Case report: response to the ERK1/2 inhibitor ulixertinib in BRAF D594G cutaneous melanoma.

Melanoma is characterized by oncogenic mutations in pathways regulating cell growth, proliferation, and metabolism. Greater than 80% of primary melanoma cases harbor aberrant activation of the mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway, with oncogenic mutations in BRAF, most notably BRAF V600E, being the most common. Significant progress has been made in BRAF-mutant melanoma using BRAF and MEK inhibitors; however, non-V600 BRAF mutations remain a challenge with limited treatment options. We report the case of an individual diagnosed with stage III BRAF D594G-mutant melanoma who experienced an extraordinary response to the ERK1/2 inhibitor ulixertinib as fourth-line therapy. Ulixertinib was obtained via an intermediate expanded access protocol with unique flexibility to permit both single-agent and combination treatments, dose adjustments, breaks in treatment to undergo surgery, and long-term preventive treatment following surgical resection offering this patient the potential for curative treatment

Part 1: CT characterisation of pancreatic neoplasms: a pictorial essay

The pancreas is a site of origin of a diverse range of benign and malignant tumours, and these are frequently detected, diagnosed and staged with computed tomography (CT). Knowledge of the typical appearance of these neoplasms as well as the features of locoregional invasion is fundamental for all general and abdominal radiologists. This pictorial essay aims to outline the characteristic CT appearances of the spectrum of pancreatic neoplasms, as well as important demographic and clinical information that aids diagnosis. The second article in this series addresses common mimics of pancreatic neoplasia

Inverse Fusion PCR Cloning

Inverse fusion PCR cloning (IFPC) is an easy, PCR based three-step cloning method that allows the seamless and directional insertion of PCR products into virtually all plasmids, this with a free choice of the insertion site. The PCR-derived inserts contain a vector-complementary 5′-end that allows a fusion with the vector by an overlap extension PCR, and the resulting amplified insert-vector fusions are then circularized by ligation prior transformation. A minimal amount of starting material is needed and experimental steps are reduced. Untreated circular plasmid, or alternatively bacteria containing the plasmid, can be used as templates for the insertion, and clean-up of the insert fragment is not urgently required. The whole cloning procedure can be performed within a minimal hands-on time and results in the generation of hundreds to ten-thousands of positive colonies, with a minimal background

Physically-based Assessment of Hurricane Surge Threat under Climate Change

Storm surges are responsible for much of the damage and loss of life associated with landfalling hurricanes. Understanding how global warming will affect hurricane surges thus holds great interest. As general circulation models (GCMs) cannot simulate hurricane surges directly, we couple a GCM-driven hurricane model with hydrodynamic models to simulate large numbers of synthetic surge events under projected climates and assess surge threat, as an example, for New York City (NYC). Struck by many intense hurricanes in recorded history and prehistory, NYC is highly vulnerable to storm surges. We show that the change of storm climatology will probably increase the surge risk for NYC; results based on two GCMs show the distribution of surge levels shifting to higher values by a magnitude comparable to the projected sea-level rise (SLR). The combined effects of storm climatology change and a 1 m SLR may cause the present NYC 100-yr surge flooding to occur every 3–20 yr and the present 500-yr flooding to occur every 25–240 yr by the end of the century.United States. National Oceanic and Atmospheric Administration (Postdoctoral Fellowship Program)National Science Foundation (U.S.

Latent Class Analysis of Sexual Risk Patterns Among Esquineros (Street Corner Men) a Group of Heterosexually Identified, Socially Marginalized Men in Urban Coastal Peru

We explored patterns of sexual risk behavior among esquineros, heterosexually-identified, socially-marginalized Peruvian men using latent class analysis. We used data from the Peru site of the National Institute of Mental Health (NIMH) Collaborative HIV/STD Prevention Trial which included n = 2,109 heterosexually-identified men. The latent class analysis used seven risk behaviors to group esquineros into risk classes. We identified four latent classes, of which two classes had lower probabilities and two classes had higher probabilities of these risk behaviors. Comparing the two lower risk classes to the two higher risk classes yielded significantly more unprotected sex acts (Chi square P value < 0.001). The risk behaviors in two of the latent classes identified were primarily related to alcohol and drug use. Future HIV/STI prevention interventions may benefit from this information by tailoring messages to fit the observed risk patterns and should focus on drug and alcohol use

Both Positive and Negative Selection Pressures Contribute to the Polymorphism Pattern of the Duplicated Human CYP21A2 Gene.

The human steroid 21-hydroxylase gene (CYP21A2) participates in cortisol and aldosterone biosynthesis, and resides together with its paralogous (duplicated) pseudogene in a multiallelic copy number variation (CNV), called RCCX CNV. Concerted evolution caused by non-allelic gene conversion has been described in great ape CYP21 genes, and the same conversion activity is responsible for a serious genetic disorder of CYP21A2, congenital adrenal hyperplasia (CAH). In the current study, 33 CYP21A2 haplotype variants encoding 6 protein variants were determined from a European population. CYP21A2 was shown to be one of the most diverse human genes (HHe=0.949), but the diversity of intron 2 was greater still. Contrary to previous findings, the evolution of intron 2 did not follow concerted evolution, although the remaining part of the gene did. Fixed sites (different fixed alleles of sites in human CYP21 paralogues) significantly accumulated in intron 2, indicating that the excess of fixed sites was connected to the lack of effective non-allelic conversion and concerted evolution. Furthermore, positive selection was presumably focused on intron 2, and possibly associated with the previous genetic features. However, the positive selection detected by several neutrality tests was discerned along the whole gene. In addition, the clear signature of negative selection was observed in the coding sequence. The maintenance of the CYP21 enzyme function is critical, and could lead to negative selection, whereas the presumed gene regulation altering steroid hormone levels via intron 2 might help fast adaptation, which broadly characterizes the genes of human CNVs responding to the environment

Are all ‘research fields’ equal? Rethinking practice for the use of data from crowd-sourcing market places

New technologies like large-scale social media sides (e.g., Facebook and Twitter) and crowdsourcing services (e.g., Amazon Mechanical Turk, Crowdflower, Clickworker) impact social science research and provide many new and interesting avenues for research. The use of these new technologies for research has not been without challenges and a recently published psychological study on Facebook led to a widespread discussion on the ethics of conducting large-scale experiments online. Surprisingly little has been said about the ethics of conducting research using commercial crowdsourcing market places. In this paper, I want to focus on the question of which ethical questions are raised by data collection with crowdsourcing tools. I briefly draw on implications of internet research more generally and then focus on the specific challenges that research with crowdsourcing tools faces. I identify fair-pay and related issues of respect for autonomy as well as problems with power dynamics between researcher and participant, which has implications for ‘withdrawal-withoutprejudice’, as the major ethical challenges with crowdsourced data. Further, I will to draw attention on how we can develop a ‘best practice’ for researchers using crowdsourcing tools

Gastrointestinal Hyperplasia with Altered Expression of DNA Polymerase β

Background: Altered expression of DNA polymerase β (Pol β) has been documented in a large percentage of human tumors. However, tumor prevalence or predisposition resulting from Pol β over-expression has not yet been evaluated in a mouse model. Methodology/Principal Findings: We have recently developed a novel transgenic mouse model that over-expresses Pol β. These mice present with an elevated incidence of spontaneous histologic lesions, including cataracts, hyperplasia of Brunner's gland and mucosal hyperplasia in the duodenum. In addition, osteogenic tumors in mice tails, such as osteoma and osteosarcoma were detected. This is the first report of elevated tumor incidence in a mouse model of Pol β over-expression. These findings prompted an evaluation of human gastrointestinal tumors with regard to Pol β expression. We observed elevated expression of Pol β in stomach adenomas and thyroid follicular carcinomas, but reduced Pol β expression in esophageal adenocarcinomas and squamous carcinomas. Conclusions/Significance: These data support the hypothesis that balanced and proficient base excision repair protein expression and base excision repair capacity is required for genome stability and protection from hyperplasia and tumor formation