Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with nonsmall cell lung cancer survival

The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing genotyping data from two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with nonsmall cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a singlelocus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression modeling of the PLCO dataset identified three potentially functional and independent SNPs (i.e., KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 (95% confidence interval [CI] = 0.79–0.94, p = 0.0007), 1.31 (1.16–1.47, p = 6.0 × 10⁻⁵) and 1.27 (1.12–1.44, p = 0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (p_trend < 0.0001 for OS and p_trend < 0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes.     

The immunological synapse of CTL contains a secretory domain and membrane bridges.

Cytotoxic T lymphocytes (CTL) rapidly destroy their targets. Here we show that although target cell death occurs within 5 min of CTL-target cell contact, an immunological synapse similar to that seen in CD4 cells rapidly forms in CTL, with a ring of adhesion proteins surrounding an inner signaling molecule domain. Lytic granule secretion occurs in a separate domain within the adhesion ring, maintaining signaling protein organization during exocytosis. Live and fixed cell studies show target cell plasma membrane markers are transferred to the CTL as the cells separate. Electron microscopy reveals continuities forming membrane bridges between the CTL and target cell membranes, suggesting a possible mechanism for this transfer.     

Inhibition of apoptosis during 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated tumour promotion in rat liver

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) oncell division and cell death (apoptosis) in glutathione S-transferase(GST-P)-positive liver foci were analyzed in diethylnitrosamine-initiatedfemale Wistar rats that were treated with TCDD, either acutelyfor 3 days or chronically for 115 days. Apoptotic bodies werequantitated in liver sections simultaneously stained for GST-Pexpression and H&E using a novel fluorescence microscopicdetection method which greatly facilitates recognition of apoptoticbodies due to their high level of eosin fluorescence. WhileTCDD treatment only marginally affected cell division in GST-P-positiveliver foci, as estimated by 5-bromo-2'-deoxyuridine-labelling,apoptotic indices were decreased to     

A Phase II Study of Telisotuzumab Vedotin in Patients With c–MET-positive Stage IV or Recurrent Squamous Cell Lung Cancer (LUNG-MAP Sub-study S1400K,NCT03574753)

IntroductionLung-MAP S1400K was designed to evaluate the response to telisotuzumab vedotin, an antibody-drug conjugate targeting c-MET, in patients with c-MET–positive squamous cell carcinoma (SCC).Patients and MethodsPatients with previously treated SCC with c-MET–positive tumors (H score ≥ 150, Ventana SP44 assay) were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor-naive) and Cohort 2 (immune checkpoint inhibitor refractory). Telisotuzumab vedotin 2.7 mg/kg was administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival, overall survival, response within cohort, duration of response, and toxicities. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment.ResultsForty-nine patients (14% of screened patients) were assigned to S1400K, 28 patients enrolled (15 in Cohort 1 and 13 in Cohort 2), and 23 were eligible. S1400K closed on December 21, 2018 owing to lack of efficacy. Two responses (response rate of 9%; 95% confidence interval, 0%-20%) were reported in cohort 1 (1 complete and 1 unconfirmed partial response), whereas 10 patients had stable disease, with a disease control rate of 52%. The median overall and progression-free survival was 5.6 and 2.4 months, respectively. There were 3 grade 5 events (2 pneumonitis, in Cohort 2, and 1 bronchopulmonary hemorrhage, in Cohort 1).ConclusionTelisotuzumab vedotin failed to meet the pre-specified response needed to justify continuing enrollment to S1400K. Pneumonitis was an unanticipated toxicity observed in patients with SCC.     

Association mapping reveals the role of purifying selection in the maintenance of genomic variation in gene expression

The evolutionary forces that maintain genetic variation in quantitative traits within populations remain poorly understood. One hypothesis suggests that variation is under purifying selection, resulting in an excess of low-frequency variants and a negative correlation between minor allele frequency and selection coefficients. Here, we test these predictions using the genetic loci associated with total expression variation (eQTLs) and allele-specific expression variation (aseQTLs) mapped within a single population of the plant Capsella grandiflora. In addition to finding eQTLs and aseQTLs for a large fraction of genes, we show that alleles at these loci are rarer than expected and exhibit a negative correlation between phenotypic effect size and frequency. Overall, our results show that the distribution of frequencies and effect sizes of the loci responsible for local expression variation within a single outcrossing population are consistent with the effects of purifying selection.Genetic variation for quantitative traits persists within populations despite the expectation that prevalent stabilizing selection will reduce genetic variance (1). One hypothesis suggests that variation is under purifying selection, resulting in an excess of low-frequency variants and a negative correlation between minor allele frequency and selection coefficients (2). Although studies of allele frequency spectra show that purifying selection on functional DNA sequences is prevalent (3–5), little is known about how the genetic variants under selection relate to phenotype, and ultimately, how phenotypic variation is maintained within populations. Association mapping can identify specific loci influencing phenotypes, providing candidates for further analysis of selection (6). In particular, mapping the local regulatory variants that affect gene expression can identify a large number of genetic loci that affect a phenotype. Additionally, mapping the genetic basis of gene expression may answer questions about the basic biology of gene regulation, for example, by testing predictions that conserved noncoding sequences (“CNSs”) are constrained because they have regulatory function (7).Early eQTL studies mapped expression divergence between two lines, finding that many genes have local expression QTL (8, 9). These studies have provided insight into selection on eQTLs; for example, a correlation between recombination rate and eQTL density implied that background selection is a dominant force acting on expression variation in Caenorhabditis elegans (10), and a skew toward rare allele frequencies in promoters of genes with eQTLs suggests that purifying selection may act on expression variation (11). However, eQTL studies of population-level genetic variation have thus far been limited to a few study systems (12–16) and only one study, in humans, has identified a negative correlation between phenotypic effect size and frequency (15). In addition, human eQTL studies have shown that loci expected to be involved in selective sweeps are more likely to be eQTLs than other loci (17), allele frequencies of eQTLs that increase expression of a potentially deleterious coding SNP are under stronger purifying selection than those that do not (18), and eQTL allele frequencies within populations are correlated with local adaptation (19, 20). To date, eQTL studies in plants have used genetic crosses (21–23) or species-wide samples (24–26), making it difficult to distinguish evolutionary forces acting within and between populations. In sum, we currently lack comprehensive tests of selection on within-population eQTLs in any system, especially in plants.Here, we map local regulatory loci affecting expression in 99 members of a single large population of Capsella grandiflora (Brassicaceae), an obligate outcrosser. As might be expected from its large effective population size (N_e) and relative lack of population structure, purifying and positive selection are prevalent in C. grandiflora (4, 27), making it an ideal system for investigating the maintenance of genetic variation in the face of selection.     

The role of diagnostic imaging in the evaluation of suspected osteomyelitis in the foot: A critical review

The early diagnosis of osteomyelitis in the foot from its clinical presentation alone can be difficult particularly in cases when the early signs are subtle. Early diagnosis and subsequent early intervention are imperative to reduce the risk of chronic infection, associated early lytic changes to bone and potential long term structural complications caused by subsequent deformity and lost anatomy.Diagnostic imaging has a major role to play in the early assessment and diagnosis of bone infection, yet the choice of approach can be controversial.Several imaging modalities have been advocated, imaging of the infected foot is complex and no single test is ideal for every situation. The clinician needs to be aware of the strengths and weaknesses of each imaging modality so that the most appropriate test is selected for the individual case. Factors such as site of infection in the foot, the aggressive nature of the organism, the time since onset, previous associated surgery and co-morbidity may all play apart in the clinician's decision making process to determine the best approach in detecting the sometimes subtle changes which may be seen in some cases of osteomyelitis.This review considers the literature and highlights the advantages and disadvantages of the main imaging techniques used for the evaluation of the foot when osteomyelitis is suspected. An evidence based algorithm for the selection of appropriate imaging techniques is suggested to aid clinicians in there decision making process.