Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy.

Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To increase our understanding of the transcriptional and epigenetic events associated with autophagy, we performed extensive genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human autophagy-proficient and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux. As a proof of principle that this resource can be used to identify novel autophagy regulators, we followed up on one identified target: EGR1 (early growth response 1), which indeed appears to be a central transcriptional regulator of autophagy by affecting autophagy-associated gene expression and autophagic flux. Taken together, these data stress the relevance of transcriptional and epigenetic regulation of autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation.

Perceptions of patients with chronic obstructive pulmonary disease and their health care providers towards using mHealth for self-management of exacerbations: a qualitative study.

BACKGROUND: Self-management of exacerbations in COPD patients is important to reduce exacerbation impact. There is a need for more comprehensive and individualized interventions to improve exacerbation-related self-management behavior. The use of mobile health (mHealth) could help to achieve a wide variety of behavioral goals. Understanding of patients and health care providers perspectives towards using mHealth in promoting self-management will greatly enhance the development of solutions with optimal usability and feasibility. Therefore, the aim of this study was to explore perceptions of COPD patients and their health care providers towards using mHealth for self-management of exacerbations. METHODS: A qualitative study using focus group interviews with COPD patients (n = 13) and health care providers (HCPs) (n = 6) was performed to explore perceptions towards using mHealth to support exacerbation-related self-management. Data were analyzed by a thematic analysis. RESULTS: COPD patients and HCPs perceived mostly similar benefits and barriers of using mHealth for exacerbation-related self-management. These perceived benefits and barriers seem to be important drivers in the willingness to use mHealth. Both patients and HCPs strengthen the need for a multi-component and tailored mHealth intervention that improves patients' exacerbation-related self-management by determining their health status and providing adequate information, decision support and feedback on self-management behavior. Most importantly, patients and HCPs considered an mHealth intervention as support to improve self-management and emphasized that it should never replace patients' own feelings nor undermine their own decisions. In addition, the intervention should be complementary to regular contact with HCPs, as personal contact with a HCP was considered to be very important. To optimize engagement with mHealth, patients should have a positive attitude toward using mHealth and an mHealth intervention should be attractive, rewarding and safe. CONCLUSIONS: This study provided insight into perceptions of COPD patients and their HCPs towards using mHealth for self-management of exacerbations. This study points out that future mHealth interventions should focus on developing self-management skills over time by providing adequate information, decision support and feedback on self-management behavior and that mHealth should complement regular care. To optimize engagement, mHealth interventions should be attractive, rewarding, safe and tailored to the patient needs.

Let's talk about sex: A qualitative study exploring the experiences of HIV nurses when discussing sexual risk behaviours with HIV-positive men who have sex with men.

BACKGROUND: Despite prevention efforts, the incidence of sexually transmitted infection among HIV-positive men who have sex with men remains high, which is indicative of unchanged sexual risk behaviour. Discussing sexual risk behaviour has been shown to help prevent sexually transmitted infections among HIV-positive men who have sex with men. OBJECTIVES: The aim of this study was to identify factors that influence whether - and how - specialised HIV nurses discuss sexual risk behaviour with HIV-positive men who have sex with men. Identifying these factors could indicate how best to improve the frequency and quality of discussions about sexual risk behaviour, thereby reducing sexual risk behaviour and sexually transmitted infections. DESIGN: Qualitative study, focus groups among HIV nurses. SETTING: Dutch HIV treatment centres. PARTICIPANTS: A purposive sample was taken of 25 out of 87 HIV nurses working in one of the 26 specialised HIV treatment centres in the Netherlands. Of the 25 HIV nurses we approached, 22 participate in our study. METHODS: Three semi-structured focus group interviews were held with 22 HIV nurses from 17 hospitals. Interviews were transcribed verbatim, and thematic analysis was performed. RESULTS: HIV nurses agreed that discussing sexual risk behaviour is important, but barriers were experienced in relation to doing so. In accordance with the theory of planned behaviour, attitudes, perceived norms and perceived behavioural control were all found to be relevant variables. Barriers to discussing sexual risk behaviour were identified as: dealing with embarrassment, the changing professional role of an HIV nurse, time constraints, and the structure of the consultation. CONCLUSIONS: To improve the frequency and quality of discussions about sexual risk behaviour with HIV-positive men who have sex with men, our data suggests it would be beneficial to support HIV nurses by developing tools and guidelines addressing what to discuss and how. Using a related topic as a conversational 'bridge' may help nurses to broach this subject with their patients. This would allow HIV nurses to discuss possible risk reduction strategies, such as pre-exposure prophylaxis for HIV-negative partners, condom use, strategic positioning, or sero-sorting.

The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe?

Development and progression of cancer are mediated by alterations in transcriptional networks, resulting in a disturbed balance between the activity of oncogenes and tumor suppressor genes. Transcription factors have the capacity to regulate global transcriptional profiles, and are consequently often found to be deregulated in their expression and function during tumorigenesis. Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) is a member of the group C subfamily of the SOX transcription factors and has a critical role during embryogenesis, where its expression is widespread and controls the development of numerous tissues. SOX4 expression is elevated in a wide variety of tumors, including leukemia, colorectal cancer, lung cancer and breast cancer, suggesting a fundamental role in the development of these malignancies. In many cancers, deregulated expression of this developmental factor has been correlated with increased cancer cell proliferation, cell survival, inhibition of apoptosis and tumor progression through the induction of an epithelial-to-mesenchymal transition and metastasis. However, in a limited subset of tumors, SOX4 has also been reported to act as a tumor suppressor. These opposing roles suggest that the outcome of SOX4 activation depends on the cellular context and the tumor origin. Indeed, SOX4 expression, transcriptional activity and target gene specificity can be controlled by signaling pathways, including the transforming growth factor-ß and the WNT pathway, as well as at the post-translational level through regulation of protein stability and interaction with specific cofactors, such as TCF, syntenin-1 and p53. Here, we provide an overview of our current knowledge concerning the role of SOX4 in tumor development and progression.

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output.

The transcription factor Sox4 is aberrantly expressed in many human tumors and can modulate tumorigenesis and metastases of murine tumors in vivo. However, mechanisms that control Sox4 function remain poorly defined. It has recently been observed that DNA damage increases Sox4 protein expression independently of Sox4 mRNA levels, suggesting an as yet undefined post-transcriptional mechanism regulating Sox4 expression and functionality. Here, we show that Sox4 protein is rapidly degraded by the proteasome as indicated by pharmacological inhibition with Mg132 and epoxymycin. Sox4 half-life was found to be less than 1 h as evident by inhibition of protein synthesis using cycloheximide. Ectopic expression of Sox4 deletion mutants revealed that the C-terminal 33 residues of Sox4 were critical in modulating its degradation in a polyubiquitin-independent manner. Syntenin, a Sox4 binding partner, associates with this domain and was found to stabilize Sox4 expression. Syntenin-induced stabilization of Sox4 correlated with Sox4-syntenin relocalization to the nucleus, where both proteins accumulate. Syntenin overexpression or knockdown in human tumor cell lines was found to reciprocally modulate Sox4 protein expression and transcriptional activity implicating its role as a regulator of Sox4. Taken together, our data demonstrate that the Sox4 C-terminal domain regulates polyubiquitin-independent proteasomal degradation of Sox4 that can be modulated by interaction with syntenin. As aberrant Sox4 expression has been found associated with many human cancers, modulation of Sox4 proteasomal degradation may impact oncogenesis and metastatic properties of tumors.

Increased risk of early virological failure in non-European HIV-1-infected patients in a Dutch cohort on highly active antiretroviral therapy.

OBJECTIVE: To compare early and late responses to highly active antiretroviral therapy (HAART) in European and non-European HIV-1 infected patients in a Dutch cohort. METHODS: We retrospectively analysed the response to HAART of 216 previously treatment-naive HIV-1-infected patients using the University Medical Centre Utrecht HIV database. African (n=51), Asian (n=7), and Central/South American (n=6) patients were classified as non-European, and others as European (n=152). Early failure was defined as a viral load that remained above 400 HIV-1 RNA copies/mL after 6 months of treatment with HAART. Late-phase failure was determined in patients who were successfully treated in the early phase and was defined as two consecutive viral load measurements above 400 copies/mL, a new AIDS-defining event or death. RESULTS: In the early phase, four of 152 (2.6%) European and eight of 64 (12.5%) non-European patients failed HAART. A significant increased risk of virological failure in the early phase of treatment was observed for non-Europeans as compared to Europeans (odds ratio 4.6; 95% confidence interval 1.1-20.2). Low serum drug levels in the absence of resistant virus were often seen at the time of early failure. No difference in late-phase failure was observed between the two groups (adjusted hazard ratio 0.6; 95% confidence interval 0.3-1.2). CONCLUSIONS: Non-European patients had a 4.6 times higher risk of virological failure than their European counterparts in the first 6 months of treatment with HAART. This failure seemed to be associated with low serum drug levels at the time of failure. However, if HAART was successful in the early phase, response rates in the late phase were similar for Europeans and non-Europeans.

Increased current delivery and sperm collection using nifedipine during electroejaculation in men with high spinal cord injuries.

Elevated blood pressure associated with autonomic hyperreflexia during electroejaculation in persons with high spinal cord injuries often prevents successful sperm retrieval. The ability of the calcium channel blocker nifedipine to reduce the effects of autonomic hyperreflexia, to facilitate greater current delivery, and to increase sperm collection was evaluated in six persons with spinal cord injuries. Ten milligrams of nifedipine given sublingually ten to 15 minutes before electroejaculation attempts helped to moderate autonomic hyperreflexia and the associated blood pressure elevations. These effects of nifedipine allowed greater current delivery and ultimately increased the chances of successful sperm retrieval in the six men. No adverse drug effects were observed.

Rectal probe electrostimulation in the treatment of anejaculatory spinal cord injured men.

This paper reviews our experience with rectal probe electroejaculation (RPE) which is part of a larger effort to determine the correlates of successful ejaculation and fertility in SCI men. RPE is performed in the outpatient clinic using specially designed rectal probes. Over the past 18 months, we have attempted RPE on 38 occasions in 12 subjects (eight paraplegics and four quadriplegics) with an age range of 23-38 years and 0.5-18 years since onset of injury. Anterograde ejaculation occurred in nine subjects with improvement in percent motility and total live sperm count on repeated stimulations in five subjects. Significant retrograde ejaculation occurred in one person and sperm acceptable for artificial insemination (AI) was obtained from four subjects. The major side effects were mild dysreflexia (three subjects) and disruption of a normal bowel program (one subject). We conclude that RPE is a safe, relatively brief outpatient procedure and, with repeated stimulations, has a good potential for producing sperm acceptable for AI in selected patients.