Radiation-driven winds of hot luminous stars XVII. Parameters of selected central stars of PN from consistent optical and UV spectral analysis and the universality of the mass-luminosity relation

Context: The commonly accepted mass-luminosity relation of central stars of planetary nebulae (CSPNs) might not be universally valid. While earlier optical analyses could not derive masses and luminosities independently (instead taking them from theoretical evolutionary models) hydrodynamically consistent modelling of the stellar winds allows using fits to the UV spectra to consistently determine also stellar radii, masses, and luminosities without assuming a mass-luminosity relation. Recent application to a sample of CSPNs raised questions regarding the validity of the theoretical mass-luminosity relation of CSPNs. Aims: The results of the earlier UV analysis are reassessed by means of a simultaneous comparison of observed optical and UV spectra with corresponding synthetic spectra. Methods: Using published stellar parameters (a) from a consistent UV analysis and (b) from fits to optical H and He lines, we calculate simultaneous optical and UV spectra with our model atmosphere code, which has been improved by implementing Stark broadening for H and He lines. Results: Spectra computed with the parameter sets from the UV analysis yield good agreement to the observations, but spectra computed with the stellar parameters from the published optical analysis and using corresponding consistent wind parameters show large discrepancies to both the observed optical and UV spectra. The published optical analyses give good fits to the observed spectrum only because the wind parameters assumed in these analyses are inconsistent with their stellar parameters. By enforcing consistency between stellar and wind parameters, stellar parameters are obtained which disagree with the core-mass-luminosity relation for the objects analyzed. This disagreement is also evident from a completely different approach: an investigation of the dynamical wind parameters.Comment: 22 pages, 18 fugre

Wig-1, a novel regulator of N-Myc mRNA and N-Myc-driven tumor growth

Wig-1 is a transcriptional target of the p53 tumor suppressor and encodes an mRNA stability-regulating protein. We show here that Wig-1 knockdown causes a dramatic inhibition of N-Myc expression and triggers differentiation in neuroblastoma cells carrying amplified N-Myc. Transient Wig-1 knockdown significantly delays development of N-Myc-driven tumors in mice. We also show that N-Myc expression is induced upon moderate p53-activating stress, suggesting a role of the p53-Wig-1-N-Myc axis in promoting cell cycle re-entry upon p53-induced cell cycle arrest and DNA repair. Moreover, our findings raise possibilities for the improved treatment of poor prognosis neuroblastomas that carry amplified N-Myc

Expert recommendations on the management of patients with metastatic castration-resistant prostate cancer who progress after CHAARTED or LATITUDE

Objective: Our aim was to provide practical recommendations on the management of patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel plus androgen-deprivation therapy (ADT) or abiraterone plus ADT. Methods: Systematic literature review (SLR), nominal group meeting, and Delphi process. A panel of 12 experts was established who defined the scope, users, and sections of the document. We performed an SLR in order to assess the efficacy and safety of available drugs in patients with mCRPC. Abstracts from the American Society of Oncology and European Society for Medical Oncology meetings were also examined. The results were discussed during an expert meeting in which 14 recommendations were generated. The level of agreement with the recommendations was also tested by 13 additional experts following the Delphi process. Recommendations were voted by means of scores ranging from 0 (total disagreement) to 10 (total agreement). We defined agreement when at least 70% of the experts voted ¿7. Next, we assigned a level of evidence and grade to the recommendation using the Oxford Centre for Evidence-based Medicine Levels of Evidence, following which the final document was drafted. Results: The literature search did not find any articles meeting the inclusion criteria. Finally, 13 out of 14 recommendations were accepted after two Delphi rounds (two were modified after the first round). They pertain to general and individual case-based treatment recommendations. Conclusions: In mCRPC patients who have progressed after docetaxel or abiraterone plus ADT in the metastatic hormone-sensitive prostate cancer setting, these recommendations may support treatment decision-making, due to the lack of evidence or other globally accepted sequencing algorithms

Pck1 Gene Silencing in the Liver Improves Glycemia Control, Insulin Sensitivity, and Dyslipidemia in db/db Mice

OBJECTIVE—Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; encoded by Pck1) catalyzes the first committed step in gluconeogenesis. Extensive evidence demonstrates a direct correlation between PEPCK-C activity and glycemia control. Therefore, we aimed to evaluate the metabolic impact and their underlying mechanisms of knocking down hepatic PEPCK-C in a type 2 diabetic model

Genomic Analysis of wig-1 Pathways

Background: Wig-1 is a transcription factor regulated by p53 that can interact with hnRNP A2/B1, RNA Helicase A, and dsRNAs, which plays an important role in RNA and protein stabilization. in vitro studies have shown that wig-1 binds p53 mRNA and stabilizes it by protecting it from deadenylation. Furthermore, p53 has been implicated as a causal factor in neurodegenerative diseases based in part on its selective regulatory function on gene expression, including genes which, in turn, also possess regulatory functions on gene expression. In this study we focused on the wig-1 transcription factor as a downstream p53 regulated gene and characterized the effects of wig-1 down regulation on gene expression in mouse liver and brain. Methods and Results: Antisense oligonucleotides (ASOs) were identified that specifically target mouse wig-1 mRNA and produce a dose-dependent reduction in wig-1 mRNA levels in cell culture. These wig-1 ASOs produced marked reductions in wig-1 levels in liver following intraperitoneal administration and in brain tissue following ASO administration through a single striatal bolus injection in FVB and BACHD mice. Wig-1 suppression was well tolerated and resulted in the reduction of mutant Htt protein levels in BACHD mouse brain but had no effect on normal Htt protein levels nor p53 mRNA or protein levels. Expression microarray analysis was employed to determine the effects of wig-1 suppression on genome-wide expression in mouse liver and brain. Reduction of wig-1 caused both down regulation and up regulation of several genes

Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-624244) in patients with advanced cancer

Fil: Cura, Jorge E. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Blanzaco, Daniel P. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Brisson, Cecilia. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Cura, Marco A. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Cabrol, Rosa. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Larrateguy, Luis. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Mendez, Carlos. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Sechi, Jose Carlos. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Silveira, Jorge Solana. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Theiller, Elvira. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: de Roodt, Adolfo R. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Producción de Biológicos; Argentina.Fil: Vidal, Juan Carlos. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Producción de Biológicos; Argentina.A Phase I clinical trial was performed on patients with solid tumors refractory to conventional therapy. Crotoxin was administered i.m. for 30 consecutive days at doses ranging from 0.03 to 0.22 mg/m(2). Patients entered the study after providing a written informed consent. Although 26 patients were entered only 23 were evaluated. Reversible, nonlimiting neuromuscular toxicity evidenced as diplopia because of pareses of the external ocular muscles was present in 13 patients. It started at doses of 0.18 mg/m(2) and lasted from 2 to 6 h. These episodes did not require dose adjustment and disappeared in 1-3 weeks of treatment. Three patients experienced palpebral ptosis, nystagmus (grade 2), and anxiety (grade 2-3) at the dose-limiting toxicity of 0.22 mg/m(2). Also at dose-limiting toxicity, 1 patient showed nystagmus (grade 2) and anxiety (grade 3) without evidence of palpebral ptosis. Transient increases (grades 1-3) in the levels of creatinine kinase, aspartate aminotransferase, and alanine transaminase attributed to crotoxin myotoxicity were observed but returned to normal by the last week of treatment. At 0.21 mg/m(2) there was a case of grade-3 anaphylactic reaction on day 31, which required treatment. Hypersensitivity was regarded as an adverse drug-related reaction, and the patient was removed from the protocol. Two patients at different doses (0.12 mg/m(2) and 0.22 mg/m(2)) had sialorrhea. Four patients had asymptomatic transient increase in blood pressure (up to 20 mm Hg) 12 h after the first injection, which lasted 24 h. No treatment was required and toxicity did not reappear. Six patients experienced slight eosinophilia during the first 2 weeks. The maximum tolerated dose was set at 0.21 mg/m(2). Objective measurable partial responses (>50% reduction of tumor mass) were noted in 2 patients treated at 0.21 mg/m(2) and 1 at 0.12 mg/m(2). One patient (at 0.21 mg/m(2)) presented a complete response on day 110. Crotoxin pharmacokinetics showed rapid absorption from the injection site to blood (t(1/2 A) = 5.2 +/- 0.6 min). Plasma concentration reached a peak (C(max) = 0.79 +/- 0.1 ng/ml) at tau(max) = 19 +/- 3 min. The half-life of the distribution (alpha) phase is 22 +/- 2 min. Starting at 1.5 h after injection, the decrease in plasma concentration becomes slower, reaching 14 +/- 3 pg/ml 24 h after injection. The profile is dominated by the elimination (beta) phase with a half-life of 5.2 +/- 0.6 h. Consequently, 24 h after the injection ( approximately 5 half-life) 97% of the product was eliminated. The area under plasma concentration versus time curve was 0.19 +/- 0.05 microg/min/ml. Assuming availability (F) approximately 1, the clearance is C(L) = 26.3 +/- 7 ml/min, and the apparent volume of distribution is V(d) = 12 +/- 3 liter/kg. The recommended dose for a Phase II study is 0.18 mg/m(2)

Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-624244) in patients with advanced cancer

Fil: Cura, Jorge E. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Blanzaco, Daniel P. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Brisson, Cecilia. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Cura, Marco A. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Cabrol, Rosa. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Larrateguy, Luis. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Mendez, Carlos. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Sechi, Jose Carlos. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Silveira, Jorge Solana. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: Theiller, Elvira. Hospital San Martín. Departamento de Medicina Oncológica, Paraná; Entre Ríos.Fil: de Roodt, Adolfo R. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Producción de Biológicos; Argentina.Fil: Vidal, Juan Carlos. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Producción de Biológicos; Argentina.A Phase I clinical trial was performed on patients with solid tumors refractory to conventional therapy. Crotoxin was administered i.m. for 30 consecutive days at doses ranging from 0.03 to 0.22 mg/m(2). Patients entered the study after providing a written informed consent. Although 26 patients were entered only 23 were evaluated. Reversible, nonlimiting neuromuscular toxicity evidenced as diplopia because of pareses of the external ocular muscles was present in 13 patients. It started at doses of 0.18 mg/m(2) and lasted from 2 to 6 h. These episodes did not require dose adjustment and disappeared in 1-3 weeks of treatment. Three patients experienced palpebral ptosis, nystagmus (grade 2), and anxiety (grade 2-3) at the dose-limiting toxicity of 0.22 mg/m(2). Also at dose-limiting toxicity, 1 patient showed nystagmus (grade 2) and anxiety (grade 3) without evidence of palpebral ptosis. Transient increases (grades 1-3) in the levels of creatinine kinase, aspartate aminotransferase, and alanine transaminase attributed to crotoxin myotoxicity were observed but returned to normal by the last week of treatment. At 0.21 mg/m(2) there was a case of grade-3 anaphylactic reaction on day 31, which required treatment. Hypersensitivity was regarded as an adverse drug-related reaction, and the patient was removed from the protocol. Two patients at different doses (0.12 mg/m(2) and 0.22 mg/m(2)) had sialorrhea. Four patients had asymptomatic transient increase in blood pressure (up to 20 mm Hg) 12 h after the first injection, which lasted 24 h. No treatment was required and toxicity did not reappear. Six patients experienced slight eosinophilia during the first 2 weeks. The maximum tolerated dose was set at 0.21 mg/m(2). Objective measurable partial responses (>50% reduction of tumor mass) were noted in 2 patients treated at 0.21 mg/m(2) and 1 at 0.12 mg/m(2). One patient (at 0.21 mg/m(2)) presented a complete response on day 110. Crotoxin pharmacokinetics showed rapid absorption from the injection site to blood (t(1/2 A) = 5.2 +/- 0.6 min). Plasma concentration reached a peak (C(max) = 0.79 +/- 0.1 ng/ml) at tau(max) = 19 +/- 3 min. The half-life of the distribution (alpha) phase is 22 +/- 2 min. Starting at 1.5 h after injection, the decrease in plasma concentration becomes slower, reaching 14 +/- 3 pg/ml 24 h after injection. The profile is dominated by the elimination (beta) phase with a half-life of 5.2 +/- 0.6 h. Consequently, 24 h after the injection ( approximately 5 half-life) 97% of the product was eliminated. The area under plasma concentration versus time curve was 0.19 +/- 0.05 microg/min/ml. Assuming availability (F) approximately 1, the clearance is C(L) = 26.3 +/- 7 ml/min, and the apparent volume of distribution is V(d) = 12 +/- 3 liter/kg. The recommended dose for a Phase II study is 0.18 mg/m(2)

Показатели качества жизни, связанного со здоровьем, у пациентов с распространенным почечно-клеточным раком при лечении ленватинибом в комбинации с пембролизумабом или эверолимусом по сравнению с монотерапией сунитинибом (CLEAR): рандомизированное клиническое исследование III фазы

.Введение. Результаты клинического исследования III фазы CLEAR показали, что комбинация ленватиниба и пембролизумаба увеличивает выживаемость без прогрессирования и общую выживаемость по сравнению с монотерапией сунитинибом у пациентов с распространенным почечно-клеточным раком.Цель исследования – оценить показатели качества жизни, связанного со здоровьем (health-related quality-of-life, HRQOL), по данным исследования CLEAR.Материалы и методы. Открытое рандомизированное клиническое исследование III фазы было проведено на базе 200 лечебных учреждений и онкологических центров в 20 странах мира. Критерии включения пациентов: возраст старше 18 лет, распространенный светлоклеточный почечно-клеточный рак, общесоматический статус по шкале Карновского 70 % или выше. Пациентов, которым ранее проводилась противоопухолевая лекарственная терапия почечно-клеточного рака, не включали в исследование. Все пациенты были рандомизированы (1:1:1) на 3 группы: комбинация ленватиниба (20 мг/сут, внутрь) с пембролизумабом (200 мг, внутривенно, каждый 21 день), комбинация ленватиниба (18 мг/сут, внутрь) с эверолимусом (5 мг/сут, внутрь) 21-дневный цикл и монотерапия сунитинибом (50 мг/сут, внутрь, режим 4/2: 28 дней лечения с последующим перерывом 14 дней, 42-дневный цикл лечения). Пациенты были распределены на группы лечения с помощью компьютерной схемы рандомизации и стратифицированы по географическим регионам и прогностическим группам Memorial Sloan Kettering Cancer Center. Первичной конечной точкой исследования была выживаемость без прогрессирования, вторичной конечной точкой – оценка HRQOL. Оценку HRQOL проводили у пациентов, прошедших рандомизацию, которые получили по крайней мере 1 дозу исследуемого препарата и заполнили данные о HRQOL. Анализ показателей завершения и соблюдения требований (соответствия) выполняли при полном наборе инструментов исследования. Анкетирование с использованием опросника функциональной оценки индекса симптомов терапии рака почки и симптомов, связанных с заболеванием (Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms, FKSI-DRS), опросника качества жизни Европейской организации по исследованию и лечению рака (EORTC QLQ-C30) и опросника Европейского фонда исследования качества жизни (EQ-5D-3L) проводили на исходном уровне и на 1-й день каждого последующего 21-дневного цикла лечения. Настоящее исследование зарегистрировано на ClinicalTrials.gov, NCT02811861 и в настоящее время закрыто для набора новых участников.Результаты. В период с 13 октября 2016 г. по 24 июля 2019 г. 355 пациентов были рандомизированы в группу лечения комбинацией ленватиниба и пембролизумаба, 357 пациентов – в группу комбинации ленватиниба и эверолимуса и 357 пациентов – в группу монотерапии сунитинибом. Медиана времени наблюдения для анализа оценки HRQOL составила 12,9 мес (межквартильный диапазон 5,6–22,3 мес). Из-за доказанной высокой эффективности и профиля безопасности комбинации ленватиниба и пембролизумаба в 1-й линии противоопухолевого лечения распространенного почечно-клеточного рака основная часть настоящего анализа оценки HRQOL посвящена сравнительному изучению этой комбинации и монотерапии сунитинибом. Среднее изменение от исходного уровня HRQOL в группе комбинации ленватиниба и пембролизумаба по сравнению с группой монотерапии сунитинибом составило –1,75 (стандартная ошибка (СО) 0,59) против –2,19 (СО 0,66) по опроснику FKSI-DRS, –5,93 (СО 0,86) против –6,73 (СО 0,94) по опроснику EORTC QLQ-C30 GHS/QOL (шкала общего статуса здоровья/качества жизни) и –4,96 (СО 0,85) против –6,64 (СО 0,94) по визуальной аналоговой шкале EQ-5D-3L. Медиана времени до первого ухудшения HRQOL в группе комбинации ленватиниба и пембролизумаба по сравнению с группой монотерапии сунитинибом составила 9,14 нед (95 % доверительный интервал (ДИ) 6,43–12,14) против 12,14 нед (95 % ДИ 9,14–15,29; отношение рисков (ОР) 1,13 (95 % ДИ 0,94–1,35); log-rank p = 0,20) по опроснику FKSI-DRS, 12,00 нед (95 % ДИ 7,29–15,14 ) против 9,14 нед (95 % ДИ 6,29–12,14; ОР 0,88 (95 % ДИ 0,74–1,05); log-rank p = 0,17) по опроснику EORTC QLQ-C30 GHS/QOL и 9,43 нед (95 % ДИ 6,43–12,29) против 9,14 нед (95 % ДИ 6,29–12,00; ОР 0,83 (95 % ДИ 0,70–0,99); log-rank p = 0,041) по визуальной аналоговой шкале EQ-5D-3L. Медиана времени до окончательного ухудшения HRQOL в группе комбинации ленватиниба и пембролизумаба по сравнению с группой монотерапии сунитинибом составила 134,14 нед (95 % ДИ 120,00–не достигнута) против 117,43 нед (95 % ДИ 90,14–131,29; ОР 0,70 (95 % ДИ 0,53–0,92); log-rank p = 0,0081) по опроснику FKSI-DRS, 114,29 нед (95 % ДИ 102,14–153,29) против 75,14 нед (95 % ДИ 57,29–105,14; ОР 0,60 (95 % ДИ 0,47–0,77); log-rank p <0,0001) по опроснику EORTC QLQ-C30 GHS/QOL и 124,86 нед (95 % ДИ 94,71–134,57) против 74,86 нед (95 % ДИ 54,14–96,00; ОР 0,67 (95 % ДИ 0,53–0,85); log-rank p = 0,0012) по визуальной аналоговой шкале EQ-5D-3L. Ни один из инструментов оценки HRQOL не показал значительного преимущества в пользу сунитиниба перед комбинацией ленватиниба и пембролизумаба. При оценке HRQOL для комбинации ленватиниба и эверолимуса по сравнению с монотерапией сунитинибом в большинстве случаев показатели были схожими или предпочтительными в пользу сунитиниба.Заключение. Результаты анализа оценки HRQOL показали, что пациенты, получающие лечение комбинацией ленватиниба с пембролизумабом, имеют аналогичные или более благоприятные показатели качества жизни, связанного со здоровьем, по сравнению с пациентами, получающими монотерапию сунитинибом, особенно в отношении времени до окончательного ухудшения. Результаты данного исследования подтверждают эффективность и безопасность применения комбинации ленватиниба и пембролизумаба в качестве 1-й линии противоопухолевой терапии у пациентов с распространенным почечно-клеточным раком

A Search for Dark Higgs Bosons

Recent astrophysical and terrestrial experiments have motivated the proposal of a dark sector with GeV-scale gauge boson force carriers and new Higgs bosons. We present a search for a dark Higgs boson using 516 fb-1 of data collected with the BABAR detector. We do not observe a significant signal and we set 90% confidence level upper limits on the product of the Standard Model-dark sector mixing angle and the dark sector coupling constant.Comment: 7 pages, 5 postscript figures, published version with improved plots for b/w printin

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE