°C. The same number of peanut seeds was used as an uninoculated control. Typical basal stem and roots rot symptoms of CBR were observed in 2 months and C. parasiticum was reisolated from these inoculated diseased plants. No symptoms were detected on the control plants. To our knowledge, this is the first finding of Cylindrocladium black rot in Jiangxi Province, which is the main peanut-producing area in China. The disease has been previously reported in Guangdong Province in southern China but is not known elsewhere (4). Because of its ability to spread through seed and soil and its destructive potential, this pathogen may pose a serious threat to peanut production in China. References: (1) D. K. Bell and E. K. Sobers. Phytopathology 56:1361, 1966. (2) P. W. Crous et al. Mycol. Res. 97:889, 1993. (3) P. W. Crous et al. Stud. Mycol. 50:415, 2004. (4) R. Pan et al. Plant Pathol. 58:1176, 2009.

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Faustini, F., H. Idborg, E. Svenungsson, S. Poetzsch, S. Okitsu, A. Larsson e I. Gunnarsson. "POS0184 URINE-GALECTINE 3 BINDING PROTEIN (U-GAL3BP) IS A SENSITIVE MARKER OF KIDNEY INFLAMMATION AND RESPONSE TO TREATMENT IN LUPUS". Annals of the Rheumatic Diseases 80, Suppl 1 (19 maggio 2021): 305.2–306. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3477.

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Background:Lupus nephritis (LN) represents a serious manifestation of systemic lupus erythematosus (SLE) which requires timely diagnosis, treatment and monitoring. Kidney biopsy is the gold standard of diagnosis and is instrumental to treatment decisions, however it is not generally performed for monitoring and evaluation of response to treatment. To such purposes, accessible biomarkers, for instance urinary, might be highly advantageous.Objectives:To evaluate urine-Galectin 3 binding protein (uGAL3BP) as a novel biomarker in biopsy-proven active lupus nephritis (A-LN) in comparison to active non-renal SLE (ANR-SLE), inactive SLE (I-SLE), and in population-based controls (HC). Furthermore, we compared uGAL3BP with known markers of renal pathology including neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), kidney injury molecule 1 (KIM-1), and galectin 3 (GAL3).Methods:Urine samples from A-LN (n=86), ANR-SLE (n=63), I-SLE (n=73) and HC (n=48) were included. uGAL3BP was measured using a commercial ELISA kit and values, adjusted for u-creatinine levels, were expressed as ng/mmol. Other markers analyzed according to clinical routine at the Department of Clinical Chemistry at Uppsala University Hospital were also adjusted for u-creatinine levels. Renal biopsies were graded according to the ISN/RPS classification(1) and evaluated for activity and chronicity index. Ten A-LN patients were evaluated before and after induction treatment.Results:In the A-LN group, median (IQR) levels of u-GAL3BP were 15.8 (6.8-24.6) ng/mmol, while in ANR-SLE, I-SLE, HC were significantly lower 4.4 (2.0-9.0), 2.8 (1.7-4.7), 2.0 (0.9-4.8) respectively (Kruskal-Wallis p<0.0001). Similarly, u-NGAL was found at higher levels in A-LN patients, 3.3 (2.0-5.7) μg/mmol, with respect to the ANR-SLE 2.0 (0.9-4.5), I-SLE 1.6 (0.8-3.2), and HC 2.4 (1.2-5.3), (p=0.008). The highest levels of OPN were found in the group of I-SLE (190.6 (85.1-299.9) μg/mmol, compared to A-LN 72.98 (37.6-118.1), ANR-SLE 92.3 (58.5-129.7) and HC 76.5 (58.2-120.3), (p<0.0001). KIM-1 levels differed among groups with higher levels in the A-LN group (188.9 (113.7-309.7) ng/mmol), in comparison to ANR-SLE 131.4 (92.2-186.1), I-SLE 123.8 (70.3-200.2), and HC 78.2 (68.8-115.1), (p<0.0001). GAL3 showed comparable levels across groups.When exploring the biomarkers across histologic subgroups of LN, u-GAL3BP could discriminate between proliferative and mesangial forms (17.7(9.6-32.5) vs 6.7(5.1-16.1) ng/mmol, p=0.027), while it did not discriminate against membranous LN. U-NGAL was higher in proliferative LN 3.7(2.4-5.8) µg/mmol with respect to membranous 2.4 (1.1-3.8) (p=0.01), while mesangial LN showed comparable levels. OPN, KIM-1 and GAL3 were comparable across groups.In the ten patients with available samples after induction therapy (mycophenolate mofetil (MMF) in 4, rituximab (RTX) in one, cyclophosphamide in 5 (one combined with MMF and one with RTX), u-GAL3BP showed a significant decrease of median levels from 218.8 to 41.5 ng/mmol (Wilcoxon p=0.03). u-GAL3BP associated with renal activity in class III/IV LN (R=0.42, p=0.004).Conclusion:Among the tested markers, high uGal3BP adjusted for creatinine was found to be a promising marker of renal involvement in SLE patients and associated with renal activity in patients with proliferative forms (class III/IV) of LN. A decrease was further seen following therapy, suggesting that u GAL3-BP could be used to monitor renal activity.References:[1]Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241-50.[2]Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121-31.Disclosure of Interests:Francesca Faustini Speakers bureau: I have received speaking fees, last time more than two years ago, Helena Idborg: None declared, Elisabet Svenungsson: None declared, Sven Poetzsch Employee of: Merck Serono, Shinji Okitsu Employee of: Merck Serono, Anders Larsson: None declared, Iva Gunnarsson: None declared

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Martin, Olufunke Y., Rasa Borhan, Aliya U. Zaidi, Deepika S. Darbari, Patrick C. Hines e Andrew D. Campbell. "The Role of Red Blood Cell Vascular Adhesion Biomarkers in Understanding Sickle Cell Disease Associated Chronic Pain". Blood 142, Supplement 1 (28 novembre 2023): 1137. http://dx.doi.org/10.1182/blood-2023-190689.

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Background: Sickle cell disease (SCD) is characterized by repeated episodes of vaso-occlusion (VOC) that can lead to a host of complications including acute and chronic pain. Prior studies have demonstrated acute changes in RBC health biomarker flow adhesion of whole blood to VCAM-1 (FA-WB-VCAM) and P-Selectin (FA-WB-Psel). Adhesive indices are significantly elevated during a proadhesive VOC. We examined whether individuals with SCD with and without chronic pain will exhibit differences in RBC health biomarkers between steady state and acute VOC pain. Methods: This was a 6-month, longitudinal, case-control cohort pilot study of FA-WB-VCAM and FA-WB-Psel indices collected in youth with SCD at Children's National Hospital in Washington, DC. SCD chronic pain patients (as defined per AAPT diagnostic criteria) were classified as “cases,” and SCD patients without chronic pain were “controls.” Controls were age (± 2 years), and genotype matched to cases. Both FA-WB-VCAM and FA-WB-Psel were collected at baseline and during acute VOC with assays performed by Functional Fluidics Inc. in Detroit, MI. Patient-reported outcomes were captured as pain scores and through completion of the centralized pain index survey to assess for centralized pain features of chronic pain. Statistical analysis included descriptive statistics and categorical analysis by t-test (GraphPad, v9, 2021). P value <0.05 was statistically significant. Results: We identified 10 pediatric patients, 4 with chronic pain “cases” and 6 without chronic pain “controls” with FA-WB-VCAM and FA-WB-Psel assays performed at baseline and during an acute VOC episode. The average age of the cohort was 17.5 years with 70% females (n=7) and 30% males (n=3). Eighty percent (n=8) of the cohort were HgbSS and 20% (n=2) HgbSC genotype. Twenty-five percent (n=1) of the chronic pain patients were on disease-modifying therapy (DMT) with hydroxyurea (HU) at study initiation [all patients had been offered ≥ 1 FDA-approved DMT and previously discontinued DMT use due to intolerable side effects or personal choice], whereas 83% (n=5) of the control patients were on DMT with 50% (n=3) being on dual DMT therapy (HU + voxelotor or HU + crizanlizumab). The chronic pain cohort had a higher average number of ED visits/year than the control cohort (14 ± 7 vs. 4 ± 2 ED visits/year, p=0.11). The average baseline pain score for the chronic pain cohort was 7.25 versus 1.16 in the control cohort (p= 0.069). Centralized pain index survey responses were similar between both groups [median (IQR): 11.5 (7.25 - 15) vs. 9 (7-16), p=0.72)]. Figures 1A and 1B show a comparison of FA-WB-VCAM and FA-WB-Psel at baseline versus acute VOC for each chronic pain (P) “case” with their respective “controls (C).” The average baseline FA-WB-VCAM (P: 555.8 ± 605.3 vs. C: 435.3 ± 217 cells/mm2, p=0.905) and the average baseline FA-WB-PSel (P: 83.5 ± 64.5 vs. C: 57.33 ± 45.4, p=0.833) were similar between the cohort of chronic pain versus control subjects. Acute VOC FA-WB-VCAM (P: 722 ± 366.6 vs. C: 553.5 ± 309.6 cells/mm2, p=0.667) and FA-WB-PSel (P: 116.3 ± 66.6 vs. C: 98.7 ±96 cells/mm2, p=0.777) adhesion values were similar between cases and controls although adhesion values trended higher than baseline for both groups. All the cases had acute VOC adhesion indices above clinically established critical thresholds [Figure 1A and 1B]. The FA-WB-VCAM adhesion values increased from baseline in 75% (n=3) of the chronic pain patients (#3, #14, #16) during acute VOC. All the chronic pain patients (#3, #7, #14, #16) showed increased FA-WB-Psel adhesion from baseline during acute VOC [Figure 1A and 1B]. Fifty percent (n=3) of the control patients (#10, #12, #28) exhibited increased FA-WB-VCAM adhesion during acute VOC, and 60% (n=4) of the controls (#4, #5, #10, #28) exhibited increased FA-WB-Psel adhesion during acute VOC. Conclusions: We showed changes in RBC health vascular adhesion markers from baseline to acute VOC in patients with and without chronic pain. FA-WB-VCAM and FA-WB-Psel trended higher in the chronic pain cohort and all acute VOC values for the chronic pain cohort were above established critical thresholds. FA-WB-Psel adhesion increased from baseline with the onset of acute VOC episodes for most of the chronic pain cohort. Mechanistically, there is a need to understand differences in acute versus chronic pain, which may provide further insight into pro-adhesive versus non-vascular pain mechanisms.

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Can, Ömer Faruk, e Muhammed Alabbas. "Numerical Investigation of Cross-Flow Water Cooling Towers". Journal of Thermal Science and Engineering Applications, 19 aprile 2023, 1–12. http://dx.doi.org/10.1115/1.4062356.

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Abstract In this study, the performance of the forced cross-flow water cooling tower was investigated with the ANSYS CFX program. The geometric dimensions and boundary condition values of the cooling towers in the study were taken to be close to the real values. The effect of air velocity, water droplet diameter and inlet water temperature change according to the temperature of the water coming out of the 2m wide, 2m long and 3m high cooling tower was investigated. For the cooling tower, data values suitable for design are selected. The study used air velocities of 2 m/s, 4 m/s, 6 m/s, and 8 m/s, water droplet diameters of 0.01, 0.008, 0.005, and 0.001 m, and inlet water temperatures of 306.15, 309.15, 311.15, and 313.15 K). In addition, the relationship between cooling range and air velocity for mass flow values of different process waters was also investigated. As a result of the study, it was observed that the process leaving water temperatures decreased with the increase of air velocities, but the cooling range increased. A similar situation was observed with the reduction of water droplet diameters. However, it has been observed that when the inlet water temperatures are increased, the outlet process water temperatures and the cooling interval also increase.

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Kaushik, Atul, Aditya Kapoor, Surendra Kumar Agarwal, Shantanu Pande, Shiridhar Kashyap, Archana Sinha, Roopali Khanna et al. "Effect of statin on perioperative myocardial injury in isolated valve surgery". Asian Cardiovascular and Thoracic Annals, 16 novembre 2020, 021849232097451. http://dx.doi.org/10.1177/0218492320974514.

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Background Statins have known pleiotropic effects that confer protection from ischemia-reperfusion injury. Because cardiopulmonary bypass is a potentially reversible ischemia-reperfusion sequence, we aimed to assess whether statin loading could help to limit myocardial injury in patients undergoing isolated heart valve replacement under cardiopulmonary bypass. Methods One hundred patients with rheumatic valvular heart disease undergoing valve replacement received either a loading dose of rosuvastatin (40 mg initiated 7 days before surgery; loaded group) or no statins (non-loaded group). Cardiac troponin I, creatine kinase MB, and brain natriuretic peptide were measured at 8, 24, and 48 hours postoperatively. The primary endpoint was the extent of perioperative myocardial injury measured by the area under the curve for each biomarker. Results Despite similar baseline levels, all biomarkers at 8, 24, and 48 h were significantly lower in the loaded group. The area under the curve of each biomarker was significantly lower in the loaded group than in the non-loaded group (troponin I: 31.43 vs. 77.21 ng·h·mL−1, creatine kinase MB 309.31 vs. 429.12 ng·h·mL−1, brain natriuretic peptide 5176.11 vs. 16119.31 pg·h·mL−1, all p < 0.001). The mean changes from baseline to peak levels were also significantly lower in the loaded group. The loaded group had a shorter hospital stay but no significant difference was seen in ventilator time, inotrope time, aortic crossclamp time, cardiopulmonary bypass time, or intensive care unit stay. Conclusion In patients undergoing valve replacement, high-dose statin loading before surgery had a favorable impact on the release kinetics of various cardiac biomarkers.

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Adam de Beaumais, T., S. Lorrain, N. Mamhoudi, M. Simonin, C. Martinez Vinson, Y. Medard, A. Petit e E. Jacqz‐Aigrain. "Key factors associated with 6TGN and 6MMPN concentrations in children treated by thiopurine for acute leukemia and inflammatory bowel disease". British Journal of Clinical Pharmacology, 24 agosto 2023. http://dx.doi.org/10.1111/bcp.15894.

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AimAzathioprine (AZA) and 6‐mercaptopurine (6MP) are prescribed in acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6‐thioguanine (6TGN) and 6‐methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation.MethodsThe first paediatric TDM samples received during year 2021 were analyzed, whatever indication and thiopurine drug. Target concentration ranges were 200‐500, <6000 pmol/8*108 RBC for 6TGN and 6MMPN.ResultsChildren (n=492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (p<0.0001). ALL received 6MP (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti‐inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [IQR: 142.5; 309.6] and 1144.6 [IQR: 419.4; 3574.3] pmol/8*108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine amino‐transaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant.ConclusionTDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow‐up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome.

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Reis, Adriana Cotta Cardoso, Hélia Maria Marques de Moura, Breno Mello Silva, Alaíde Braga de Oliveira e Geraldo Célio Brandão. "Antiviral activity and chemical characterization of Cissus erosa (Vitaceae) ethanol extracts". Rodriguésia 71 (2020). http://dx.doi.org/10.1590/2175-7860202071052.

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Abstract Cissus erosa (Vitaceae), popularly known in Brazil as Cipó-fogo, is a medicinal plant used in the treatment of warts and external ulcers. The present study aimed to evaluate the activity of stems and leaves ethanol extracts of C. erosa against the Dengue and Zika virus by the MTT colorimetric method and to carry on the phytochemical characterization of active extracts by high performance liquid chromatography coupled to mass spectrometry (UPLC-MS). Only the leaves ethanol extract showed anti-Dengue virus activity EC50 18.2 µg/ml (SI > 27.5) and low cytotoxicity for LLCMK2 cells (CC50 > 500 mg/ml). Both extracts (stems and leaves) showed anti-Zika virus activity with EC50 of 45.8 mg/ml and 82.8 mg/ml, respectively. These extracts presented CC50 of 309.2 µg/ml (leaves) and 387.6 µg/ml (stems) to Vero cells. Analysis by CCD and HPLC-DAD detected the presence of triterpenes, steroids, flavonoids and tannins. UPLC-MS analyses of these extracts, allowed the identification of the majority of flavonoids present known as vitexin, isovitexin, orientin, isoorientin and two flavones derivatives, methoxyluteolin-6(8)-C-hexosyl and luteolin-7,4’-di-O-glycosylflavone. The results of the phytochemical studies here described suggest that flavonoids and terpenoids are the substances that contribute to the antiviral activity of the ethanol extracts within this species.

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Gouado, Inocent, Adelaide Demasse Mawamba, Ruphine Solange Meyimgo Ouambo, Issa Touridomon Some e Tchouanguep Mbiapo Félicité. "Provitamin A Carotenoïd Content of Dried Fermented Cassava Flour: The Effect of Palm Oil Addition During Processing". International Journal of Food Engineering 4, n. 4 (17 giugno 2008). http://dx.doi.org/10.2202/1556-3758.1167.

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Vitamin A deficiency is a public health problem in developing countries. Cassava is a major staple food for most Africans. Most often, it is processed into dried fermented cassava (commonly called gari) to limit post harvest losses. The white or yellow type of gari can be obtained without or with the addition of red palm oil respectively. However in most African countries, the process is still traditional and the quantity of red palm oil varies from one producer to another. This study aimed to standardize the processing of cassava into gari and determine the carotenoïd content of dried fermented cassava roots cooked with different quantities of red palm oil. Grated samples from 210g of cassava tubers were fermented and fried at 120°C ± 5 for 10 minutes with (yellow gari) and without whole red palm oil (white gari). The quantities of red palm oil used were 2, 3, 4, 5 and 8 ml. The alpha and beta carotene contents of gari (experimental samples) and of yellow gari bought from a local market (commercial samples) were evaluated by HPLC. The organoleptic properties of the gari were assessed using 18 volunteers aged between 20 to 30 years accustomed to gari. From the results, the provitamin A carotenoïd content of gari obtained increased significantly (P< 0.05) with the quantity of oil used and were higher than that of the commercial samples. The alpha carotene ranged from 352.6 ± 5.5 µg/g to 1572.5 ± 15.9 µg/g (for 2 and 8 ml of palm oil respectively) and the beta carotene from 309.7 ± 24.8 µg/g to 1624.3 ± 45.8 µg/g (for 2 and 8 ml of oil respectively). These results suggest that the addition of red palm oil (4 ml/210 g of cassava) during the processing of cassava into yellow gari resulted in good retention of carotenoïd. Gari is a dry product, thus if it is well conserved after processing in dark airtight packages, it could be used as a good tool to reduce vitamin A deficiency.

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Wu, Songsong, Bin Lin, Xi Li, Shengkai Chen, Haonan Zhang, Zhanglin Wu, Shenghui Tang, Yuehua Yang e Biru Liang. "Single-stage debridement via autogenous iliac bone graft through the OLIF corridor and lateral fixation in treating spontaneous single-level lumbar pyogenic spondylodiscitis". BMC Musculoskeletal Disorders 22, n. 1 (15 novembre 2021). http://dx.doi.org/10.1186/s12891-021-04815-3.

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Abstract Background The aim of the present study was to investigate the efficacy and safety of mini-open oblique debridement and lumbar interbody fusion combined with lateral screw fixation for treating single-level pyogenic spondylodiscitis. Methods Twelve patients with single-level lumbar pyogenic spondylodiscitis underwent OLIF combined with lateral screw fixation were analyzed. Patients underwent follow-up for 12 to 24 months. The clinical characteristics, etiological examinations, operative time, intraoperative blood loss, Oswestry Disability Index (ODI), visual analog scale score (VAS), postoperative complications, and the bony fusion rate were recorded. Results The mean follow-up period of time was 14.8 months. The average operative time and intra-operative blood loss were 129.0 ± 19.76 min and 309.2 ± 92.96 mL, respectively. No severe intra-operative complications were observed during surgery, except in 1 case that develops abdominal pain and distension after surgery, 2 cases that develop left-sided transient thigh pain/numbness and 8 cases that complains of donor site (iliac crest) pain. All of these symptoms disappeared 8 weeks after surgery. Tissue sample cultures were obtained from all patients intraoperatively and four (33.3%) were positive, including 2 with Staphylococcus aureus, 1 with Staphylococcus epidermidis, and 1 with Escherichia coli. During an average of 22.5 ± 2.1 days (range, 14–29 days) after surgery, WBC, CPR, and ESR levels in all patients had returned to normal. All patients were pain free with no recurring infection. Solid bony fusions were observed in all cases within 6 months, including 10 with I grade fusion, 2 with II grade fusion according to the classification suggested by Burkus et al. No fixation failure was observed during follow up and solid bony fusions were observed in all 12 patients at finally follow-up. A significant postoperative increase was also observed in the mean segmental height and lordosis (P < 0.05), followed by a slight decrease of segmental height and lordosis at final follow-up. At the final follow up, the mean VAS (1.5 ± 0.6) and ODI (18.9 ± 7.6) were significantly lower than VAS (8.4 ± 2.7) and ODI (71.2 ± 16.5) before surgery (P < 0.01). Conclusion Single-stage debridement with autogenous iliac bone graft through the OLIF corridor and lateral fixation was a feasible surgical approach in our consecutive 12 cases of pyogenic spondylitis.

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Leicher, Niklas, Lorenzo Monaco, Biagio Giaccio, Sebastien Nomade, Alison Pereira, Giorgio Mannella, Sabine Wulf et al. "Central Mediterranean tephrochronology for the time interval 250–315 ka derived from the Fucino sediment succession". Boreas, 17 ottobre 2023. http://dx.doi.org/10.1111/bor.12637.

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In the lacustrine succession F4‐F5 of the Fucino Basin, central Italy, 20 visible tephra layers were identified in the time interval 250–315 ka (Marine Isotope Stages 8–9). Fifteen of them contained suitable material to explore their volcanic sources. Among these tephra some well‐known eruptions and eruptive sequences of the Roman and Roccamonfina volcanoes were identified, such as the Tufo Giallo di Sacrofano and the Lower White Trachytic Tuff, respectively. Furthermore, the sediment succession documents a more complex eruptive history of the Sabatini, Vulsini, Colli Albani and Roccamonfina volcanic complexes during the investigated period, as inferred from previously undescribed tephra deposits. Single‐crystal‐fusion 40Ar/39Ar dating of two of the inspected tephra layers combined with two already published tephra ages provided the basis for a Bayesian age‐depth model. The modelled tephra ages allow chronological constraining of so‐far undefined eruptions of the Sabatini (272.5±4.7, 281.8±4.7, 308.5±2.8, 312.8±2.1 ka), the Vulsini (311.7±2.3, 311.9±2.3 ka) and the Colli Albani (301.0±3.6 ka) volcanic districts. Two tephra layers of an undefined volcanic source from the Roman volcanoes have modelled ages of 309.5±2.7 and 310.5±2.6 ka. The new 40Ar/39Ar and modelled ages were further used for a reassessment of the timing of already known and dated eruptive units, such as the Tufo Giallo di Sacrofano (40Ar/39Ar: 289.3±4.8 ka). Tephra tentatively correlated with the Valle Santa Maria, Case Pisello and the White Trachytic Tuff Unit E3 or Unit F offer modelled ages for these eruptions of 296.6±3.9, 301.8±3.5 and 303.6±3.4 ka, respectively. The results complete the tephrostratigraphical investigations of the c. 425 ka old F4‐F5 record, extend the Mediterranean tephrostratigraphical framework and provide a significant contribution for improving knowledge on Italian volcanic explosive activity.

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Li, Caifeng, Qian Ren, Xin Li, Hongqiu Han, Min Peng, Keliang Xie, Zhiqiang Wang e Guolin Wang. "Effect of sigh in lateral position on postoperative atelectasis in adults assessed by lung ultrasound: a randomized, controlled trial". BMC Anesthesiology 22, n. 1 (11 luglio 2022). http://dx.doi.org/10.1186/s12871-022-01748-9.

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Abstract Background Postoperative atelectasis occurs in 90% of patients receiving general anesthesia. Recruitment maneuvers (RMs) are not always effective and frequently associated with barotrauma and hemodynamic instability. It is reported that many natural physiological behaviors interrupted under general anesthesia could prevent atelectasis and restore lung aeration. This study aimed to find out whether a combined physiological recruitment maneuver (CPRM), sigh in lateral position, could reduce postoperative atelectasis using lung ultrasound (LUS). Methods We conducted a prospective, randomized, controlled trial in adults with open abdominal surgery under general anesthesia lasting for 2 h or longer. Subjects were randomly allocated to either control group (C-group) or CPRM-group and received volume-controlled ventilation with the same ventilator settings. Patients in CPRM group was ventilated in sequential lateral position, with the addition of periodic sighs to recruit the lung. LUS scores, dynamic compliance (Cdyn), the partial pressure of arterial oxygen (PaO2) and fraction of inspired oxygen (FiO2) ratio (PaO2/FiO2), and other explanatory variables were acquired from each patient before and after recruitment. Results Seventy patients were included in the analysis. Before recruitment, there was no significant difference in LUS scores, Cdyn and PaO2/FiO2 between CPRM-group and C-group. After recruitment, LUS scores in CPRM-group decreased significantly compared with C-group (6.00 [5.00, 7.00] vs. 8.00 [7.00, 9.00], p = 4.463e-11 < 0.05), while PaO2/FiO2 and Cdyn in CPRM-group increased significantly compared with C-group respectively (377.92 (93.73) vs. 309.19 (92.98), p = 0.008 < 0.05, and 52.00 [47.00, 60.00] vs. 47.70 [41.00, 59.50], p = 6.325e-07 < 0.05). No hemodynamic instability, detectable barotrauma or position-related complications were encountered. Conclusions Sigh in lateral position can effectively reduce postoperative atelectasis even without causing severe side effects. Further large-scale studies are necessary to evaluate it’s long-term effects on pulmonary complications and hospital length of stay. Trial registration ChiCTR1900024379. Registered 8 July 2019,

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Dudenbostel, Tanja, Maria C. Acelajado, Peng Li, Suzanne Oparil e David A. Calhoun. "Abstract 204: Non-dipper Pattern Is Associated With Urinary Metanephrines In Patients With Refractory Hypertension". Hypertension 64, suppl_1 (settembre 2014). http://dx.doi.org/10.1161/hyp.64.suppl_1.204.

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Refractory hypertension (HTN) is an extreme phenotype of treatment-resistant HTN and is defined as blood pressure (BP) ≥140/90 mm Hg on ≥5 antihypertensive drug classes including a diuretic and mineralocorticoid antagonist. Observational data indicate that African Americans, males, body mass index, kidney function, and diabetes are associated with refractory HTN. Available BP data of refractory HTN are based on clinic or in-home evaluations. Less is known about ambulatory blood pressure (ABP) levels, circadian patterns and pathophysiologic mechanisms. Aim: Prospective study of ABP levels, nocturnal BP fall, and urinary (U-) 24-hour metanephrines as index of sympathetic activity. Methods: Over a 2 year period, 44 subjects were prospectively enrolled (15 subjects with refractory HTN matched with 29 controlled resistant hypertensive subjects who served as comparator group). All subjects underwent 24-ABP monitoring (ABPM) and U-24-hour metanephrines testing. Results: Subjects with refractory HTN were on more antihypertensive drugs (6±1 vs 4.1±1.1, p≤ 0.05) and had significantly higher 24-hour systolic BP(SBP) (174±20.2 vs 139.8±16.3 mm Hg, p=0.0017), higher 24-hour diastolic BP (DBP) (94.7±19.8 vs 75.7±11.8 mm Hg, p=0.006), higher daytime SBP (178.1±97.4 vs 141±15.7 mm Hg, p=0.0046), higher daytime DBP (97.4±19.8 vs 77.2±11.4 mm Hg, p=0.007), higher nighttime SBP (165.2±19.2 vs 133.5±19.8 mm Hg, p=0.0002), and higher nighttime DBP (87.7±16.5 vs 70.2±15.1 mm Hg, p=0.007). Analysis of circadian patterns revealed significant increase in non-dipper pattern, defined as nocturnal BP fall of 0-10%, in subjects with refractory HTN (53.3 % (8 of 15) vs 14.3 % (3 of 28), p=0.0267). Biochemical analysis of U-24-hr fractionated metanephrines revealed significantly higher levels in refractory compared to controlled resistant HTN indicative of higher sympathetic activity (U-24-h total metanephrines (592.2 ±246.9 vs 409.3±167.0 μg, p=0.021, and U-24-h total normetanephrines 464.4 ±250.2 vs 309.8±147.6 μg, p=0.039). These findings suggest that increased sympathetic activity may play a role in treatment failure and may promote blunted nocturnal BP fall in refractory hypertension.

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