Simeprevir added to peginterferon and ribavirin lessens time with fatigue,depressive symptoms and functional limitations in patients with chronic hepatitis C compared with peginterferon and ribavirin: results from 1161 patients in the QUEST‐1, QUEST‐2 and PROMISE studies

The value of adding simeprevir (SMV) vs placebo (PBO) to peginterferon and ribavirin (PR) for treatment of chronic hepatitis C virus infection was examined using patient‐reported outcomes (PROs); further, concordance of PROs with virology endpoints and adverse events (AEs) was explored. Patients (n = 768 SMV/PR, n = 393 PBO/PR) rated fatigue (FSS), depressive symptoms (CES‐D) and functional impairment (WPAI: Hepatitis C Productivity, Daily Activity and Absenteeism) at baseline and throughout treatment in three randomised, double‐blind trials comparing the addition of SMV or PBO during initial 12 weeks of PR. PR was administered for 48 weeks (PBO group) and 24/48 weeks (SMV group) using a response‐guided therapy (RGT) approach. Mean PRO scores (except Absenteeism) worsened from baseline to Week 4 to the same extent in both groups but reverted after Week 24 for SMV/PR and only after Week 48 for PBO/PR. Accordingly, there was a significantly lower area under the curve (baseline–Week 60, AUC₆₀) and fewer weeks with clinically important worsening of scores in the SMV/PR group at any time point. Incidences of patients with fatigue and anaemia AEs were similar in both groups, but FSS scores showed that clinically important increases in fatigue lasted a mean of 6.9 weeks longer with PBO/PR (P < 0.001). PRO score subgroup analysis indicated better outcomes for patients who met the criteria for RGT or achieved sustained virological response 12 weeks post‐treatment (SVR12); differences in mean PRO scores associated with fibrosis level were only observed with PBO/PR. Greater efficacy of SMV/PR enabled reduced treatment duration and reduced time with PR‐related AEs without adding to AE severity.     

The tragic fate of group 3 innate lymphoid cells during HIV-1 infection

HIV-1 infection usually leads to systemic chronic inflammation that is associated with gut microbial translocation. The recently defined group 3 innate lymphoid cells (ILC3s) are critical for maintenance of intestinal barrier function; however, it is not clear whether and how HIV-1 infection influences the function of these cells. In this issue of the JCI, Zhang and colleagues present compelling evidence that the survival and function of ILC3s are dramatically impaired by HIV-1 infection. The authors provide evidence that HIV-1 infection induces persistent activation of plasmacytoid dendritic cells (pDCs) and production of type I IFNs, which together increase expression of death receptor CD95 on ILC3s and thereby promote subsequent ILC3 apoptosis. Together, these results identify a mechanism that explains the impaired intestinal barrier function that results from chronic HIV-1 infection and shed light on the role of pDCs in HIV-1 immunopathogenesis and therapy.     

Psychosocial mechanisms of a behavioral treatment for urinary incontinence of prostate cancer survivors

Abstract

Purpose: We examined underlying psychosocial processes of a behavioral treatment for urinary incontinence (UI) of prostate cancer survivors.

Design: Secondary analysis of data collected from a clinical trial.

Sample: Two hundred forty-four prostate cancer survivors who participated in a clinical trial of behavioral intervention to UI as intervention or control subjects.

Methods: The participants had a 3-month behavioral intervention or usual care and were followed up for an additional 3?months. They were assessed at baseline, 3, and 6?months. Latent growth curve models were performed to examine trajectories of each study variable and relationships among the variables.

Findings: Increasing self-efficacy and social support were significantly and independently associated with more reduction of urinary leakage frequency over time.

Implications for psychosocial oncology: Providing problem-solving skills and social support, including peer support, are essential for empowering patients to reduce UI.     

Reversal of diabetes in BB rats by transplantation of encapsulated pancreatic islets

Prolonged survival of pancreatic islet allografts implanted in diabetic BB rats was achieved by encapsulation of individual islets in a protective biocompatible alginate-polylysine-alginate membrane without immunosuppression. Intraperitoneal transplantation of the encapsulated islets reversed the diabetic state of the recipients within 3 days and maintained normoglycemia for 190 days. Normal body weight and urine volume were maintained during this period, and no cataracts were detected in the transplant recipients. In contrast, control rats receiving transplants of unencapsulated islets experienced normoglycemia for less than 2 wk. These results demonstrated that microencapsulation can protect allografted islets from both graft rejection and autoimmune destruction without immunosuppression in an animal model that mimics human insulin-dependent diabetes.     

Elimination of antibiotic-resistant plasmids by quinolone antibiotics

Of 7 plasmids we tested, the plasmid pORF2 was eliminated in vitro with the most efficiency by treatment with subinhibitory concentrations of novobiocin, coumermycin and 10 quinolones. It showed a cure rate of 43% by enoxacin; 12% by novobiocin, pefloxacin, ciprofloxacin and CI-934; 7% by coumermycin and ofloxacin; 9% by amifloxacin; and 4% by AM-833. On the other hand, pSC194, pBR322 and pMH612 were poorly cured in vitro by quinolones, except pSC194 which was cured 33% by enoxacin. R1, pP1603, and pUB110 were unaffected by the treatment. Mice were challenged intraperitoneally with a 2XLD50 of Escherichia coli carrying the ORF2 plasmid and were treated per os with 1 X or 1/2 X ED50 of either enoxacin or CI-934. The frequency of loss of ampicillin resistance determined 3 h after treatment shows curing effects of 92% for CI-934, 89% for enoxacin and 20% for untreated control.     

Delivery of therapeutic doses of doxorubicin to the mouse lung using lung-accumulating liposomes proves unsuccessful

Cancer Chemotherapy and Pharmacology - Addition of solid doxorubicin or solutions to pre-formed liposomes proved to be the optimal method for incorporating the drug into liposomes whilst...     

Serine hydroxymethyltransferase isoforms are differentially inhibited by leucovorin: characterization and comparison of recombinant zebrafish serine hydroxymethyltransferases.

Serine hydroxymethyltransferase (SHMT) provides activated one-carbon units required for the biosynthesis of nucleotides, protein, and methyl group by converting serine and tetrahydrofolate to glycine and N(5),N(10)-methylenetetrahydrofolate. It is postulated that SHMT activity is associated with the development of methotrexate resistance and the in vivo activity of SHMT is regulated by the binding of N(5)-CHO-THF, the rescue agent in high-dose methotrexate chemotherapy. The aim of this study is to advance our understanding of the folate-mediated one-carbon metabolism in zebrafish by characterizing zebrafish mitochondrial SHMT. The cDNA encoding zebrafish mitochondrial SHMT was cloned, overexpressed in Escherichia coli, and purified with a three-step purification protocol. Similarities in structural, physical, and kinetic properties were revealed between the recombinant zebrafish mitochondrial SHMT and its mammalian orthologs. Surprisingly, leucovorin significantly inhibits the aldol cleavage of serine catalyzed by zebrafish cytosolic SHMT but inhibits to a lesser extent the reaction catalyzed by the mitochondrial isozyme. This is, to our knowledge, the first report on zebrafish mitochondrial folate enzyme as well as the differential inhibition of leucovorin on these two SHMT isoforms. Western blot analysis revealed tissue-specific distribution with the highest enrichment present in liver for both cytosolic and mitochondrial SHMTs. Intracellular localization was confirmed by confocal microscopy for both mitochondrial and cytosolic SHMTs. Unexpectedly, the cytosolic isoform was observed in both nucleus and cytosol. Together with the previous report on zebrafish cytosolic SHMT, we suggest that zSHMTs can be used in in vitro assays for folate-related investigation and antifolate drug discovery.