Miracle-dz/UniFAR-FTUs huggingface dataset:
The Double-Edged Sword of Oleuropein in Ovarian Cancer Cells: From Antioxidant Functions to Cytotoxic Effects

Oleuropein plays a key role as a pro-oxidant as well as an antioxidant in cancer. In this study, the activity of oleuropein, in an in vitro model of ovarian (OCCs) and breast cancer cells (BCCs) was investigated. Cell viability and cell death were analyzed. Oxidative stress was measured by CM-H2DCFDA flow cytometry assay. Mitochondrial dysfunction was evaluated based on mitochondrial reactive oxygen species (ROS) and GPX4 protein levels. Further, the effects on iron metabolism were analyzed by measuring the intracellular labile iron pool (LIP). We confirmed that high doses of oleuropein show anti-proliferative and pro-apoptotic activity on HEY and MCF-7 cells. Moreover, our results indicate that low doses of oleuropein impair cell viability without affecting the mortality of cells, and also decrease the LIP and ROS levels, keeping them unchanged in MCF-7 cells. For the first time, our data show that low doses of oleuropein reduce erastin-mediated cell death. Interestingly, oleuropein decreases the levels of intracellular ROS and LIP in OCCs treated with erastin. Noteworthily, we observed an increased amount of ROS scavenging enzyme GPX4 together with a consistent reduction in mitochondrial ROS, confirming a reduction in oxidative stress in this model.
Proteome-Wide Structural Computations Provide Insights into Empirical Amino Acid Substitution Matrices

The relative contribution of mutation and selection to the amino acid substitution rates observed in empirical matrices is unclear. Herein, we present a neutral continuous fitness-stability model, inspired by the Arrhenius law (qij=aije−ΔΔGij). The model postulates that the rate of amino acid substitution (i→j) is determined by the product of a pre-exponential factor, which is influenced by the genetic code structure, and an exponential term reflecting the relative fitness of the amino acid substitutions. To assess the validity of our model, we computed changes in stability of 14,094 proteins, for which 137,073,638 in silico mutants were analyzed. These site-specific data were summarized into a 20 square matrix, whose entries, ΔΔGij, were obtained after averaging through all the sites in all the proteins. We found a significant positive correlation between these energy values and the disease-causing potential of each substitution, suggesting that the exponential term accurately summarizes the fitness effect. A remarkable observation was that amino acids that were highly destabilizing when acting as the source, tended to have little effect when acting as the destination, and vice versa (source → destination). The Arrhenius model accurately reproduced the pattern of substitution rates collected in the empirical matrices, suggesting a relevant role for the genetic code structure and a tuning role for purifying selection exerted via protein stability.
Analgesic Action of Acetaminophen via Kv7 Channels

The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP’s analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI.
Therapeutic Outcomes of 177Lu-PSMA Targeted Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer: A Single-Center Study

Objective(s): This study aimed to evaluate the therapeutic outcomes of 177Lutetium (177Lu)-PSMA-617 in metastatic castrate-resistant prostate cancer (mCRPC) patients, based on post-treatment imaging findings. Methods: All post-therapeutic scans were collected retrospectively from patients treated with 100-200 mCi 177Lu-PSMA-617 from March 2018 to December 2020 for mCRPC. Two independent readers interpreted the scans and visually categorized them into three strata: responsive, stable, and progressive. The responses were defined based on changes in the number of detected lesions, as well as the intensity of the hottest lesion. Data were registered, and the trend of changes was descriptively discussed. Results: Out of 36 patients (aged 67±8.8 years), 23 underwent at least two treatment cycles. Nineteen patients (82.6%) had bone metastases, 12 (52.2%) had nodal metastases, 5 (21.7%) had liver metastases, and 3 (13.0%) had lung metastases. Eleven patients (47.8%) were considered responsive in the post-therapeutic scans, two of which experienced complete eradication of the metastatic sites. Three patients (13%) were categorized as progressive, and 9 (39.1%) patients remained stable. Regarding mortality, nine patients died during the late follow-up (median of 24 months). In the surviving population, 65% reported no or mild pain in the final follow-up, based on a 5-point scale pain assessment. Conclusion: The treatment of mCRPC patients with 177Lu-PSMA-617 may limit their disease progression and preserve their physical performance, which are important factors in their survival and quality of life.
Proteomics Characterization of Clear Cell Renal Cell Carcinoma

Purpose: To explore the tumor proteome of patients diagnosed with localized clear cell renal cancer (ccRCC) and treated with surgery. Material and methods: A total of 165 FFPE tumor samples from patients diagnosed with ccRCC were analyzed using DIA-proteomics. Proteomics ccRCC subtypes were defined using a consensus cluster algorithm (CCA) and characterized by a functional approach using probabilistic graphical models and survival analyses. Results: We identified and quantified 3091 proteins, including 2026 high-confidence proteins. Two proteomics subtypes of ccRCC (CC1 and CC2) were identified by CC using the high-confidence proteins only. Characterization of molecular differences between CC1 and CC2 was performed in two steps. First, we defined 514 proteins showing differential expression between the two subtypes using a significance analysis of microarrays analysis. Proteins overexpressed in CC1 were mainly related to translation and ribosome, while proteins overexpressed in CC2 were mainly related to focal adhesion and membrane. Second, a functional analysis using probabilistic graphical models was performed. CC1 subtype is characterized by an increased expression of proteins related to glycolysis, mitochondria, translation, adhesion proteins related to cytoskeleton and actin, nucleosome, and spliceosome, while CC2 subtype showed higher expression of proteins involved in focal adhesion, extracellular matrix, and collagen organization. Conclusions: ccRCC tumors can be classified in two different proteomics subtypes. CC1 and CC2 present specific proteomics profiles, reflecting alterations of different molecular pathways in each subtype. The knowledge generated in this type of studies could help in the development of new drugs targeting subtype-specific deregulated pathways.
Morphological and Functional Effects of Ultrasound on Blood–Brain Barrier Transitory Opening: An In Vitro Study on Rat Brain Endothelial Cells

With the recent advances in medicine, human life expectancy is increasing; however, the extra years of life are not necessarily spent in good health or free from disability, resulting in a significantly higher incidence of age-associated pathologies. Among these disorders, neurodegenerative diseases have a significant impact. To this end, the presence of the protective blood–brain barrier (BBB) represents a formidable obstacle to the delivery of therapeutics. Thus, this makes it imperative to define strategies to bypass the BBB in order to successfully target the brain with the appropriate drugs. It has been demonstrated that targeting the BBB by ultrasound (US) can transiently make this anatomical barrier permeable and in so doing, allow the delivery of therapeutics. Thus, our aim was to carry out an in depth in vitro molecular and morphological study on the effects of US treatment on the BBB. The rat brain endothelial (RBE4) cell line was challenged with exposure to 12 MHz diagnostic US treatment for 10, 20, and 30 min. Cell viability assays, Western blotting analysis on the endoplasmic reticulum (ER), and oxidative stress marker evaluation were then performed, along with cytological and immunofluorescence staining, in order to evaluate the effects of US on the intercellular spaces and tight junction distribution of the brain endothelial cells. We observed that the US treatment exerted no toxic effects on either RBE4 cell viability or the upregulation/dislocation of the ER and oxidative stress marker (GRP78 and cytochrome C, respectively). Further, we observed that the application of US induced an increase in the intercellular spaces, as shown by Papanicolaou staining, mainly due to the altered distribution of the tight junction protein zonula occludens-1 (ZO-1). This latter US-dependent effect was transient and disappeared 20 min after the removal of the stimulus. In conclusion, our results show that US induces a transient alteration of the BBB, without altering the intracellular signaling pathways such as the ER and oxidative stress that could potentially be toxic for endothelial cells. These results suggested that US treatment could represent a potential strategy for improving drug delivery to the brain.
miR-34a Regulates Lipid Droplet Deposition in 3T3-L1 and C2C12 Cells by Targeting LEF1

Intramuscular fat (IMF) content plays a key role in improving the flavor and palatability of pork. The IMF content varies between species, breeds, and individuals of the same breed. Hence, it is necessary to elucidate the mechanisms of IMF deposition to improve pork quality. Herein, the IMF content in the longissimus dorsi muscles of 29 Laiwu pigs was detected and divided into two groups, the H group (IMF > 12%) and the L group (IMF < 5%). RNA sequencing analysis showed 24 differentially expressed (DE) miRNA, and GO and KEGG analysis demonstrated that the DE miRNAs were significantly enriched in lipid metabolic process, lipid storage, Wnt, mTOR, and PPAR signaling pathways. miR-34a was found to be increased in the H group and 3T3-L1-derived adipocytes, while Lef1 was decreased. Luciferase reporter assays demonstrated that Lef1 was a potential target of miR-34a. Mechanism analysis revealed that miR-34a could increase lipid droplet deposition in 3T3-L1 and C2C12 cells by dampening the suppressive function of Lef1 on the transcription of adipogenic markers (i.e., Pparg, Cebpa, Fabp4, and Plin1). Moreover, overexpression of miR-34a could enhance the lipid deposition in the co-culture system of 3T3-L1 and C2C12 cells as well as in C2C12 cells cultured with conditioned medium from the progress of adipocyte differentiation. Taken together, our study indicated that miR-34a was an important positive modulator in the regulation of fatty metabolism and fat deposition by inhibiting the suppressive function of Lef1. These results might provide insight for the exploration of potential strategies to promote intramuscular fat deposition in livestock.
Iatrogenic Injury of Biliary Tree—Single-Centre Experience

Cholecystolithiasis is among the most prevalent gastrointestinal disorders requiring surgical intervention, and iatrogenic damage to the bile tree is a severe complication. We aimed to present the frequency of bile duct injuries and how our facility handles these complications. We retrospectively analyzed bile duct injuries in patients undergoing surgery. We concentrated on factors such as sex, age, indications for surgery, type of surgery, primary procedure, bile tree injury, repair, and timing as well as early and late complications. There were 22 cases of bile duct injury in the studied material, primarily affecting women—15 individuals (68.2%). Eleven cases (45.7%) of acute cholecystitis were the primary reason for surgery, and an injury to the common bile duct that extended up to 2 cm from the common hepatic duct was the most common complication (European Association for Endoscopic Surgery grade 2). Roux-en-Y hepaticojejunostomy was the most common repair procedure in 14 cases (63.6%). Eleven patients (50%) experienced early complications following reconstruction surgery, whereas five patients (22.7%) experienced late complications. An annual mortality rate of 22.7% (five patients) was observed. Iatrogenic bile duct injury is a severe complication of surgical treatment for cholecystolithiasis. Reconstruction procedures are characterized by high complication rates and high mortality.
Error Bounds for Asymptotic Approximations of the Linear Discriminant Function When the Sample Sizes and Dimensionality are Large

Theoretical accuracies are studied for asymtotic approximations of the expected probabilities of misclassification (EPMC) when the linear discriminant function is used to classify an observation as coming from one of two multivariate normal populations with a common covariance matrix. The asymptotic approximations considered are the ones under the situation where both the sample sizes and the demensionality are large. We give explicit error bounds for asymptotic approximations of EPMC, based on a general approximation result. We also discuss with a method of obtaining asymptotic expansions for EPMC and their error bounds.
Mutational Analysis of EGFR Mutations in Non-Small Cell Lung Carcinoma—An Indian Perspective of 212 Patients

Lung cancer is the world’s leading cause of cancer-related deaths. Epidermal growth factor receptor (EGFR) is one of the critical oncogenes and plays a significant role in tumor proliferation and metastasis. Patients with sensitizing mutations in the EGFR gene have better clinical outcomes when treated with tyrosine kinase inhibitors (TKI). This study expands our knowledge of the spectrum of EGFR mutations among lung cancer patients in the Indian scenario. This is a retrospective descriptive study of all newly diagnosed patients with lung cancer in tertiary care hospital in India. All the samples were subjected to real-time PCR (q-PCR) analysis and confirmation of rare novel mutations was done using Sanger sequencing. Clinicopathological characteristics, mutational EGFR status, and location on the exon and metastatic sites were evaluated. An analysis of total 212 samples showed mutations in 38.67% of cases. Among these, five (5.9%) samples had mutations in exon 18, 41 (48.8%) samples had mutations in exon 19, 12 (14.28%) samples had mutations in exon 20, and 26 (30.95%) samples had mutations in exon 21. Eleven (13.41%) were found to be uncommon EGFR mutations. Additionally, six (21.4%) samples that had EGFR mutations were also positive for brain metastasis. Future testing on bigger panels will help to characterize the incidence of genetic mutations and to determine the appropriate targeted treatment choices for NSCLC patients.
Transient regime duration in continuous-time neural networks with delay

K. Pakdaman, C. Grotta-Ragazzo, and C. P. Malta Department of Biophysical Engineering, Faculty of Engineering Science, Osaka University, Toyonaka 560-8531, Osaka, Japan Instituto de Matematica e Estatistica, Universidade de Sao Paulo, Caixa Postal 66281, 05315-970 Sao Paulo, Brazil Instituto de Fisica, Universidade de Sao Paulo, Caixa Postal 66318, 05315-970 Sao Paulo, Brazil ~Received 2 March 1998!
Variable threshold outlier identification in PIV data

This paper describes a variable threshold technique that can be applied to any particle image velocimetry (PIV) post-analysis outlier identification algorithm which uses a threshold such as the local median or the cellular neural network techniques. Although these techniques have been shown to work quite well with constant thresholds, the selection of the threshold is not always clear when working with real data. Moreover, if a small threshold is selected, a very large number of valid vectors can be mistakenly rejected. Although careful monitoring may alleviate this danger in many cases, that is not always practical when large data sets are being analysed and there is significant variability in the properties of the vector fields. The method described in this paper adjusts the threshold by calculating a mean variation between a candidate vector and its eight neighbours. The main benefit is that much smaller thresholds can be used without suffering catastrophic loss of valid vectors. The main challenge in obtaining this threshold field is that it must be based on a filtered field to be representative of the underlying velocity field. In this work, a simple median filter which requires no threshold was used for preliminary rejection. A local threshold was then calculated from the mean difference between each vector and its neighbours. The threshold field was also filtered with a Gaussian kernel before use. The algorithm was tested and compared to the base techniques by generating artificial velocity fields with known numbers of spurious vectors. For these tests, the ability of the algorithms to identify bad vectors and preserve good vectors was monitored. In addition, the technique was tested on real PIV data from the developing region of an axisymmetric jet. The variable threshold versions of these algorithms were found to be much less susceptible to erroneously rejecting good vectors. This is because the variable threshold techniques extract information about the local velocity gradient from the data themselves. The user-adjustable parameters for the variable threshold methods were found to be more universal than the constant threshold methods.
Asymptotically Efficient Estimation in Semiparametric Generalized Linear Models

We use the method of maximum likelihood and regression splines to derive estimates of the parametric and nonparametric components of semiparametric generalized linear models. The resulting estimators of both components are shown to be consistent. Also, the asymptotic theory for the estimator of the parametric component is derived, indicating that the parametric component can be estimated efficiently without under-smoothing the nonparametric component.
Physical Healthcare for People with a Severe Mental Illness in Belgium by Long-Term Community Mental Health Outreach Teams: A Qualitative Descriptive Study on Physicians’, Community Mental Health Workers’ and Patients’ Perspectives

Background: People with a severe mental illness (pSMI) often have comorbid physical health problems, resulting in a lower life expectancy compared to the global population. In Belgium, it remains unclear how to approach health disparities in pSMI in a community setting. This study explores the perspectives of both care professionals and patients on physical healthcare in Belgian community mental services, aiming to identify good practices, barriers and points of improvement. Methods: An exploratory qualitative design that used a semi-structured focus group interview with physicians combined with individual face-to-face interviews with physicians, mental health professionals and patients. Results: We identified care professional-, patient-related and organizational factors, as well as points of improvement. The identified themes linked to care professionals were communication, task distribution, knowledge, time and stigmatization. The co-location of services was the main theme on an organizational level. Conclusions: As community-based mental health services in Belgium emerged in the past decade, addressing physical health in pSMI is still challenging. Our findings suggest that there is a need for improvement in the current healthcare provision. Multidisciplinary guidelines, shared patient records, enlarging nurses’ tasks, providing financial incentives and a structural integration of primary and psychiatric care were perceived as major points of improvement to the current Belgian healthcare organization.
The Impact of Biosecurity on Biological and Psychosocial Risks for Health Workers of COVID Hospitals in Guadalajara, Jalisco, Mexico

Background: Some data support that health care workers (HCWs) must have sufficient and good quality personal protective equipment (PPE) and the necessary training to manage COVID patients to avoid contagion that can lead to death. The objective of this study was to determine the relationship between biosafety on the biological risks of SARS-CoV-2 and risks of fatigue, anxiety, or depression in health workers who care for patients in COVID hospitals, from September 2020 to August 2021. Material and methods: The questionnaire used in this study (Q6S64I) consisted of 6 spheres: Sociodemographic aspects, working conditions; Personal Protection Equipment; safety and health; training and knowledge about COVID-19, the form of transport, and personal health conditions. The answers were online. The Goldberg questionnaire (EADG) measures anxiety and depression, and the questionnaire measures fatigue (Barrientos-Gutiérrez et al.) (PSSF). Results: In total, 76.5% of the HCWs were doctors, 25.2% worked in the emergency services, 79.3% received PPE from their institution, 82.9% cared for COVID-19 patients, and 27.9% tested positive for COVID-19. The PPE provided by the employer was 80%, but the quality was deficient, insufficient, and associated with a relative risk of 4.6. A total of 99% acquired better PPE on their own. The exposure to COVID-19 and the surgical mask provided by the institution had an associated relative risk of 2.8 for the HCWs. A total of 39% of the HCWs reported being calm. Conclusions: PPE, risk exposure, and safety at work were significantly associated with drowsiness and heaviness, difficulty concentrating, anxiety, and depression.
Structural Equation Model on the Problem Behavior of Adolescents

This study aimed to explain direct and indirect relationship between psychological maltreatment, socio-psychological prevention factors, and problem behavior of adolescents based upon Jessor’s protective-risk model and Haase’s adolescent resilience model (ARM). A convenience sample of 138 Korean adolescents was recruited for the cross-sectional survey design. Using the collected data, the developed model was verified by structural equation modeling analysis using SPSS and AMOS program. Regarding model fit, χ2 = 151.62 (p < 0.001), GFI = 0.908, AGFI = 0.836, CFI = 0.911, SRMR = 0.060, and RMSEA = 0.10, showing acceptable fit levels. Psychological maltreatment explained 11.5% of perceived social support; psychological maltreatment, perceived social support, and self-control explained 89.9% of resilience; psychological maltreatment and perceived social support explained 53.2% of self-control; and psychological maltreatment, perceived social support, resilience, and self-control explained 39.7% of problem behavior. Psychological maltreatment directly and indirectly influenced perceived social support, self-control, and problem behavior. Psychological maltreatment and self-control were the factors that influence problem behavior of adolescents. The findings suggest that psychological maltreatment must be eradicated to reduce problem behavior of adolescents and enhance their socio-psychological protection factors.