Tumour-derived prostaglandin E2 and transforming growth factor-β synergize to inhibit plasmacytoid dendritic cell-derived interferon-α

In previous studies we reported that plasmacytoid dendritic cells (PDC) infiltrating head and neck cancer tissue are functionally impaired, but the molecular basis for the functional deficiency remained unclear. Here we demonstrate that tumour-derived prostaglandin E2 (PGE₂) and transforming growth factor-β (TGF-β) increase interleukin-8 (IL-8) but synergistically inhibit interferon-α (IFN-α) and tumour necrosis factor (TNF) production of Toll-like receptor 7 (TLR7)- and Toll-like receptor 9 (TLR9)-stimulated PDC. The inhibitory effect of PGE₂ could be mimicked by the induction of cyclic AMP (cAMP) and by inhibitors of cyclooxygenase. The contribution of tumour-derived TGF-β was confirmed by the TGF-β antagonist SB-431542. Suppression of tumour-derived PGE₂ and TGF-β restored TLR-induced IFN-α production of PDC. Additionally, PGE₂- and TGF-β-treated PDC display a ‘tolerogenic’ phenotype because of a downregulation of CD40 accompanied by an upregulation of CD86. Finally, in TLR-stimulated PDC, PGE₂ and TGF-β reduce the CCR7 : CXCR4 ratio, suggesting that PDC are impaired in their ability to migrate to tumour-draining lymph nodes but are retained in stromal cell-derived factor 1 (SDF-1)-expressing tissues. Based on these data, cyclooxygenase inhibitors and TGF-β antagonists may improve TLR7- and TLR9-based tumour immunotherapy.     

Heterogeneity in clinical presentations of posttraumatic stress disorder among medical patients: testing factor structure variation using factor mixture modeling

The present study used factor mixture modeling to explore empirically defined subgroups of psychological trauma victims based on confirmatory factor analysis (CFA) and latent class analysis of posttraumatic stress disorder (PTSD) symptoms. We sampled 310 medical patients with a history of trauma exposure. Confirmatory factor analysis revealed that the 4-factor emotional numbing PTSD model yielded the best model fit. Using latent factor means derived from this model and the 4-factor dysphoria PTSD model (indexing severity on PTSD factors), 3 latent classes of participants were identified using factor mixture modeling. The 3-class model fit the data very well and was validated against external measures of anxiety and rumination.     

Optoinjection for efficient targeted delivery of a broad range of compounds and macromolecules into diverse cell types

Efficient delivery of compounds and macromolecules into living cells is essential in many fields including basic research, applied drug discovery, and clinical gene therapy. Unfortunately, current delivery methods, such as cationic lipids and electroporation, are limited by the types of macromolecules and cells that can be employed, poor efficiency, and/or cell toxicity. To address these issues, novel methods were developed based on laser-mediated delivery of macromolecules into cells through optoinjection. An automated high-throughput instrument, the laser-enabled analysis and processing (LEAP) system, was utilized to elucidate and optimize several parameters that influence optoinjection efficiency and toxicity. Techniques employing direct cell irradiation (i.e., targeted to specific cell coordinates) and grid-based irradiation (i.e., without locating individual cells) were both successfully developed. With both techniques, it was determined that multiple, sequential low radiant exposures produced more favorable results than a single high radiant exposure. Various substances were efficiently optoinjected--including ions, small molecules, dextrans, siRNAs (small interfering RNAs), plasmids, proteins, and semiconductor nanocrystals--into numerous cell types. Notably, cells refractory to traditional delivery methods were efficiently optoinjected with lower toxicity. We establish the broad utility of optoinjection, and furthermore, are the first to demonstrate its implementation in an automated, high-throughput manner.     

Sexual and reproductive health and human rights of women living with HIV: a global community survey

Objective

To determine the sexual and reproductive health priorities of women living with human immunodeficiency virus (HIV) and to allow the values and preferences of such women to be considered in the development of new guidelines.

Methods

A core team created a global reference group of 14 women living with HIV and together they developed a global community online survey. The survey, which contained mandatory and optional questions, was based on an appreciative enquiry approach in which the life-cycle experiences of women living with HIV were investigated. The same set of questions was also used in focus group discussions led by the global reference group.

Findings

The study covered 945 women (832 in the survey and 113 in the focus groups) aged 15–72 years in 94 countries. Among the respondents to the optional survey questions, 89.0% (427/480) feared or had experienced gender-based violence, 56.7% (177/312) had had an unplanned pregnancy, 72.3% (227/314) had received advice on safe conception and 58.8% (489/832) had suffered poor mental health after they had discovered their HIV-positive status.

Conclusion

The sexual and reproductive health needs and rights of women living with HIV are complex and require a stronger response from the health sector. The online survey placed the voices of women living with HIV at the start of the development of new global guidelines. Although not possible in some contexts and populations, a similar approach would merit replication in the development of guidelines for many other health considerations.     

An epidemiological study of orofacial clefts in Croatia 1988-1998.

INTRODUCTION: The objective of this epidemiological study was to assess the incidence at birth of orofacial clefts in Croatia. AIM: The aim of the present study was to analyse the character and incidence of orofacial clefts in Croatia and to compare the data with reports from other countries. MATERIAL AND METHODS: All the material for the epidemiological study was retrieved from the documented files from all the neonatal units and hospitals in Croatia providing surgical treatment. RESULTS: A total of 525,298 livebirths were documented during 11 years (1988-1998); 903 among them with orofacial clefts, 24 (2.7%) of them twins. Sixty (6.6%) infants died between birth and the age of 6 months. The incidence of orofacial clefts during the study period was 1.71 per thousand. When eliminating syndromic clefts, the incidence of non-syndromic clefts was 1.56 per thousand. Analysis of cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate only (CP) revealed their incidence to be 1.05 and 0.66 per 1000, respectively. Of all types of clefting, CL and CLA was found in 17.2%, CL+/-P in 43.9%, CP in 38.2% and atypical facial clefts (AFC) in 0.8% of children. Left-sided clefts were most common (51%), followed by bilateral (30.5%) and right-sided (18.5%) clefts. The male to female ratio was 1.3. CL+/-P predominated in male and CP in female children. In 220 cases (24.4%) orofacial clefts were either associated with other anomalies or the clefts occurred as one feature of a syndrome. CONCLUSION: Data obtained from different sources yielded a cleft incidence of 1.71 per 1000 in Croatia. There were no differences in the incidences of orofacial clefts in comparison with similar data from other European countries.     

Polyhydramnios with bidirectional fetal ductus arteriosus flow in a fetus with congenital diaphragmatic hernia: case report

The etiology of polyhydramnios may be attributed to either increased production of amniotic fluid (fetal polyuria or high-output cardiac failure) or decreased fetal swallowing (obstruction or neurological impairment). Although idiopathic polyhydramnios occurs in nearly half of all cases, it is often associated with fetal abnormalities. Fetal ductus arteriosus flow is normally from right to left. We report a case of antenatally detected bidirectional fetal ductus arteriosus flow diagnosed concomitantly with polyhydramnios. Amnioreduction was performed due to severe maternal symptoms, which resulted in correction of the fetal ductus arteriosus flow. Postnatal diagnosis of a Morgagni diaphragmatic hernia indicates that our sonographic findings collectively may have been a diagnostic clue.     

Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?

Androgen deprivation therapy (ADT) is the longstanding treatment for advanced prostate cancer (PC) because androgen receptor (AR) is the key therapeutic vulnerability for this disease. Bipolar androgen therapy (BAT) — the rapid cycling of supraphysiologic androgen (SPA) and low serum testosterone levels — is an alternative concept, but not all patients respond and acquired resistance can occur. In this issue of the JCI, Sena et al. developed a gene signature indicative of high AR activity to predict patient response to BAT, including a decline in both serum prostate-specific antigen (PSA) and tumor volume. Preclinical models showed that AR-mediated suppression of MYC, known to drive PC, was associated with decreased cell growth following SPA treatment. Because BAT eventually leads to resistance, the authors tested cycling between SPA and AR antagonism in a patient-derived xenograft and observed a delay in tumor growth. These findings represent a major step toward the informed use of BAT for advanced PC.