Dual and opposing roles of primary cilia in medulloblastoma development.

Recent work has shown that primary cilia are essential for Hedgehog (Hh) signaling during mammalian development. It is also known that aberrant Hh signaling can lead to cancer, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children. The primary cilium and Hh signaling are required for GNP proliferation. We asked whether primary cilia in GNPs have a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma formation when this tumor was driven by a constitutively active Smoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active glioma-associated oncogene family zinc finger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either required for or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence or absence of cilia was associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis

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

Cross-talk between epidermal growth factor receptor and protein kinase C during calcium-induced differentiation of keratinocytes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74029/1/j.1600-0625.2000.009003192.x.pd

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Helicobacter pylori (H. pylori) infection is widespread all over the world. The greatest number of infected people are in developing countries, whereas in developed countries the rate of infection is the smallest. Among risk factors of infection, the socioeconomic environment is regarded as one of the most important. In developed countries, the incidence of H. pylori infection in children is smaller than 12% and shows a tendency to decrease, while in developing countries it may exceed 40% (1). Multicenter studies conducted in Poland in the years [2002][2003] have demonstrated a high rate of H. pylori seroprevalence in both children and adults. In children aged 6 month to 18 years H. pylori seroprevalence rate was 32% and in adults aged 19 to 89 years 84% and varied depending on the region of the country (2). An influence of poor sanitary and hygiene conditions, economical status and parents education on the infection rate was demonstrated. In the last years a tendency to the decrease of infection rate has been shown, which could be linked to the improvement of social condition (3). H. pylori infection is a principal cause of chronic gastritis and peptic ulcer disease in children. In adulthood it leads to many diseases of the gastrointestinal tract including in particular JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2014, 65, 6, 801-807 www. Helicobacter pylori (H. pylori) plays an important role in the pathogenesis of the upper gastrointestinal tract diseases in both children and adults. The aim of this paper was to assess the differences between the clinical course of the disease in children and adults. This paper also presents an analysis of clinical symptoms, endoscopic and histopathological findings, H. pylori cagA and vacA genotypes rates and analysis of the sensitivity of these strains to antibiotics in the Polish population, with possible practical and therapeutic implications. The multicenter study on the frequency of H. pylori infections assessed by the presence of antibodies in IgG class against H. pylori in serum was conducted in the years 2002 and 2003. The study group included 6565 children and adults, in 3827 of whom antibodies levels were above 24 U/mL. The authors analyzed clinical and endoscopic symptoms and in some patients with H. pylori seropositivity also histopathological changes, and cagA and vacA genes. Sensitivity of H. pylori strains to antibiotics were also analyzed. Differences between the frequency of infection between children and adults were determined. Endoscopic examination in adults revealed more frequent cases of gastropathy (P=0.003) and erosive gastritis (P=0.001), and in children-thick mucosal folds (P<0.0001). Histopathological examinations carried out in adults have revealed atrophic gastritis and intestinal metaplasia. In children, cagA(+)s1m1 was observed more frequently than in adults (34.0% versus 23.1%; P=0.02) contrary to cagA(-)s2m2 which occurred more frequently in adults (27.1% versus 14.0%; P=0.003). No effect of the infection on nausea, regurgitation, vomiting, heartburn, and abdominal pain in children was detected. However, adults infected with H. pylori suffered from more frequent episodes of heartburn and abdominal pain. The H. pylori strain exhibited a high resistance to metronidazole (higher in adults: 41.7% versus 27.4%; P=0.002), and to clarithromycin (higher in children: 20.2% versus 15.4%; P>0.05), and dual resistance to metronidazole and clarithromycin (higher in children: 9.9% versus 8.4%; P>0.05). Resistance of the H. pylori to amoxicillin and tetracycline was not detected. The conducted study indicated clinical differences in the H. pylori infection in children and adults. Among the differences in children, especially the more frequent infections by the cagA(+)s1m1/m2 strain could have an influence on further consequences of the infection. The obtained results could be useful in therapeutic decisions

Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6

Ibrutinib may inhibitintestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 μg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion

Coupling Constant pH Molecular Dynamics with Accelerated Molecular Dynamics

An extension of the constant pH method originally implemented by Mongan et al. (J. Comput. Chem.2004, 25, 2038−2048) is proposed in this study. This adapted version of the method couples the constant pH methodology with the enhanced sampling technique of accelerated molecular dynamics, in an attempt to overcome the sampling issues encountered with current standard constant pH molecular dynamics methods. Although good results were reported by Mongan et al. on application of the standard method to the hen egg-white lysozyme (HEWL) system, residues which possess strong interactions with neighboring groups tend to converge slowly, resulting in the reported inconsistencies for predicted pKa values, as highlighted by the authors. The application of the coupled method described in this study to the HEWL system displays improvements over the standard version of the method, with the improved sampling leading to faster convergence and producing pKa values in closer agreement to those obtained experimentally for the more slowly converging residues

Multi-Jet Event Rates in Deep Inelastic Scattering and Determination of the Strong Coupling Constant

Jet event rates in deep inelastic ep scattering at HERA are investigated applying the modified JADE jet algorithm. The analysis uses data taken with the H1 detector in 1994 and 1995. The data are corrected for detector and hadronization effects and then compared with perturbative QCD predictions using next-to-leading order calculations. The strong coupling constant alpha_S(M_Z^2) is determined evaluating the jet event rates. Values of alpha_S(Q^2) are extracted in four different bins of the negative squared momentum transfer~\qq in the range from 40 GeV2 to 4000 GeV2. A combined fit of the renormalization group equation to these several alpha_S(Q^2) values results in alpha_S(M_Z^2) = 0.117+-0.003(stat)+0.009-0.013(syst)+0.006(jet algorithm).Comment: 17 pages, 4 figures, 3 tables, this version to appear in Eur. Phys. J.; it replaces first posted hep-ex/9807019 which had incorrect figure 4