Tin(II) Ureide Complexes:Synthesis, Structural Chemistry and Evaluation as SnO precursors

In an attempt to tailor precursors for application in the deposition of phase pure SnO, we have evaluated a series of tin (1-6) ureide complexes. The complexes were successfully synthesized by employing N,N′-Trialkyl-functionalized ureide ligands, in which features such as stability, volatility, and decomposition could be modified with variation of the substituents on the ureide ligand in an attempt to find the complex with the ideal electronic, steric, or coordinative properties, which determine the fate of the final products. The tin(II) ureide complexes 1-6 were synthesized by direct reaction [Sn{NMe2}2] with aryl and alkyl isocyanates in a 1:2 molar ratio. All the complexes were characterized by NMR spectroscopy as well as elemental analysis and, where applicable, thermogravimetric (TG) analysis. The single-crystal X-ray diffraction studies of 2, 3, 4, and 6 revealed that the complexes crystallize in the monoclinic space group P2(1)/n (2 and 4) or in the triclinic space group P-1 (3 and 6) as monomers. Reaction with phenyl isocyanate results in the formation of the bimetallic species 5, which crystallizes in the triclinic space group P-1, a consequence of incomplete insertion into the Sn-NMe2 bonds, versus mesityl isocyanate, which produces a monomeric double insertion product, 6, under the same conditions, indicating a difference in reactivity between phenyl isocyanate and mesityl isocyanate with respect to insertion into Sn-NMe2 bonds. The metal centers in these complexes are all four-coordinate, displaying either distorted trigonal bipyramidal or trigonal bipyramidal geometries. The steric influence of the imido-ligand substituent has a clear effect on the coordination mode of the ureide ligands, with complexes 2 and 6, which contain the cyclohexyl and mesityl ligands, displaying κ2-O,N coordination modes, whereas κ2-N,N′ coordination modes are observed for the sterically bulkier tert-butyl and adamantyl derivatives, 3 and 4. The thermogravimetric analysis of the complexes 3 and 4 exhibited excellent physicochemical properties with clean single-step curves and low residual masses in their TG analyses suggesting their potential utility of these systems as MOCVD and ALD precursors.</p

SUPREME-HN: a retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND:Programmed cell death ligand-1 (PD-L1) expression on tumor cells (TCs) is associated with improved survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy, although its role as a prognostic factor is controversial. This study investigates whether tumoral expression of PD-L1 is a prognostic marker in patients with recurrent and/or metastatic (R/M) HNSCC treated with standard chemotherapy. METHODS:This retrospective, multicenter, noninterventional study assessed PD-L1 expression on archival R/M HNSCC tissue samples using the VENTANA PD-L1 (SP263) Assay. PD-L1 high was defined as PD-L1 staining of ≥ 25% TC, with exploratory scoring at TC ≥ 10% and TC ≥ 50%. The primary objective of this study was to estimate the prognostic value of PD-L1 status in terms of overall survival (OS) in patients with R/M HNSCC. RESULTS:412 patients (median age, 62.0 years; 79.9% male; 88.2% Caucasian) were included from 19 sites in seven countries. 132 patients (32.0%) had TC ≥ 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC ≥ 10% and ≥ 50%, respectively. OS did not differ significantly across PD-L1 expression (at TC ≥ 25% cutoff median OS: 8.2 months vs TC &lt; 25%, 10.1 months, P = 0.55) or the ≥ 10% and ≥ 50% cutoffs (at TC ≥ 10%, median OS: 9.6 months vs TC &lt; 10%, 9.4 months, P = 0.32, and at TC ≥ 50%, median OS 7.9 vs TC &lt; 50%, 10.0 months, P = 0.39, respectively). CONCLUSIONS:PD-L1 expression, assessed using the VENTANA PD-L1 (SP263) Assay, was not prognostic of OS in patients with R/M HNSCC treated with standard of care chemotherapies. Trial registration ClinicalTrials.gov, NCT02543476. Registered September 4, 2015

Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open -label phase III study

Background: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. Patients and methods: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. Results: Patients were randomly assigned to receive durvalumab (n 1⁄4 240), durvalumab plus tremelimumab (n 1⁄4 247), or SoC (n 1⁄4 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72e1.08; P 1⁄4 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85e1.26; P 1⁄4 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9e43.1), 30.4% (24.7e36.3), and 30.5% (24.7 e36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade !3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Conclusion: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab

Membrane Fusion Mediated by Non-covalent Binding of Re-engineered Cholera Toxin Assemblies to Glycolipids

Membrane fusion is essential for the transport of macromolecules and viruses across membranes. While glycan-binding proteins (lectins) often initiate cellular adhesion, subsequent fusion events require additional protein machinery. No mechanism for membrane fusion arising from simply a protein binding to membrane glycolipids has been described thus far. Herein, we report that a biotinylated protein derived from cholera toxin becomes a fusogenic lectin upon cross-linking with streptavidin. This novel reengineered protein brings about hemifusion and fusion of vesicles as demonstrated by mixing of fluorescently labeled lipids between vesicles as well as content mixing of liposomes filled with fluorescently labeled dextran. Exclusion of the complex at vesicle–vesicle interfaces could also be observed, indicating the formation of hemifusion diaphragms. Discovery of this fusogenic lectin complex demonstrates that new emergent properties can arise from simple changes in protein architecture and provides insights into new mechanisms of lipid-driven fusion

Childbearing postponement and child well-being: a complex and varied relationship?

Over the past several decades, U.S. fertility has followed a trend toward the postponement of motherhood. The socioeconomic causes and consequences of this trend have been the focus of attention in the demographic literature. Given the socioeconomic advantages of those who postpone having children, some authors have argued that the disadvantage experienced by certain groups would be reduced if they postponed their births. The weathering hypothesis literature, by integrating a biosocial perspective, complicates this argument and posits that the costs and benefits of postponement may vary systematically across population subgroups. In particular, the literature on the weathering hypothesis argues that as a consequence of their unique experiences of racism and disadvantage, African American women may experience a more rapid deterioration of their health, which could offset or eventually reverse any socioeconomic benefit of postponement. But because very few African American women postpone motherhood, efforts to find compelling evidence to support the arguments of this perspective rely on a strategy of comparison that is problematic because a potentially selected group of older black mothers are used to represent the costs of postponement. This might explain why the weathering hypothesis has played a rather limited role in the way demographers conceptualize postponement and its consequences for well-being. In order to explore the potential utility of this perspective, we turn our attention to the UK context. Because first-birth fertility schedules are similar for black and white women, we can observe (rather than assume) whether the meaning and consequences of postponement vary across these population subgroups. The results, obtained using linked UK census and birth record data, reveal evidence consistent with the weathering hypothesis in the United Kingdom and lend support to the arguments that the demographic literature would benefit from integrating insights from this biosocial perspective

Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study

Head and neck squamous cell carcinoma (HNSCC) is among the 10 most common cancers worldwide, with increasing incidence.1 Approximately 10% of patients with HNSCC will be diagnosed with metastatic disease, and even when treated early, around half will have disease recurrence.2,3 The platinum-based doublet chemotherapy with cetuximab regimen has been the most widely-used therapy and considered standard of care (SoC) since it was proven effective in 2007 for recurrent/metastatic (R/M) HNSCC in the first-line setting.3,4 However, patients typically progress even after aggressive first-line therapy, and, until recently, the available options (e.g. cetuximab, methotrexate, and taxanes) have delivered limited survival benefits.3 Durvalumab is an immunotherapeutic agent that blocks the interaction between programmed cell death ligand 1 (PD-L1) and its receptors.5 Durvalumab demonstrated encouraging response rates and duration of response (DoR) with a manageable safety profile in patients with HNSCC.6 Although monotherapy agents that block the programmed cell death protein 1 (PD-1)/PD-L1 axis have shown clinical activity, immunotherapy combinations have the potential to improve upon monotherapy activity.7e9 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and PD-L1/PD-1 pathways have largely non-redundant roles, suggesting that blockade of both could have additive or synergistic effects.10 Indeed, the combination of durvalumab and tremelimumab, an anti-CTLA-4 monoclonal antibody, was explored based on improved efficacy over monotherapy in other solid tumor types.7 This observation, in addition to the activity demonstrated by durvalumab in earlier R/M HNSCC studies, served as the rationale to evaluate durvalumab and tremelimumab in patients with R/M HNSCC. Several studies, including the EAGLE study, were initiated to evaluate combination immunotherapy regimens in various patient groups.11,12 The EAGLE study was the first phase III study to investigate durvalumab and tremelimumab in patients with R/M HNSCC who had progressed after platinumbased therapy. During the conduct of the EAGLE study, anti-PD-1 monoclonal antibodies were approved for use for R/M HNSCC progression following a platinum-based regimen. Treatment with these immunotherapies resulted in a median overall survival (OS) of 7.5e8.4 months.13,14 These immunotherapies are now recommended for second-line treatment as monotherapies for patients with R/M HNSCC.3,13,14 More recently, immunotherapy alone or in combination with platinum-based chemotherapy has shown improvements in OS in the first-line setting, underscoring the clinical utility of immunotherapy in HNSCC.15 Here, we report the results of the randomized phase III EAGLE trial evaluating durvalumab and durvalumab plus tremelimumab versus SoC therapies in patients with R/M HNSCC who have progressed following a platinumcontaining regimen

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome