Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma

Identification of prognostic phenotypes of esophageal adenocarcinoma in two independent cohorts.

BACKGROUND & AIMS: Most patients with esophageal adenocarcinoma (EAC) present de novo. Although this may be due to inadequate screening strategies, the precise reason for this observation is not clear.. We compared survival of patients with prevalent EAC with and without synchronous BE/intestinal metaplasia of the esophagus (IM) at the time of EAC diagnosis. METHODS: Clinical data were studied using Cox Proportional Hazards regression to evaluate the effect of synchronous BE/IM on EAC survival independent of age, sex, TNM stage and tumor location. Two cohorts from the Mayo Clinic and a U.K. multicenter prospective cohort were included. RESULTS: The Mayo cohort had 411 EAC patients with 49.3% with BE/IM demonstrating a survival benefit as compared to those without (hazard ratio (HR), 0.44; 95% CI: 0.34 - 0.57, P<0.001). In a multivariable analysis BE/IM was associated with better survival independent of age, sex, stage and tumor location and length (adjusted HR: 0.66, 95% CI: 0.5-0.88, P=0.005). The UK cohort contained 1417 patients, 45% with BE/IM demonstrating a survival benefit as compared with non-BE/IM patients (HR 0.59, 95% CI: 0.5-0.69, P<0.001) with continued significance in multivariable analysis that included age, sex, stage, and tumor location (adjusted HR 0.77, 95% CI: 0.64-0.93, P=0.006). CONCLUSION: Two types of esophageal adenocarcinoma can be characterized based on the presence or absence of Barrett's epithelium. These findings have implications for understanding the etiology of EAC and determining prognosis as well as for development of optimal clinical strategies to identify patients at risk

Krt19\u3csup\u3e+\u3c/sup\u3e/Lgr5\u3csup\u3e-\u3c/sup\u3e Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine

Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5+ cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identification of Lgr5- stem cell pools has proven more challenging. Here, we demonstrate that the intermediate filament keratin-19 (Krt19) marks long-lived, radiation-resistant cells above the crypt base that generate Lgr5+ CBCs in the colon and intestine. In colorectal cancer models, Krt19+ cancer-initiating cells are also radioresistant, while Lgr5+ stem cells are radiosensitive. Moreover, Lgr5+ stem cells are dispensable in both the normal and neoplastic colonic epithelium, as ablation of Lgr5+ stem cells results in their regeneration from Krt19-expressing cells. Thus, Krt19+ stem cells are a discrete target relevant for cancer therapy

Prevalence of Hepatitis B surface antigen (HBsAg) among visitors of Shashemene General Hospital voluntary counseling and testing center

<p>Abstract</p> <p>Background</p> <p>Hepatitis B virus (HBV) infection is significant health problem, as it can lead to chronic hepatitis, liver cirrhosis, and hepatic carcinoma. Due to shared routes of transmission, HBV and human immunodeficiency virus (HIV) co-infection is common and is an emerging concern in the clinical management of patients because of increased mortality, accelerated hepatic disease progression, and the frequent hepatotoxicity caused by anti-retroviral therapy. The aim of this study was to determine the prevalence of Hepatitis B surface antigen (HBsAg) and its risk factors, among individuals visiting Shashemene General Hospital VCT center.</p> <p>Findings</p> <p>Institution based cross-sectional study was performed from November 3, 2008 to December 29, 2008 and 384 voluntary counseling and testing (VCT) clients were investigated. Data on socio demographic and HBV risk factors was collected using structured questionnaires. Blood samples were collected and screened for hepatitis B surface antigen (HBsAg) and HIV by commercially available rapid test kits. The prevalence of HBsAg in this study group was 5.7%. Fourteen percent of HIV positive subjects (8/57) and 4.3% (14/327) of HIV negative subjects were positive for HBsAg. Significantly high prevalence of HBsAg was observed among individuals who had history of invasive procedures, like tooth extraction, abortion and ear piercing; history of hospital admission, history of unsafe inject and HIV positives.</p> <p>Conclusions</p> <p>Although HBsAg prevalence is much higher among subjects who are HIV positive (14.0% versus 4.3%), the prevalence of HBsAg in HIV negative subjects is high enough to warrant a recommendation to screen all clients at VCT centers irrespective of HIV status.</p

Bile acid and inflammation activate gastric cardia stem cells in a mouse model of barrett-like metaplasia

Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5+ gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling. © 2012 Elsevier Inc

Primordial He4 Abundance Constrains the Possible Time Variation of the Higgs Vacuum Expectation Value

We constrain the possible time variation of the Higgs vacuum expectation value ($v$) by recent results on the primordial $^4He$ abundance ($Y_P$). For that, we use an analytic approach which enables us to take important issues into consideration, that have been ignored by previous works, like the $v$-dependence of the relevant cross sections of deuterium production and photodisintegration, including the full Klein- Nishina cross section. Furthermore, we take a non-equilibrium Ansatz for the freeze-out concentration of neutrons and protons and incorporate the latest results on the neutron decay. Finally, we approximate the key-parameters of the primordial $^4He$ production (the mean lifetime of the free neutron and the binding energy of the deuteron) by terms of $v\over v_0$ (where $v_0$ denotes the present theoretical estimate). Eventually, we derive the relation $Y_P \simeq 0.2479 - 5.54 (\frac{v-v_0}{v_0})^2 - 0.808~ (\frac{v-v_0}{v_0})$ and the most stringent limit on a possible time variation of $v$ is given by: $-5.4 \cdot 10^{-4} \leq \frac{v-v_0}{v_0} \leq 4.4 \cdot 10^{-4}$.Comment: Accepted for publication in IJT

The Role of Quantitative Pharmacology in an Academic Translational Research Environment

Translational research is generally described as the application of basic science discoveries to the treatment or prevention of disease or injury. Its value is usually determined based on the likelihood that exploratory or developmental research can yield effective therapies. While the pharmaceutical industry has evolved into a highly specialized sector engaged in translational research, the academic medical research community has similarly embraced this paradigm largely through the motivation of the National Institute of Health (NIH) via its Roadmap initiative. The Clinical and Translational Science Award (CTSA) has created opportunities for institutions which can provide the multidisciplinary environment required to engage such research. A key component of the CTSA and an element of both the NIH Roadmap and the FDA Critical Path is the bridging of bench and bedside science via quantitative pharmacologic relationships. The infrastructure of the University of Pennsylvania/Children’s Hospital of Philadelphia CTSA is highlighted relative to both research and educational objectives reliant upon quantitative pharmacology. A case study, NIH-sponsored research program exploring NK1r antagonism for the treatment NeuroAIDS is used to illustrate the application of quantitative pharmacology in a translational research paradigm

Identification of Lynch syndrome among patients with colorectal cancer

CONTEXT: Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. OBJECTIVE: To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. DESIGN, SETTING, AND PATIENTS: Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. MAIN OUTCOME: Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening). RESULTS: Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. CONCLUSION: Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest