Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors.

Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.

Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas.

Immunohistochemistry of the PD-L1 protein may be predictive for anti-PD-1 and anti-PD-L1 immunotherapy in pulmonary adenocarcinoma and in clinically unselected cohorts of so-called non-small-cell lung cancer. Several PD-L1 immunohistochemistry assays with custom reagents and scoring-criteria are developed in parallel. Biomarker testing and clinical decision making would profit from harmonized PD-L1 diagnostics.

Endothelial Dysfunction, and A Prothrombotic, Proinflammatory Phenotype Is Caused by Loss of Mitochondrial Thioredoxin Reductase in Endothelium.

Objective: Although the investigation on the importance of mitochondria-derived reactive oxygen species (ROS) in endothelial function has been gaining momentum, little is known on the precise role of the individual components involved in the maintenance of a delicate ROS balance. Here we studied the impact of an ongoing dysregulated redox homeostasis by examining the effects of endothelial cell-specific deletion of murine thioredoxin reductase 2 (Txnrd2), a key enzyme of mitochondrial redox control.

Approach And Results: We analyzed the impact of an inducible, endothelial cell-specific deletion of Txnrd2 on vascular remodeling in the adult mouse after femoral artery ligation.

[HER2 testing in gastric cancer : Results of a meeting of German experts].

Valid HER2 testing is essential for the optimal care of patients with HER2-positive gastric cancer and the correct use of first-line treatment. Although all cases of breast cancer are routinely tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is usually only done upon request by the therapist. An interdisciplinary group of German experts has taken on the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions on the practical use of HER2 testing in this indication from the perspective of pathologists and therapists.

EWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma.

Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene.

Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group.

Background: To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy.

Patients And Methods: A total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan-Meier method, log-rank tests and Cox models.

Human HLA-A*02:01/CHM1+ allo-restricted T cell receptor transgenic CD8+ T cells specifically inhibit Ewing sarcoma growth in vitro and in vivo.

The endochondral bone protein Chondromodulin-I (CHM1) provides oncogene addiction in Ewing sarcoma (ES). We pre-clinically tested the targetability of CHM1 by TCR transgenic, allo-restricted, peptide specific T cells to treat ES. We previously generated allo-restricted wildtype CD8+ T cells directed against the ES specific antigen CHM1319 causing specific responses against ES.

CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial).

Background: To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab.

Patients And Methods: CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders.

Implementation of a Multimodal Mobile System for Point-of-Sale Surveillance: Lessons Learned From Case Studies in Washington, DC, and New York City.

Background: In tobacco control and other fields, point-of-sale surveillance of the retail environment is critical for understanding industry marketing of products and informing public health practice. Innovations in mobile technology can improve existing, paper-based surveillance methods, yet few studies describe in detail how to operationalize the use of technology in public health surveillance.

Objective: The aims of this paper are to share implementation strategies and lessons learned from 2 tobacco, point-of-sale surveillance projects to inform and prepare public health researchers and practitioners to implement new mobile technologies in retail point-of-sale surveillance systems.

American Spirit Pack Descriptors and Perceptions of Harm: A Crowdsourced Comparison of Modified Packs.

Introduction: In 2015, the Food and Drug Administration issued warnings to three tobacco manufacturers who label their cigarettes as "additive-free" and/or "natural" on the grounds that they make unauthorized reduced risk claims. The goal of this study was to examine US adults' perceptions of three American Spirit (AS) pack descriptors ("Made with Organic Tobacco," "100% Additive-Free," and "100% US Grown Tobacco") to assess if they communicate reduced risk.

Methods: In September 2012, three cross-sectional surveys were posted on Amazon Mechanical Turk.

CYB5R1 links epithelial-mesenchymal transition and poor prognosis in colorectal cancer.

Colorectal cancers show significant tumor cell heterogeneity within the same core genetic background. Epithelial-mesenchymal transition (EMT) is an important functional aspect of this heterogeneity and hallmark of colorectal cancer progression. Here, we identify CYB5R1, an enzyme involved in oxidative stress protection and drug metabolism, as an indicator of EMT in colon cancer.

The Moment Study: protocol for a mixed method observational cohort study of the Alternative Nicotine Delivery Systems (ANDS) initiation process among adult cigarette smokers.

Introduction: Alternative Nicotine Delivery Systems (ANDS) such as e-cigarettes are battery-powered devices that aerosolize nicotine and other substances to simulate smoking without using tobacco. Little is known about the ANDS initiation process among adult smokers. The aims of this research are threefold to: (1) examine how ANDS use affects cigarette use; (2) examine how the immediate environmental and psychosocial contexts of cigarette and ANDS use vary within-and between-participants in general and by menthol preference and race; and, (3) examine participants' 'lived experience' of the subjective perceptions, meaning, influences and utility of cigarette and ANDS use.

Isolated pulmonary metastases define a favorable subgroup in metastatic pancreatic cancer.

Purpose: Liver metastasis represents the first site of dissemination in >80% of metastatic pancreatic cancer (PC) patients. Pulmonary metastasis as first site of dissemination in PC is a rare event and might define a biologically distinct subgroup in metastatic PC.

Methods: Consecutive PC patients who were diagnosed or treated with isolated pulmonary metastases at our high-volume comprehensive cancer center were included in a prospectively maintained database between 2002 and 2015.

NGS-based BRCA1/2 mutation testing of high-grade serous ovarian cancer tissue: results and conclusions of the first international round robin trial.

With the approval of olaparib as monotherapy treatment in platinum-sensitive, relapsed high-grade serous ovarian cancer by the European Medical Agency (EMA), comprehensive genotyping of BRCA1 and BRCA2 in tumor tissue has become a mandatory pre-therapeutic test. This requires significant advances in routine tumor test methodologies due to the large size of both genes and the lack of mutational hot spots. Classical focused screening approaches, like Sanger sequencing, do not allow for a sensitive, rapid, and economic analysis of tumor tissue.

Tobacco outlet density and converted versus native non-daily cigarette use in a national US sample.

Objective: Investigate whether non-daily smokers' (NDS) cigarette price and purchase preferences, recent cessation attempts, and current intentions to quit are associated with the density of the retail cigarette product landscape surrounding their residential address.

Participants: Cross-sectional assessment of N=904 converted NDS (CNDS). who previously smoked every day, and N=297 native NDS (NNDS) who only smoked non-daily, drawn from a national panel.

Acute stress enhances the expression of neuroprotection- and neurogenesis-associated genes in the hippocampus of a mouse restraint model.

Stress arises from an external demand placed on an organism that triggers physiological, cognitive and behavioural responses in order to cope with that request. It is thus an adaptive response useful for the survival of an organism. The objective of this study was to identify and characterize global changes in gene expression in the hippocampus in response to acute stress stimuli, by employing a mouse model of short-term restraint stress.

Mechanisms of SNR and line shape improvement by B correction in overdiscrete MRSI reconstruction.

Purpose: Inhomogeneities of the main magnetic field cause line broadening and location-dependent frequency shifts in brain MRSI. These are often visible despite advanced B shimming. The purpose of this work is to propose an advanced B correction method that can easily be applied during postprocessing.

Impact of reassessment of colonic hyperplastic polyps by expert GI pathologists.

Background: Recommended follow-up intervals after endoscopic removal of hyperplastic polyps (HP) and sessile serrated adenomas (SSA) differ because of assumed differences in biological behaviour. However, histopathologic differentiation is difficult, with higher SSA rates reported from specialist GI histopathologists.

Objective: The objective of this study was to clarify the relevance of histologic reassessment of HP.

Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1): a master regulator of mRNA translation involved in tumorigenesis.

Protein synthesis activity is abnormally enhanced in cancer cells to support their uncontrolled growth. However, this process needs to be tightly restricted under metabolic stress-a condition often found within the tumor microenvironment-to preserve cell viability. mTORC1 is critical to link protein synthesis activity to nutrient and oxygen levels, in part by controlling the 4E-BP1-eIF4E axis.

A Randomized Trial Comparing the Effect of Nicotine Versus Placebo Electronic Cigarettes on Smoking Reduction Among Young Adult Smokers.

Introduction: Electronic cigarette (EC) use is growing dramatically with use highest among young adults and current smokers. One of the most common reasons for using ECs is interest in quitting or reducing cigarettes per day (CPD); however there are few randomized controlled trials (RCT) on the effect of ECs on smoking abstinence and reduction.

Methods: We conducted a two-arm; double-blind RCT.

Disease kinetics but not disease burden is relevant for survival in melanoma of unknown primary tumor.

Melanoma of unknown primary (MUP) is a type of metastatic melanoma with no evidence of a primary tumor. Recent evidence suggested better survival in MUP as compared to melanoma with a known primary site (MKP). However, prognostic markers that reliably predict overall survival in MUP are lacking.

Desmogleins as prognostic biomarkers in resected pancreatic ductal adenocarcinoma.

Background: Frequent disease relapse and a lack of effective therapies result in a very poor outcome in pancreatic ductal adenocarcinoma (PDAC) patients. Thus, identification of prognostic biomarkers and possible therapeutic targets is essential. Besides their function in cell-cell adhesion, desmogleins may play a role in tumour progression and invasion that has not been investigated in PDAC to date.

Aggressive systemic mastocytosis of the liver with cholangitis.

Mastocytosis is a clonal, neoplastic mast cell proliferation, which is in most cases restricted to the skin (cutaneous mastocytosis), but may infiltrate other organs as well (systemic mastocytosis). Involvement of the liver by a systemic mastocytosis with impairment of liver function has been recognized as sign of an aggressive course of disease (C-finding). This article presents a case of aggressive systemic mastocytosis in a 26-year-old male patient with involvement of the liver mimicking primary sclerosing cholangitis.

Jejunitis and brown bowel syndrome with multifocal carcinogenesis of the small bowel.

This is the first report describing a case where prolonged, severe malabsorption from brown bowel syndrome progressed to multifocally spread small bowel adenocarcinoma. This case involves a female patient who was initially diagnosed with chronic jejunitis associated with primary diffuse lymphangiectasia at the age of 26 years. The course of the disease was clinically, endoscopically, and histologically followed for 21 years until her death at the age 47 due to multifocal, metastasizing adenocarcinoma of the small bowel.

ITF-2B protein levels are correlated with favorable prognosis in patients with colorectal carcinomas.

The majority of sporadic forms of colorectal carcinomas is characterized by deregulation of Wnt/β-catenin signaling early in colorectal carcinogenesis. As a consequence, ITF-2B protein levels are increased in adenomas of these patients. However, ITF-2B protein levels are strongly reduced with increasing carcinoma stages, suggesting that reduction of ITF-2B protein is required for progression of adenomas to colorectal carcinomas.