Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer

Colorectal cancer (CRC) shows aggregation in some families but no alterations in the known hereditary CRC genes. We aimed to identify new candidate genes which are potentially involved in germline predisposition to familial CRC. An integrated analysis of germline and tumor whole-exome sequencing data was performed in 18 unrelated CRC families. Deleterious single nucleotide variants (SNV), short insertions and deletions (indels), copy number variants (CNVs) and loss of heterozygosity (LOH) were assessed as candidates for first germline or second somatic hits. Candidate tumor suppressor genes were selected when alterations were detected in both germline and somatic DNA, fulfilling Knudson's two-hit hypothesis. Somatic mutational profiling and signature analysis were also performed. A series of germline-somatic variant pairs were detected. In all cases, the first hit was presented as a rare SNV/indel, whereas the second hit was either a different SNV (3 genes) or LOH affecting the same gene (141 genes). BRCA2, BLM, ERCC2, RECQL, REV3L and RIF1 were among the most promising candidate genes for germline CRC predisposition. The identification of new candidate genes involved in familial CRC could be achieved by our integrated analysis. Further functional studies and replication in additional cohorts are required to confirm the selected candidates

Comparison of Bone and Renal Effects In HIV-infected Adults Switching to Abacavir or Tenofovir Based Therapy in a Randomized Trial

Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy.In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms.Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (-1.8% and -2.5%) and week 48 (-2.1% and -2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients.Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed.Clinicaltrials.gov NCT00647244

Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial

Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial

Immediate vs. deferred switching from a boosted protease inhibitor (PI/r) based regimen to a Dolutegravir (DTG) based regimen in virologically suppressed patients with high cardiovascular risk or Age ≥50 years: final 96 weeks results of NEAT 022 study

Background Both immediate and deferred switching from a ritonavir-boosted protease inhibitor (PI/r)–based regimen to a dolutegravir (DTG)–based regimen may improve lipid profile. Methods European Network for AIDS Treatment 022 Study (NEAT022) is a European, open-label, randomized trial. Human immunodeficiency virus (HIV)–infected adults aged ≥50 years or with a Framingham score ≥10% were eligible if HIV RNA was <50 copies/mL. Patients were randomized to switch from PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D). Week 96 endpoints were proportion of patients with HIV RNA <50 copies/mL, percentage change of lipid fractions, and adverse events (AEs). Results Four hundred fifteen patients were randomized: 205 to DTG-I and 210 DTG-D. The primary objective of noninferiority at week 48 was met. At week 96, treatment success rate was 92.2% in the DTG-I arm and 87% in the DTG-D arm (difference, 5.2% [95% confidence interval, –.6% to 11%]). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AEs or treatment-modifying AEs. Total cholesterol and other lipid fractions (except high-density lipoprotein) significantly (P < .001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV-infected patients ≥50 years old or with a Framingham score ≥10% was highly efficacious and well tolerated, and improved the lipid profile

Acute pancreatitis promotes the generation of two different exosome populations

Exosomes are small extracellular vesicles that act as intercellular messengers. Previous studies revealed that, during acute pancreatitis, circulating exosomes could reach the alveolar compartment and activate macrophages. However, proteomic analysis suggested that the most likely origin of these exosomes could be the liver instead of the pancreas. The present study aimed to characterize the exosomes released by pancreas to pancreatitis-associated ascitic fluid (PAAF) as well as those circulating in plasma in an experimental model of taurocholate-induced acute pancreatitis in rats. We provide evidence that during acute pancreatitis two different populations of exosomes are generated with relevant differences in cell distribution, protein and microRNA content as well as different implications in their physiological effects. During pancreatitis plasma exosomes, but not PAAF exosomes, are enriched in the inflammatory miR-155 and show low levels of miR-21 and miR-122. Mass spectrometry-based proteomic analysis showed that PAAF exosomes contains 10–30 fold higher loading of histones and ribosomal proteins compared to plasma exosomes. Finally, plasma exosomes have higher pro-inflammatory activity on macrophages than PAAF exosomes. These results confirm the generation of two different populations of exosomes during acute pancreatitis. Deep understanding of their specific functions will be necessary to use them as therapeutic targets at different stages of the disease.This work was supported by the projects FIS PI16/00060 and PI17/01003 from Instituto de Salud Carlos III (co-funded by FEDER-European Union) and Beca Gonzalo Miño 2017 from Asociacion Española de Gastroenterologia. The CSIC/UAB Proteomics Facility of IIBB-CSIC belongs to ProteoRed, PRB3-ISCIII, (supported by grant PT17/0019/0008). CIBEREHD is funded by the Instituto de Salud Carlos III and FEDER

Comparison of two different strategies of treatment with zoledronate in HIV-infected patients with low bone mineral density: single dose versus two doses in 2 years

Objectives Given the need for easily managed treatment of osteoporosis in HIV-infected patients, we evaluated the efficacy and tolerability of two doses of zoledronate, by comparing three groups of patients: those with annual administration, those with biennial administration (one dose in 2 years) and a control group with no administration of zoledronate. Methods We randomized (2:1) 31 patients on antiretroviral therapy with low bone mineral density (BMD) to zoledronate (5 mg administered intravenously; 21 patients) plus diet counselling and to a control group (diet counselling; 10 patients). At week 48, patients treated with zoledronate were randomized again to receive a second dose (two-dose group; n = 12) or to continue with diet counselling only (single-dose group; n = 9). Changes in lumbar spine and hip BMD and bone turnover markers were compared. Results The median percentage change from baseline to week 96 in L1−L4 BMD was −1.74% [interquartile range (IQR) −2.56, 3.60%], 7.90% (IQR 4.20, 16.57%) and 5.22% (IQR 2.02, 7.28%) in the control, two-dose and single-dose groups, respectively (P < 0.01, control vs. two doses; P = 0.02, control vs. single dose; P = 0.18, two doses vs. single dose). Hip BMD changed by a median of 2.12% (IQR −0.12, 3.08%), 5.16% (IQR 3.06, 6.74%) and 4.47% (IQR 1, 5.58%), respectively (P = 0.04, control vs. two doses; P = 0.34, two doses vs. single dose). No differences between the two-dose and single-dose groups were detected in bone markers at week 96. Conclusions The benefits for BMD of a single dose of zoledronate in 2 years may be comparable to those obtained with two doses of the drug after 96 weeks, although this study is insufficiently powered to exclude a real difference. Future studies should explore whether biennial administration of zoledronate is a useful alternative in the treatment of osteoporosis in HIV-infected patients