Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity.

Although immunotherapies have achieved remarkable salutary effects among subgroups of advanced cancers, most patients do not respond. We comprehensively evaluated biomarkers associated with the "cancer-immunity cycle" in the pan-cancer setting in order to understand the immune landscape of metastatic malignancies as well as anti-PD-1/PD-L1 inhibitor resistance mechanisms. Interrogation of 51 markers of the cancer-immunity cycle was performed in 101 patients with diverse malignancies using a clinical-grade RNA sequencing assay. Overall, the immune phenotypes demonstrated overexpression of multiple checkpoints including VISTA (15.8% of 101 patients), PD-L2 (10.9%), TIM3 (9.9%), LAG3 (8.9%), PD-L1 (6.9%) and CTLA4 (3.0%). Additionally, aberrant expression of macrophage-associated markers (e.g. CD68 and CSF1R; 11-23%), metabolic immune escape markers (e.g. ADORA2A and IDO1; 9-16%) and T-cell priming markers (e.g. CD40, GITR, ICOS and OX40; 4-31%) were observed. Most tumors (87.1%, 88/101) expressed distinct immune portfolios, with a median of six theoretically actionable biomarkers (pharmacologically tractable by Food and Drug Administration approved agents [on- or off-label] or with agents in clinical development). Overexpression of TIM-3, VISTA and CD68 were significantly associated with shorter progression-free survival (PFS) after anti-PD-1/PD-L1-based therapies (among 39 treated patients) (all P < .01). In conclusion, cancer-immunity cycle biomarker evaluation was feasible in diverse solid tumors. High expression of alternative checkpoints TIM-3 and VISTA and of the macrophage-associated markers CD68 were associated with significantly worse PFS after anti-PD-1/PD-L1-based therapies. Most patients had distinct and complex immune expression profiles suggesting the need for customized combinations of immunotherapy

Revisiting Epidermal Growth Factor Receptor (EGFR) Amplification as a Target for Anti-EGFR Therapy: Analysis of Cell-Free Circulating Tumor DNA in Patients With Advanced Malignancies.

PurposeTo date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of EGFR amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response.MethodsWe assessed EGFR amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test.ResultsOverall, EGFR amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non-small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle-associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). EGFR amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with EGFR amplification were treated with anti-EGFR-based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked EGFR amplification.ConclusionEGFR amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring EGFR amplification in cfDNA merits additional study

The relationship between chronic diseases and number of sexual partners: an exploratory analysis

Background: We investigated sex-specific associations between lifetime number of sexual partners and several health outcomes in a large sample of older adults in England. Methods: We used cross-sectional data from 2,537 men and 3,185 women aged ≥50 years participating in the English Longitudinal Study of Ageing. Participants reported the number of sexual partners they had had in their lifetime. Outcomes were self-rated health and self-reported limiting long-standing illness, cancer, coronary heart disease (CHD), and stroke. We used logistic regression to analyse associations between lifetime number of sexual partners and health outcomes, adjusted for relevant sociodemographic and health-related covariates. Results: Having had 10 or more lifetime sexual partners was associated with higher odds of reporting a diagnosis of cancer than having had 0-1 sexual partners in men (OR=1.69, 95% CI 1.01-2.83) and women (OR=1.91, 95% CI 1.04-3.51), respectively. Women who had 10 or more lifetime sexual partners also had higher odds of reporting a limiting long-standing illness (OR=1.64, 95% CI 1.15 2.35). No other statistically significant associations were observed. Conclusions: A higher lifetime number of sexual partners is associated with increased odds of reported cancer. Longitudinal research is required to establish causality. Understanding the predictive value of lifetime number of sexual partner as a behavioural risk factor may improve clinical assessment of cancer risk in older adults

Associations between sexual activity and weight status: Findings from the English Longitudinal Study of Ageing.

OBJECTIVE: To investigate the association between weight status and sexual activity in middle-aged and older adults. METHODS: Cross-sectional analysis on Wave 6 (2012/13) of the English Longitudinal Study of Ageing. Data were from 2,200 men and 2,737 women aged ≥50 years (mean 68.2 years). The explanatory variable was weight status, defined as normal-weight (BMI: ≤24.9), overweight (BMI: 25.0-29.9) or obese (BMI: ≥30) based on objective measurements of height and weight. Outcome variables were any self-reported sexual activity in the last year (yes/no) and, if yes, frequency of sexual intercourse in the last month. Covariates included a range of sociodemographic, lifestyle, and health-related variables. Associations were analysed using binary (past-year sexual activity) and ordinal (frequency of past-month sexual intercourse) logistic regression models. RESULTS: The majority (73.3%) of men and half (50.0%) of women reported any sexual activity in the last year. The odds of reporting any sexual activity in the last year did not differ significantly by weight status in either men or women. However, among those who were sexually active, men with overweight (OR = 1.45, 95% CI 1.15-1.81, p = 0.002) or obesity (OR = 1.38, 95% CI 1.07-1.77, p = 0.015), and women with overweight (OR = 1.34, 95% CI 1.05-1.71, p = 0.017) reported significantly more frequent sexual intercourse in the last month compared with those who had a BMI in the normal-weight range, after adjustment for covariates. CONCLUSION: Older adults with overweight or obesity who are sexually active engage in more frequent sexual activity than those who are normal weight

Modification of polyelectrolyte multilayer coatings using nanoparticles to optimize adhesion and proliferation of different cell types

Adapting characteristics of biomaterials specifically for in vitro and in vivo applications is becoming increasingly important in order to control interactions between material and biological systems. These complex interactions are influenced by surface properties like chemical composition, charge, mechanical and topographic attributes. In many cases it is not useful or even not possible to alter the base material but changing surface, to improve biocompatibility or to make surfaces bioactive, may be achieved by thin coatings. An already established method is the coating with polyelectrolyte multilayers (PEM). To adjust adhesion, proliferation and improve vitality of certain cell types, we modified the roughness of PEM coatings. We included different types nanoparticles (NP’s) in different concentrations into PEM coatings for controlling surface roughness. Surface properties were characterized and the reaction of 3 different cell types on these coatings was tested

Bacterial infection elicits heat shock protein 72 release from pleural mesothelial cells

Heat shock protein 70 (HSP70) has been implicated in infection-related processes and has been found in body fluids during infection. This study aimed to determine whether pleural mesothelial cells release HSP70 in response to bacterial infection in vitro and in mouse models of serosal infection. In addition, the in vitro cytokine effects of the HSP70 isoform, Hsp72, on mesothelial cells were examined. Further, Hsp72 was measured in human pleural effusions and levels compared between non-infectious and infectious patients to determine the diagnostic accuracy of pleural fluid Hsp72 compared to traditional pleural fluid parameters. We showed that mesothelial release of Hsp72 was significantly raised when cells were treated with live and heat-killed Streptococcus pneumoniae. In mice, intraperitoneal injection of S. pneumoniae stimulated a 2-fold increase in Hsp72 levels in peritoneal lavage (p,0.01). Extracellular Hsp72 did not induce or inhibit mediator release from cultured mesothelial cells. Hsp72 levels were significantly higher in effusions of infectious origin compared to non-infectious effusions (p,0.05). The data establish that pleural mesothelial cells can release Hsp72 in response to bacterial infection and levels are raised in infectious pleural effusions. The biological role of HSP70 in pleural infection warrants exploration

Molecular recognition of DNA base pairs by the formamido/pyrrole and formamido/imidazole pairings in stacked polyamides

Polyamides containing an N-terminal formamido (f) group bind to the minor groove of DNA as staggered, antiparallel dimers in a sequence-specific manner. The formamido group increases the affinity and binding site size, and it promotes the molecules to stack in a staggered fashion thereby pairing itself with either a pyrrole (Py) or an imidazole (Im). There has not been a systematic study on the DNA recognition properties of the f/Py and f/Im terminal pairings. These pairings were analyzed here in the context of f-ImPyPy, f-ImPyIm, f-PyPyPy and f-PyPyIm, which contain the central pairing modes, –ImPy– and –PyPy–. The specificity of these triamides towards symmetrical recognition sites allowed for the f/Py and f/Im terminal pairings to be directly compared by SPR, CD and ΔT(M) experiments. The f/Py pairing, when placed next to the –ImPy– or –PyPy– central pairings, prefers A/T and T/A base pairs to G/C base pairs, suggesting that f/Py has similar DNA recognition specificity to Py/Py. With –ImPy– central pairings, f/Im prefers C/G base pairs (>10 times) to the other Watson–Crick base pairs; therefore, f/Im behaves like the Py/Im pair. However, the f/Im pairing is not selective for the C/G base pair when placed next to the –PyPy– central pairings

JBrowse: a dynamic web platform for genome visualization and analysis

BACKGROUND: JBrowse is a fast and full-featured genome browser built with JavaScript and HTML5. It is easily embedded into websites or apps but can also be served as a standalone web page. RESULTS: Overall improvements to speed and scalability are accompanied by specific enhancements that support complex interactive queries on large track sets. Analysis functions can readily be added using the plugin framework; most visual aspects of tracks can also be customized, along with clicks, mouseovers, menus, and popup boxes. JBrowse can also be used to browse local annotation files offline and to generate high-resolution figures for publication. CONCLUSIONS: JBrowse is a mature web application suitable for genome visualization and analysis

Linking Human Diseases to Animal Models Using Ontology-Based Phenotype Annotation

A novel method for quantifying the similarity between phenotypes by the use of ontologies can be used to search for candidate genes, pathway members, and human disease models on the basis of phenotypes alone

The Role of Risk Aversion and Lay Risk in the Probabilistic Externality Assessment for Oil Tanker Routes to Europe

Oil spills are a major cause of environmental concern, in particular for Europe. However, the traditional approach to the evaluation of the expected external costs of these accidents fails to take into full account the implications of their probabilistic nature. By adapting a methodology originally developed for nuclear accidents to the case of oil spills, we extend the traditional approach to the assessment of the welfare losses borne by potentially affected individuals for being exposed to the risk of an oil spill. The proposed methodology differs from the traditional approach in three respects: it allows for risk aversion; it adopts an ex-ante rather than an ex-post perspective; it allows for subjective oil spill probabilities (held by the lay public) higher than those assessed by the experts in the field. In order to illustrate quantitatively this methodology, we apply it to the hypothetical (yet realistic) case of an oil spill in the Aegean Sea. We assess the risk premiums that potentially affected individuals would be willing to pay in order to avoid losses to economic activities such as tourism and fisheries, and non-use damages resulting from environmental impacts on the Aegean coasts. In the scenarios analysed, the risk premiums on expected losses for tourism and fisheries turn out to be substantial when measured as a percentage of expected losses; by contrast, they are quite small for the case of damages to the natural environment