Drug resistance in B and non-B subtypes amongst subjects recently diagnosed as primary/recent or chronic HIV-infected over the period 2013–2016: Impact on susceptibility to first-line strategies including integrase strand-transfer inhibitors

Objectives To characterize the prevalence of transmitted drug resistance mutations (TDRMs) by plasma analysis of 750 patients at the time of HIV diagnosis from January 1, 2013 to November 16, 2016 in the Veneto region (Italy), where all drugs included in the recommended first line therapies were prescribed, included integrase strand transfer inhibitors (InNSTI). Methods TDRMs were defined according to the Stanford HIV database algorithm. Results Subtype B was the most prevalent HIV clade (67.3%). A total of 92 patients (12.3%) were expected to be resistant to one drug at least, most with a single class mutation (60/68–88.2% in subtype B infected subjectsand 23/24–95.8% in non-B subjects) and affecting mainly NNRTIs. No significant differences were observed between the prevalence rates of TDRMs involving one or more drugs, except for the presence of E138A quite only in patients with B subtype and other NNRTI in subjects with non-B infection. The diagnosis of primary/recent infection was made in 73 patients (9.7%): they had almost only TDRMs involving a single class. Resistance to InSTI was studied in 484 subjects (53 with primary-recent infection), one patient had 143C in 2016, a total of thirteen 157Q mutations were detected (only one in primary/recent infection). Conclusions Only one major InSTI-TDRM was identified but monitoring of TDRMs should continue in the light of continuing presence of NNRTI-related mutation amongst newly diagnosed subjects, sometime impacting also to modern NNRTI drugs recommended in first-line therapy

Atributos de qualidade mercadológica.

Atributos físicos; atributos químicos; presença de defeitos; classificação.bitstream/item/211297/1/ATRIBUTOS-DE-QUALIDADE-MERCADOLOGICA0001.pd

Oral and anal high-risk human papilloma virus infection in HIV-positive men who have sex with men over a 24-month longitudinal study: Complexity and vaccine implications

BackgroundFew studies focused on longitudinal modifications over time of high-risk HPV (HR-HPV) at anal and oral sites in HIV+ men who have sex with men (MSM).MethodsWe described patterns and longitudinal changes of HR-HPV detection and the prevalence of HR-HPV covered by the nonavalent HPV vaccine (vax-HPV) at oral and anal sites in 165 HIV+ MSM followed in an Italian hospital. The samples were collected at baseline and after 24months (follow-up). The presence of HPV was investigated with Inno-LiPA HPV Genotyping Extra II.ResultsMedian age was 44years (IQR 36-53), median CD4+ cell count at nadir was 312 cells/mm(3) (IQR 187-450). A total of 120 subjects (72.7%) were receiving successful antiretroviral therapy (ART). At baseline and follow-up, the frequency of HR-HPV was significantly higher in the anal site (65.4% vs 9.4 and 62.4% vs 6.8%, respectively). Only 2.9% of subjects were persistently HR-HPV negative at both sites. All oral HR-HPV were single at baseline vs 54.6% at baseline at the anal site (p=0.005), and all oral HR-HPV were single at follow-up vs 54.4% at anal site at follow-up (p=0.002). The lowest rate of concordance between the oral and anal results was found for HR-HPV detection; almost all HR-HPV positive results at both anal and oral sites had different HR-HPV.The most frequent HR-HPV in anal swabs at baseline and follow-up were HPV-16 and HPV-52.At follow-up at anal site, 37.5% of patients had different HR-HPV genotypes respect to baseline, 28.8% of subjects with 1 HR-HPV at baseline had an increased number of HR-HPV, and patients on ART showed a lower frequency of confirmed anal HR-HPV detection than untreated patients (p=0.03) over time. Additionally,54.6 and 50.5% of patients had only HR-vax-HPV at anal site at baseline and follow-up, respectively; 15.2% had only HR-vax-HPV at baseline and follow-up.ConclusionsWe believe that it is important testing multiple sites over time in HIV-positive MSM. ART seems to protect men from anal HR-HPV confirmed detection. Vaccination programmes could reduce the number of HR-HPV genotypes at anal site and the risk of the first HR-HPV acquisition at the oral site

Elevated levels of eEF1A2 protein expression in triple negative breast cancer relate with poor prognosis

Eukaryotic elongation factor 1 alpha 2 (eEF1A2) is a translation factor selectively expressed by heart, skeletal muscle, nervous system and some specialized cells. Its ectopic expression relates with tumorigenesis in several types of human cancer. No data are available about the role of eEF1A2 in Triple Negative Breast Cancers (TNBC). This study investigated the relation between eEF1A2 protein levels and the prognosis of TNBC. A total of 84 TNBC diagnosed in the period 2002-2011 were included in the study. eEF1A2 protein level was measured in formalin-fixed paraffin-embedded tissues by immunohistochemistry in a semi-quantitative manner (sum of the percentage of positive cells x staining intensity) on a scale from 0 to 300. Cox regression assessed the association between eEF1A2 levels and disease-free survival (DFS) and breast cancer-specific survival (BCSS). Elevated values of eEF1A2 were associated with older age at diagnosis (p = 0.003), and androgen receptors positivity (p = 0.002). At univariate Cox analysis, eEF1A2 levels were not significantly associated with DFS and BCSS (p = 0.11 and p = 0.08, respectively) whereas adjusting for stage of disease, elevated levels of eEF1A2 protein resulted associated with poor prognosis (HR = 1.05, 95% CI: 1.01-1.11, p = 0.04 and HR = 1.07, 95% CI: 1.01-1.14, p = 0.03 for DFS and BCSS, respectively). This trend was confirmed analyzing negative versus positive samples by using categorized scores. Our data showed a negative prognostic role of eEF1A2 protein in TNBC, sustaining further investigations to confirm this result by wider and independent cohorts of patients

Cell-free DNA analysis in healthy individuals by next-generation sequencing: a proof of concept and technical validation study.

Pre-symptomatic screening of genetic alterations might help identify subpopulations of individuals that could enter into early access prevention programs. Since liquid biopsy is minimally invasive it can be used for longitudinal studies in healthy volunteers to monitor events of progression from normal tissue to pre-cancerous and cancerous condition. Yet, cell-free DNA (cfDNA) analysis in healthy individuals comes with substantial challenges such as the lack of large cohort studies addressing the impact of mutations in healthy individuals or the low abundance of cfDNA in plasma. In this study, we aimed to investigate the technical feasibility of cfDNA analysis in a collection of 114 clinically healthy individuals. We first addressed the impact of pre-analytical factors such as cfDNA yield and quality on sequencing performance and compared healthy to cancer donor samples. We then confirmed the validity of our testing strategy by evaluating the mutational status concordance in matched tissue and plasma specimens collected from cancer patients. Finally, we screened our group of healthy donors for genetic alterations, comparing individuals who did not develop any tumor to patients who developed either a benign neoplasm or cancer during 1-10 years of follow-up time. To conclude, we have established a rapid and reliable liquid biopsy workflow that allowed us to study genomic alterations with a limit of detection as low as 0.08% of variant allelic frequency in healthy individuals. We detected pathogenic cancer mutations in four healthy donors that later developed a benign neoplasm or invasive breast cancer up to 10 years after blood collection. Even though larger prospective studies are needed to address the specificity and sensitivity of liquid biopsy as a clinical tool for early cancer detection, systematic screening of healthy individuals will help understanding early events of tumor formation

Targeting Non-Coding RNAs for the Development of Novel Hepatocellular Carcinoma Therapeutic Approaches

Hepatocellular carcinoma (HCC) remains a global health challenge, representing the third leading cause of cancer deaths worldwide. Although therapeutic advances have been made in the few last years, the prognosis remains poor. Thus, there is a dire need to develop novel therapeutic strategies. In this regard, two approaches can be considered: (1) the identification of tumor-targeted delivery systems and (2) the targeting of molecule(s) whose aberrant expression is confined to tumor cells. In this work, we focused on the second approach. Among the different kinds of possible target molecules, we discuss the potential therapeutic value of targeting non-coding RNAs (ncRNAs), which include micro interfering RNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). These molecules represent the most significant RNA transcripts in cells and can regulate many HCC features, including proliferation, apoptosis, invasion and metastasis. In the first part of the review, the main characteristics of HCC and ncRNAs are described. The involvement of ncRNAs in HCC is then presented over five sections: (a) miRNAs, (b) lncRNAs, (c) circRNAs, (d) ncRNAs and drug resistance and (e) ncRNAs and liver fibrosis. Overall, this work provides the reader with the most recent state-of-the-art approaches in this field, highlighting key trends and opportunities for more advanced and efficacious HCC treatments

Acute intracerebral haemorrhage: diagnosis and management

Intracerebral haemorrhage (ICH) accounts for half of the disability-adjusted life years lost due to stroke worldwide. Care pathways for acute stroke result in the rapid identification of ICH, but its acute management can prove challenging because no individual treatment has been shown definitively to improve its outcome. Nonetheless, acute stroke unit care improves outcome after ICH, patients benefit from interventions to prevent complications, acute blood pressure lowering appears safe and might have a modest benefit, and implementing a bundle of high-quality acute care is associated with a greater chance of survival. In this article, we address the important questions that neurologists face in the diagnosis and acute management of ICH, and focus on the supporting evidence and practical delivery for the main acute interventions

The nest-holding grass goby (Zosterisessor ophiocephalus) male adjusts the spawning activity in relation to parasitic nest intrusions.

This study examines the temporal pattern of spawning behavior by the territorial (i.e. nest-holding) grass goby male, Zosterisessor ophiocephalus, in response to sneak intrusions by the small parasitic male under controlled laboratory conditions. The spawning activity of the territorial male consists of a sequence of upside-down movements on the ceiling of the nest accompanied by undulations of the body and sperm release. Five pairs of one territorial male and one parasitic male, each kept inside a large tank provided with an artificial buried nest (always occupied by the territorial male) and one small tunnel-shaped shelter (always occupied by the small male), were observed during one-female spawning taking place in the innermost part of the nest (i.e. the nest chamber). During the spawning, the presence of the small male nearby the nest openings elicited aggressive behavior and increased nest patrolling by the territorial male. In one spawn the small male never attempted to enter the nest. In four spawns the small male entered one to three times the nest chamber (sneaks), staying there from 2 to 203 s until the large male chased him away. The temporal patterning of the spawning activity by the territorial male (bouts of upside-down, U-D), and its changes following a sneak by the small male, were investigated using bout analysis and correlative tests. Results showed the length of bouts U-D did not change significantly after a sneak intrusion. whereas gap length (i.e. the period between subsequent bouts U-D) decreased significantly after each sneak intrusion. The mean duty cycle of bouts U-D tended to be positively correlated to the number of sneaker intrusions of each replicate. Results are discussed in the light of current knowledge on sperm competition among externally fertilizing teleosts

Ephemeris refinement of 21 Hot Jupiter exoplanets with high timing uncertainties

Transit events of extrasolar planets offer a wealth of information for planetary characterization. However, for many known targets, the uncertainty of their predicted transit windows prohibits an accurate scheduling of follow-up observations. In this work, we refine the ephemerides of 21 Hot Jupiter exoplanets with the largest timing uncertainty. We collected 120 professional and amateur transit light curves of the targets of interest, observed with 0.3m to 2.2m telescopes, and analyzed them including the timing information of the planets discovery papers. In the case of WASP-117b, we measured a timing deviation compared to the known ephemeris of about 3.5 hours, for HAT-P-29b and HAT-P-31b the deviation amounted to about 2 hours and more. For all targets, the new ephemeris predicts transit timings with uncertainties of less than 6 minutes in the year 2018 and less than 13 minutes until 2025. Thus, our results allow for an accurate scheduling of follow-up observations in the next decade