Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.pancreatic ductal adenocarcinoma | glutaminolysis | glucose metabolism | KRAS mutation | intratumoral hypoxia P atients with pancreatic ductal adenocarcinoma (PDAC) have among the highest fatality rates of all cancers (1). Pancreatic cancer is predicted to become the second-leading cause of cancer death in the United States by the year 2030 (2). Over 90% of PDACs display mutations in oncogenic KRAS (Kirsten rat sarcoma viral oncogene homolog) (3, 4), a known regulator of glutamine metabolism that can render cancer cells dependent on glutamine for survival and proliferation (5, 6)-a state known as "glutamine addiction" (7, 8)-suggesting that dependency on glutamine could be exploited to develop new therapies for KRAS-mutated PDAC. The first step of glutamine metabolism is the conversion of glutamine to glutamate and ammonia, which is catalyzed by glutaminase (GLS). Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), which is an allosteric, time-dependent (9), and specific inhibitor of GLS1, exhibits unique binding at the oligomerization interface of the glutaminase tetramer (10, 11). Although BPTES is more selective than other prototype glutaminase inhibitors, such as 6-diazo-5-oxo-L-norleucine (12) or ebselen (9), and can effectively inhibit GLS1 (13) and tumor growth (13-15), poor solubility (0.144 μg/mL) (16) has limited its clinical development. Recently, CB-839 (17) was tested in a phase I clinical trial. Abnormal liver and kidney function tests, lymphop...

Suboptimal HIV/STI testing uptake has a profound impact on morbidity and mortality. Incentives have been effective in other areas of medicine and may improve HIV/STI testing uptake rates. This study reviewed the effects of incentives on HIV/STI testing uptake. A systematic search of seven databases was undertaken. Testing uptake was defined as test implementation and/or test result retrieval. Incentives were defined as monetary or non-monetary rewards or free-of-charge testing vouchers. Seven studies were included. All seven studies demonstrated higher rates of uptake in an incentivized group. Incentives offered at a nonclinical setting demonstrated more significant differences in uptake rates compared to incentives offered at a clinical setting. Incentivizing HIV/STI testing uptake, especially testing at a non-clinical setting, may be a useful tool to modify health behavior. Further research is needed to understand how incentives could be an effective component within a comprehensive HIV/STI control strategy.

The Boston keratoprosthesis type II is a viable option to salvage vision in patients with poor prognosis for other corneal procedures. Retroprosthetic membranes, keratoprosthesis retention, and glaucoma are major challenges in the postoperative period; however, the keratoprosthesis can still provide improved vision in a select group of patients.

PurposeTo describe spectral-domain optical coherence tomography (OCT) methods for quantifying neuroretinal rim tissue in glaucoma and to compare these methods to the traditional retinal nerve fiber layer thickness diagnostic parameter.MethodsNeuroretinal rim parameters derived from three-dimensional (3D) volume scans were compared with the two-dimensional (2D) Spectralis retinal nerve fiber layer (RNFL) thickness scans for diagnostic capability. This study analyzed one eye per patient of 104 glaucoma patients and 58 healthy subjects. The shortest distances between the cup surface and the OCT-based disc margin were automatically calculated to determine the thickness and area of the minimum distance band (MDB) neuroretinal rim parameter. Traditional 150-μm reference surface–based rim parameters (volume, area, and thickness) were also calculated. The diagnostic capabilities of these five parameters were compared with RNFL thickness using the area under the receiver operating characteristic (AUROC) curves.ResultsThe MDB thickness had significantly higher diagnostic capability than the RNFL thickness in the nasal (0.913 vs. 0.818, P = 0.004) and temporal (0.922 vs. 0.858, P = 0.026) quadrants and the inferonasal (0.950 vs. 0.897, P = 0.011) and superonasal (0.933 vs. 0.868, P = 0.012) sectors. The MDB area and the three neuroretinal rim parameters based on the 150-μm reference surface had diagnostic capabilities similar to RNFL thickness.ConclusionsThe 3D MDB thickness had a high diagnostic capability for glaucoma and may be of significant clinical utility. It had higher diagnostic capability than the RNFL thickness in the nasal and temporal quadrants and the inferonasal and superonasal sectors.

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BackgroundHealth services for men who have sex with men (MSM) are inadequate in many areas around the world. HIV and syphilis test uptake remain suboptimal among MSM in China and many other regions. To inform the development of more comprehensive sexually transmitted disease (STD) testing programs among MSM, we collected descriptive data on MSM testing practices and preferences.MethodsMSM in two large urban Chinese cities were recruited through community-based organizations and clinics to participate in semi-structured interviews. We purposively sampled MSM across a range of sociodemographic characteristics and testing history, and assessed preferences for HIV and syphilis testing in the context of facilitators and barriers to testing and previous testing experiences. Each interview transcript was coded and thematically analyzed using Atlas.ti 7.0.Results35 MSM were interviewed. Confidentiality and privacy were the most important factors influencing participants’ decisions about whether and where to get tested. Men preferred rapid testing (results available within 30 minutes) compared to conventional tests where results take several hours or days to return. Participants described concerns about quality and accuracy of rapid tests offered in non-clinical settings such as community-based organizations. Men preferred testing service providers who were MSM-friendly, non-discriminatory, and medically trained. Preferred service center environments included: convenient but discrete location, MSM-friendly atmosphere, and clean/standard medical facilities.ConclusionOur data highlight the need for HIV/syphilis testing services that are confidential and inclusive of MSM. Rapid testing in decentralized (i.e. peripheral health facilities and community-level, non-clinical venues) settings provides an opportunity to reach individuals who have not been tested before, but must be accompanied by quality assurance systems and technical competence. Implementation research could further evaluate HIV/syphilis testing programs responsive to MSM preferences.Short SummaryA qualitative study of MSM in South China found that men preferred rapid STD testing at MSM-focused test centers, but were concerned about test quality assurance and confidentiality.

BackgroundUNAIDS has called for greater HIV/syphilis testing worldwide just as local HIV/syphilis testing programs are cut or altered. New models are needed to make HIV/syphilis testing services sustainable while retaining their essential public health function. Social entrepreneurship, using business principles to promote a social cause, provides a framework to pilot programs that sustainably expand testing. Drawing on fieldwork in two South Chinese cities, we examined organizational and financial characteristics of current HIV/syphilis testing systems for men who have sex with men (MSM) in addition to new pilot programs focused on revenue-generation for sustainability.MethodsWe undertook a qualitative study to explore organizational and financial characteristics of HIV/syphilis testing for MSM. Data were collected from men who have sex with men and policy stakeholders in Guangzhou and Hong Kong. Framework analysis was used to identify themes and then code the data.ResultsOur qualitative research study included MSM and policy stakeholders (n = 84). HIV/syphilis testing services were implemented at a wide range of organizations which we grouped broadly as independent community-based organizations (CBOs), independent clinics, and hybrid CBO-clinic sites. From an organizational perspective, hybrid CBO-clinic sites offered the inclusive environment of an MSM CBO linked to the technical capacity and trained staff of a clinic. From a financial perspective, stakeholders expressed concern about the sustainability and effectiveness of sexual health services reliant on external funding. We identified four hybrid CBO-clinic organizations that launched pilot testing programs in order to generate revenue while expanding HIV testing.ConclusionMany MSM CBOs are searching for new organizational models to account for decreased external support. Hybrid CBO-clinic organizations create a strong foundation to increase HIV/syphilis testing using social entrepreneurship models in China.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0601-5) contains supplementary material, which is available to authorized users.

Comprehensive interventions that address both individual and structural determinants associated with HIV/STI risk are gaining increasing attention over the past decade. Microenterprise development offers an appealing model for HIV prevention by addressing poverty and gender equality. This study systematically reviewed the effects of microenterprise development interventions on HIV/STI incidence and sexual risk behaviors. Microenterprise development was defined as developing small business capacity among individuals to alleviate poverty. Seven eligible research studies representing five interventions were identified and included in this review. All of the studies targeted women, and three focused on sex workers. None measured biomarker outcomes. All three sex worker studies showed significant reduction in sexual risk behaviors when compared to the control group. Non-sex worker studies showed limited changes in sexual risk behavior. This review indicates the potential utility of microenterprise development in HIV risk reduction programs. More research is needed to determine how microenterprise development can be effectively incorporated in comprehensive HIV control strategies.