Streptococcus pyogenes, also known as group A Streptococcus (GAS), causes mild human infections such as pharyngitis and impetigo and serious infections such as necrotizing fasciitis and streptococcal ...toxic shock syndrome. Furthermore, repeated GAS infections may trigger autoimmune diseases, including acute poststreptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease. Combined, these diseases account for over half a million deaths per year globally. Genomic and molecular analyses have now characterized a large number of GAS virulence determinants, many of which exhibit overlap and redundancy in the processes of adhesion and colonization, innate immune resistance, and the capacity to facilitate tissue barrier degradation and spread within the human host. This improved understanding of the contribution of individual virulence determinants to the disease process has led to the formulation of models of GAS disease progression, which may lead to better treatment and intervention strategies. While GAS remains sensitive to all penicillins and cephalosporins, rising resistance to other antibiotics used in disease treatment is an increasing worldwide concern. Several GAS vaccine formulations that elicit protective immunity in animal models have shown promise in nonhuman primate and early-stage human trials. The development of a safe and efficacious commercial human vaccine for the prophylaxis of GAS disease remains a high priority.
Many neuropsychiatric symptoms of fragile X syndrome (FXS) are believed to be a consequence of altered regulation of protein synthesis at synapses. We discovered that lovastatin, a drug that is ...widely prescribed for the treatment of high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent one of the robust functional consequences of increased protein synthesis in FXS, epileptogenesis. These data suggest that lovastatin is potentially disease modifying and could be a viable prophylactic treatment for epileptogenesis in FXS.
► Epilepsy is one consequence of excess protein synthesis in the Fmr1−/y mouse ► Lovastatin inhibits Ras-ERK1/2 and normalizes protein synthesis ► Lovastatin prevents epileptogenesis in the Fmr1−/y mouse ► Lovastatin, approved for human use, is potentially disease modifying in FXS
Osterweil et al. show that lovastatin, a widely prescribed HMG-CoA reductase inhibitor (statin), can correct multiple pathological changes in the mouse model of fragile X syndrome, including the induction of epilepsy (epileptogenesis).
The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care ...bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups.
IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor EGFR or anaplastic lymphoma kinase ALK genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov, number NCT02366143, and is ongoing.
Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17·0-NE) with ABCP (34 of 400) and 18·7 months (95% CI 13·4-NE) with BCP (45 of 400; hazard ratio HR 0·61 95% CI 0·29-1·28). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE 95% CI NE-NE with ABCP 26 of 400 vs 17·5 months 95% CI 11·7-NE with BCP 32 of 400; HR 0·31 95% CI 0·11-0·83) and in the intention-to-treat population (19·8 months 17·4-24·2 vs 14·9 months 13·4-17·1; HR 0·76 0·63-0·93). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13·3 months 11·6-NE with ABCP 52 of 400 vs 9·4 months 7·9-11·7 with BCP 57 of 400; HR 0·52 0·33-0·82). Median overall survival was 21·4 months (95% CI 13·8-NE) with ACP versus 18·7 months (95% CI 13·4-NE) with BCP in EGFR-positive patients (HR 0·93 95% CI 0·51-1·68). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0·90 95% CI 0·47-1·74), in the intention-to-treat population (HR 0·85 0·71-1·03), or in patients with baseline liver metastases (HR 0·87 0·57-1·32). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.
Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.
F. Hoffmann-La Roche, Genentech.
Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory ...disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated.
Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP.
We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls.
Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma.
The human genome contains "dark" gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations ...within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions.
Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer's Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer's disease gene, found in disease cases but not in controls.
While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer's disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.
This study aims at evaluating the symptom response, response duration, and toxicity of single dose palliative liver radiotherapy (RT) for symptomatic HCC patients. We reviewed unresectable HCC ...patients treated with palliative RT in our institution. Eligible patients were unsuitable or refractory to trans-arterial chemoembolization (TACE) and stereotactic body radiotherapy (SBRT), with an index symptom of pain or abdominal discomfort. The primary outcome was the percentage of patients with clinical improvement of index symptom at 1 month. Secondary outcomes were response duration, toxicities, alpha-feto protein (AFP) response, and radiological response. Fifty-two patients were included in the study. The index symptom was pain in 34 patients (65.4%), and abdominal discomfort (34.6%) in 18 patients. At 1 month, 51.9% of patients had improvement of symptoms. Median time to symptom progression was 89 days (range: 12-392 days). Treatment was well tolerated with only 2 patients (3.8%) developing grade 3 GI toxicities. AFP response, radiological response rate, and disease control rate at 3 months were 48.6%, 15.1%, and 54.5% respectively. Half of the patients had improvement of index symptoms after receiving palliative liver RT with median response duration of 3 months. The treatment was well tolerated with minimal toxicities.
The Numerical Rating Scale (NRS), Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), and Faces Pain Scale-Revised (FPS-R) are valid measures of pain intensity. However, ratings on these measures ...may be influenced by factors other than pain intensity. The purpose of this study was to evaluate the influence of non-pain intensity factors on the pain intensity scales.
We administered measures of pain intensity (NRS, VAS, VRS, FPS-R), pain unpleasantness, catastrophizing, depressive symptoms, and pain interference to 101 individuals with chronic lower back or knee pain. Correlation analyses examined the associations among the pain intensity scales, and regression analyses evaluated the contributions of the non-pain intensity factors (depressive symptoms, and pain unpleasantness, catastrophizing, and interference) to the VAS, VRS, and FPS-R ratings, while controlling for NRS, age, and gender.
Although the NRS, VAS, VRS, FPR-S, scales were strongly associated with one another, supporting their validity as measures of pain intensity, regression analyses showed that the VRS also reflected pain interference, the FPS-R also reflected pain unpleasantness, and the VAS was not associated with any of the additional non-pain intensity factors when controlling for NRS, age, and gender.
The VAS appears to be most similar to the NRS and less influenced by non-pain intensity factors than the VRS or FPS-R. Although the VRS and FPS-R ratings both reflect pain intensity, they also contain additional information about pain interference and pain unpleasantness, respectively. These findings should be kept in mind when selecting pain measures and interpreting the results of research studies using these scales.
The influence of pain interference and pain unpleasantness on VRS and FPS-R, respectively should be kept in mind when selecting pain measures and interpreting the results of research studies using these scales.
NEGLECTED CLOUDS IN T AND Y DWARF ATMOSPHERES MORLEY, Caroline V; FORTNEY, Jonathan J; MARLEY, Mark S ...
Astrophysical journal/The Astrophysical journal,
09/2012, Volume:
756, Issue:
2
Journal Article
Peer reviewed
Open access
As brown dwarfs cool, a variety of species condense in their atmospheres, forming clouds. Iron and silicate clouds shape the emergent spectra of L dwarfs, but these clouds dissipate at the L/T ...transition. A variety of other condensates are expected to form in cooler T dwarf atmospheres. These include Cr, MnS, Na sub(2)S, ZnS, and KCl, but the opacity of these optically thinner clouds has not been included in previous atmosphere models. Here, we examine their effect on model T and Y dwarf atmospheres. The cloud structures and opacities are calculated using the Ackerman & Marley cloud model, which is coupled to an atmosphere model to produce atmospheric pressure-temperature profiles in radiative-convective equilibrium. We generate a suite of models between T sub(eff) = 400 and 1300 K, log g = 4.0 and 5.5, and condensate sedimentation efficiencies from functionof sub(sed) = 2 to 5. Model spectra are compared to two red T dwarfs, Ross 458C and UGPS 0722-05; models that include clouds are found to match observed spectra significantly better than cloudless models. The emergence of sulfide clouds in cool atmospheres, particularly Na sub(2)S, may be a more natural explanation for the "cloudy" spectra of these objects, rather than the reemergence of silicate clouds that wane at the L-to-T transition. We find that sulfide clouds provide a mechanism to match the near- and mid-infrared colors of observed T dwarfs. Our results indicate that including the opacity of condensates in T dwarf atmospheres is necessary to accurately determine the physical characteristics of many of the observed objects.
Abstract
BACKGROUND
Infection and inflammation of the reproductive tract are significant causes of male factor infertility. Ascending infections caused by sexually transmitted bacteria or urinary ...tract pathogens represent the most frequent aetiology of epididymo-orchitis, but viral, haematogenous dissemination is also a contributory factor. Limitations in adequate diagnosis and therapy reflect an obvious need for further understanding of human epididymal and testicular immunopathologies and their contribution to infertility. A major obstacle for advancing our knowledge is the limited access to suitable tissue samples. Similarly, the key events in the inflammatory or autoimmune pathologies affecting human male fertility are poorly amenable to close examination. Moreover, the disease processes generally have occurred long before the patient attends the clinic for fertility assessment. In this regard, data obtained from experimental animal models and respective comparative analyses have shown promise to overcome these restrictions in humans.
OBJECTIVE AND RATIONALE
This narrative review will focus on male fertility disturbances caused by infection and inflammation, and the usefulness of the most frequently applied animal models to study these conditions.
SEARCH METHODS
An extensive search in Medline database was performed without restrictions until January 2018 using the following search terms: ‘infection’ and/or ‘inflammation’ and ‘testis’ and/or ‘epididymis’, ‘infection’ and/or ‘inflammation’ and ‘male genital tract’, ‘male infertility’, ‘orchitis’, ‘epididymitis’, ‘experimental autoimmune’ and ‘orchitis’ or ‘epididymitis’ or ‘epididymo-orchitis’, antisperm antibodies’, ‘vasectomy’. In addition to that, reference lists of primary and review articles were reviewed for additional publications independently by each author. Selected articles were verified by each two separate authors and discrepancies discussed within the team.
OUTCOMES
There is clear evidence that models mimicking testicular and/or epididymal inflammation and infection have been instructive in a better understanding of the mechanisms of disease initiation and progression. In this regard, rodent models of acute bacterial epididymitis best reflect the clinical situation in terms of mimicking the infection pathway, pathogens selected and the damage, such as fibrotic transformation, observed. Similarly, animal models of acute testicular and epididymal inflammation using lipopolysaccharides show impairment of reproduction, endocrine function and histological tissue architecture, also seen in men. Autoimmune responses can be studied in models of experimental autoimmune orchitis (EAO) and vasectomy. In particular, the early stages of EAO development showing inflammatory responses in the form of peritubular lymphocytic infiltrates, thickening of the lamina propria of affected tubules, production of autoantibodies against testicular antigens or secretion of pro-inflammatory mediators, replicate observations in testicular sperm extraction samples of patients with ‘mixed atrophy’ of spermatogenesis. Vasectomy, in the form of sperm antibodies and chronic inflammation, can also be studied in animal models, providing valuable insights into the human response.
WIDER IMPLICATIONS
This is the first comprehensive review of rodent models of both infectious and autoimmune disease of testis/epididymis, and their clinical implications, i.e. their importance in understanding male infertility related to infectious and non-infectious/autoimmune disease of the reproductive organs.
An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR ...expression and often have neuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.
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