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Purpose: Previous studies have shown that the replication checkpoint, which involves the kinases ataxia telangiectasia mutated and Rad3 related (ATR) and Chk1, contributes to cytarabine resistance in cell lines. In the present study, we examined whether this checkpoint is activated in clinical acute myelogenous leukemia (AML) during cytarabine infusion in vivo and then assessed the impact of combining cytarabine with the recently described Chk1 inhibitor SCH 900776 in vitro.Experimental design: AML marrow aspirates harvested before and during cytarabine infusion were examined by immunoblotting. Human AML lines treated with cytarabine in the absence or presence of SCH 900776 were assayed for checkpoint activation by immunoblotting, nucleotide incorporation into DNA, and flow cytometry. Long-term effects in AML lines, clinical AML isolates, and normal myeloid progenitors were assayed using clonogenic assays.Results: Immunoblotting revealed increased Chk1 phosphorylation, a marker of checkpoint activation, in more than half of Chk1-containing AMLs after 48 hours of cytarabine infusion. In human AML lines, SCH 900776 not only disrupted cytarabine-induced Chk1 activation and S-phase arrest but also markedly increased cytarabine-induced apoptosis. Clonogenic assays demonstrated that SCH 900776 enhanced the antiproliferative effects of cytarabine in AML cell lines and clinical AML samples at concentrations that had negligible impact on normal myeloid progenitors.Conclusions: These results not only provide evidence for cytarabine-induced S-phase checkpoint activation in AML in the clinical setting, but also show that a selective Chk1 inhibitor can overcome the S-phase checkpoint and enhance the cytotoxicity of cytarabine. Accordingly, further investigation of the cytarabine/SCH 900776 combination in AML appears warranted. Clin Cancer Res; 18(19); 5364–73. ©2012 AACR.

PDF file, 105K, This file contains Supplemental Table 1 (Description of Patients Providing Samples for Assessment of Chk1 phosphorylation ), Supplemental Table 2 (Quantitative Effects of Cytarabine, SCH 900776 and the Combination on Samples from Patients in Cohort 2) and Supplemental Figure 1 (effects of SCH 900776 on cytarabine-induced killing in additional myeloid cell lines).

BACKGROUND: The real-world impact of breathing zone air purification and coronavirus disease 2019 (COVID-19) mitigation measures on healthcare-associated infections is not well documented. Engineering solutions to treat airborne transmission of disease may yield results in controlled test chambers or single rooms, but have not been reported on hospital-wide applications, and the impact of COVID-19 mitigation measures on healthcare-associated infection rates is unknown. AIM: To determine the impact of hospital-wide bioaerosol treatment and COVID-19 mitigation measures on clinical outcomes. METHODS: The impact of the step-wise addition of air disinfection technology and COVID-19 mitigation measures to standard multi-modal infection control on particle counts, viral and bacterial bioburden, and healthcare-associated infection rates was investigated in a 124-bed hospital (>100,000 patient-days over 30 months). FINDINGS AND CONCLUSION: The addition of air disinfection technology and COVID-19 mitigation measures reduced airborne ultrafine particles, altered hospital bioburden, and reduced healthcare-associated infections from 11.9 to 6.6 (per 1000 patient-days) and from 6.6 to 1.0 (per 1000 patient-days), respectively (P

BACKGROUND: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5?*?5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. FINDINGS: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). INTERPRETATION: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. FUNDING: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

This study aimed to evaluate the effects of the dietary supplementation Curcuma longa hydrolate on Nile tilapia (Oreochromis niloticus) reared in a recirculation system. Hemato-immunological parameters, growth performance, nitrogen and phosphorus retention, as well as body composition and its interaction with the intestinal microbiota, were studied. Nile tilapia fingerlings (120) were distributed randomly in 8 polyethylene tanks (40 L). The experimental units were divided into two treatments, in quadruplicate: commercial diet supplemented with 2.5% of C. longa hydrolate and commercial diet without supplementation (control). After 45 days, the treatment supplemented hydrolate showed higher survival than the control group, 95.25% and 82.22%, receptively. In the blood profile, fish supplemented with hydrolate had a higher count of total leukocytes and neutrophils, as well as mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, than control group. The hydrolate group showed a substantial increase in the relative abundance of Cetobacterium and Romboutsia, as well as lower diversity in gut microbiota. The dietary addition of C. longa hydrolate for Nile tilapia seems to have a beneficial effect on gut microbiota, in addition to a likely positive effect on the physiological performance of Nile tilapia by maintaining intestinal homeostasis and promoting survival in reared conditions.

ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

1,4‐Triazolyl combretacoumarins have been prepared by linking the trimethoxyarene unit of combretastatin A4 with coumarins, via a 1,2,3‐triazole. For this, 4‐azidocoumarins were accessed by a sequential two‐step, one‐pot reaction of 4‐hydroxycoumarins with (benzotriazol‐1‐yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), followed by reaction with NaN3. In the reaction with BOP, a coumarin‐derived phosphonium ion intermediate seems to form, leading to an O 4‐(benzotriazolyl)coumarin derivative. For the CuAAC reaction of azidocoumarins with 5‐ethynyl‐1,2,3‐trimethoxybenzene, catalytic [(MeCN)4Cu]PF6 in CH2Cl2/MeOH with 2,6‐lutidine, at 50 oC, was suitable. The 4‐azidocoumarins were less reactive as compared to PhN3 and the NBO coefficients of the azido groups were compared by DFT analysis. Compound solubility was a problem in biological assays. On the basis of the biological and solubility data of one 1,4‐triazolyl combretacoumarin, four analogs lacking one or two methoxy groups were synthesized. Reactivity differences among the phenylacetylenes were noted and the NBO coefficients of the alkynes were compared by DFT analysis. In cytotoxicity assays, 1‐phenyl‐4‐(3,4,5‐trimethoxyphenyl)‐1H‐1,2,3‐triazole showed activity in CEM and MDA‐MB‐231 cell lines by apoptosis. The desmethoxy 6‐bromo‐4‐(4‐(4‐methoxyphenyl)‐1H‐1,2,3‐triazol‐1‐yl)‐2H‐chromen‐2‐one also showed cytotoxicity against the two cell lines, but this did not appear to be consistent with apoptosis. The antiviral activity of the compounds was unremarkable., A facile, one‐pot synthesis of 4‐azidocoumarins from 4‐hydroxycoumarins has been developed. Cu‐catalyzed azide‐alkyne cycloaddition of these compounds with 5‐ethynyl‐1,2,3‐trimethoxybenzene or mono and dimethoxy phenylacetylenes gave a series of 1,4‐triazolyl combretacoumarins and desmethoxy analogs. These were analyzed for their antiproliferative and antiviral properties.John Wiley & Sons, Ltd.This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

SummaryPurpose BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. Methods This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-day cycle. Patients received oral BAL101553 on Days 15–21 of cycle 2 to assess oral bioavailability. Results BAL101553 was well tolerated at doses up to ≤70 mg/m2. Three grade 3 DLTs occurred: hypotension (70 mg/m2), hyponatremia and neutropenia (both 90 mg/m2). The MTD for 48-h IV BAL101553 was 70 mg/m2. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the Cmax was 144 ng/mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was >80%. Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.

The antiretroviral agent nelfinavir has antimyeloma activity and can overcome resistance to bortezomib. Our phase I/II trial investigated whether adding nelfinavir to lenalidomide–dexamethasone can overcome lenalidomide resistance in lenalidomide-refractory multiple myeloma (MM). Twenty-nine patients were included (high-risk cytogenetic aberrations 31%; ≥2 prior therapy lines 93%; lenalidomide–bortezomib double-refractory 34%). Twenty-four patients (83%) had prior bortezomib and 10 (34%) were lenalidomide–bortezomib double-refractory. They received four cycles of nelfinavir 2500 mg/day with standard-dose lenalidomide (25 mg days 1–21) and dexamethasone (40/20 mg days 1, 8, 15, 22). Minor response or better was achieved in 16 patients (55%; 95% CI 36–74%), including 40% of those who were lenalidomide–bortezomib double-refractory, and partial response or better in nine patients (31%; 95% CI 15–51%). Median progression-free survival was 3.4 (95% CI 2.0–4.9) months and median overall survival 21.6 (13.0–50.1) months. Lenalidomide-related pneumonitis, pneumonia, and neutropenic fever occurred, but there were no unexpected adverse events. Peripheral blood mononuclear cells showed a 45% (95% CI 40–51%) reduction in total proteasome activity from baseline and significant induction of unfolded protein response and autophagy. Thus, nelfinavir–lenalidomide–dexamethasone is an active oral combination in lenalidomide-refractory MM.

This phase I trial evaluated the safety, tolerability, and preliminary activity of inotuzumab ozogamicin in combination with temsirolimus in patients with relapsed/refractory CD22 positive B-cell non-Hodgkin lymphomas. Nineteen patients received at least one dose of both study drugs. Dose-limiting toxicities consisted of thrombocytopenia, hypertriglyceridemia, oral mucositis, clinical deterioration, and the inability to receive at least three doses of temsirolimus during cycle 1. The most common grade ≥3 treatment-related adverse events were thrombocytopenia (

Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγ agonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγ and HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound

Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγ agonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγ and HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound 7i was the most potent, with activity toward PPARγ EC50 = 0.245 μM and HDAC4 IC50 = 1.1 μM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC50 = 2.8 and 9.6 μM, respectively), induced apoptosis, and caused DNA fragmentation. Furthermore, compound 7c modulated the expression of c-Myc, cleaved caspase-3, and caused in vivo tumor regression in CCRF-CEM tumor xenografts. Thus, this study provides a basis for the rational design of dual/multitargeting agents that could be developed further as anticancer therapeutics.

Prostate cancer is a common malignancy in men worldwide. In the initial treatment, ADT has been used as the cornerstone, but unfortunately, mainstream patients transition to the refractory state of prostate cancer, i.e., CRPC. Thus, newer therapeutics are required for the treatment of patients un or less responsive to ADT. Epigenetic aberrations, namely, DNA methylation and histone modifications are the ultimate chauffeurs of prostate cancer with an emerging role to erase the roadmaps to this disease. However, more robust clinical evidence would be indispensable to put forward reliable therapeutics with the scope to effectively combat this disease. In this review, we have described the present status of epigenetic biomarkers and their clinical impacts on prostate cancer. We have also comprehensively deliberated the role of different epigenetic master regulators involved in the management of disease, appropriate treatment landscape, and the recent preclinical and ongoing clinical evaluations in prostate adenocarcinoma.

Recent evidences highlight the usefulness of small molecule (Histone deacetylase 4) HDAC4 inhibitors in the several preclinical paradigms. Major toxicity and mutagenicity issues associated with hydroxamate HDAC inhibitors, stimulated us to develop potent non-hydroxamate inhibitors. In the present work a novel series of thiazolidinedione (TZD) derivatives with pyridine as cyclic linker and TZD ring as zinc binding group was designed and screened in a panel of isoenzymes of HDACs, wherein the most potent compounds exhibiting HDAC4 IC50-values

Eugenia candolleana D.C. (Myrtaceae) é uma espécie florestal frutífera endêmica da Mata Atlântica. Apesar da planta possuir propriedades medicinais e de seus frutos serem apreciados para o consumo in natura e na culinária, carece de informações técnicas no âmbito agronômico, principalmente para as condições do litoral nordeste de Santa Catarina. Este trabalho teve por objetivos verificar aspectos relativos ao potencial agronômico de E. candolleana D.C. em área de restinga litorânea. em Araquari-SC, Brasil. O estudo foi realizado em uma população plantas existentes na área do IFC-Campus Araquari (26°22'12'' S e 48°43' 19'' O), durante o período 01/08/2019 a 31/07/2020. Foram analisados: o período de colheita; a estimativa de produção de frutos, determinada pelo acumulado de colheita de todos os frutos maduros por planta; o comportamento pós-colheita, por meio da determinação do “tempo de vida de prateleira” de frutos frescos maduros e recém colhidos, mantidos a 10°C e 25°C, sendo determinadas a matéria fresca (g) e o teor total de sólidos solúveis (°Brix) aos 0, 2, 4, 6 e 8 dias após a colheita, bem como verificadas a ocorrência de alterações visuais nos frutos. Também foi observada a ocorrência de danos causados por pássaros, insetos ou doenças, obtida pela análise visual dos frutos durante a colheita e respectivo cálculo do percentual de frutos danificados. Os frutos foram acondicionados em bandejas plásticas. Da população de plantas observadas, foi possível realizar a colheita em apenas uma, possivelmente devido à juvenilidade das demais. O período de colheita de frutos foi de 29 dias, de 28/02/2020 à 28/03/2020, sendo realizadas ao todo 11 colheitas. Foi possível verificar duas etapas de produção, a primeira de 11 dias, referente à primeira florada e a outra de 14 dias de maior intensidade e produção. A produção total estimada foi 22,17 kg.planta-1 e o pesomédio dos frutos foi de 5,09g. Houveram danos decorrentes de pássaros e/ou queda natural em 21% dos frutos. O tempo de prateleira foi maior para frutos mantidos refrigerados, com redução de 12,06 para 11,24 °Brix e de 3% para matéria fresca aos 8 dias após a colheita. Frutos mantidos à 25°C reduziram de 12,5 para 11,42, 7,42 e 7,24 °Brix aos 4, 6 e 8 dias após a colheita, respectivamente, com cerca de 14% de redução de matéria fresca no final do período. Aos quatro dias após a colheita à 25°C, os frutos apresentaram odor desagradável, possivelmente devido a presença de larvas de insetos (mosca das frutas), sendo esta a principal causa de danos observada em frutos no final do tempo de prateleira. De acordo com as condições em que o trabalho foi desenvolvido pode-se concluir que: E. candolleana apresenta potencial agronômico quanto à produtividade de frutos; o reduzido tempo de prateleira demanda cuidados na comercialização de frutos frescos in natura e a refrigeração é uma alternativa na conservação da qualidade dos frutos em pós-colheita; Mosca das frutas é a principal praga encontrada, com potencial de dano econômico principalmente em pós-colheita.

A key challenge in conservation biology is to identify natural populations with compromised health and identify causative agents. However, wildlife are exposed to a complex matrix of natural and anthropogenic stressors such that identifying particular agents of distress is difficult. Yet, establishing cause and effect between human-induced environmental changes and adverse health is necessary to guide conservation planning. Transcriptome profiling, with thoughtful experimental design and appropriate metadata, is useful for establishing cause and effect between exposures to environmental stressors and adverse health outcomes. Here we describe transcriptome profiling and associated paradigms that are useful for wildlife health assessment and conservation planning, with particular emphasis on pollution. We emphasize that these tools are important for testing hypotheses about causative agents of distress, but also for generating new hypotheses about causes and consequences. We outline two case studies that highlight attributes of transcriptomics tools and approaches that add value for conservation practitioners.

Cancer cells increase their glucose uptake and glycolytic activity to meet the high energy requirements of proliferation. Glucose transporters (GLUTs), which facilitate the transport of glucose and related hexoses across the cell membrane, play a vital role in tumor cell survival and are overexpressed in various cancers. GLUT1, the most overexpressed GLUT in many cancers, is emerging as a promising anti-cancer target. To develop GLUT1 inhibitors, we rationally designed, synthesized, structurally characterized, and biologically evaluated in-vitro and in-vivo a novel series of furyl-2-methylene thiazolidinediones (TZDs). Among 25 TZDs tested, F18 and F19 inhibited GLUT1 most potently (IC50 11.4 and 14.7 μM, respectively). F18 was equally selective for GLUT4 (IC50 6.8 μM), while F19 was specific for GLUT1 (IC50 152 μM in GLUT4). In-silico ligand docking studies showed that F18 interacted with conserved residues in GLUT1 and GLUT4, while F19 had slightly different interactions with the transporters. In in-vitro antiproliferative screening of leukemic/lymphoid cells, F18 was most lethal to CEM cells (CC50 of 1.7 μM). Flow cytometry analysis indicated that F18 arrested cell cycle growth in the subG0-G1 phase and lead to cell death due to necrosis and apoptosis. Western blot analysis exhibited alterations in cell signaling proteins, consistent with cell growth arrest and death. In-vivo xenograft study in a CEM model showed that F18 impaired tumor growth significantly.

CPX-351 is a liposomally encapsulated 5:1 molar ratio of cytarabine and daunorubicin that recently received regulatory approval for the treatment of therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes based on improved overall survival compared to standard cytarabine/daunorubicin therapy. Checkpoint kinase 1 (CHK1), which is activated by DNA damage and replication stress, diminishes sensitivity to cytarabine and anthracyclines as single agents, suggesting that CHK1 inhibitors might increase the effectiveness of CPX-351. The present studies show that CPX-351 activates CHK1 as well as the S and G2/M cell cycle checkpoints. Conversely, CHK1 inhibition diminishes the cell cycle effects of CPX-351. Moreover, CHK1 knockdown or addition of a CHK1 inhibitor such as MK-8776, rabusertib or prexasertib enhances CPX-351-induced apoptosis in multiple TP53-null and TP53-wildtype AML cell lines. Likewise, CHK1 inhibition increases the antiproliferative effect of CPX-351 on primary AML specimens ex vivo, offering the possibility that CPX-351 may be well suited to combine with CHK1-targeted agents.

Theories pertaining to social rejection often posit that rejected individuals are motivated to both pursue belonging and protect the self. The present study examined whether rejection indeed produc...

Background PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor. Patients and methods This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Results Twenty-eight patients were included in six dosing cohorts and treated at a daily PQR309 dose ranging from 10 to 150 mg. Common adverse events (AEs; ≥30% patients) included fatigue, hyperglycaemia, nausea, diarrhoea, constipation, rash, anorexia and vomiting. Grade (G) 3 or 4 drug-related AEs were seen in 13 (46%) and three (11%) patients, respectively. Dose-limiting toxicity (DLT) was observed in two patients at 100 mg OD (>14-d interruption in PQR309 due to G3 rash, G2 hyperbilirubinaemia, G4 suicide attempt; dose reduction due to G3 fatigue, G2 diarrhoea, G4 transaminitis) and one patient at 80 mg (G3 hyperglycaemia >7 d). PK shows fast absorption (Tmax 1-2 h) and dose proportionality for Cmax and area under the curve. A partial response in a patient with metastatic thymus cancer, 24% disease volume reduction in a patient with sinonasal cancer and stable disease for more than 16 weeks in a patient with clear cell Bartholin's gland cancer were observed. Conclusion The MTD and RP2D of PQR309 is 80 mg of orally OD. PK is dose-proportional. PD shows PI3K pathway phosphoprotein downregulation in paired tumour biopsies. Clinical activity was observed in patients with and without PI3K pathway dysregulation. Clinical trial registration ClinicalTrials.gov # NCT01940133.

Reactions of cis-PtCl2(P((CH2)mCH═CH2)3)2 and Grubbs’ first generation catalyst and then hydrogenations afford cis-PtCl2(P((CH2)n)3P) (cis-2; n = 2m + 2 = 12 (b), 14 (c), 16 (d), 18 (e), 20 (f), 22 (g); 6–40%), derived from 3-fold interligand metatheses. The phosphite complexes cis-PtCl2(P(O(CH2)m*CH═CH2)3)2 are similarly converted to cis-PtCl2(P(O(CH2)n*O)3P) (cis-5; n* = 8 (a), 10 (b), 12 (c), 10–20%). The substitution products cis-PtPh2(P((CH2)n)3P) (cis-6c,d) and cis-PtI2(P(O(CH2)10O)3P) are prepared using Ph2Zn and NaI, respectively. Crystal structures of cis-2c,d,f, cis-5a,b, and cis-6c show one methylene bridge that roughly lies in the platinum coordination plane and two that are perpendicular. The thermal behavior of the complexes is examined. When the bridges are sufficiently long, they rapidly exchange via an unusual “triple jump rope” motion over the PtX2 moieties. NMR data establish ΔH⧧, ΔS⧧, and ΔG298K⧧/ΔG393K⧧ values of 7.8 kcal/mol, −27.9 eu, and 16.1/18.8 kcal/mol for cis-2d, and a ΔG393K⧧...

© 2017 Elsevier Inc. The practice of using covariates in experimental designs has become controversial. Traditionally touted by statisticians as a useful method to soak up noise in a dependent variable and boost power, the practice recently has been recast in a negative light because of Type I error inflation. But in order to make informed decisions about research practices like this one, researchers need to know more about the actual size of the benefits and costs of these practices. In a series of simulations, we compared the Type I error rates and power of two analytic practices that researchers might use when confronted with an unanticipated, independent covariate. In the baseline practice, a researcher only analyzes the effect of the manipulation on the dependent variable; in the flexible-covariate practice, she analyzes both the effect of the manipulation on the dependent variable and the effect adjusting for the unanticipated covariate. We show that the flexible-covariate (vs. baseline) practice inflates Type I error by a small amount, and that it boosts power substantially under certain circumstances. The flexible-covariate practice tends to be most beneficial when the covariate is strongly correlated with the dependent variable in the population, and when the experimental design would have been only moderately powered (40%–60%) without including the covariate in the analysis. We offer concrete recommendations for when and how to use independent covariates in experimental designs, and contextualize our findings within the movement toward quantifying trade-offs in choosing among research practices and optimizing the choice of practice within a given research context.

Reactions of Re(CO)5(X) (X = Cl, Br) or [Re2(CO)4(NO)2(μ-Cl)2(Cl)2] and the phosphines P((CH2)mCH═CH2)3 (m = 6, a; 7, b; 8, c) give mer,trans-Re(CO)3(X)(P((CH2)mCH═CH2)3)2 (53–95%) or cis,trans-Re(CO) (NO) (Cl)2(P((CH2)6CH═CH2)3)2 (57%), respectively. Additions of Grubbs’ catalyst (5–10 mol %, 0.0010–0.0012 M) and subsequent hydrogenations (PtO2, ≤5 bar) yield the gyroscope-like complexes mer,trans-Re(CO)3(X)(P((CH2)n)3P) (n = 2m + 2; X = Cl, 7a,c; Br, 8a,c; 18–61%) or cis,trans-Re(CO)(NO)(Cl)2(P((CH2)14)3P) (14%), respectively, and/or the isomers mer,trans-Re(CO)3(X)(P(CH2)n−1CH2)((CH2)n)(P(CH2)n−1CH2) (X = Cl, 7′a–c; Br, 8′b; 6–27%). The latter are derived from a combination of interligand and intraligand metatheses. Reactions of 7a or 8a with NaI, Ph2Zn, or MeLi give mer,trans-Re(CO)3(X)(P((CH2)14)3P) (X = I, 11a; Ph, 12a; Me, 13a; 34–87%). The 13C NMR spectra of 7a–c, 8a–c, 11a, and 13a show rotation of the Re(CO)3(X) moieties to be fast on the NMR time scale at room temperature (and at −90 °C for 8a)...

Hypoxia is a pervasive stressor in aquatic environments, and both phenotypic plasticity and evolutionary adaptation could shape the ability to cope with hypoxia. We investigated evolved variation in hypoxia tolerance and the hypoxia acclimation response across fundulid killifishes that naturally experience different patterns of hypoxia exposure. We compared resting O(2) consumption rate (Ṁ(O(2))), and various indices of hypoxia tolerance [critical O(2) tension (P(crit)), regulation index (RI), O(2) tension (P(O(2))) at loss of equilibrium (P(LOE)) and time to LOE (t(LOE)) at 0.6 kPa O(2)] in Fundulus confluentus, Fundulus diaphanus, Fundulus heteroclitus, Fundulus rathbuni, Lucania goodei and Lucania parva. We examined the effects of chronic (28 days) exposure to constant hypoxia (2 kPa) or nocturnal intermittent hypoxia (12 h normoxia:12 h hypoxia) in a subset of species. Some species exhibited a two-breakpoint model in Ṁ(O(2)) caused by early, modest declines in Ṁ(O(2)) in moderate hypoxia. We found that hypoxia tolerance varied appreciably across species: F. confluentus was the most tolerant (lowest P(LOE) and P(crit), longest t(LOE)), whereas F. rathbuni and F. diaphanus were the least tolerant. However, there was not a consistent pattern of interspecific variation for different indices of hypoxia tolerance, with or without taking phylogenetic relatedness into account, probably because these different indices are underlain by partially distinct mechanisms. Hypoxia acclimation generally improved hypoxia tolerance, but the magnitude of plasticity and responsiveness to different hypoxia patterns varied interspecifically. Our results therefore suggest that hypoxia tolerance is a complex trait that is best appreciated by considering multiple indices of tolerance.

Tiffany & Company was the leading U.S. luxury jewelry brand, generating more than $2.6 billion in revenue through 167 retail outlets globally and from catalogue and Internet sales. For nearly 170 years, Tiffany had managed its brand. In February 2007, a hedge fund, Trian Fund Management LP, announced that it had bought a 5.5% stake in Tiffany, and became its largest shareholder. Trian believed that Tiffany was undervalued and stated that it wanted to help the company “improve its earnings per share by addressing various operational and strategic issues.” In response, Tiffany began to consider different actions to increase shareholder value.

Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8-activating enzyme inhibitor MLN4924 and standard-of-care agent cytarabine as examples. Utilizing a multicolor flow cytometry antibody panel for identification of hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, granulocyte-monocyte progenitors, and megakaryocyte-erythroid progenitors present in mononuclear cell fractions isolated from bone marrow aspirates, we compare stem and progenitor cell counts after treatment for 24 hours with drug versus diluent. We demonstrate that MLN4924 exerts a cytotoxic effect on MDS and AML stem and progenitor cell populations, whereas cytarabine has more limited effects. Further application of this method for evaluating drug effects on these populations ex vivo and in vivo may inform rational design and selection of therapies in the clinical setting.

Does the timing and frequency of program benefits influence student school outcomes? The poor may be especially vulnerable to income scarcity at the end of welfare program benefit cycles. Such scarcity may strain other aspects of family life and exacerbate children’s behavior problems. We use data from the Supplemental Nutrition Assistance Program (SNAP) and school disciplinary records to compare the incidence of disciplinary infractions at the beginning and end of months among Chicago Public School students in grades 5–8 whose families did and did not receive SNAP. Controlling for student and school characteristics, our estimates show that student disciplinary infractions generally spike at the end of the month irrespective of SNAP receipt status. However, spikes are exacerbated among students who receive SNAP benefits. The within-month difference in disciplinary infractions for students in SNAP recipient families is 7 percentage points larger than for nonrecipients. These differences are particu...

We examine legislative activity targeting the Federal Reserve to determine when Congress takes an interest in the Fed and whether this interest has an effect on monetary policy. Using a keyword search of the THOMAS catalogue for the period from January 1973 through December 2010, we identify 1575 bills in the House and 728 bills in the Senate pertaining to the Federal Reserve. We classify these bills into several categories including those that expand Fed powers and those that threaten or usurp Fed powers. Using the Romer and Romer (2004) series of monetary policy shocks, we find that, prior to the early 1980s, the Fed responded to bills credibly threatening Fed powers by lowering the federal funds target below that prescribed by current and forecast economic conditions. However, this accommodation ceased following the end of the non-borrowed reserves targeting period in October 1982. Analyzing the determinants of bill sponsorship, we find that high unemployment, high inflation, and high long-term real borrowing costs— failures of the Fed along the three dimensions of its mandate—all lead to a greater number of bills seeking to alter the Fed’s powers. Importantly, we also find that the relative importance of these three dimensions has changed over time. Under Chairmen Burns and Miller, Congress took greater interest when unemployment was high. Under Chairman Greenspan, Congress took greater interest when inflation was high. We believe that these findings are consistent with the view that the lessons of the Great Inflation changed the public perception of the Fed’s macroeconomic responsibilities, which in turn better aligned Congressional views on policy with those of the Fed, and allowed the Fed to better resist remaining Congressional pressure to its independence.

The authors add to the sales management literature in three ways. First, they demonstrate that a firm can benefit from higher sales uncertainty. This is contrary to the finding from the standard principal–agent models that more sales uncertainty hurts the firm when agents are risk-averse. Second, the authors find that the risk-averse agent's total pay can increase when there is high sales uncertainty, and this too is contrary to the standard principal–agent model. Third, they provide intuition for this surprising result by showing that it holds when the slope of the sales response function is random but not when the intercept is random. When the responsiveness (slope) of sales to a decision variable (of the firm or the agent) is random, information about randomness becomes decision-relevant and the firm can exploit learned information. In this study's model, the agent and firm can receive noisy signals of random demand. When the customers’ response to effort (or price) is random, the decision about effort (price) responds optimally to information in a way that benefits the firm. When uncertainty is high, there is more potential information for the firm to exploit profitably, owing to the convexity of the sales with respect to the uncertainty parameter. This is enough to dominate the negative impact of uncertainty owing to agents’ risk aversion. When randomness affects only baseline sales (intercept), received signals are not decision-relevant. In that case, higher uncertainty has only a negative impact, just as in standard principal–agent models.

Introduction La prevention des infections respiratoires basses par la vaccination anti-grippale (AG) et anti-pneumococcique (AP) fait partie de la prise en charge recommandee pour tout patient atteint de BPCO, au meme titre que l’aide au sevrage tabagique et l’activite physique. Elle contribue notamment a limiter le risque d’exacerbations dont l’impact sur les patients, leur evolution et la societe est majeur. Les donnees vaccinales de cohortes francaises sont anciennes. La connaissance des facteurs associes a la vaccination peut contribuer a mieux construire les campagnes d’incitation. L’objectif de ce travail etait d’evaluer le taux de couverture vaccinale AG et AP, et les determinants de la vaccination chez des patients atteints de BPCO pris en charge par les pneumologues. Methodes Les donnees de 3 cohortes ont ete colligees: Colibri et Palomb ont ete lancees en 2012 et 2014 et impliquent des pneumologues hospitaliers et liberaux, Initiatives BPCO a ete lancee en 2004 essentiellement en centres hospitalo-universitaires. Seuls les dossiers renseignes entre 2012 et 2018 ont ete pris en compte par souci d’homogeneite entre les 3 cohortes. La couverture vaccinale rapportee a ete decrite, ses liens avec les donnees cliniques et fonctionnelles respiratoires ont ete analyses de maniere uni- puis multivariee. Resultats Au total 5927 patients (sur 7200) de la multicohorte ainsi constituee avaient des donnees suffisantes pour l’analyse ( Tableau 1 ). L’âge moyen etait de 66 ans, 33 % etaient des femmes, la repartition des stades GOLD 1/2/3/4 etait de 15 %/48 %/28 %/10 %, celle des GOLD A/B/C/D de 31 %/32 %/8 %/21 %, respectivement. Les % de patients avec historique d’asthme, de maladies cardio-vasculaires, de diabete etaient de 9 %, 52 % et 13 %, respectivement. Le tableau rapporte les taux de vaccination AG et AP globalement et par categorie GOLD A/B/C/D determinee a partir des symptomes et de l’historique d’exacerbation. Les analyses multivariees ont montre une association entre les vaccinations AG et AP et l’âge, le statut fumeur (moindre vaccination des fumeurs actifs), la severite de la BPCO (VEMS, exacerbations), les comorbidites (asthme, et pour la vaccination AG HTA et diabete). Conclusion Les taux de vaccination restent tres insuffisants, meme pour les patients suivis en pneumologie. La communication doit porter sur l’importance de ne pas limiter la vaccination a des profils de patients particuliers mais d’en faire beneficier l’integralite des BPCO.

Introduction La nouvelle version de la consultation digitale Colibri-BPCO lancee en fevrier 2020 a pour objectif principal d’assister le pneumologue pour etablir un diagnostic phenotypique a partir duquel il pourra, au fil des visites, verifier l’evolution de la trajectoire grâce a une serie de fonctionnalites incluant des developpements d’Intelligence Artificielle. Parmi ces caracteristiques phenotypiques, une implication particuliere du pneumologue est necessaire pour identifier les risques de declin et les formuler explicitement afin d’induire les decisions therapeutiques et programmer les modalites de suivi. Ce processus se deroule en 2 etapes : a partir des informations notees au cours de la consultation, Colibri repere parmi les 8 risques de declin identifies par les donnees de la litterature ceux qui sont susceptibles de concerner le patient. L’application demande au pneumologue de confirmer ou infirmer ces propositions selon que ces risques de declin sont conformes ou non a son opinion de clinicien. Apres quelques mois d’utilisation (discontinue pour cause de Covid) de la version 2020 de Colibri-BPCO, nous avons voulu analyser le taux de confirmation par les cliniciens de chacun des risques identifies a partir des criteres de la litterature. Methodes Deux cent onze patients avaient des donnees analysables de la nouvelle version de Colibri-BPCO. Nous avons verifie si le clinicien avait confirme, infirme, ou signale son incertitude par rapport aux risques de declin identifies par l’application a partir des criteres de la litterature. Resultats Voir Tableau 1 . Conclusion Cette analyse preliminaire montre qu’il n’y a pas de concordance entre les risques de declin reperes par la litterature et ceux confirmes par l’opinion du clinicien. Cette premiere constatation necessite d’etre confirmee mais peut expliquer en partie la frequence des prescriptions hors AMM constatee dans la litterature internationale. En effet, le choix du traitement repose avant tout sur la perception des risques par le clinicien plutot que sur les recommandations de la litterature. L’analyse des donnees de Colibri-BPCO devrait permettre de comprendre de maniere plus fine le processus de la decision medicale des praticiens confrontes au patient, et verifier de facon longitudinale si la subjectivite liee au sens clinique et a l’experience est un atout ou une impasse.

Introduction L’interrogatoire aide par des questionnaires specifique (QV-Dyspnee) permet de distinguer assez facilement les patients BPCO excessivement inactifs (EI) de ceux qui maintiennent une activite physique suffisante. Entre ces deux situations le doute subsiste ou n’est pas evoque, alors que les etudes s’accordent pour detecter, grâce aux mesures d’accelerometrie, plus de 40 % de patients inactifs dans cette sous population independamment de la severite de l’obstruction bronchique. Partant de l’hypothese que l’EI pouvait impacter, comme cause ou consequence, de multiples variables recueillies en consultation de routine, nous avons verifie si le comportement EI pouvait etre predit individuellement a partir de ces variables excluant de fait toutes les mesures d’exercice realisees au-dela du temps de la consultation. Methodes A partir de 5035 consultations Colibri-BPCO, nous avons selectionne 1409 dossiers ayant des informations completes sur 22 variables d’interet. Nous avons determine sur une base clinique un groupe de 172 patients denome SBPI associant un comportement sedentaire (SB) et physiquement inactif (PI) et un autre de 660 patients qui ne l’etait pas (non-SBPI). Sur les 832 patients SBPI et non SBPI, les donnees de 80 % (n = 666) ont ete utilisees pour mettre au point un algorithme d’apprentissage automatique pour predire le statut SBPI, et les donnees des 20 % (n = 166) restants ont ete utilisees pour tester sa fiabilite, (c’est dire l’erreur de prediction). L’algorithme a ensuite ete applique pour predire le statut SBPI des 577 patients « intermediaires » (1409–[172 + 660]). Resultats L’erreur globale de l’algorithme de prediction du statut SBPI etait de 13,7 %, avec une aire sous la courbe ROC de 0,84 (intervalles de confiance de 95 %: 0.75–0.92). Sur les 577 patients de la categorie intermediaire, 306 (53 %) ont ete classes comme SBPI par l’algorithme, ce qui suggere que les patients et/ou les medecins ont subjectivement a surestime les veritables niveaux d’AP des patients. Conclusion Cette etude demontre la fiabilite et l’utilite potentielle d’un algorithme predictif pour identifier a partir d’une consultation de routine, sans aucune mesure d’activite ou de capacite physique, si un patient presente une inactivite morbide necessitant une intervention prioritaire.