Transarterial embolization is an acceptable bridging therapy to hepatocellular carcinoma prior to liver transplantation.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that requires liver transplantation (LT). Despite patients with HCC being prioritized by most organ allocation systems worldwide, they still have to wait for long periods. Locoregional therapies (LRTs) are employed as bridging therapies in patients with HCC awaiting LT. Although largely used in the past, transarterial embolization (TAE) has been replaced by transarterial chemoembolization (TACE). However, the superiority of TACE over TAE has not been consistently shown in the literature. AIM: To compare the outcomes of TACE and TAE in patients with HCC awaiting LT. METHODS: All consecutive patients with HCC awaiting LT between 2011 and 2020 at a single center were included. All patients underwent LRT with either TACE or TAE. Some patients also underwent percutaneous ethanol injection (PEI), concomitantly or in different treatment sessions. The choice of LRT for each HCC nodule was determined by a multidisciplinary consensus. The primary outcome was waitlist dropout due to tumor progression, and the secondary outcome was the occurrence of adverse events. In the subset of patients who underwent LT, complete pathological response and post-transplant recurrence-free survival were also assessed. RESULTS: Twelve (18.5%) patients in the TACE group (only TACE and TACE + PEI; n = 65) and 3 (7.9%) patients in the TAE group (only TAE and TAE + PEI; n = 38) dropped out of the waitlist due to tumor progression (P log-rank test = 0.29). Adverse events occurred in 8 (12.3%) and 2 (5.3%) patients in the TACE and TAE groups, respectively (P = 0.316). Forty-eight (73.8%) of the 65 patients in the TACE group and 29 (76.3%) of the 38 patients in the TAE group underwent LT (P = 0.818). Among these patients, complete pathological response was detected in 7 (14.6%) and 9 (31%) patients in the TACE and TAE groups, respectively (P = 0.145). Post-LT, HCC recurred in 9 (18.8%) and 4 (13.8%) patients in the TACE and TAE groups, respectively (P = 0.756). Posttransplant recurrence-free survival was similar between the groups (P log-rank test = 0.71). CONCLUSION: Dropout rates and posttransplant recurrence-free survival of TAE were similar to those of TACE in patients with HCC. Our study reinforces the hypothesis that TACE is not superior to TAE as a bridging therapy to LT in patients with HCC.

Comparison between melatonin versus melatonin and photobiomodulation versus photobiomodulation in the treatment of Alopecia X in German Spitz dogs: Clinical, randomized, double-blind, parallel, non-inferiority protocol.

Canine Alopecia X is a non-inflammatory hair loss disorder of unknown etiology that predominantly affects German Spitz dogs. Treatment modalities include hormone and/or melatonin supplementation and low trauma microneedling. Melatonin influences hair growth and pigmentation in several species and presents a low risk of adverse effects when used in dogs with Alopecia X. Photobiomodulation (PBM) is frequently used in human androgenetic alopecia and alopecia areata; despite this, PBM remains unexplored in canine Alopecia X. To address this knowledge gap, sixty dogs of both sexes will be randomly assigned to three groups: (i) melatonin only group (3 mg/Kg, n = 20); (ii) PBM only group (diode laser, wavelength 660nm, 100mw power, with 3 J/point, 2 sessions/week for 3 months, n = 20); (ii) PBM + melatonin group (n = 20). The objective is to determine the potential of PBM alone or in conjunction with melatonin supplementation in promoting hair regrowth (hair density and diameter) by means of dermatoscopy and planimetry over a period of 90 days.

Significant and Distinct Impacts of Sleeve Gastrectomy and Roux-en-Y Gastric Bypass on Esophageal Acid Exposure, Esophageal Motility and Endoscopic Findings: A Systematic Review and Meta-analysis.

OBJECTIVE: To study esophageal acid exposure, esophageal motility, and endoscopic findings before and after Sleeve Gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB BACKGROUND: The lack of standardized objective assessment of esophageal physiology and anatomy contributes to the controversies regarding the impact of SG and RYGB on gastroesophageal reflux disease. METHODS: We conducted a systematic review and meta-analysis of studies reporting at least one objective measure of esophageal physiology and/or EGD, at baseline and after SG or RYGB. The changes in pH-test, manometry, and EGD parameters were summarized. RESULTS: Acid exposure time (AET) and DeMeester Score (DMS) significantly increased after SG: Mean Difference (MD) 2.1 (95%CI 0.3 to 3.9) and 8.6 (95%CI 2 to 15.2), respectively. After RYGB, both AET and DMS significantly decreased: MD -4.2 (95%CI -6.1 to -2.3) and - 16.6 (95%CI -25.4 to -7.8). Lower esophageal sphincter resting pressure and length significantly decreased following SG: MD - 2.8 (95%CI - 4.6 to - 1.1) and - 0.1 (95%CI - 0.2 to - 0.02), respectively. There were no significant changes in esophageal manometry after RYGB. The Relative Risk of erosive esophagitis after SG was 2.3 (95%CI 1.5 to 3.5), while after RYGB it was 0.4 (95%CI 0.2 - 0.8). The prevalence of Barrett's Esophagus changed from 0% to 3.6% after SG, and from 2.7% to 1.4% after RYGB. CONCLUSIONS: SG resulted in worsening of all objective parameters, while RYGB showed improvement in AET, DMS, and EGD findings. Determining the risk factors associated with those outcomes could aid in surgical choice.

Insights on the endogenous labile iron pool binding properties.

Under normal physiological conditions, the endogenous Labile Iron Pool (LIP) constitutes a ubiquitous, dynamic, tightly regulated reservoir of cellular ferrous iron. Furthermore, LIP is loaded into new apo-iron proteins, a process akin to the activity of metallochaperones. Despite such importance on iron metabolism, the LIP identity and binding properties have remained elusive. We hypothesized that LIP binds to cell constituents (generically denoted C) and forms an iron complex termed CLIP. Combining this binding model with the established Calcein (CA) methodology for assessing cytosolic LIP, we have formulated an equation featuring two experimentally quantifiable parameters (the concentrations of the cytosolic free CA and CA and LIP complex termed CALIP) and three unknown parameters (the total concentrations of LIP and C and their thermodynamic affinity constant Kd). The fittings of cytosolic CALIP × CA concentrations data encompassing a few cellular models to this equation with floating unknown parameters were successful. The computed adjusted total LIP (LIPT) and C (CT) concentrations fall within the sub-to-low micromolar range while the computed Kd was in the 10-2 µM range for all cell types. Thus, LIP binds and has high affinity to cellular constituents found in low concentrations and has remarkably similar properties across different cell types, shedding fresh light on the properties of endogenous LIP within cells.

Outcomes of urethral meatal preservation ventral urethroplasty for female urethral stricture: a series of cases.

Objective: To present a series of cases with our initial experience and short-term outcomes of a modified vaginal mucosal flap urethroplasty. Methods: Patients diagnosed with urethral stricture and operated by the same operative technique between January 2012 and January 2018 were followed for at least 6 months. Uroflowmetry and clinical outcomes were evaluated. Results: Nineteen patients were included with an average age of 56.4 years, mean preoperative Qmax of 5.3 ml/s, and PVR of 101.4 mL. After 6 months of the procedure, the mean Qmax improved to 14.7 mL/s (p<0.05), PVR decreased to 47.3 mL (p<0.05), and 84.2% of all patients reported improvement in clinical self-reported symptoms. There was an improvement in symptoms such as voiding effort in 84.2% of patients, weak stream (89.5%), and recurrent urinary tract infection (85.7%). The success rate (absence of symptoms and normal Qmax with no significant PVR) of the procedure was 84.2%. Conclusion: The described technique was considered effective for the treatment of female urethra stricture, with a high clinical success rate and an objective improvement of Qmax and decrease in PVR after 6 months of the procedure.

Polycyclic aromatic hydrocarbons in surface water of rivers in Sergipe State, Brazil: A comprehensive analysis of sources, spatial and temporal variation, and ecotoxicological risk.

This study conducted in Sergipe State, Brazil, aimed to investigate the presence of polycyclic aromatic hydrocarbons (PAHs) in the surface water of five rivers, determining their sources, spatial and temporal variations, and ecotoxicological risks. Correlation and principal component analyses were utilized to identify the relationship between PAH concentrations and water sample properties. Results indicated higher PAH concentrations during the rainy season, attributed to increased run-off and sediment resuspension. The composition of PAHs suggested a main petroleum source with organic material combustion in minor scale. Ecological risk assessment revealed potential risks to the ecosystem, emphasizing the need for continuous monitoring of PAHs pollution. This study highlights the importance of understanding and mitigating PAHs contamination in rivers to protect aquatic ecosystems.

High-throughput prediction of protein conformational distributions with subsampled AlphaFold2.

This paper presents an innovative approach for predicting the relative populations of protein conformations using AlphaFold 2, an AI-powered method that has revolutionized biology by enabling the accurate prediction of protein structures. While AlphaFold 2 has shown exceptional accuracy and speed, it is designed to predict proteins' ground state conformations and is limited in its ability to predict conformational landscapes. Here, we demonstrate how AlphaFold 2 can directly predict the relative populations of different protein conformations by subsampling multiple sequence alignments. We tested our method against nuclear magnetic resonance experiments on two proteins with drastically different amounts of available sequence data, Abl1 kinase and the granulocyte-macrophage colony-stimulating factor, and predicted changes in their relative state populations with more than 80% accuracy. Our subsampling approach worked best when used to qualitatively predict the effects of mutations or evolution on the conformational landscape and well-populated states of proteins. It thus offers a fast and cost-effective way to predict the relative populations of protein conformations at even single-point mutation resolution, making it a useful tool for pharmacology, analysis of experimental results, and predicting evolution.

Autobench V1.0: Benchmarking Automation for Electronic Structure Calculations.

This work reports on new software for automatic conformer energy benchmarking calculations for flexible molecules. The software workflow consists of four parts: conformational search, preoptimization, optimization, and frequency calculations at a higher level and last calculations using several theoretical levels. The software was written to be user-friendly and versatile to be used by nonexperts in computational chemistry. Any theoretical levels available in either Gaussian 16 or ORCA 5 may be applied in the benchmarking study. The workflow will automatically run conformational search calculations and deal with conformers that converge to the same minimum and those that show a negative frequency. At the end of the workflow, the user will have the mean absolute deviations and the most accurate method/DFT functional and basis set in comparison to the benchmark to be applied for the molecular system of interest. Case examples are given at the end of the paper that may help users to get insight into the software's main features.

Gas-Phase Phenyl Radical + O2 Reacts via a Submerged Transition State.

In the gas-phase chemistry of the atmosphere and automotive fuel combustion, peroxyl radical intermediates are formed following O2 addition to carbon-centered radicals which then initiate a complex network of radical reactions that govern the oxidative processing of hydrocarbons. The rapid association of the phenyl radical-a fundamental radical related to benzene-with O2 has hitherto been modeled as a barrierless process, a common assumption for peroxyl radical formation. Here, we provide an alternate explanation for the kinetics of this reaction by deploying double-hybrid density functional theory (DFT), at the DSD-PBEP86-D3(BJ)/aug-cc-pVTZ level of theory, and locate a submerged adiabatic transition state connected to a prereaction complex along the reaction entrance pathway. Using this potential energy scheme, experimental rate coefficients k(T) for the addition of O2 to the phenyl radical are accurately reproduced within a microcanonical kinetic model. This work highlights that purportedly barrierless radical oxidation reactions may instead be modeled using stationary points, which in turn provides insight into pressure and temperature dependence.

Effect of Aerobic Training with Blood Flow Restriction on Strength and Hypertrophy: A Meta-analysis.

The objective of this meta-analysis is to compare the effects on muscle strength and hypertrophy of low and high-intensity aerobic training with BFR (LI-BFR and HI-BFR) versus low and high-intensity aerobic training without BFR (LI and HI). The search was performed in five databases, by two independent researchers, and the terms and keywords used to optimize the searches were related to blood flow restriction and aerobic training. All studies were evaluated for methodological quality using the PEDro scale and for quality of evidence using the GRADE system. Meta-analyses were conducted using RevMan software. After data extraction, 11 studies met all eligibility criteria and were included in the systematic review. The results of the overall analysis between LI-BFR vs. LI showed a significant difference in muscle strength of knee extensors; for hypertrophy, LI was superior to LI-BFR with clinical relevance. Comparing HI-BFR vs. HI there was no superiority for muscle strength. In conclusion, for strength gains very low-quality evidence was found to support no superiority between LI-BFR and HI-BFR compared to LI and HI, respectively. For muscle hypertrophy, superiority of LI was found compared to LI-BFR, with a very low level of evidence.

The accumulation of sphingosine kinase 2 disrupts the DNA damage response and promotes resistance to genotoxic agents.

There is a known correlation between cancer and changes in sphingolipids, specifically the production of sphingosine-1-phosphate (S1P) by sphingosine kinases 1 and 2 (SPHK1/SPHK2). However, a potential relationship between bioactive lipid molecules, SPHK, and the response to DNA damage is unknown. We aimed to evaluate the response of oral keratinocytes and head and neck cancer cell lines with SPHK2/S1P alterations to DNA damage. This assessment is intended to establish a link between these alterations and tumorigenesis as well as resistance to therapy. SPHK2 overexpression in oral squamous cells promoted evasion of apoptosis and cell cycle control, which increased the resistance to genotoxic agents (chemical and physical). Cells that have SPHK2 overexpression are more prone to DNA damage, which allows those damaged cells to survive and multiply. This is associated with a decrease in overall DNA methylation. These discoveries help to clarify the connection between SPHK2 and the response to DNA damage, as well as its capacity to aid in the resistance against genotoxic agents, including those used in cancer treatment.

Celiac trunk stenosis by median arcuate ligament in orthotopic liver transplantation: a potential hidden foe to the biliary tree.

BACKGROUND: Celiac trunk compression by the median arcuate ligament (MAL) increases the risk of ischemic complications following gastrointestinal surgical procedures. Previous studies suggest increased risk of hepatic artery thrombosis (HAT) in orthotopic liver transplant (OLT) recipients. The aim of this study is to investigate the impact of untreated MAL compression (MAL-C) on biliary complications in OLT. METHODS: Contrast-enhanced imaging was used to classify celiac trunk stenosis by MAL-C. Medical records were reviewed to extract pre-transplant, transplant and post-transplant data. Patients were divided into two groups: no MAL compression (nMAL-C) and MAL-C. The primary endpoint was biliary complications. Secondary endpoints were HAT and graft survival. RESULTS: 305 OLT were performed from 2010 to 2021, of which 219 were included for analysis: 185 (84.5%) patients without and 34 (15.5%) with MAL-C. The incidence of HAT was 5.9% in both groups. Biliary complications were more common in the MAL-C group (35.3% vs. 17.8%, p = 0.035). Graft survival was decreased in patients with MAL-C (p = 0.035). CONCLUSIONS: MAL-C of the celiac trunk was associated with increased risk of biliary complications and inferior graft survival in OLT patients. These findings highlight the importance of preoperative screening and treatment of MAL in this population.

Bioactive alkaloids from the venom of Dendrobatoidea Cope, 1865: a scoping review.

Bioactive compounds derived from secondary metabolism in animals have refined selectivity and potency for certain biological targets. The superfamily Dendrobatoidea is adapted to the dietary sequestration and secretion of toxic alkaloids, which play a role in several biological activities, and thus serve as a potential source for pharmacological and biotechnological applications. This article constitutes a scoping review to understand the trends in experimental research involving bioactive alkaloids derived from Dendrobatoidea based upon scientometric approaches. Forty-eight (48) publications were found in 30 journals in the period of 60 years, between 1962 and 2022. More than 23 structural classes of alkaloids were cited, with 27.63% for batrachotoxins, 13.64% for pyridinics, with an emphasis on epibatidine, 16.36% for pumiliotoxins, and 11.82% for histrionicotoxins. These tests included in vivo (54.9%), in vitro (39.4%), and in silico simulations (5.6%). Most compounds (54.8%) were isolated from skin extracts, whereas the remainder were obtained through molecular synthesis. Thirteen main biological activities were identified, including acetylcholinesterase inhibitors (27.59%), sodium channel inhibitors (12.07%), cardiac (12.07%), analgesic (8.62%), and neuromuscular effects (8.62%). The substances were cited as being of natural origin in the "Dendrobatidae" family, genus "Phyllobates," "Dendrobates," and seven species: Epipedobates tricolor, Phyllobates aurotaenia, Oophaga histrionica, Oophaga pumilio, Phyllobates terribilis, Epipedobates anthonyi, and Ameerega flavopicta. To date, only a few biological activities have been experimentally tested; hence, further studies on the bioprospecting of animal compounds and ecological approaches are needed.

Spermidine Suppresses Oral Carcinogenesis through Autophagy Induction, DNA Damage Repair, and Oxidative Stress Reduction.

Autophagy has been proposed to play a dual role in cancer-as a tumor suppressor in early stages and oncogenic in late stages of tumorigenesis. This study investigated the role of autophagy in oral carcinogenesis using the model of oral squamous cell carcinoma (OSCC) induced by carcinogen 4-nitroquinoline 1-oxide (4NQO), mimicking molecular and histopathologic aspects of human OSCC. The induction of autophagy by spermidine (SPD) treatment reduced the severity of lesions and the incidence of OSCC in mice exposed to 4NQO. On the other hand, autophagy inhibition by chloroquine treatment had no protection. The comet assay indicated that SPD reduced 4NQO-induced DNA damage, likely related to the activation of DNA repair and the decrease of reactive oxygen species. As sphingolipid alterations have been reported in OSCC, sphingolipids in the tongue and plasma of animals were analyzed and plasma C16 ceramide levels were shown to increase proportionally to lesion severity, indicating its potential as a biomarker. Mice exposed to 4NQO plus SPD had lower levels of C16 ceramide than the 4NQO group, which indicated SPD's ability to prevent the 4NQO-induced carcinogenesis. Together, these data indicate that activation of autophagy has a tumor suppressor role during the early stages of oral carcinogenesis. Because of its ability to induce autophagy accompanied by reduced oxidative stress and DNA damage, SPD may have a protective action against chemically induced oral cancer.

Predicting Relative Populations of Protein Conformations without a Physics Engine Using AlphaFold2.

This paper presents a novel approach for predicting the relative populations of protein conformations using AlphaFold 2, an AI-powered method that has revolutionized biology by enabling the accurate prediction of protein structures. While AlphaFold 2 has shown exceptional accuracy and speed, it is designed to predict proteins' single ground state conformations and is limited in its ability to predict fold switching and the effects of mutations on conformational landscapes. Here, we demonstrate how AlphaFold 2 can directly predict the relative populations of different conformations of proteins and even accurately predict changes in those populations induced by mutations by subsampling multiple sequence alignments. We tested our method against NMR experiments on two proteins with drastically different amounts of available sequence data, Abl1 kinase and the granulocyte-macrophage colony-stimulating factor, and predicted changes in their relative state populations with accuracies in excess of 80%. Our method offers a fast and cost-effective way to predict protein conformations and their relative populations at even single point mutation resolution, making it a useful tool for pharmacology, analyzing NMR data, and studying the effects of evolution.

Predicting Relative Populations of Protein Conformations without a Physics Engine Using AlphaFold 2.

This paper presents a novel approach for predicting the relative populations of protein conformations using AlphaFold 2, an AI-powered method that has revolutionized biology by enabling the accurate prediction of protein structures. While AlphaFold 2 has shown exceptional accuracy and speed, it is designed to predict proteins' ground state conformations and is limited in its ability to predict conformational landscapes. Here, we demonstrate how AlphaFold 2 can directly predict the relative populations of different protein conformations by subsampling multiple sequence alignments. We tested our method against NMR experiments on two proteins with drastically different amounts of available sequence data, Abl1 kinase and the granulocyte-macrophage colony-stimulating factor, and predicted changes in their relative state populations with more than 80% accuracy. Our subsampling approach worked best when used to qualitatively predict the effects of mutations or evolution on the conformational landscape and well-populated states of proteins. It thus offers a fast and cost-effective way to predict the relative populations of protein conformations at even single-point mutation resolution, making it a useful tool for pharmacology, NMR analysis, and evolution.

Exploring the Therapeutic Potential of trans-Chalcone: Modulation of MicroRNAs Linked to Breast Cancer Progression in MCF-7 Cells.

Breast cancer is responsible for 25% of all cancers that affect women. Due to its high heterogeneity pattern in clinical diagnosis and its molecular profile differences, researchers have been seeking new targets and therapies, with more specificity and fewer side effects. Thus, one compound that has garnered our attention is trans-chalcone, which is naturally occurring in various plants and possesses promising biological properties, including antitumor effects. MiRNA is an extensive class of non-coding small, endogenous, and single-stranded RNAs, and it is involved in post-translational gene regulation. Therefore, the objective of this study was to investigate the effects of TChal on miRNAs expression and its relationship with anticancer activity against MCF-7. Initially, the trans-chalcone IC50 value was established by MTT assay for MCF-7and HaCat (non-cancer cell), in which we found out that it was 53.73 and 44.18 µM, respectively. Subsequently, we treated MCF-7 cells with trans-chalcone at its IC50 concentration and performed Mi-seq analysis, which unveiled 23 differentially expressed miRNAs. From this set, we selected five miRNAs (miR-25-5p, miR-27a-3p, miR-891a, miR-449a, and miR-4485) for further validation using qRT-PCR, guided by in silico analysis and their known association with tumorigenesis. In conclusion, our research provides valuable insights into the potential use of TChal to reveal MicroRNAs molecular targets that can be applied in breast cancer therapy.

Low hepatic artery resistive index on Doppler ultrasound performed on the first post-liver transplant day is associated both with hepatic artery thrombosis and decreased graft survival.

PURPOSE: Although liver transplantation (LT) outcomes have improved significantly over the last decades, early vascular complications are still associated with elevated risks of graft failure. Doppler ultrasound (DUS) enables detection of vascular complications, provides hepatic artery Resistive Index (RI). The aim of our study was to evaluate the association of the RI parameters of DUS performed in the first post-transplant week with post-transplant outcomes. METHODS: All consecutive patients undergoing a first LT between 2001 and 2019 at a single center were included. Patients were divided into two groups: RI < 0.55 and RI ≥ 0.55. Patients were also divided according to the presence or absence of hepatic artery thrombosis (HAT). Graft survival was compared between groups. RESULTS: Overall, 338 patients were included. HAT occurred in 23 patients (6.8%), of which 7 were partial and 16, complete. Biliary complications were more common in patients with HAT (10 [43.5%]) vs. 38 [12.1%] [p < 0.001]). Graft survival was lower for patients with HAT (p = 0.047). Also, RI < 0.55 was associated with increased incidence of HAT (p < 0.001). Additionally, patients with RI < 0.55 on post-operative day 1 had decreased graft survival as compared to patients with RI > 0.55 (p = 0.041). RI on post-operative day 3 and 5 was not predictive of inferior graft outcomes. CONCLUSIONS: Intensive use of DUS in the early post-LT period offers the possibility of early diagnosis of vascular complications, guiding medical and surgical management of HAT. Additionally, according to our data, low RI (< 0.55) on the first postoperative day also is a predictor of HAT and decreased graft-survival.

Barriers to and facilitators of populational adherence to prevention and control measures of COVID-19 and other respiratory infectious diseases: a qualitative evidence synthesis.

AIMS: To summarise the evidence on barriers to and facilitators of population adherence to prevention and control measures for coronavirus disease 2019 (COVID-19) and other respiratory infectious diseases. METHODS: A qualitative synthesis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis and the Cochrane Effective Practice and Organization of Care: Qualitative Evidence Synthesis. We performed an electronic search on MEDLINE, Embase and PsycINFO from their inception to March 2023. RESULTS: We included 71 studies regarding COVID-19, pneumonia, tuberculosis, influenza, pertussis and H1N1, representing 5966 participants. The measures reported were vaccinations, physical distancing, stay-at-home policy, quarantine, self-isolation, facemasks, hand hygiene, contact investigation, lockdown, infection prevention and control guidelines, and treatment. Tuberculosis-related measures were access to care, diagnosis and treatment completion. Analysis of the included studies yielded 37 barriers and 23 facilitators. CONCLUSIONS: This review suggests that financial and social support, assertive communication, trust in political authorities and greater regulation of social media enhance adherence to prevention and control measures for COVID-19 and infectious respiratory diseases. Designing and implementing effective educational public health interventions targeting the findings of barriers and facilitators highlighted in this review are key to reducing the impact of infectious respiratory diseases at the population level.