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Τετάρτη 4 Ιανουαρίου 2023

Birth weight, gestational age and risk of cardiovascular disease in early adulthood: Influence of familial factors

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Abstract
The association between intrauterine growth restriction (IUGR) and cardiovascular disease (CVD) later in life might be confounded by familial factors. We conducted a bi-national register-based cohort study to assess associations of birthweight for gestational age (GA), a proxy for IUGR, and GA with CVD risk in early adulthood, before and after addressing familial factors via sibling comparison. We included 3,410,334 live non-malformed singleton births in Sweden (1973-1996) and Denmark (1978-1998). During a median follow-up of 10 years from age 18 onwards, 29,742 individuals developed incident CVD (hypertensive, ischemic heart, and cerebrovascular diseases). Compared with individuals born with appropriate birthweight for GA (AGA, 10th-90th percentiles) or full term (39-40 gestational weeks), individuals born severely small for GA (SGA, <3rd percentile) or preterm (22-36 weeks) were at increased risk of CVD [HRs (95% CIs): 1.38 (1.32-1.45) and 1 .31 (1.25-1.38), respectively]. The association was attenuated when comparing individuals born SGA with their AGA siblings (1.11, 0.99-1.25), but remained robust when comparing individuals born preterm with their term siblings (1.21, 1.07-1.37). Our findings suggest that both SGA and preterm birth are associated with CVD risk in early adulthood, with greater familial confounding noted for SGA.
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Τρίτη 3 Ιανουαρίου 2023

Temporal Trends in Variability of Respirable Dust and Respirable Quartz Concentrations in the European Industrial Minerals Sector

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Abstract
While between- and within-worker variability have been studied quite extensively, hardly any research is available that examines long-term trends in the variability of occupational exposure. In this first study on trends in occupational exposure variability temporal changes in the variability of respirable dust and respirable quartz concentrations within the European industrial minerals sector were demonstrated. Since 2000 the European Industrial Minerals Association's Dust Monitoring Program (IMA-DMP) has systematically collected respirable dust and respirable quartz measurements. The resulting IMA-DMP occupational exposure database contains at present approximately 40 000 personal full-shift measurements, collected at 177 sites owned by 39 companies, located in 23 European countries. Repeated measurements of workers performing their duties within a specific site-job-campaign combination allowed estimation of within- and between-worker variabi lity in exposure concentrations. Overall day-to-day variability predominated the between-worker variability for both respirable dust concentrations and quartz concentrations. The within-worker variability in concentrations by job was two to three times higher for respirable quartz than for respirable dust. The median between-worker variability in respirable dust concentrations was low and further reduced over time. For quartz concentrations the same phenomenon albeit somewhat less strong was observed. In contrast, for the within-worker variability in concentrations downward and upward temporal trends were apparent for both respirable dust and respirable quartz. The study shows that the (relative) size of temporal variability is large and unpredictable and therefore regular measurement campaigns are needed to ascertain compliance to occupational exposure limit values.
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Δευτέρα 2 Ιανουαρίου 2023

Small Molecule-mediated Disruption of Ribosome Biogenesis Synergizes With FGFR Inhibitors to Suppress Glioma Cell Growth

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Abstract
Background
High-grade gliomas are malignant brain tumors characterized by aggressiveness and resistance to chemotherapy. Prognosis remains dismal, highlighting the need to identify novel molecular dependencies and targets. Ribosome biogenesis (RiBi), taking place in the nucleolus, represents a promising target as several cancer types rely on high RiBi rates to sustain proliferation. Publicly available transcriptomics data of glioma patients revealed a positive correlation between RiBi rates and histological grades. We, therefore, hypothesized that glioma cells could be susceptible to RiBi inhibition.
Methods
Transcriptomics data from glioma patients were analyzed for RiBi-related processes. BMH-21, a small molecule inhibitor of RNA polI transcription, was tested in adult and pediatric high-grade glioma cell lines and a zebrafish transplant model. Cellular phenotypes were evaluated by transcriptomics, cell cycle analysis, and vi ability assays. A chemical synergy screen was performed to identify drugs potentiating BMH-21-mediated effects.
Results
BMH-21 reduced glioma cell viability, induced apoptosis, and impaired the growth of transplanted glioma cells in zebrafish. Combining BMH-21 with TMZ potentiated cytotoxic effects. Moreover, BMH-21 synergized with FGFR inhibitor Erdafitinib, a top hit in the chemical synergy screen. RiBi inhibition using BMH-21, POLR1A siRNA, or Actinomycin D revealed engagement of the FGFR-FGF2 pathway. BMH-21 downregulated FGFR1 and SOX2 levels, whereas FGF2 was induced and released from the nucleolus.
Conclusions
This study conceptualizes the implementation of RiBi inhibition as a viable future therapeutic strategy for glioma and reveals an FGFR connection to the cellular response upon RiBi inhibition with potential translational value.
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Wnt Signaling Regulates MFSD2A-dependent Drug Delivery through Endothelial Transcytosis in Glioma

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Abstract
Background
Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed.
Methods
Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient and Mfsd2a EC specific inducible mice were developed to study the underlying molecular mechanisms.
Results
We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MSFD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice.
Conclusions
These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ deli very through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.
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Τετάρτη 28 Δεκεμβρίου 2022

Esthetic and clinical outcomes after immediate placement and restoration: Comparison of two implant systems in the anterior maxilla—A cross‐sectional study

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Abstract

Aim

To assess the esthetic and clinical performance of a novel self-tapping implant system for single-tooth restorations in the esthetic zone after immediate placement and provisionalization.

Materials and Methods

This cross-sectional study included 52 patients contributing a total of 52 immediately placed and restored implants with ≥12 months after functional loading, comparing two different implant systems: Straumann® BLX (Institut Straumann AG, Basel, Switzerland; 25 patients) and Ankylos® (Dentsply Sirona, Hanau, Germany; 27 patients). As the primary outcome measure, peri-implant tissue esthetics were assessed by means of pink esthetics score (PES) rated by three independent clinicians. Moreover, as secondary outcome measures, the peri-implant tissue health was assessed by means of bleeding on probing, probing depth, and suppuration. Apart from that, the modified plaque index, keratinized mucosa width, and the presence of mucosal recessions were also assessed. When clinical signs suggested the possibility of peri-implantitis, radiographs were indicated to assess progressive bone loss.

Results

The mean PES ratings were 12.10 ± 1.10 for Ankylos versus 11.2 ± 1.86 for BLX, both achieving good esthetic results without significant differences (p = 0.143). There were no differences among most clinical parameters (plaque, bleeding on probing, probing depth, peri-implant mucosal recession), although peri-implant mucositis was present in one-third of the cases. The inter-rater agreement on esthetics was not significant (p < 0.250).

Conclusion

Within the limitations of the present study, it was concluded that the use of either BLX or Ankylos implant systems was associated to comparable peri-implant health and good pink esthetic outcomes during immediate implantation and restoration protocols, for at least 12 months.

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Τρίτη 27 Δεκεμβρίου 2022

Transmitted drug resistance to integrase based first-line HIV antiretroviral regimens in the Mediterranean Europe

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Objective
To study the prevalence of transmitted drug resistance (TDR) to INSTIs and NRTIs, and of clinically relevant resistance (CRR), in newly-diagnosed people with HIV (PWH) naïve to antiretroviral therapy (ART) in Europe.
Methods
MeditRes HIV is a consortium that includes ART naïve PWH newly diagnosed in France, Greece, Italy, Portugal, and Spain during the years 2018-2021. Reverse transcriptase (RT) and Integrase (INSTI) sequences were provided by participating centers. To evaluate the prevalence of surveillance drug resistance mutations (SDRM) we used the CPR tools from Stanford HIV-website. To evaluate clinically relevant resistance (CRR), defined as any resistance level >= 3, we used the Stanford v.9.1HIVDB Algorithm.
Results
We included 2705 PWH, 72% men, median age of 37 (IQR, 30-48); 43.7% infected by non-B subtypes. The prevalence of INSTI-SDRMs was 0.30% (T66I, T66A, E92Q, E138T, E138K, Y143R, S147G and R263K, all n = 1), and of NRTI-SDRMs was 5.77% (M184V n = 23, 0.85%; M184I n = 5, 0.18%; K65R/N n = 3, 0.11%; K70E n = 2, 0.07%; L74V/I n = 5, 0.18%; any TAMs n = 118, 4.36%). INSTI-CRR was 2.33% (0.15% dolutegravir/bictegravir; 2.29% raltegravir/elvitegravir), and 1.74% to first-line NRTIs (0.89% tenofovir/tenofovir alafenamide fumarate; 1.74% abacavir; 1.07% lamivudine/emtricitabine).
Conclusions
We present the most recent data on TDR to integrase based first-line regimens in Europe. Given the low prevalence of CRR to second generation integrase inhibitors and to first-line NRTIs, in the years 2018-2021 it is unlikely that newly diagnosed PWH in MeditRes countries would present with baseline resistance to a first-line regimen based on second generation integrase inhibitors.
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Viruses Responsible for Acute Respiratory Infections Before (2016‐2019) and During (2021) Circulation of the SARS‐CoV‐2 virus in Pediatric Patients in a Reference Center at Barranquilla Colombia: A Pattern Analysis

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Summary

Objective

To evaluate the behavior of the viruses responsible for acute respiratory infections before (2016-2019) and after (2020-2021) the start of the circulation of the SARS-CoV-2 virus in pediatric patients treated at a reference center from Barranquilla, Colombia.

Materials and methods

A descriptive observational study was carried out, and data were obtained by reviewing the influenza-like illness and severe acute respiratory infection database in the pediatric population of the sentinel surveillance reference center in the district of Barranquilla during the years 2016 - 2021, applying inclusion and exclusion criteria.

Results

During 2016-2019, the average age of individuals was 1.3 (±1.7) years, during 2021, it was 2.3 (±3.5) years. The distribution by sex was similar, predominantly male. August and February were the months with the highest record of symptoms for 2016-2019 and 2021, respectively, the most frequent being cough, fever, shortness of breath, and diarrhea. By 2021 there was a higher use of antibiotics and antivirals reported than in 2016-2019. Most patients tested negative for viral detection. When comparing the percentage of viruses detected by age group and years of detection, positivity was lower in 2021 by every age group, and respiratory Syncytial Virus (RSV) was the most frequently detected.

Conclusions

There was less virus positivity in viral detection tests in the pediatric population in 2021. RSV persists as the main etiology affecting this population, especially infants. The use of antibiotic therapy in viral infections continues to be a problematic practice in their management. Sentinel surveillance can be strengthened throughout the country.

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The HBV web: An insight into molecular interactomes between the Hepatitis B virus and its host en route to hepatocellular carcinoma.

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ABSTRACT

Hepatitis B virus (HBV) is a major aetiology associated with the development and progression of hepatocellular carcinoma (HCC), the most common primary liver malignancy. Over the past few decades, direct and indirect mechanisms have been identified in the pathogenesis of HBV-associated HCC which include altered signaling pathways, genome integration, mutation-induced genomic instability, chromosomal deletions and rearrangements. Intertwining of the HBV counterparts with the host cellular factors, though well established, needs to be systemized to understand the dynamics of host-HBV crosstalk and its consequences on HCC progression. Existence of a vast array of protein-protein and protein-nucleic acid interaction databases has led to the uncoiling of the compendia of genes/gene products associated with these interactions. This review covers the existing knowledge about the HBV-host interplay and brings it down under one canopy emphasizing on the HBV-host interactomics; and thereby highlights new strategies for therapeutic advancements against HBV-induced HCC.

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Infectivity of pseudotyped SARS‐CoV‐2 variants of concern in different human cell types and inhibitory effects of recombinant spike protein and entry‐related cellular factors

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Abstract

Since the report of the first COVID-19 case in 2019, SARS-CoV-2 variants of concern (VOCs) have continued to emerge, manifesting diverse infectivity, evasion of host immunity and pathology. While ACE2 is the predominant receptor of SARS-CoV-2, TMPRSS2, Kim-1, NRP-1, CD147, furin, CD209L and CD26 have also been implicated as viral entry-related cofactors. To understand the variations in infectivity and pathogenesis of VOCs, we conducted infection analysis in human cells from different organ systems using pseudoviruses of VOCs including Alpha, Beta, Gamma and Delta. Recombinant spike S1, RBD, ACE2, Kim-1 and NRP-1 proteins were tested for their ability to block infection to dissect their roles in SARS-CoV-2 entry into cells. Compared with wild type SARS-CoV-2 (WT), numerous VOCs had significant increases of infectivity across a wide spectrum of cell types. Recombinant ACE2 protein more effectively inhibited the infection of VOCs including Delta and Omicron (BA .1 and BA.2) than that of WT. Interestingly, recombinant S1, RBD, Kim-1 and NRP-1 proteins inhibited the infection of all pseudoviruses in a manner dependent on the levels of ACE2 expression in different cell types. These results provide insights into the diverse infectivity of SARS-CoV-2 VOCs, which might be helpful for managing the emergence of new VOCs.

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No Association of IFNL4 Genotype With Opportunistic Infections and Cancers Among Men With Human Immunodeficiency Virus 1 Infection

alexandrossfakianakis shared this article with you from Inoreader

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Abstract
Background
IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers.
Methods
We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984–1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies.
Results
We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76–1.11]), cytomegalovirus infection (0.94 [.71� �1.24]), herpes simplex virus infection (1.37 [.68–2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count.
Conclusions
The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.
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