Small bowel malignant melanoma presenting as a perforated jejunal diverticulum: a case report and literature review.

Although usually harmless and asymptomatic, jejuno-ileal diverticulae are associated with various non-specific gastrointestinal symptoms, and rarely cause surgical emergencies. This case report describes the presentation and management of a patient with an acute abdomen, whose jejunal diverticulum was perforated. Unexpectedly, histopathological assessment demonstrated malignant melanoma lining the diverticulum. Whether this was primary or metastatic is discussed, together with a synopsis of the literature on small bowel diverticulae

Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors.

Purpose Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin.Patients and methods This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies.Results Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate.Conclusion To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed

Interpersonal and affective dimensions of psychopathic traits in adolescents : development and validation of a self-report instrument

We report the development and psychometric evaluations of a self-report instrument designed to screen for psychopathic traits among mainstream community adolescents. Tests of item functioning were initially conducted with 26 adolescents. In a second study the new instrument was administered to 150 high school adolescents, 73 of who had school records of suspension for antisocial behavior. Exploratory factor analysis yielded a 4-factor structure (Impulsivity α = .73, Self-Centredness α = .70, Callous-Unemotional α = .69, and Manipulativeness α = .83). In a third study involving 328 high school adolescents, 130 with records of suspension for antisocial behaviour, competing measurement models were evaluated using confirmatory factor analysis. The superiority of a first-order model represented by four correlated factors that was invariant across gender and age was confirmed. The findings provide researchers and clinicians with a psychometrically strong, self-report instrument and a greater understanding of psychopathic traits in mainstream adolescents

Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity

BACKGROUND: Acute RT-induced damage to the lung is characterized by inflammatory changes, which proceed to the development of fibrotic lesions in the late phase of injury. Ultimately, complete structural ablation will ensue, if the source of inflammatory / fibrogenic mediators and oxidative stress is not removed or attenuated. Therefore, the purpose of this study is to determine whether overexpression of extracellular superoxide dismutase (EC-SOD) in mice ameliorates acute radiation induced injury by inhibiting activation of TGFβ1 and downregulating the Smad 3 arm of its signal transduction pathway. METHODS: Whole thorax radiation (single dose, 15 Gy) was delivered to EC-SOD overexpressing transgenic (XRT-TG) and wild-type (XRT-WT) animals. Mice were sacrificed at 1 day, 1 week, 3, 6, 10 and 14 weeks. Breathing rates, right lung weights, total/differential leukocyte count, activated TGFβ1 and components of its signal transduction pathway (Smad 3 and p-Smad 2/3) were assessed to determine lung injury. RESULTS: Irradiated wild-type (XRT-WT) animals exhibited time dependent increase in breathing rates and right lung weights, whereas these parameters were significantly less increased (p < 0.05) at 3, 6, 10 and 14 weeks in irradiated transgenic (XRT-TG) mice. An inflammatory response characterized predominantly by macrophage infiltration was pronounced in XRT-WT mice. This acute inflammation was significantly attenuated (p < 0.05) in XRT-TG animals at 1, 3, 6 and 14 weeks. Expression of activated TGFβ1 and components of its signal transduction pathway were significantly reduced (p < 0.05) at later time-points in XRT-TG vs. XRT-WT. CONCLUSION: This study shows that overexpression of EC-SOD confers protection against RT-induced acute lung injury. EC-SOD appears to work, in part, via an attenuation of the macrophage response and also decreases TGFβ1 activation with a subsequent downregulation of the profibrotic TGFβ pathway

Targeted kinase inhibition relieves slowness and tremor in a Drosophila model of LRRK2 Parkinson’s disease

Disease models: A reflex reaction A simple reflex in flies can be used to test the effectiveness of therapies that slow neurodegeneration in Parkinson’s disease (PD). Christopher Elliott and colleagues at the University of York in the United Kingdom investigated the contraction of the proboscis muscle which mediates a taste behavior response and is regulated by a single dopaminergic neuron. Flies bearing particular mutations in the PD-associated gene leucine-rich repeat kinase 2 (LRRK2) in dopaminergic neurons lost their ability to feed on a sweet solution. This was due to the movement of the proboscis muscle becoming slower and stiffer, hallmark features of PD. The authors rescued the impaired reflex reaction by feeding the flies l-DOPA or LRRK2 inhibitors. These findings highlight the proboscis extension response as a useful tool to identify other PD-associated mutations and test potential therapeutic compounds

Poor glycated haemoglobin control and adverse pregnancy outcomes in type 1 and type 2 diabetes mellitus: Systematic review of observational studies

BACKGROUND: Glycaemic control in women with diabetes is critical to satisfactory pregnancy outcome. A systematic review of two randomised trials concluded that there was no clear evidence of benefit from very tight versus tight glycaemic control for pregnant women with diabetes. METHODS: A systematic review of observational studies addressing miscarriage, congenital malformations and perinatal mortality among pregnant women with type 1 and type 2 diabetes was carried out. Literature searches were performed in MEDLINE, EMBASE, CINAHL and Cochrane Library. Observational studies with data on glycated haemoglobin (HbA(1c)) levels categorised into poor and optimal control (as defined by the study investigators) were selected. Relative risks and odds ratios were calculated for HbA(1c )and pregnancy outcomes. Adjusted relative risk estimates per 1-percent decrease in HbA(1c )were calculated for studies which contained information on mean and standard deviations of HbA(1c). RESULTS: The review identified thirteen studies which compared poor versus optimal glycaemic control in relation to maternal, fetal and neonatal outcomes. Twelve of these studies reported the outcome of congenital malformations and showed an increased risk with poor glycaemic control, pooled odds ratio 3.44 (95%CI, 2.30 to 5.15). For four of the twelve studies, it was also possible to calculate a relative risk reduction of congenital malformation for each 1-percent decrease in HbA(1c), these varied from 0.39 to 0.59. The risk of miscarriage was reported in four studies and was associated with poor glycaemic control, pooled odds ratio 3.23 (95%CI, 1.64 to 6.36). Increased perinatal mortality was also associated with poor glycaemic control, pooled odds ratio 3.03 (95%CI, 1.87 to 4.92) from four studies. CONCLUSION: This analysis quantifies the increase in adverse pregnancy outcomes in women with diabetes who have poor glycaemic control. Relating percentage risk reduction in HbA(1c )to relative risk of adverse pregnancy events may be useful in motivating women to achieve optimal control prior to conception

Crossmodal duration perception involves perceptual grouping, temporal ventriloquism, and variable internal clock rates

Here, we investigate how audiovisual context affects perceived event duration with experiments in which observers reported which of two stimuli they perceived as longer. Target events were visual and/or auditory and could be accompanied by nontargets in the other modality. Our results demonstrate that the temporal information conveyed by irrelevant sounds is automatically used when the brain estimates visual durations but that irrelevant visual information does not affect perceived auditory duration (Experiment 1). We further show that auditory influences on subjective visual durations occur only when the temporal characteristics of the stimuli promote perceptual grouping (Experiments 1 and 2). Placed in the context of scalar expectancy theory of time perception, our third and fourth experiments have the implication that audiovisual context can lead both to changes in the rate of an internal clock and to temporal ventriloquism-like effects on perceived on- and offsets. Finally, intramodal grouping of auditory stimuli diminished any crossmodal effects, suggesting a strong preference for intramodal over crossmodal perceptual grouping (Experiment 5)

A chemical biology toolbox to study protein methyltransferases and epigenetic signaling

© 2019, The Author(s). Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4 + T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond

Serum levels of selenium and smoking habits at age 50 influence long term prostate cancer risk; a 34 year ULSAM follow-up

Background: Serum selenium level (s-Se) has been associated with prostate cancer (PrCa) risk. We investigated the relation between s-Se, smoking and non-screening detected PrCa and explored if polymorphisms in two DNA repair genes: OGG1 and MnSOD, influenced any effect of s-Se. Methods: ULSAM, a population based Swedish male cohort (n = 2322) investigated at age 50 for s-Se and s-Se influencing factors: serum cholesterol, erythrocyte sedimentation rate and smoking habits. At age 71 a subcohort, (n = 1005) was genotyped for OGG1 and MnSOD polymorphisms. Results: In a 34-year-follow-up, national registries identified 208 PrCa cases further confirmed in medical records. Participants with s-Se in the upper tertile had a non-significantly lower risk of PrCa. Smokers with s-Se in the two lower tertiles (&lt;= 80 mu g/L) experienced a higher cumulative incidence of PrCa than smokers in the high selenium tertile (Hazard Ratio 2.39; 95% CI: 1.09-5.25). A high tertile selenium level in combination with non-wt rs125701 of the OGG1 gene in combination with smoking status or rs4880 related variation of MnSOD gene appeared to protect from PrCa. Conclusions: S-Se levels and smoking habits influence long-term risk of PrCa. Smoking as a risk factor for PrCa in men with low s-Se is relevant to explore further. Exploratory analyses of variations in OGG1 and MnSOD genes indicate that hypotheses about patterns of exposure to selenium and smoking combined with data on genetic variation in genes involved in DNA repair can be valuable to pursue