Apparent-Strain Correction for Combined Thermal and Mechanical Testing

Combined thermal and mechanical testing requires that the total strain be corrected for the coefficient of thermal expansion mismatch between the strain gage and the specimen or apparent strain when the temperature varies while a mechanical load is being applied. Collecting data for an apparent strain test becomes problematic as the specimen size increases. If the test specimen cannot be placed in a variable temperature test chamber to generate apparent strain data with no mechanical loads, coupons can be used to generate the required data. The coupons, however, must have the same strain gage type, coefficient of thermal expansion, and constraints as the specimen to be useful. Obtaining apparent-strain data at temperatures lower than -320 F is challenging due to the difficulty to maintain steady-state and uniform temperatures on a given specimen. Equations to correct for apparent strain in a real-time fashion and data from apparent-strain tests for composite and metallic specimens over a temperature range from -450 F to +250 F are presented in this paper. Three approaches to extrapolate apparent-strain data from -320 F to -430 F are presented and compared to the measured apparent-strain data. The first two approaches use a subset of the apparent-strain curves between -320 F and 100 F to extrapolate to -430 F, while the third approach extrapolates the apparent-strain curve over the temperature range of -320 F to +250 F to -430 F. The first two approaches are superior to the third approach but the use of either of the first two approaches is contingent upon the degree of non-linearity of the apparent-strain curve

Nivolumab versus investigator's choice in patients with recurrent or metastatic squamous cell carcinoma of the head and neck : efficacy and safety in CheckMate 141 by age

Objectives: Many patients with squamous cell carcinoma of the head and neck (SCCHN) are 6565 years old; comorbidities and other age-related factors may affect their ability to tolerate traditional chemotherapy. Nivolumab is the only immunotherapy to significantly improve overall survival (OS) versus investigator's choice (IC) of single-agent chemotherapy at primary analysis in a phase 3 trial (CheckMate 141) in patients with recurrent/metastatic SCCHN post-platinum therapy. In this post hoc analysis, we report efficacy and safety by age. Patients and methods: Eligible patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks (n = 240) or IC (methotrexate, docetaxel, or cetuximab n = 121). The primary endpoint of the trial was OS. For this analysis, outcomes were analyzed by age < 65 and 6565 years. The data cut-off date was September 2017 (minimum follow-up 24.2 months). Results: At baseline, 68 patients (28.3%) receiving nivolumab and 45 patients (37.2%) receiving IC were 6565 years. Baseline characteristics were generally similar across age groups. OS and tumor response benefits with nivolumab versus IC were maintained regardless of age. The 30-month OS rates of 11.2% (<65 years) and 13.0% ( 6565 years) with nivolumab were more than tripled versus corresponding IC rates of 1.4% and 3.3%, respectively. The nivolumab arm had a lower rate of treatment-related adverse events versus IC regardless of age, consistent with the overall patient population. Conclusion: In CheckMate 141, nivolumab resulted in a higher survival versus IC in patients <65 and 6565 years, with a manageable safety profile in both age groups. ClinicalTrials.gov: NCT02105636

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

Forest Biodiversity Assessment in Peruvian Andean Montane Cloud Forest

Cloud forests are unusual and fragile habitats, being one of the least studied and least understood ecosystems. The tropical Andean dominion is considered one of the most significant places in the world as rega rds biological diversity, with a very high level of endemism. The biodiversity was analysed in an isolated remnant area of a tropical montane cloud forest known as the ?Bosque de Neblina de Cuyas?, in the North of the Peruvian Andean range. Composition, structure and dead wood were measured or estimated. The values obtained were compared with other cloud forests. The study revealed a high level of forest biodiversity, although the level of biodiversity differs from one area to another: in the inner areas, where human pressure is almost inexistent, the biodiversity values increase. The high species richness and the low dominance among species bear testimony to this montane cloud forest as a real enclave of biodiversity

Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans

Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations

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

A Multitrait Locus Regulates Sarbecovirus Pathogenesis

Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genomewide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. IMPORTANCE Host genetic variation is an important determinant that predicts disease outcomes following infection. In the setting of highly pathogenic coronavirus infections genetic determinants underlying host susceptibility and mortality remain unclear. To elucidate the role of host genetic variation on sarbecovirus pathogenesis and disease outcomes, we utilized the Collaborative Cross (CC) mouse genetic reference population as a model to identify susceptibility alleles to SARS-CoV and SARS-CoV-2 infections. Our findings reveal that a multitrait loci found in chromosome 9 is an important regulator of sarbecovirus pathogenesis in mice. Within this locus, we identified and validated CCR9 and CXCR6 as important regulators of host disease outcomes. Specifically, both CCR9 and CXCR6 are protective against severe SARS-CoV, SARS-CoV-2, and SARS-related HKU3 virus disease in mice. This chromosome 9 multitrait locus may be important to help identify genes that regulate coronavirus disease outcomes in humans

The evolution of language: a comparative review

For many years the evolution of language has been seen as a disreputable topic, mired in fanciful "just so stories" about language origins. However, in the last decade a new synthesis of modern linguistics, cognitive neuroscience and neo-Darwinian evolutionary theory has begun to make important contributions to our understanding of the biology and evolution of language. I review some of this recent progress, focusing on the value of the comparative method, which uses data from animal species to draw inferences about language evolution. Discussing speech first, I show how data concerning a wide variety of species, from monkeys to birds, can increase our understanding of the anatomical and neural mechanisms underlying human spoken language, and how bird and whale song provide insights into the ultimate evolutionary function of language. I discuss the ‘‘descended larynx’ ’ of humans, a peculiar adaptation for speech that has received much attention in the past, which despite earlier claims is not uniquely human. Then I will turn to the neural mechanisms underlying spoken language, pointing out the difficulties animals apparently experience in perceiving hierarchical structure in sounds, and stressing the importance of vocal imitation in the evolution of a spoken language. Turning to ultimate function, I suggest that communication among kin (especially between parents and offspring) played a crucial but neglected role in driving language evolution. Finally, I briefly discuss phylogeny, discussing hypotheses that offer plausible routes to human language from a non-linguistic chimp-like ancestor. I conclude that comparative data from living animals will be key to developing a richer, more interdisciplinary understanding of our most distinctively human trait: language