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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

The severity of climatic effects of a regional nuclear conflict between India and Pakistan, involving the use of a hundred Hiroshima-scale nuclear weapons, is contested between two groups; Mills et al. from the National Center for Atmospheric Research (NCAR), University of Colorado, and Rutgers University conclude that a global Nuclear Winter would occur; Reisner et al. from Los Alamos National Laboratory (LANL) conclude that No Nuclear Winter would occur. This paper discusses the different assumptions that lead to the two different conclusions. Specifically, it highlights the use of different fuel loading and different input methods for the amount and initial location of black carbon (BC) into the climate models, and discusses some underlying reasons for these different choices, including the question of what kind of fire will occur in the aftermath of a nuclear weapon being dropped on a densely populated city. The paper also briefly discusses some physical phenomena that have not been considered by either group and lays out some questions for research before any definitive conclusion about the climatic effects of a limited nuclear war can be reached. However, until these problems are resolved, from a disarmament point of view, the precautionary principle is, in situations of such high stakes involving millions of deaths, there is an obligation to assume a worst-case scenario. Such a scenario would include the possibility that a limited nuclear conflict could cause a Nuclear Winter by leading to a broader nuclear conflict.

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.

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.

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

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.

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⧧...

In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC50) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability.

© 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.

Introduction Les PID constituent un groupe heterogene de maladies peu frequentes, dont la frequence variable selon les etudes, est generalement appreciee a partir d’etudes conduites essentiellement en CHU. Neanmoins, les pneumologues liberaux et des hopitaux generaux sont le plus souvent les initiateurs de la demarche diagnostique qui devrait aboutir idealement a une DMD pour securiser le diagnostic. L’usage d’une consultation digitale commune aux divers lieux d’exercice permet de faciliter le cheminement diagnostique multi intervenant et notamment d’observer les differences des etiologies retenues par les DMD selon le lieu d’exercice du pneumologue referent. Methodes Sur les 3007 consultations initiales colligees dans Colibri-PID, nous avons retenu pour l’analyse uniquement les dossiers pour lesquels la DMD a retenu un diagnostic soit formel, soit provisoire de travail. Selon le lieu d’exercice du pneumologue referent, nous avons compare les principales etiologies (FPI, Autre PI idiopathiques, PI de cause ou maladie connue, Sarcoidose & Granulomatoses, PI particulieres, PI inclassables), les caracteristiques cliniques, et les modalites diagnostiques. Resultats Globalement les dossiers presentes en DMD par l’intermediaire de la consultation digitale colibri-PID proviennent majoritairement de CHU (45%) Fig. 1 ). 42% des etiologies retenues concernait les PID idiopathiques dont 30% considerees comme FPI. Parmi les dossiers presentes: le % de FPI etait identique quel que soit le lieu d’exercice (environ 30%) alors que le diagnostic de PID Idiopathiques non FPI etait plus frequemment retenu pour les dossiers de CH ou liberal. Par contre, les PID retenues comme inclassables representaient un % plus eleve des dossiers presentes par un pneumologue liberal qu’hospitalier (CH et CHU). Bien que moins frequemment retenus (14,3% du total des etiologies) les diagnostiques de Sarcoidose/granulomatose et PID particulieres etaient proportionnellement semblables quel que soit le lieu d’exercice. Conclusion L’utilisation croissante de la consultation digitale Colibri-PID (environ 80 nouveaux dossiers/mois) permet d’observer les caracteristiques cliniques et l’evolution des etiologies retenues par diverses DMD hospitalieres ou non, rendant compte de certaines differences liees a l’origine du pneumologue referent. La generalisation de cette application pour la constitution des dossiers de PID et la gestion des DMD permettrait de valoriser la prise en charge individuelle et collective des PID.

Soil splash is the first step of water erosion. There are many methods for splash investigations however the use of high-speed cameras is becoming increasingly popular. This study describes the methodological aspects of using high-speed cameras and a PTV (Particle Tracking Velocimetry) system to investigate the soil splash phenomenon. The purpose of the research was to examine the impact of image processing and the choice of settings for particle tracking software on the effectiveness of detecting and identifying splashed/ejected particles (with their flight trajectories). Experiments were carried out on moisturized Haplic Luvisol soil samples and the impact of single water-drop onto the surface was recorded by three calibrated Phantom Miro M310 high-speed cameras. Registered frames were subjected to image processing in Dantec DynamicStudio software, where the selection of the optimal set of parameters/settings was validated, in the context of maximum detection of the splashed particles. The resulted images provided the input data for the Volumetric 3D PTV module (DynamicStudio) to identify/track the ejected particles and then determine their trajectories. The study presents the use of different settings (variants) of tracking modules, enabling the most efficient identification and description of the particles’ trajectories (76%). The incomplete trajectories detected (excluding starting and landing fragments), were subjected to a reconstruction process based on mathematical extrapolation. The analyze of the registered images and reconstructed trajectories of splashed particles gave the possibility to determine the following parameters describing soil splash phenomenon: a) number of splashed particles, b) ejection angle (for each particle), c) ejection velocity, d) displacement range, e) altitude (the maximal height reached by the particle).

Cancer is a heterogeneous disease, and its treatment requires the identification of new ways to thwart tumor cells. Amongst such emerging targets are glucose transporters (GLUTs, SLC2 family), which are overexpressed by almost all types of cancer cells; their inhibition provides a strategy to disrupt tumor metabolism selectively, leading to antitumor effects. Here, novel thiazolidinedione (TZD) derivatives were designed, synthesized, characterized, and evaluated for their GLUT1, GLUT4, and GLUT5 inhibitory potential, followed by in-vitro cytotoxicity determination in leukemic cell lines. Compounds G5, G16, and G17 inhibited GLUT1, with IC50 values of 5.4 ± 1.3, 26.6 ± 1.8, and 12.6 ± 1.2 μM, respectively. G17 was specific for GLUT1, G16 inhibited GLUT4 (IC50 = 21.6 ± 4.5 μM) comparably but did not affect GLUT5. The most active compound, G5, inhibited all three GLUT types, with GLUT4 IC50 = 9.5 ± 2.8 μM, and GLUT5 IC50 = 34.5 ± 2.4 μM. Docking G5, G16, and G17 to the inward- and outward-facing structural models of GLUT1 predicted ligand binding affinities consistent with the kinetic inhibition data and implicated E380 and W388 of GLUT1 vs. their substitutions in GLUT5 (A388 and A396, respectively) in inhibitor preference for GLUT1. G5 inhibited the proliferation of leukemia CEM cells at low micromolar range (IC50 = 13.4 μM) while being safer for normal blood cells. Investigation of CEM cell cycle progression after treatment with G5 showed that cells accumulated in the G2/M phase. Flow cytometric apoptosis studies revealed that compound G5 induced both early and late-stage apoptosis in CEM cells.

Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC50 – 9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC50 – 28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC50 – 104.2 μM) and human fibroblasts (HS27) (CC50 – 105.0 μM). Thus, among this novel series of TZD derivatives, compound P19 was most promising HDAC8 inhibitor and cytotoxic on leukemic cells. Thus, P19 could serve as a lead for further development of optimized molecules with enhanced selectivity and potency.

Introduction On constate que les traitements inhales prescrits au cours de la BPCO ne correspondent pas toujours aux recommandations des societes savantes ni ne respectent scrupuleusement les differentes AMM. Pour tenter de comprendre le rationnel de ces prescriptions, nous avons analyse les donnees de la cohorte Colibri-BPCO. Methodes L’analyse a ete realisee a partir de 1171 patients (sur 4860 patients recenses) dont les dossiers etaient renseignes de facon exhaustive (caracteristiques cliniques, comorbidites, exacerbations, questionnaires CAT-DIRECT-HAD, fonction respiratoire, et traitements prescrits). Plusieurs modeles de statistique predictive ont ete appliques pour reconnaitre les variables qui influencent le choix therapeutique, et pour verifier la probabilite de choisir l’une ou l’autre des 5 charges therapeutiques suivantes : A : aucun traitement inhale, ou simplement de courte duree d’action B : 1 bronchodilatateur a action prolongee (LABA ou LAMA) C : LABA + LAMA D : 1 LABA ou LAMA + corticosteroide inhale (CSI) E : triple therapie (LABA + LAMA + ICS). Resultats Une tritherapie (E) a ete prescrite chez 32,9 % des patients et 29,8 % ont recu une combinaison de deux traitements (C ou D) ; 44 % des patients ont recu un traitement contenant un CSI (D + E). La bronchodilatation simple ou double sans CSI etait moins frequente (B et C : 19 % chacune). Alors que la fonction pulmonaire etait associee a toutes les decisions de traitement, les antecedents d’exacerbation, les scores d’impact clinique (questionnaires) et le sexe etaient associes a la prescription de plus d’1 traitement d’entretien. Prenant en compte toutes ces dimensions, les modeles permettent de predire le choix d’une charge therapeutique par rapport aux 4 autres avec un taux d’erreur inferieur a 35 %. Conclusion Malgre la constatation de la prescription a priori non justifiee de corticoide inhale, nos resultats montrent que le choix d’une charge therapeutique repond a un rationnel base sur les donnees cliniques des patients.

Adrenocorticotropic hormone (ACTH) challenges are frequently performed in repetition when evaluating stress or welfare in animals. To our knowledge, the repeatability of ACTH challenges in cattle, although fundamental to further studies of this type, has not yet been the subject of research. Therefore, the objective of this study was to evaluate the repeatability of ACTH challenges in fattening bulls of different horn status. Eight-one bulls were subjected to 3 consecutive ACTH challenges. The first challenge (C1) was performed in calves aged 1.5 mo. Subsequently, animals were characterized as high or low cortisol responders and either disbudded or left with horns. They were then assigned to 1 of 3 rearing groups: a horned group (H+), a disbudded group (H−), and a mixed group (M; 50% horned and 50% disbudded), with each group containing an equal number of high and low responders. The second ACTH challenge (C2) was performed at the age of 11 mo. Time of day (TOD) of challenge was either fixed (ST = same TOD) or alternated (AT = alternate TOD) between C1 and C2. The third ACTH challenge (C3) was performed 7 d after and at the same TOD as C2. Saliva samples were taken 60 and 30 min before and 30, 60, 90, 120, and 150 min after each intravenous ACTH injection. The area under the curve (AUC) was calculated with respect to both ground (AUCG) and to increase (AUCI). The AUCI increased markedly between C1 and C2 (P 0.1). The overall repeatability of AUCG and AUCI between C1 and C2, reflecting the repeatability between 2 different physiological states, was poor and moderate, respectively, for ST bulls (AUCG: r = 0.24, P > 0.1, intraclass correlation coefficient (ICC) = 0.21; AUCI: r = 0.48, P 0.1; ICC = 0.03; AUCI: r = 0.08, P > 0.1, ICC = 0.06). The repeatability of AUCG and AUCI between C2 and C3, reflecting the repeatability within the same physiological state, was moderate (AUCG: r = 0.59, P

Reactions of cis-PtCl

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies. Currently, approved drugs are given with non-curative intent as the only known cure is allogeneic bone marrow transplantation, which relies on the donor's immune system driving an allogeneic effect. Previous efforts to harness the endogenous immune system have been less successful. We present the results of a pilot study of K562/GM-CSF (GVAX) whole-cell vaccination in MDS patients. The primary objective of safety was met as there were no serious adverse events. One patient had a decrease in transfusion requirements and another demonstrated hematologic improvement suggesting a signal for clinical activity. In vitro correlative studies indicated biological effects on immune cells following vaccination. Although only a pilot study, results are encouraging that an immunotherapeutic approach with a whole-cell vaccine may be feasible in MDS patients.

Collinearity is inevitable in moderated regression models. Marketing scholars use a variety of collinearity diagnostics including variance inflation factors (VIFs) and condition indices in order to diagnose the extent of collinearity in moderated models. In this paper, we show that VIFs are likely to misdiagnose the extent of collinearity problems by conflating lack of variability (small variance) or lack of magnitude (small mean) in data for collinearity. Condition indices accurately diagnose collinearity, however, they fail to identify when collinearity is actually harmful to statistical inferences. We propose a new measure, C 2 , based on raw data, which diagnoses the extent of collinearity in moderated regression models. More importantly, this C 2 measure, in conjunction with the t-statistic of the non-significant coefficient, can indicate adverse effects of collinearity in terms of distorting statistical inferences and how much collinearity would have to disappear to generate significant results. The efficacy of C 2 over VIFs and condition indices is demonstrated using simulated data and its usefulness in moderated regressions is illustrated in an empirical study of brand extensions.

Purpose: Post-operative radiotherapy (PORT) for resected cutaneous squamous cell carcinoma (CSCC) with perineural invasion (PNI) is controversial. Therefore, we conducted a survey to review treatment recommendations among Radiation Oncologists (ROs) in the management of CSCC with PNI. Materials & Methods: In March 2011, we contacted all ROs and trainees in the US through email addresses listed in the 2009 ASTRO directory. Our web-based survey presented clinical vignettes involving Mohs micrographically resected CSCC with microscopic PNI (mPNI) or clinical PNI (cPNI). For each vignette, ROs were asked to indicate if PORT was appropriate and to further specify the dose and volume to treat. Results: Three hundred fifty two responses were completed and analyzed. The majority of ROs (72%) had over 10 years of post residency experience. 64% of the sampled ROs had a special interest in treating head and neck cancers, and 64% treated 4 or more cases per year. Approximately 95% recommended PORT for cPNI whereas 59% recommended PORT for mPNI. Post residency experience (10+ yrs vs. = 0.005) and for mPNI of deep subcutaneous non-named nerve involvement (80% vs. 60%, p = 0.001). ROs treating 8 or more cases per year (vs. = 0.01). Conclusions: Our study demonstrates significant variability among ROs in the management of CSCC with mPNI. For cases of cPNI, an overwhelming majority recommended PORT. In cases of mPNI, there was no consensus for recommending PORT, although experienced practitioners had a lower threshold for offering treatment. These results indicate the need for prospective clinical studies to clarify the role of PORT in CSCC patients with mPNI.

MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.

Aims Namitecan is a new camptothecan compound undergoing early clinical development. This study was initiated to build an integrated pharmacokinetic (PK) and pharmacodynamic (PD) population model of namitecan to guide future clinical development. Methods Plasma concentration–time data, neutrophils and thrombocytes were pooled from two phase 1 studies in 90 patients with advanced solid tumours, receiving namitecan as a 2 h infusion on days 1 and 8 every 3 weeks (D1,8) (n = 34), once every 3 weeks (D1) (n = 29) and on 3 consecutive days (D1–3) (n = 27). A linear three compartment PK model was coupled to a semiphysiological PD-model for neutrophils and thrombocytes. Data simulations were used to interrogate various dosing regimens and give dosing recommendations. Results Clearance was estimated to be 0.15 l h–1, with a long terminal half-life of 48 h. Body surface area was not associated with clearance, supporting flat-dosing of namitecan. A significant and clinically relevant association was found between namitecan area under the concentration–time curve (AUC) and the percentage drop of neutrophils (r2 = 0.51, P < 10−4) or thrombocytes (r2 = 0.49, P < 10−4). With a target for haematological dose-limiting toxicity of

Bacterial and fungal infections remain a significant cause of transplant-related mortality following allogeneic stem cell transplantation (SCT). Granulocyte transfusions (GTs) may reduce the neutropenic period after SCT and prevent further progression of the existing infection (that is, therapeutic GT) in addition to standard antibacterial and antifungal therapy. A retrospective analysis was performed on 28 consecutive pediatric SCT recipients who received at least one dose of GT between March 2003 and November 2013 at a single institution. All donors were conditioned with G-CSF+dexamethasone with harvest performed 12-18 h later. Indications for SCT were acute leukemia in 46% (13/28) and severe aplastic anemia in 21% (6/28). The main indications for GT were invasive fungal disease in 50%, bacterial infection in 21% and co-morbidities with predicted reduced tolerance to sepsis in 18% (5/28). The median number of GT was 6 (range 1-14) with a median dose of 3.56 × 10(10) granulocytes infused. The median increment in ANC was 1.06 × 10(9)/L and correlated with the granulocyte dose infused. Adverse reactions observed were mild and infrequent. Sixty-four percent of patients (18/28) are alive with only 2 of the 10 deaths being related to progression of infection. In addition there was a low overall incidence of grade 3-4 acute mucositis and a very low incidence (7%) of acute GvHD grade 3-4. Single-donor GTs afford protection to children undergoing SCT at additional risk of infection and may reduce the overall incidence of severe GvHD.

Purpose: This is a first-in-human, phase I, dose-escalation study to determine the maximum tolerated dose (MTD) of intravenous, flat-dosed ST-1968 (namitecan), a new hydrophilic camptothecan derivative. Methods: Namitecan was administered intravenously over 2 h on day 1 and day 8 every 21 days (D1-D8-Q21D), starting at a flat dose of 2.5 mg, and increased according to a 3 + 3 cohort design. Due to frequent skipping of day 8 dosing for cytopenias, the study was expanded to test namitecan dosing on day 1 every 21 days (D1-Q21) at a starting dose of 17.5 mg. Major dose-limiting toxicity (DLT) was defined as grade (G) 4 neutropenia persisting >5 days, febrile neutropenia, G3 thrombocytopenia or G2 non-hematological toxicity. Results: Thirty-four patients were included into the D1-D8-Q21D group (2.5, 5, 10, 15, 17.5, 20 mg dosing cohorts), 29 patients into the D1-21D group (17.5, 20, 23, 27, 30 mg dosing cohorts). Neutropenia was the DLT in both groups, with 15 mg being defined as the recommended dose (RD) for the D1-D8-Q21D group, and 23 mg for the D1-Q21D group. Non-hematological toxicity was negligible. One patient with endometrial cancer in the D1-D8-Q21D group and one patient with cholangiocellular carcinoma in the D1-Q21D group experienced a partial remission. Namitecan exhibited fully dose-proportional pharmacokinetics. Conclusions: This study demonstrates clinical safety, favourable pharmacokinetics and preliminary antitumor activity of the novel hydrophilic camptothecin analogue namitecan in patients with heavily pretreated solid malignancies, when given either on a 2 out of 3 weeks or 3-weekly regimen.