Immune checkpoint blockade improves survival in a subset of patients with non-small-cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. ...Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited.
We performed comprehensive flow cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next-generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC).
Cytometric profiling identified an immunologically "hot" cluster with abundant CD8
T cells expressing high levels of PD-1 and TIM-3 and an immunologically "cold" cluster with lower relative abundance of CD8
T cells and expression of inhibitory markers. The "hot" cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the "hot" cluster. Additionally, approximately 20% of cases had high B cell infiltrates with a subset producing IL-10.
Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer.
The Robert A. and Renée E. Belfer Family Foundation, Expect Miracles Foundation, Starr Cancer Consortium, Stand Up to Cancer Foundation, Conquer Cancer Foundation, International Association for the Study of Lung Cancer, National Cancer Institute (R01 CA205150), and the Damon Runyon Cancer Research Foundation.
Fatigue in bamboo Keogh, Lauren; O’Hanlon, Patrick; O’Reilly, Peter ...
International journal of fatigue,
06/2015, Letnik:
75
Journal Article
Recenzirano
•First ever fatigue data for bamboo.•Two different species of bamboo tested.•Bamboo displays fatigue when loaded perpendicular to fibres, but not when loaded parallel to fibres.
This paper describes ...the results of an experimental programme to determine the fatigue behaviour of bamboo. Bamboo is subjected to cyclic loading, both in the plant itself and subsequently when the material is used in load-bearing applications in the construction industry. However, there is currently no data in the literature describing fatigue in this material. We found that sections of bamboo culm loaded parallel to the culm axis did not undergo fatigue failure: samples either failed on the first loading cycle, or not at all. By contrast, fatigue was readily apparent in samples loaded in compression across the diameter of the culm. The number of cycles to failure increased as the cyclic load range decreased in a manner similar to that found in many engineering materials: fatigue occurred at applied loads as small as 40% of the ultimate strength. Two different species of bamboo were tested and found to have different ultimate strengths but similar high-cycle fatigue strengths. Finite element analysis was used to help understand the progression of fatigue damage and the effect of stress concentration features. Some tentative design rules are proposed to define stress levels for the safe use of bamboo, taking fatigue into account.
With the emergence of checkpoint blockade and other immunotherapeutic drugs, and the growing adoption of smaller, more flexible adaptive clinical trial designs, there is an unmet need to develop ...diagnostics that can rapidly immunophenotype patient tumors. The ability to longitudinally profile the tumor immune infiltrate in response to immunotherapy also presents a window of opportunity to illuminate mechanisms of resistance. We have developed a fine needle aspirate biopsy (FNA) platform to perform immune profiling on thoracic malignancies. Matching peripheral blood, bulk resected tumor, and FNA were analyzed from 13 mesothelioma patients. FNA samples yielded greater numbers of viable cells when compared to core needle biopsies. Cell numbers were adequate to perform flow cytometric analyses on T cell lineage, T cell activation and inhibitory receptor expression, and myeloid immunosuppressive checkpoint markers. FNA samples were representative of the tumor as a whole as assessed by head-to-head comparison to single cell suspensions of dissociated whole tumor. Parallel analysis of matched patient blood enabled us to establish quality assurance criteria to determine the accuracy of FNA procedures to sample tumor tissue. FNA biopsies provide a diagnostic to rapidly phenotype the tumor immune microenvironment that may be of great relevance to clinical trials.
To determine how distinct combinations of resistance training prescription (RTx) variables (load, sets and frequency) affect muscle strength and hypertrophy.
MEDLINE, Embase, Emcare, SPORTDiscus, ...CINAHL, and Web of Science were searched until February 2022.
Randomised trials that included healthy adults, compared at least 2 predefined conditions (non-exercise control (CTRL) and 12 RTx, differentiated by load, sets and/or weekly frequency), and reported muscle strength and/or hypertrophy were included.
Systematic review and Bayesian network meta-analysis methodology was used to compare RTxs and CTRL. Surface under the cumulative ranking curve values were used to rank conditions. Confidence was assessed with threshold analysis.
The strength network included 178 studies (n=5097; women=45%). The hypertrophy network included 119 studies (n=3364; women=47%). All RTxs were superior to CTRL for muscle strength and hypertrophy. Higher-load (>80% of single repetition maximum) prescriptions maximised strength gains, and all prescriptions comparably promoted muscle hypertrophy. While the calculated effects of many prescriptions were similar, higher-load, multiset, thrice-weekly training (standardised mean difference (95% credible interval); 1.60 (1.38 to 1.82) vs CTRL) was the highest-ranked RTx for strength, and higher-load, multiset, twice-weekly training (0.66 (0.47 to 0.85) vs CTRL) was the highest-ranked RTx for hypertrophy. Threshold analysis demonstrated these results were extremely robust.
All RTx promoted strength and hypertrophy compared with no exercise. The highest-ranked prescriptions for strength involved higher loads, whereas the highest-ranked prescriptions for hypertrophy included multiple sets.
CRD42021259663 and CRD42021258902.
Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain ...development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.
Species face multiple selective pressures that may require opposing responses to mitigate. On rocky shorelines, fitness of the intertidal snail Littorina littorea is determined by both parasitism and ...predation. We experimentally demonstrated that L. littorea was at greatest risk of infection from trematode parasites high in the intertidal zone where it was in closest proximity to abundant gull feces (the vector for the snail's parasites). However, because of extreme, size‐selective predation pressure at low tidal elevations, small snails often live high in the intertidal until they have grown sufficiently large. By prolonging their exposure to infection higher on the shore, ontogenetic responses to predation risk accentuate parasite risk. Counterintuitively, snails exhibited the highest trematode prevalence at the lowest tidal elevations where they had almost no risk of contracting infection. By carrying contracted infections into the lowest tidal zones, the larger, predation‐resistant snails invert hotspots of infection risk and prevalence, underscoring that size‐dependent selection pressures can decouple infection process and pattern even over small scales.
Disruption of the adaptor protein SH2B1 (SH2-B, PSM) is associated with severe obesity, insulin resistance, and neurobehavioral abnormalities in mice and humans. Here, we identify 15
variants in ...severely obese children. Four obesity-associated human
variants lie in the Pleckstrin homology (PH) domain, suggesting that the PH domain is essential for SH2B1's function. We generated a mouse model of a human variant in this domain (P322S). P322S/P322S mice exhibited substantial prenatal lethality. Examination of the P322S/+ metabolic phenotype revealed late-onset glucose intolerance. To circumvent P322S/P322S lethality, mice containing a two-amino acid deletion within the SH2B1 PH domain (ΔP317, R318 ΔPR) were studied. Mice homozygous for ΔPR were born at the expected Mendelian ratio and exhibited obesity plus insulin resistance and glucose intolerance beyond that attributable to their increased adiposity. These studies demonstrate that the PH domain plays a crucial role in how SH2B1 controls energy balance and glucose homeostasis.
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