Structure-based virtual screening as a tool for the identification of novel inhibitors against Mycobacterium tuberculosis 3-dehydroquinate dehydratase.

3-Dehydroquinate dehydratase (DHQase), the third enzyme of the shikimate pathway, catalyzes the reversible reaction of 3-dehydroquinate into 3-dehydroshikimate. The aim of the present study was to identify new drug-like molecules as inhibitors for Mycobacterium tuberculosis DHQase employing structure-based pharmacophore modeling technique using an in house database consisting of about 2500 small molecules. Further the pharmacophore models were validated using enrichment calculations, and finally three models were employed for high-throughput virtual screening and docking to identify novel small molecules as DHQase inhibitors.

Gene-by-Environment Interactions in Pancreatic Cancer: Implications for Prevention.

Pancreatic cancer (PC) has been estimated to have higher incidence and correspondingly higher mortality rates in more developed regions worldwide. Overall, the age-adjusted incidence rate is 4.9/10(5) and age-adjusted mortality rate is at 4.

[The first Danish paediatric ethical committee].

We report the experiences from the first two years of a paediatric ethical committee at Rigshospitalet. The committee consists of five clinicians (nurses and doctors) and five non-clinicians. Themes of the sixteen reported case were: genetic testing, life-sustaining treatment ("when is enough enough?"), non-consensus between the parents and health personal and between different health personal, controversies to different religious wishes and to optimizing resources of the department versus individual care of a critically ill child.

New DNA Methylation Markers for Pancreatic Cancer: Discovery, Tissue Validation, and Pilot Testing in Pancreatic Juice.

Purpose: Discriminant markers for pancreatic cancer detection are needed. We sought to identify and validate methylated DNA markers for pancreatic cancer using next-generation sequencing unbiased by known targets.

Experimental Design: At a referral center, we conducted four sequential case-control studies: discovery, technical validation, biologic validation, and clinical piloting.

The magnitude of placebo analgesia effects depends on how they are conceptualized.

Objective: Placebo effects are usually calculated as the difference between placebo treatments and no treatments. Recently, placebo-like effects have been investigated using open and hidden administrations of active treatments. The aim of the study was to directly compare the two types of placebo effects and examine how they are influenced by personality traits.

Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium.

Background: The potential role of vitamin D in the aetiology of pancreatic cancer is unclear, with recent studies suggesting both positive and negative associations.

Patients And Methods: We used data from nine case-control studies from the International Pancreatic Cancer Case-Control Consortium (PanC4) to examine associations between pancreatic cancer risk and dietary vitamin D intake. Study-specific odds ratios (ORs) were estimated using multivariable logistic regression, and ORs were then pooled using a random-effects model.

TERT gene harbors multiple variants associated with pancreatic cancer susceptibility.

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681.

Early detection of sporadic pancreatic cancer: summative review.

Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society.

Zinc transporter genes and urological cancers: integrated analysis suggests a role for ZIP11 in bladder cancer.

Although zinc transporters were shown to play roles in the development of prostate, bladder, and renal cancer, no study has evaluated the genetic variants in zinc transporter genes with risk of urological cancers. A candidate gene association study using genome-wide association study (GWAS) datasets was conducted for variants in 24 zinc transporter genes. Genotypes were analyzed using logistic regression models adjusted for covariates.

Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling.

Objectives: To further elucidate the anticancer mechanisms of metformin against pancreatic cancer, we evaluated the inhibitory effects of metformin on pancreatic tumorigenesis in a genetically engineered mouse model and investigated its possible anti-inflammatory and antiangiogenesis effects.

Methods: Six-week-old LSL-Kras;Trp53 mice (10 per group) were administered once daily intraperitoneally with saline (control) for 1 week or metformin (125 mg/kg) for 1 week (Met_1wk) or 3 weeks (Met_3wk) before tumor initiation. All mice continued with their respective injections for 6 weeks after tumor initiation.

Vitamin D metabolic pathway genes and pancreatic cancer risk.

Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma.

Characterization of large structural genetic mosaicism in human autosomes.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals.

Impact of childlessness on life and attitudes towards continuation of medically assisted reproduction and/or adoption.

Infertility and fertility treatment have the potential to impact and disrupt a couple's overall life. In order to study the associations between the impact of childlessness on one's life, and men and women's attitudes towards fertility treatment continuation and/or adoption, we analysed data from a one-year follow-up questionnaire in a prospective, longitudinal cohort study of consecutive couples initiating fertility treatment in Denmark. The study comprised 302 couples with no children at baseline and no joint children at one-year follow-up.

Do variants associated with susceptibility to pancreatic cancer and type 2 diabetes reciprocally affect risk?

Objectives: Although type 2 diabetes mellitus is a known risk factor for pancreatic cancer, the existence of shared genetic susceptibility is largely unknown. We evaluated whether any reported genetic risk variants of either disease found by genome-wide association studies reciprocally confer susceptibility.

Methods: Data that were generated in previous genome-wide association studies (GENEVA Type 2 Diabetes; PanScan) were obtained through the National Institutes of Health database of Genotypes and Phenotypes (dbGaP).

Combining clinicopathological predictors and molecular biomarkers in the oncogenic K-RAS/Ki67/HIF-1α pathway to predict survival in resectable pancreatic cancer.

Background: The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS hyperactivation is virtually universal in pancreatic cancer, that confers drug resistance, drives aggressive tumorigenesis and rapid metastasis. Pancreatic tumours are often marked by hypovascularity, increased hypoxia and ineffective drug delivery.

Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.

Background & Aims: We investigated the prevalence of germline mutations in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic cancer.

Methods: The Ontario Pancreas Cancer Study enrolls consenting participants with pancreatic cancer from a province-wide electronic pathology database; 708 probands were enrolled from April 2003 through August 2012. To improve the precision of BRCA2 prevalence estimates, 290 probands were selected from 3 strata, based on family history of breast and/or ovarian cancer, pancreatic cancer, or neither.

Efficient transduction of equine adipose-derived mesenchymal stem cells by VSV-G pseudotyped lentiviral vectors.

Equine adipose-derived mesenchymal stem cells (EADMSC) provide a unique cell-based approach for treatment of a variety of equine musculoskeletal injuries, via regeneration of diseased or damaged tissue, or the secretion of immunomodulatory molecules. These capabilities can be further enhanced by genetic modification using lentiviral vectors, which provide a safe and efficient method of gene delivery. We investigated the suitability of lentiviral vector technology for gene delivery into EADMSC, using GFP expressing lentiviral vectors pseudotyped with the G glycoprotein from the vesicular stomatitis virus (V-GFP) or, for the first time, the baculovirus gp64 envelope protein (G-GFP).

Case-only exome sequencing and complex disease susceptibility gene discovery: study design considerations.

Whole exome sequencing (WES) provides an unprecedented opportunity to identify the potential aetiological role of rare functional variants in human complex diseases. Large-scale collaborations have generated germline WES data on patients with a number of diseases, especially cancer, but less often on healthy controls under the same sequencing procedures. These data can be a valuable resource for identifying new disease susceptibility loci if study designs are appropriately applied.

BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study.

Purpose: Familial pancreatic cancer kindreds contain at least two affected first-degree relatives. Comprehensive data are needed to assist clinical risk assessment and genetic testing.

Methods: Germ-line DNA samples from 727 unrelated probands with positive family history (521 met criteria for familial pancreatic cancer) were tested in compliance with the Clinical Laboratory Improvement Amendments for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A.

Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction.

Purpose: Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown.

[Cancer patients' experiences contribute to more patient-centred care].

In the Region of Southern Denmark, Vejle Hospital has taken the first step toward measuring patient-centred care from cancer patient's perspective. Based on results from a local patient survey this article aims to evaluate how Vejle Hospital is performing with regard to principles for patient-centred care in different parts of the cancer trajectory. The survey provides unique data at ward level and opportunities to initiate targeted improvement efforts for cancer patients to monitor improve-ments in patient-experienced care, which is crucial to become truly patient-centred.

Placebo effects in idiopathic and neuropathic pain conditions.

The magnitude of placebo analgesia effect appears to be large in chronic pain patients experiencing hyperalgesic states. So far, placebo effects have primarily been investigated in idiopathic pain conditions, such as irritable bowel pain syndrome, but more recently they have also been investigated in neuropathic pain patients, in which the underlying nerve injury is known. Expected pain levels and emotional feelings are central to placebo effects in both types of pain.

Risk factors for pancreatic neuroendocrine tumors: a clinic-based case-control study.

Objectives: Pancreatic neuroendocrine tumors (PNETs) are uncommon, and little is known about their risk factors and association with other cancers. We evaluated whether the following risk factors known to be associated with pancreatic adenocarcinoma are also associated with PNETs: smoking, alcohol use, family history of PNET, and other cancers, and personal history of diabetes as potential risk factors.

Methods: Patients with PNETs seen at Mayo Clinic Rochester between 2000 and 2011 were compared with controls seen for a general medical evaluation.

Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions.

Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain-relieving (lidocaine) or pain-inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M-VAS).