Current status and advances in esophageal drug delivery technology:influence of physiological, pathophysiological and pharmaceutical factors

Diseases affecting the esophagus are common. However, targeted drug delivery to the esophagus is challenging due to the anatomy and physiology of this organ. Current pharmacological treatment for esophageal diseases predominantly relies on the off-label use of drugs in various dosage forms, including those for systemic drug delivery (e.g. oral tablets, sublingual tablets, and injections) and topical drug delivery (e.g. metered dose inhaler, viscous solution or suspension, and endoscopic injection into the esophagus). In general, systemic therapy has shown the most efficacy but requires the use of high drug doses to achieve effective concentrations in the esophagus, which increases the risk of adverse effects and toxicity. Topical drug delivery has enormous potential in improving the way we treat patients with acute and chronic esophageal diseases, especially those requiring drugs that have low therapeutic index and/or significant adverse effects to non-targeted organs and tissues. This review will address the physiological, pathophysiological, and pharmaceutical considerations influencing topical drug delivery in the esophagus. The main conventional (e.g. liquid formulations, orodispersible tablets, lozenges, pastilles, troches, chewing gum) and innovative (e.g. stent-based, film-based, nanoparticulate-based) drug delivery approaches will be comprehensively discussed, along with the developments to improve their effectiveness for topical esophageal drug delivery. The translational challenges and future clinical advances of this research will also be discussed.</p

Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Wnt-11 is a secreted protein that modulates cell growth, differentiation and morphogenesis during development. We previously reported that Wnt-11 expression is elevated in hormone-independent prostate cancer and that the progression of prostate cancer from androgen-dependent to androgen-independent proliferation correlates with a loss of mutual inhibition between Wnt-11- and androgen receptor-dependent signals. However, the prevalence of increased expression of Wnt-11 in patient tumours and the functions of Wnt-11 in prostate cancer cells were not known.</p> <p>Results</p> <p>Wnt-11 protein levels in prostate tumours were determined by immunohistochemical analysis of prostate tumour tissue arrays. Wnt-11 protein was elevated in 77/117 of tumours when compared with 27 benign prostatic hypertrophy specimens and was present in 4/4 bone metastases. In addition, there was a positive correlation between Wnt-11 expression and PSA levels above 10 ng/ml. Androgen-depleted LNCaP prostate cancer cells form neurites and express genes associated with neuroendocrine-like differentiation (NED), a feature of prostate tumours that have a poor prognosis. Since androgen-depletion increases expression of Wnt-11, we examined the role of Wnt-11 in NED. Ectopic expression of Wnt-11 induced expression of NSE and ASCL1, which are markers of NED, and this was prevented by inhibitors of cyclic AMP-dependent protein kinase, consistent with the known role of this kinase in NED. In contrast, Wnt-11 did not induce NSE expression in RWPE-1 cells, which are derived from benign prostate, suggesting that the role of Wnt-11 in NED is specific to prostate cancer. In addition, silencing of Wnt-11 expression in androgen-depleted LNCaP cells prevented NED and resulted in apoptosis. Silencing of Wnt-11 gene expression in androgen-independent PC3 cells also reduced expression of NSE and increased apoptosis. Finally, silencing of Wnt-11 reduced PC3 cell migration and ectopic expression of Wnt-11 promoted LNCaP cell invasion.</p> <p>Conclusions</p> <p>These observations suggest that the increased level of Wnt-11 found in prostate cancer contributes to tumour progression by promoting NED, tumour cell survival and cell migration/invasion, and may provide an opportunity for novel therapy in prostate cancer.</p

Current status and advances in esophageal drug delivery technology: influence of physiological, pathophysiological and pharmaceutical factors

Diseases affecting the esophagus are common. However, targeted drug delivery to the esophagus is challenging due to the anatomy and physiology of this organ. Current pharmacological treatment for esophageal diseases predominantly relies on the off-label use of drugs in various dosage forms, including those for systemic drug delivery (e.g. oral tablets, sublingual tablets, and injections) and topical drug delivery (e.g. metered dose inhaler, viscous solution or suspension, and endoscopic injection into the esophagus). In general, systemic therapy has shown the most efficacy but requires the use of high drug doses to achieve effective concentrations in the esophagus, which increases the risk of adverse effects and toxicity. Topical drug delivery has enormous potential in improving the way we treat patients with acute and chronic esophageal diseases, especially those requiring drugs that have low therapeutic index and/or significant adverse effects to non-targeted organs and tissues. This review will address the physiological, pathophysiological, and pharmaceutical considerations influencing topical drug delivery in the esophagus. The main conventional (e.g. liquid formulations, orodispersible tablets, lozenges, pastilles, troches, chewing gum) and innovative (e.g. stent-based, film-based, nanoparticulate-based) drug delivery approaches will be comprehensively discussed, along with the developments to improve their effectiveness for topical esophageal drug delivery. The translational challenges and future clinical advances of this research will also be discussed

No Evidence of XMRV or MuLV Sequences in Prostate Cancer, Diffuse Large B-Cell Lymphoma, or the UK Blood Donor Population

Xenotropic murine leukaemia virus-related virus (XMRV) is a recently described retrovirus which has been claimed to infect humans and cause associated pathology. Initially identified in the US in patients with prostate cancer and subsequently in patients with chronic fatigue syndrome, doubt now exists that XMRV is a human pathogen. We studied the prevalence of genetic sequences of XMRV and related MuLV sequences in human prostate cancer, from B cell lymphoma patients and from UK blood donors. Nucleic acid was extracted from fresh prostate tissue biopsies, formalin-fixed paraffin-embedded (FFPE) prostate tissue and FFPE B-cell lymphoma. The presence of XMRV-specific LTR or MuLV generic gag-like sequences was investigated by nested PCR. To control for mouse DNA contamination, a PCR that detected intracisternal A-type particle (IAP) sequences was included. In addition, DNA and RNA were extracted from whole blood taken from UK blood donors and screened for XMRV sequences by real-time PCR. XMRV or MuLV-like sequences were not amplified from tissue samples. Occasionally MuLV gag and XMRV-LTR sequences were amplified from Indian prostate cancer samples, but were always detected in conjunction with contaminating murine genomic DNA. We found no evidence of XMRV or MuLV infection in the UK blood donors

Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology

A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD

Excellent Adherence to Antiretrovirals in HIV+ Zambian Children Is Compromised by Disrupted Routine, HIV Nondisclosure, and Paradoxical Income Effects

INTRODUCTION: A better understanding of pediatric antiretroviral therapy (ART) adherence in sub-Saharan Africa is necessary to develop interventions to sustain high levels of adherence. METHODOLOGY/PRINCIPAL FINDINGS: Adherence among 96 HIV-infected Zambian children (median age 6, interquartile range [IQR] 2,9) initiating fixed-dose combination ART was measured prospectively (median 23 months; IQR 20,26) with caregiver report, clinic and unannounced home-based pill counts, and medication event monitoring systems (MEMS). HIV-1 RNA was determined at 48 weeks. Child and caregiver characteristics, socio-demographic status, and treatment-related factors were assessed as predictors of adherence. Median adherence was 97.4% (IQR 96.1,98.4%) by visual analog scale, 94.8% (IQR 86,100%) by caregiver-reported last missed dose, 96.9% (IQR 94.5,98.2%) by clinic pill count, 93.4% (IQR 90.2,96.7%) by unannounced home-based pill count, and 94.8% (IQR 87.8,97.7%) by MEMS. At 48 weeks, 72.6% of children had HIV-1 RNA <50 copies/ml. Agreement among adherence measures was poor; only MEMS was significantly associated with viral suppression (p = 0.013). Predictors of poor adherence included changing residence, school attendance, lack of HIV disclosure to children aged nine to 15 years, and increasing household income. CONCLUSIONS/SIGNIFICANCE: Adherence among children taking fixed-dose combination ART in sub-Saharan Africa is high and sustained over two years. However, certain groups are at risk for treatment failure, including children with disrupted routines, no knowledge of their HIV diagnosis among older children, and relatively high household income, possibly reflecting greater social support in the setting of greater poverty

Role of the HSP90-Associated Cochaperone p23 in Enhancing Activity of the Androgen Receptor and Significance for Prostate Cancer

Prostate tumor growth initially depends on androgens, which act via the androgen receptor (AR). Despite androgen ablation therapy, tumors eventually progress to a castrate-resistant stage in which the AR remains active. The mechanisms are poorly understood but it may be that changes in levels or activity of AR coregulators affect trafficking and activation of the receptor. A key stage in AR signaling occurs in the cytoplasm, where unliganded receptor is associated with the heat shock protein (HSP)90 foldosome complex. p23, a key component of this complex, is best characterized as a cochaperone for HSP90 but also has HSP90-independent activity and has been re-ported as having differential effects on the activity of different steroid receptors. Here we report that p23 increases activity of the AR, and this appears to involve steps both in the cytoplasm (increasing ligand-binding capacity, possibly via direct interaction with AR) and the nucleus (en-hancing AR occupancy at target promoters). We show, for the first time, that AR and p23 can interact, perhaps directly, when HSP90 is not present in the same complex. The effects of p23 on AR activity are at least partly HSP90 independent because a mutant form of p23, unable to bind HSP90, nevertheless increases AR activity. In human prostate tumors, nuclear p23 was higher in malignant prostate cells compared with benign/normal cells, supporting the utility of p23 as a therapeutic target in prostate cancer. © 2012 by The Endocrine Society

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC