The rockefeller university

Deregulated WNT signaling has been shown to favor malignant transformation, tumor progression, and resistance to conventional cancer therapy in a variety of preclinical and clinical settings. Accumulating evidence suggests that aberrant WNT signaling may also subvert cancer immunosurveillance, hence promoting immunoevasion and resistance to multiple immunotherapeutics, including immune checkpoint blockers. Here, we discuss the molecular and cellular mechanisms through which WNT signaling influences cancer immunosurveillance and present potential therapeutic avenues to harness currently available WNT modulators for cancer immunotherapy.

The 2nd Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) took place on 03-05 November 2017 in Detroit, Michigan, USA. This symposium was a joint meeting of the Hidradenitis Suppurativa Foundation (HSF Inc.) founded in the USA, and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This was the second annual meeting of the SHSA with experts from different disciplines arriving from North America, Europe and Australia, in a joint aim to discuss most recent innovations, practical challenges and potential solutions to issues related in the management and care of Hidradenitis Suppurativa patients. The last session involved clinicians, patients and their families in an effort to educate them more about the disease.

Usually, population aging is measured to inform fiscal and social planning because it is considered to indicate the burden that an elderly population presents to the economic, social security, and health systems of a society. Measures of population aging are expected to indicate shifts in the distribution of individuals' attributes (e.g., chronological age, health) within a population that are relevant to assessing the burden. We claim that chronological age - even though it is the attribute most broadly used - may frequently not be the best measure to satisfy this purpose. A distribution of chronological age per se does not present a burden. Rather, burdens arise from the characteristics that supposedly or actually accompany chronological ages. We posit that in addition to chronological age, meaningful measures of population aging should reflect, for instance, the distribution of economic productivity, health, functional capacities, or biologial age, as these attributes may more directly assess the burden on the socioeconomic and health systems. Here, we illustrate some limitations of measures of population aging based on each kind of measure, including chronological age, and review alternative measures that may better inform fiscal, social, and health planning. (C) 2018 S. Karger AG, Basel

An outbreak of methicillin-resistant Staphylococcus aureus (MRSA)

Individuals prone to ethanol overconsumption may have preexisting neurochemical disturbances that contribute to their vulnerability. This study examined the paraventricular nucleus of the thalamus (PVT), a limbic structure recently shown to participate in ethanol intake. To identify individuals prone to ethanol overconsumption, we tested Long-Evans rats in behavioral paradigms and found high levels of vertical time (rearing behavior) in a novel activity chamber to be a consistent predictor of subsequent excessive 20 percent ethanol drinking under the intermittent access model. Examining neurochemicals in the PVT, we found before ethanol exposure that prone rats with high rearing, compared with non-prone rats, had significantly lower levels of neurotensin (NTS) mRNA and peptide in the posterior (pPVT) but not anterior (aPVT) subregion of the PVT. Our additional finding that ethanol intake has no significant impact on either rearing or NTS levels indicates that these measures, which are different in prone rats before ethanol consumption, remain stable after ethanol consumption. The possibility that NTS directly controls ethanol drinking is supported by our finding that NTS administration specifically suppresses ethanol drinking when injected into the pPVT but not aPVT, with this effect occurring exclusively in higher drinkers that presumably have lower endogenous levels of NTS. Further, an NTS antagonist in the pPVT augments intake in lower drinkers with presumably more endogenous NTS, while NTS in the pPVT inhibits novelty-induced rearing that predicts excessive drinking. Together, these results provide strong evidence that low endogenous levels of NTS in the pPVT contribute to an increased propensity toward excessive ethanol drinking.

The amyloid-beta protein precursor (A beta PP) is critical in the pathophysiology of Alzheimer's disease (AD), since two-step proteolytic processing of A beta PP generates the neurotoxic amyloid-beta peptide (A beta). We developed a dual fluorescence labeling system to study the exact subcellular location of gamma-secretase cleavage of A beta PP. The C-terminal tail of A beta PP was fluorescently labeled using a SNAP-tag, while the A beta region of A beta PP was fluorescently tagged with a dye at a genetically-encoded noncanonical amino acid (ncAA). The ncAA was introduced at specific positions in A beta PP using a genetic code expansion strategy and afterwards, the reactive side-chain of the ncAA was coupled to the dye using a bioorthogonal labeling chemistry. In proof-of-concept experiments, HEK293T cells were transfected with plasmids containing engineered A beta PP harboring an amber mutation and an amber codon suppression system with an evolved tRNA synthetase/tRNA pair and grown in the presence of a lysine-derived ncAA. Processing of the A beta PP variants was validated with ELISA and immunoblotting, and seven A beta PP mutants that showed similar cleavage pattern as wild-type A beta PP were identified. The A beta PP mutant was fluorescently labeled with 6-methyl-tetrazine-BDP-FL and TMR-Star at the ncAA and SNAP-tag, respectively. Using this approach, A beta PP was fluorescently labeled at two sites in living cells with minimal background to allow monitoring of A beta and C-terminal cleavage products simultaneously. The method described provides a powerful tool to label A beta with minimal perturbations of its processing, thus enabling studies of the trafficking of the cleavage products of A beta PP.

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary-metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

A method for mapping nucleosome contacts and relative nucleosome orientations reveals new detail about the folding of the S. cerevisiae genome. Two new chromatin folding patterns emerge, with one enriched and the other depleted at transcription start and end sites.

Despite substantial progress in our understanding of the players involved and the regulatory mechanisms controlling the initiation and elongation steps of transcription, little is known about the recruitment of elongation factors at promoter-proximal regions for the initiation-to-elongation transition. Here, we show evidence that human TFIID, which initiates pre-initiation complex (PIC) assembly, contributes to regulating the recruitment of super-elongation complex (SEC) components at the promoter-proximal region through interactions among selective TAF and SEC components. In vitro direct interactions, coupled with cell-based assays, identified an important poly-Ser domain within SEC components that are involved in their interaction with TFIID. DNA template-based recruitment assays, using purified components, further show a direct role for poly-Ser domain-dependent TFIID interaction in recruiting SEC components on target DNA. Consistently, ChIP and RNA analyses have shown the importance of this mechanism in TFIID-dependent SEC recruitment and target gene expression within mammalian cells.