The Ubiquity of the Reaction of the Labile Iron Pool That Attenuates Peroxynitrite-Dependent Oxidation Intracellularly.

Although the labile iron pool (LIP) biochemical identity remains a topic of debate, it serves as a universal homeostatically regulated and essential cellular iron source. The LIP plays crucial cellular roles, being the source of iron that is loaded into nascent apo-iron proteins, a process akin to protein post-translational modification, and implicated in the programmed cell death mechanism known as ferroptosis. The LIP is also recognized for its reactivity with chelators, nitric oxide, and peroxides. Our recent investigations in a macrophage cell line revealed a reaction of the LIP with the oxidant peroxynitrite. In contrast to the LIP's pro-oxidant interaction with hydrogen peroxide, this reaction is rapid and attenuates the peroxynitrite oxidative impact. In this study, we demonstrate the existence and antioxidant characteristic of the LIP and peroxynitrite reaction in various cell types. Beyond its potential role as a ubiquitous complementary or substitute protection system against peroxynitrite for cells, the LIP and peroxynitrite reaction may influence cellular iron homeostasis and ferroptosis by changing the LIP redox state and LIP binding properties and reactivity.

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 Although largely used in the past, transarterial embolization (TAE) has been replaced by transarterial chemoembolization (TACE).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.

Effects of plasticizer Di(2-ethylhexyl) phthalate (DEHP) on the microbiome of the marine sponge Hymeniacidon heliophila.

Marine pollution research in the last 15 years focused on an emerging anthropogenic contaminant: plastic debris and more specifically, microplastics. Since, not only its physical impacts on marine invertebrates were studied, but also its additives. Phthalate, a plasticizer commonly found in the ocean and known endocrine disruptor was already observed in different aquatic invertebrates, but few is known about its presence and possible effects in Porifera physiology. Our study aimed to analyze potential shifts in Hymeniacidon heliophila (Desmosponge) microbiome after exposure to Di(2-ethylhexyl) phthalate (DEHP), the most common phthalate found in the ocean, in three different doses for 4 and 24 h. Results indicate that alpha diversity had significantly changed between control and exposed organisms but not in all multicomparisons. Microbial community structure changed after exposure as well although most abundant phyla did not vary along the experiment. The core microbiome between control and each exposed organisms contained the vast majority of total ASVs and a few ASVs were exclusive to each experimental group. After DEHP exposure, microbial classes had significant changes and species with phthalate degradation enzymes were identified in a specifically dose dependent manner pointing to a possible bacterial consortium responsible for the phthalate degradation. The bacterial detoxification activity may lead to H. heliophila resistance during DEHP exposure in polluted environmental conditions.

Acute effects of atrazine on the immunoexpressions of sertoli and germ cells molecular markers, cytokines, chemokines, and sex hormones levels in mice testes and epididymides.

Atrazine is currently one of the most commonly used agrochemicals in the United States and elsewhere. Here, we studied the immunoexpression of molecular markers of mammalian testicular functions: androgen receptor (AR), promyelocytic leukemia zinc finger (PLZF), GDNF family receptor alpha-1 (GFRA1), VASA/DDX4 (DEAD-Box Helicase 4) as well as the levels of intratesticular and intra-epididymal estradiol (E2) and dihydrotestosterone (DHT), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukins (IL-1ß and IL-6, IL-10) and testicular chemokines (CXCL-1, CCL-2 and CCL3) in BalB/c mice after a sub-acute gavage treatment with a gonado-toxin, atrazine (50 mg/kg body wt.) for three days. We found high numbers of AR immunopositive Sertoli cells and low numbers of GFRA1, PLZF and VASA/DDX4-positive germ cells in the seminiferous tubule regions of the testes. While TNF-α level in the testes fell and remained unchanged in the epididymides, IFN-γ levels in the testes remained constant but increased in the epididymides. E2 and DHT concentrations remained unaltered in the testes but were changed in the epididymides. There were no significant changes in the levels of interleukins in the testis and epididymis. Intratesticular chemokines were also not significantly altered, except for CCL-4, which was increased in the testis. Light microscopy of the epididymis showed detached epithelium and some detached cells in the lumen. It is concluded that atrazine changed the inflammatory status of the gonads and highlighted Sertoli and undifferentiated spermatogonia as important targets for atrazine's toxic effects in the testis of mice. Concerning the epididymis, atrazine altered the epididymal hormonal concentrations and promoted histopathological modifications in its parenchyma.

Measurement Uncertainty and Risk of False Compliance Assessment Applied to Carbon Isotopic Analyses in Natural Gas Exploratory Evaluation.

The concept of uncertainty in an isotopic analysis is not uniform in the scientific community worldwide and can compromise the risk of false compliance assessment applied to carbon isotopic analyses in natural gas exploratory evaluation. In this work, we demonstrated a way to calculate one of the main sources of this uncertainty, which is underestimated in most studies focusing on gas analysis: the δ13C calculation itself is primarily based on the raw analytical data. The carbon isotopic composition of methane, ethane, propane, and CO2 was measured. After a detailed mathematical treatment, the corresponding expanded uncertainties for each analyte were calculated. Next, for the systematic isotopic characterization of the two gas standards, we calculated the standard uncertainty, intermediary precision, combined standard uncertainty, and finally, the expanded uncertainty for methane, ethane, propane, and CO2. We have found an expanded uncertainty value of 1.8‰ for all compounds, except for propane, where a value of 1.6‰ was obtained. The expanded uncertainty values calculated with the approach shown in this study reveal that the error arising from the application of delta calculation algorithms cannot be neglected, and the obtained values are higher than 0.5‰, usually considered as the accepted uncertainty associated with the GC-IRMS analyses. Finally, based on the use of uncertainty information to evaluate the risk of false compliance, the lower and upper acceptance limits for the carbon isotopic analysis of methane in natural gas are calculated, considering the exploratory limits between -55‰ and -50‰: (i) for the underestimated current uncertainty of 0.5‰, the lower and upper acceptance limits, respectively, are -54.6‰ and -50.4‰; and (ii) for the proposed realistic uncertainty of 1.8‰, the lower and upper acceptance limits would be more restrictive; i.e., -53.5‰ and -51.5‰, respectively.

HPV Detection in Breast Tumors and Associated Risk Factors in Northeastern Brazil.

Breast cancer risk factors include lifestyle, genetic-hormonal influences, and viral infections. Human papillomavirus (HPV), known primarily as the etiological agent of cervical cancer, also appears active in breast carcinogenesis, as evidenced in our study of 56 patients from northeastern Brazil. We assessed the clinical and sociodemographic characteristics, correlating them with various breast cancer tumor types. HPV detection involved amplifying the L1 region, with viral load measured using the E2/E6 ratio and viral activity indicated by E5 oncogene expression. Predominantly, patients over 56 years of age with healthy lifestyles showed a high incidence of invasive ductal carcinoma and triple-negative breast cancer. HPV was detected in 35.7% of cases, mostly HPV16, which is associated with high viral loads (80 copies per cell) and significant E5 expression. These results hint at a possible link between HPV and breast carcinogenesis, necessitating further studies to explore this association and the underlying viral mechanisms.

Thermographic analysis of perforations in polyurethane blocks performed with experimental conical drill bit in comparison to conventional orthopedic drill bit: a preliminary study.

OBJECTIVE: Conical orthopedic drill bits may have the potential to improve the stabilization of orthopedic screws. During perforations, heat energy is released, and elevated temperatures could be related to thermal osteonecrosis. This study was designed to evaluate the thermal behavior of an experimental conical drill bit, when compared to the conventional cylindrical drill, using polyurethane blocks perforations. RESULTS: The sample was divided into two groups, according to the method of drilling, including 25 polyurethane blocks in each: In Group 1, perforations were performed with a conventional orthopedic cylindrical drill; while in Group 2, an experimental conical drill was used. No statistically significant difference was observed in relation to the maximum temperature (MT) during the entire drilling in the groups, however the perforation time (PT) was slightly longer in Group 2. Each drill bit perforated five times and number of perforations was not correlated with a temperature increase, when evaluated universally or isolated by groups. The PT had no correlation with an increase in temperature when evaluating the perforations universally (n = 50) and in Group 1 alone; however, Group 2 showed an inversely proportional correlation for these variables, indicating that, for the conical drill bit, drillings with longer PT had lower MT.

Reconstrução mamária: Experiência de 10 anos / Breast reconstruction: 10 years experience

Introdução: A reconstrução mamária pós-tratamento cirúrgico do câncer de mama (um dos principais cânceres que acometem as mulheres) tem sido progressivamente mais indicada, haja vista o benefício da recuperação psicológica e da qualidade de vida, seja utilizando implantes e/ou tecidos autólogos. O presente trabalho visa demonstrar a experiência da equipe, discutir técnicas operatórias e complicações em relação aos dados da literatura mundial, além de verificar a aplicabilidade da técnica na prática clínica da equipe. Método: Estudo observacional retrospectivo desenvolvido em hospital universitário em Juiz de Fora a partir da revisão de prontuários de pacientes submetidas a mastectomia com reconstrução mamária entre 2010 e 2020. Resultados: Das 860 mamas abordadas, 84% foram imediatas à cirurgia oncológica e 16% foram tardias; o principal acesso ao tecido mamário foi a incisão de Stewart, seguido de incisões inframamárias estendidas, periareolares e T invertido; quanto às técnicas reconstrutoras, destaca-se 35% dos casos com retalho com músculo grande dorsal, 25% com prótese pré-peitoral, 20% com retalho miocutâneo transverso do músculo reto abdominal e 10% com retalho muscular local. As complicações mais incidentes foram deiscência de sítio cirúrgico, seguida de necrose cutânea, seroma, infecção de sítio cirúrgico e hematoma, além de outros menos comuns como dor crônica e ruptura de prótese após mamografia. Conclusão: A reconstrução mamária pós-mastectomia é indispensável para a recuperação física e emocional da mulher, sendo as técnicas utilizadas nos últimos dez anos consistentes, confiáveis, de baixa morbidade e com ótimos resultados estéticos quando bem indicadas.

Introduction: Breast reconstruction after surgical treatment for breast cancer (one of the main cancers that affect women) has been progressively more recommended, given the benefits of psychological recovery and quality of life, whether using implants and/or autologous tissues. The present work aims to demonstrate the team's experience, and discuss operative techniques and complications concerning data from the world literature, in addition to verifying the applicability of the technique in the team's clinical practice. Method: Retrospective observational study developed at a university hospital in Juiz de Fora based on a review of medical records of patients who underwent mastectomy with breast reconstruction between 2010 and 2020. Results: Of the 860 breasts treated, 84% underwent immediate oncological surgery and 16% were late; the main access to the breast tissue was the Stewart incision, followed by extended inframammary, periareolar, and inverted T incisions; regarding reconstructive techniques, 35% of cases used a latissimus dorsi muscle flap, 25% used a prepectoral prosthesis, 20% used a transverse rectus abdominis myocutaneous flap and 10% used a local muscle flap. The most common complications were surgical site dehiscence, followed by skin necrosis, seroma, surgical site infection, and hematoma, in addition to other less common complications such as chronic pain and prosthesis rupture after mammography. Conclusion: Postmastectomy breast reconstruction is essential for a woman's physical and emotional recovery, with the techniques used in the last ten years being consistent, reliable, with low morbidity, and with excellent aesthetic results when correctly indicated.

Ultraviolet Resistance of Microorganisms Isolated from Uranium-Rich Minerals from Perus, Brazil.

The district of Perus, located in the city of São Paulo, Brazil, is renowned for its weathered granitic-pegmatitic masses, which harbor a significant number of uraniferous minerals that contribute to ionizing radiation levels up to 20 times higher than the background levels. In this study, aseptically collected mineral samples from the area were utilized to isolate 15 microorganisms, which were subjected to pre-screening tests involving UV-C and UV-B radiation. The microorganisms that exhibited the highest resistance to ultraviolet (UV) radiation were selected for the construction of survival curves for UV-C, broad-band UV-B, and solar simulation resistance testing. Subsequently, the four strains that demonstrated superior survival capabilities under UV radiation exposure were chosen for 16S rRNA gene sequencing. Among these, Nocardioides sp. O4R and Nocardioides sp. MA2R demonstrated the most promising outcomes in the UV radiation resistance assessments, showcasing comparable performance to the well-established radioresistant model organism Deinococcus radiodurans. These findings underscore the potential of naturally occurring high-radiation environments as valuable resources for the investigation of UV-resistant microorganisms.

Siderite and vivianite as energy sources for the extreme acidophilic bacterium Acidithiobacillus ferrooxidans in the context of mars habitability.

Past and present habitability of Mars have been intensely studied in the context of the search for signals of life. Despite the harsh conditions observed today on the planet, some ancient Mars environments could have harbored specific characteristics able to mitigate several challenges for the development of microbial life. In such environments, Fe2+ minerals like siderite (already identified on Mars), and vivianite (proposed, but not confirmed) could sustain a chemolithoautotrophic community. In this study, we investigate the ability of the acidophilic iron-oxidizing chemolithoautotrophic bacterium Acidithiobacillus ferrooxidans to use these minerals as its sole energy source. A. ferrooxidans was grown in media containing siderite or vivianite under different conditions and compared to abiotic controls. Our experiments demonstrated that this microorganism was able to grow, obtaining its energy from the oxidation of Fe2+ that came from the solubilization of these minerals under low pH. Additionally, in sealed flasks without CO2, A. ferrooxidans was able to fix carbon directly from the carbonate ion released from siderite for biomass production, indicating that it could be able to colonize subsurface environments with little or no contact with an atmosphere. These previously unexplored abilities broaden our knowledge on the variety of minerals able to sustain life. In the context of astrobiology, this expands the list of geomicrobiological processes that should be taken into account when considering the habitability of environments beyond Earth, and opens for investigation the possible biological traces left on these substrates as biosignatures.

Subchronic intake of arsenic at environmentally relevant concentrations causes histological lesions and oxidative stress in the prostate of adult Wistar rats.

The prostate gland is one of the main sites of hyperplasia and cancer in elderly men. Numerous factors have been demonstrated to disrupt prostate homeostasis, including exposure to environmental pollutants. Arsenic is a metalloid found ubiquitously in soil, air, and water, which favors human poisoning through the involuntary intake of contaminated drinking water and food and has harmful effects by increasing the oxidative stress response. This study aimed to investigate the effects of prolonged exposure to arsenic at environmentally relevant concentrations on the prostate biology of adult Wistar rats. Thirty 80-day-old male rats were divided into three experimental groups. Rats from the control group received filtered water, whereas animals from the arsenic groups ingested 1 mg L-1 and 10 mg L-1 of arsenic, in the form of sodium arsenite, daily. The arsenic solutions were provided ad libitum in the drinking water for eight weeks. Our results showed that 1 mg L-1 and 10 mg L-1 of arsenic made the prostate susceptible to evolving benign and premalignant histopathological changes. While the ingestion of 1 mg L-1 of arsenic reduced SOD activity only, 10 mg L-1 diminished SOD and CAT activity in the prostate tissue, culminating in high MDA production. These doses, however, did not affect the intraprostatic levels of DHT and estradiol. In conclusion, exposure to arsenic at environmentally relevant concentrations through drinking water induces histological and oxidative stress-related changes in the prostate of adult rats, strengthening the between arsenic exposure and prostate disorders.

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.

BACKGROUND: The lack of standardized objective assessment of esophageal physiology and anatomy contributes to controversies regarding the effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on gastroesophageal reflux disease. This study aimed to investigate esophageal acid exposure, esophageal motility, and endoscopic findings before and after SG and RYGB. METHODS: This was a systematic review and meta-analysis of studies reporting at least 1 objective measure of esophageal physiology and/or esophagogastroduodenoscopy (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, 0.3-3.9] and 8.6 [95% CI, 2.0-15.2], 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], respectively). Lower esophageal sphincter resting pressure and length significantly decreased after 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 risks of erosive esophagitis were 2.3 (95% CI, 1.5-3.5) after SG and 0.4 (95% CI, 0.2-0.8) after RYGB. The prevalence rates of Barrett esophagus changed from 0% to 3.6% after SG and from 2.7% to 1.4% after RYGB. CONCLUSION: SG resulted in the worsening of all objective parameters, whereas RYGB resulted in the improvement in AET, DMS, and EGD findings. Determining the risk factors associated with these outcomes can help 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.

Classification of Sleep Quality and Aging as a Function of Brain Complexity: A Multiband Non-Linear EEG Analysis.

Understanding and classifying brain states as a function of sleep quality and age has important implications for developing lifestyle-based interventions involving sleep hygiene. Current studies use an algorithm that captures non-linear features of brain complexity to differentiate awake electroencephalography (EEG) states, as a function of age and sleep quality. Fifty-eight participants were assessed using the Pittsburgh Sleep Quality Inventory (PSQI) and awake resting state EEG. Groups were formed based on age and sleep quality (younger adults n = 24, mean age = 24.7 years, SD = 3.43, good sleepers n = 11; older adults n = 34, mean age = 72.87; SD = 4.18, good sleepers n = 9). Ten non-linear features were extracted from multiband EEG analysis to feed several classifiers followed by a leave-one-out cross-validation. Brain state complexity accurately predicted (i) age in good sleepers, with 75% mean accuracy (across all channels) for lower frequencies (alpha, theta, and delta) and 95% accuracy at specific channels (temporal, parietal); and (ii) sleep quality in older groups with moderate accuracy (70 and 72%) across sub-bands with some regions showing greater differences. It also differentiated younger good sleepers from older poor sleepers with 85% mean accuracy across all sub-bands, and 92% at specific channels. Lower accuracy levels (<50%) were achieved in predicting sleep quality in younger adults. The algorithm discriminated older vs. younger groups excellently and could be used to explore intragroup differences in older adults to predict sleep intervention efficiency depending on their brain complexity.

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.

The estrogen signaling pathway reprograms prostate cancer cell metabolism and supports proliferation and disease progression.

Just like the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ERα functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen-targeted therapies for the treatment of this disease. Using 2 human PCa tissue microarray cohorts, we first demonstrate that nuclear ERα expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ERα levels were correlated with disease recurrence, progression to metastatic PCa, and patient survival. Using in vitro and in vivo models of the normal prostate and PCa, bulk and single-cell RNA-Seq analyses revealed that estrogens partially mimicked the androgen transcriptional response and activated specific biological pathways linked to proliferation and metabolism. Bioenergetic flux assays and metabolomics confirmed the regulation of cancer metabolism by estrogens, supporting proliferation. Using cancer cell lines and patient-derived organoids, selective estrogen receptor modulators, a pure anti-estrogen, and genetic approaches impaired cancer cell proliferation and growth in an ERα-dependent manner. Overall, our study revealed that, when expressed, ERα functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes.

Endogenous Cholinergic System Involved in Peripheral Analgesic Control in Mice Is Activated by TNF-α, CXCL-1, and IL-1ß.

INTRODUCTION: Tissue injury results in the release of inflammatory mediators, including a cascade of algogenic substances, which contribute to the development of hyperalgesia. During this process, endogenous analgesic substances are peripherally released to counterbalance hyperalgesia. The present study aimed to investigate whether inflammatory mediators TNF-α, IL-1ß, CXCL1, norepinephrine (NE), and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the cholinergic system. METHODS: Male Swiss mice were subjected to paw withdrawal test. All the substances were injected via the intraplantar route. RESULTS: The main findings of this study were as follows: (1) carrageenan (Cg), TNF-α, CXCL-1, IL1-ß, NE, and PGE2 induced hyperalgesia; (2) the acetylcholinesterase enzyme inhibitor, neostigmine, reversed the hyperalgesia observed after Cg, TNF-α, CXCL-1, and IL1-ß injection; (3) the non-selective muscarinic receptor antagonist, atropine, and the selective muscarinic type 1 receptor (m1AChr) antagonist, telenzepine, potentiated the hyperalgesia induced by Cg and CXCL-1; (4) mecamylamine, a non-selective nicotinic receptor antagonist, potentiated the hyperalgesia induced by Cg, TNF-α, CXCL-1, and IL1-ß; (5) Cg, CXCL-1, and PGE2 increased the expression of the m1AChr and nicotinic receptor subunit α4protein. CONCLUSION: These results suggest that the cholinergic system may modulate the inflammatory pain induced by Cg, PGE2, TNF-α, CXCL-1, and IL1-ß.

Machine learning for predicting Chagas disease infection in rural areas of Brazil.

INTRODUCTION: Chagas disease is a severe parasitic illness that is prevalent in Latin America and often goes unaddressed. Early detection and treatment are critical in preventing the progression of the illness and its associated life-threatening complications. In recent years, machine learning algorithms have emerged as powerful tools for disease prediction and diagnosis. METHODS: In this study, we developed machine learning algorithms to predict the risk of Chagas disease based on five general factors: age, gender, history of living in a mud or wooden house, history of being bitten by a triatomine bug, and family history of Chagas disease. We analyzed data from the Retrovirus Epidemiology Donor Study (REDS) to train five popular machine learning algorithms. The sample comprised 2,006 patients, divided into 75% for training and 25% for testing algorithm performance. We evaluated the model performance using precision, recall, and AUC-ROC metrics. RESULTS: The Adaboost algorithm yielded an AUC-ROC of 0.772, a precision of 0.199, and a recall of 0.612. We simulated the decision boundary using various thresholds and observed that in this dataset a threshold of 0.45 resulted in a 100% recall. This finding suggests that employing such a threshold could potentially save 22.5% of the cost associated with mass testing of Chagas disease. CONCLUSION: Our findings highlight the potential of applying machine learning to improve the sensitivity and effectiveness of Chagas disease diagnosis and prevention. Furthermore, we emphasize the importance of integrating socio-demographic and environmental factors into neglected disease prediction models to enhance their performance.