In Vitro Framework to Assess the Anti-Helicobacter pylori Potential of Lactic Acid Bacteria Secretions as Alternatives to Antibiotics.

Helicobacter pylori is a prevalent bacterium that can cause gastric ulcers and cancers. Lactic acid bacteria (LAB) ameliorate treatment outcomes against H. pylori, suggesting that they could be a source of bioactive molecules usable as alternatives to current antibiotics for which resistance is mounting. We developed an in vitro framework to compare the anti-H. pylori properties of 25 LAB and their secretions against H. pylori. All studies were done at acidic and neutralized pH, with or without urea to mimic various gastric compartments. Eighteen LAB strains secreted molecules that curtailed the growth of H. pylori and the activity was urea-resistant in five LAB. Several LAB supernatants also reduced the urease activity of H. pylori. Pre-treatment of H. pylori with acidic LAB supernatants abrogated its flagella-mediated motility and decreased its ability to elicit pro-inflammatory IL-8 cytokine from human gastric cells, without reverting the H. pylori-induced repression of other pro-inflammatory cytokines. This study identified the LAB that have the most anti-H. pylori effects, decreasing its viability, its production of virulence factors, its motility and/or its ability to elicit pro-inflammatory IL-8 from gastric cells. Once identified, these molecules can be used as alternatives or complements to current antibiotics to fight H. pylori infections.

Treatment options in BRAF-mutant metastatic colorectal cancer.

B-type Raf kinase (BRAF) mutations occur in approximately 10% of patients with metastatic colorectal cancers (mCRC). Tumors harboring this mutation have a unique molecular profile and clinical phenotype. Response rate to systemic chemotherapy is poor and associated with shorter survival rate. Although BRAF inhibition dramatically changed treatment for melanoma patients, similar clinical responses were not observed in BRAF-mutant CRC, proposing a distinct mechanism of carcinogenesis. The aggressive biology of BRAF-mutated mCRC has underlined the importance of developing new therapeutic agents to improve outcomes in these patients. Despite numerous attempts, chemotherapy regimens are limited for this population. Reactivation of mitogen activated protein kinase pathway may explain the resistance to monotherapy, thus different combinations to target the pathway at different levels have been studied. This article will describe most suitable treatment options for CRC patients with BRAF mutation and discuss new emerging agents.

Characterization of Helicobacter pylori†HP0231 (DsbK): role in disulfide bond formation, redox homeostasis and production of Helicobacter cystein-rich protein HcpE.

Helicobacter pylori is a human gastric pathogen that colonizes ∼ 50% of the world's population. It can cause gastritis, gastric or duodenal ulcers and also gastric cancer. The numerous side effects of available treatments and the emergence of antibiotic resistant strains are severe concerns that justify further research into H. pylori's pathogenic mechanisms. H. pylori produces secreted proteins that may play a role in virulence, including the Helicobacter cysteine-rich protein HcpE (aka HP0235). We demonstrate herein that HcpE is secreted in the culture supernatant both as a soluble protein and in association with outer membrane vesicles. We show that the structure of HcpE comprises an organized array of disulfide bonds. We identify DsbK (aka HP0231) as a folding factor necessary for HcpE production and secretion in H. pylori and show that recombinant DsbK can interact with and refold unprocessed, reduced HcpE in vitro. These experiments highlight the first biologically relevant substrate for DsbK. Furthermore, we show that DsbK has disulfide bond (Dsb) forming activity on reduced lysozyme and demonstrate a DsbA-type of activity for DsbK upon expression in E. coli, despite its similarity with DsbG. Finally, we show a role of DsbK in maintaining redox homeostasis in H. pylori.

Intravenous thiotepa for treatment of breast cancer-related leptomeningeal carcinomatosis: case series.

Leptomeningeal carcinomatosis (LMC) secondary to metastatic breast cancer (MBC) has increased in incidence with improved systemic disease control. Current treatment options include radiation therapy (to symptomatic sites) and systemic treatment [intrathecal (IT) or intravenous (IV) chemotherapy]. Methotrexate (MTX), thiotepa and cytarabine are the most commonly used IT agents, while high-dose MTX is the most common IV regimen. While IT treatments are generally well tolerated, complications like chemical meningitis, leukoencephalopathy, etc. occur. LMC may cause a breakdown in the blood-brain barrier and thus allow systemic agents to penetrate; however, efficacy is reported only for agents administered at high doses (MTX). We report our institution's experience in using IV thiotepa as treatment for LMC secondary to MBC. We conducted a retrospective chart review of 13 patients with MBC who developed LMC and treated with IV thiotepa at our institution. It was administered at 40 mg/m(2) every 21 days; median number of thiotepa cycles administered was 5 with the major dose-limiting toxicity being myelosuppression. Four had partial response, 3 had stable disease and 6 had progressive disease. The 6-month survival rate was 69 % and 1-year survival rate was 31 %. Despite retrospective nature of our case series, we found the use of IV thiotepa as sole treatment for LMC in patients with MBC to be well tolerated, easily administered in the ambulatory setting, and with efficacy comparable to the other chemotherapeutic agents commonly used in the treatment of LMC. This regimen warrants further investigation in prospective studies.

Identifying Invalid Responders in a Campus Climate Survey: Types, Impact on Data, and Best Indicators.

Self-report surveys that are online, lengthy, and contain sensitive material greatly increase the probability of invalid responding (IR) on the instrument. Most research to inform our identification of invalid responders have not been able to test their methodologies where all these conditions are present. This study systematically adopted 10 IR indicators based on direct, archival, and statistic strategies to identify IR providing answers on a lengthy survey collecting campus climate/violence information that college students (N = 6,995) accessed online. Exploratory factor analysis indicated two internal factors (i.e., careless and extreme responding) underlying these IR indicators. Latent class analysis identified 4.8% of the sample as being invalid responders. Compared with honest responders, invalid responders were significantly more likely to report forms of victimization and a greater negative impact from physical abuse or sexual assault. Of importance, mean scores on victimization scales were significantly higher for invalid responders, illustrating the potential for IR data to skew prevalence rates. IR indicators differentially identified honest and invalid responders. The findings of this study contribute to the systematic investigation of IR with college students completing online and lengthy surveys that address sensitive material.

Are College Students' Attitudes Related to Their Application of Sanctions for Campus Sexual Assault Cases?

With growing attention to adjudication of campus sexual assault cases, more is known regarding students' views of sexual assault, but little the literature focuses on how students perceive "justice" in terms of assigning sanctions or guilt/responsibility for such cases. The present study focused on understanding whether college students' preformed attitudes and beliefs were associated with the severity of sanctions they applied across a range of sexual assault cases as well as their assignments of guilt and responsibility to the parties involved. To determine students' attitudes and beliefs mediating effects on sanction choices, five scales (i.e., rape myth acceptance, downplaying the severity of rape, sexism, just world beliefs, and right-wing authoritarianism) were adapted and used for this project. College students (n = 846) responded to one of four versions of a randomly distributed survey each containing eight vignettes varied to represent levels of 14 factors employed because of their relevance to campus sexual assault cases. Across all versions, sexism was associated with increased responsibility given to the victim. In addition, stronger endorsement of both downplaying significance of rape and rape myth acceptance scales were associated with giving a milder sanction to the perpetrator and increased responsibility and guilt assigned to the victim. Just world beliefs and right-wing authoritarianism associations were inconsistent across the four versions, suggesting these beliefs were situation-specific. Preformed attitudes that are more directly related to the context of sexual assault influenced the designation of sanctions applied to perpetrators and perceptions of guilt and responsibility. Findings are discussed in terms of implications for research and prevention programming.

A Campus Climate/Violence Survey's Psychometrics and Findings.

Data from a campus climate/violence survey (CCS) include psychometric information for survey items/scales plus findings from a large state university to promote its usefulness for assessment of interpersonal violence/harassment. This CCS can thus be evaluated for its measurement and documented findings, allowing for benchmarking purposes. An innovative measurement strategy is introduced to comprehensively capture incidence of victimization types through streamlined questioning. Tables provide detailed data for 6,995 undergraduate and graduate/professional students over a 1-year period. Adding to published literature on existing CCSs, this article provides the range of information needed for universities to determine the potential usefulness of a CCS.

Regulation of insulin-response element binding protein-1 in obesity and diabetes: potential role in impaired insulin-induced gene transcription.

One of the major mechanisms by which insulin modulates glucose homeostasis is through regulation of gene expression. Therefore, reduced expression of transcription factors that are required for insulin-regulated gene expression may contribute to insulin resistance. We recently identified insulin response element-binding protein-1 (IRE-BP1) as a transcription factor that binds and transactivates multiple insulin-responsive genes, but the regulation of IRE-BP1 in vivo is largely unknown. In this study, we show that IRE-BP1 interacts with the insulin response sequence of the IGF-I, IGFBP-1, and IGFBP-3 genes using chromatin immunoprecipitation assay. Furthermore, activation by IRE-BP1 is sequence specific and mimics that of the insulin effect on gene transcription. Tissue expression of IRE-BP1 is 50- to 200-fold higher in classical insulin target compared with nontarget tissues in lean animals, with a significantly reduced level of expression in the skeletal muscle and adipose tissue in obese and diabetic animals. In the liver, IRE-BP1 is localized to the nucleus in lean rats but is sequestered to the cytoplasm in obese and diabetic animals. Cytoplasmic sequestration appears to be related to inhibition of insulin-mediated phosphatidylinositol-3 kinase signaling. Therefore, in diabetes and obesity, the mechanisms involved in reducing the transactivation of the insulin response sequence by IRE-BP1 include decreased gene transcription and nuclear exclusion to prevent DNA binding. Our study supports the notion that IRE-BP1 may be relevant to the action of insulin in vivo and may play a role in the development of insulin resistance and diabetes.

Do Guns in the Home Predict Gender and Relationship Attitudes? An Exploratory Study.

This study explores the potential relationship of guns in students' homes with attitudes indicative of tolerance of violence, negative attitudes toward women and their roles, and attitudes suggestive of myths regarding sexual assault. Seniors in Kentucky high schools whose families possessed guns (N=1749) produced higher scores on scales measuring these variables as well as on scales of relationship dependency and religious involvement than seniors whose families did not own guns (N=912). Students whose families owned more than 10 guns tended to score highest on these measures compared with students whose families owned no or a few guns. Because of lower effect sizes, these significant associations require further investigation.

Hyperprolactinemia.

In several respects prolactin is unique among anterior pituitary hormones. The primary regulation of prolactin secretion is mediated through hypothalamic inhibition, and the diagnosis of hyperprolactinemia can be established without the use of stimulation or suppression tests. Documenting the presence of hyperprolactinemia is not difficult-the challenge is in identifying the cause of the hormone hypersecretion. With immunoradiometric assays falsely low levels of prolactin are occasionally seen in patients with macroadenomas and very high serum prolactin (the hook effect). Macroprolactin should be suspected when a patient with hyperprolactinemia does not present with typical clinical symptoms, and all hyperprolactinemic sera should be screened for macroprolactin. With prolactinomas, prolactin levels generally parallel tumor size. Prolactin secreting macroadenomas are typically associated with levels that exceed 250 microg/l and may exceed 1,000 microg/l. Large non-functioning adenomas also lead to hyperprolactinemia but levels virtually never exceed 94 microg/l. Acquired and isolated prolactin deficiency is rare.