Miracle-dz/UniFAR-FTUs huggingface dataset:
HeLa Cell-Derived Paclitaxel-Loaded Microparticles Efficiently Inhibit the Growth of Cervical Carcinoma

Aim Tumor cell-derived microparticles (MP) can function as a targeted delivery carrier for anti-tumor drugs. Here, we aimed to generate paclitaxel-loaded microparticles (MP-PTX) from HeLa cells and examined its therapeutic potential on human cervical carcinoma. Methods MP-PTX was generated from HeLa cells by ultraviolet radiation and subsequent centrifugation. The particle size, drug loading rate, and stability of MP-PTX were examined in vitro. Flow cytometry and the MTT assay were performed to test the inhibitory effect of MP-PTX using different cell lines. Immunodeficient mice bearing HeLa cervical carcinoma were treated with 0.9% normal saline, MP, paclitaxel (PTX) (2.5 mg/kg), or MP-PTX (PTX content identical to PTX group) every day for 6 consecutive days. Tumor volume and animal survival were observed. Micro 18F-FDG PET/CT was performed to monitor the therapeutic efficacy. The proliferation activity of cells and microvessel density in tumor tissues were determined by immunohistochemical staining using Ki-67 and CD31, respectively. Results Dynamic laser scattering measurements showed that the particle size of MP-PTX was 285.58 ± 2.95 nm and the polydispersity index was 0.104 ± 0.106. And the particle size of MP-PTX was not change at 4°C for at least one week. More than 1% of PTX in the medium could be successfully encapsulated into HeLa cell-derived MP. When compared with PTX, MP-PTX treatment significantly increased apoptosis of tumor cells and reduced their proliferation. In addition, MP-PTX showed lower toxicity to normal human umbilical vein endothelial cells (HUVEC) than PTX. In vivo studies further demonstrated that MP-PTX treatment significantly inhibited the growth of cervical carcinoma, prolonged the survival of tumor-bearing mice, and reduced the toxicity of PTX. Immunohistochemical staining revealed that MP-PTX treatment led to decreased Ki-67 positive tumor cells and decreased microvessel density in tumor tissues. Conclusion Our results demonstrated that HeLa-derived MP-PTX significantly enhanced the anti-cancer effects of PTX with reduced toxicity, which may provide a novel strategy for the treatment of cervical carcinoma.
Automated classification of coronary plaque calcification in OCT pullbacks with 3D deep neural networks

Abstract. Significance: Detection and characterization of coronary atherosclerotic plaques often need reviews of a large number of optical coherence tomography (OCT) imaging slices to make a clinical decision. However, it is a challenge to manually review all the slices and consider the interrelationship between adjacent slices. Approach: Inspired by the recent success of deep convolutional network on the classification of medical images, we proposed a ResNet-3D network for classification of coronary plaque calcification in OCT pullbacks. The ResNet-3D network was initialized with a trained ResNet-50 network and a three-dimensional convolution filter filled with zeros padding and non-zeros padding with a convolutional filter. To retrain ResNet-50, we used a dataset of ∼4860 OCT images, derived by 18 entire pullbacks from different patients. In addition, we investigated a two-phase training method to address the data imbalance. For an improved performance, we evaluated different input sizes for the ResNet-3D network, such as 3, 5, and 7 OCT slices. Furthermore, we integrated all ResNet-3D results by majority voting. Results: A comparative analysis proved the effectiveness of the proposed ResNet-3D networks against ResNet-2D network in the OCT dataset. The classification performance (F1-scores = 94 % for non-zeros padding and F1-score = 96 % for zeros padding) demonstrated the potential of convolutional neural networks (CNNs) in classifying plaque calcification. Conclusions: This work may provide a foundation for further work in extending the CNN to voxel segmentation, which may lead to a supportive diagnostic tool for assessment of coronary plaque vulnerability.
The influence of bait on remote underwater video observations in shallow-water coastal environments associated with the North-Eastern Atlantic

The use of baited remote underwater video (BRUV) for examining and monitoring marine biodiversity in temperate marine environments is rapidly growing, however many aspects of their effectiveness relies on assumptions based on studies from the Southern Hemisphere. The addition of bait to underwater camera systems acts as a stimulus for attracting individuals towards the camera field of view, however knowledge of the effectiveness of different bait types in northern temperate climbs is limited, particularly in dynamic coastal environments. Studies in the Southern Hemisphere indicate that oily baits are most effective whilst bait volume and weight do not impact BRUV effectiveness to any great degree. The present study assesses the influence of four bait types (mackerel, squid, crab and no bait (control)) on the relative abundance, taxonomic diversity and faunal assemblage composition at two independent locations within the North-Eastern Atlantic region; Swansea Bay, UK and Ria Formosa Lagoon, Portugal. Two different bait quantities (50 g and 350 g) were further trialled in Swansea Bay. Overall, patterns showed that baited deployments recorded statistically higher values of relative abundance and taxonomic diversity when compared to un-baited deployments in Swansea Bay but not in Ria Formosa Lagoon. No statistical evidence singled out one bait type as best performing for attracting higher abundances and taxonomic diversity in both locations. Faunal assemblage composition was however found to differ with bait type in Swansea Bay, with mackerel and squid attracting higher abundances of scavenging species compared to the crab and control treatments. With the exception of squid, bait quantity had minimal influence on bait attractiveness. It is recommended for consistency that a minimum of 50 g of cheap, oily fish such as mackerel is used as bait for BRUV deployments in shallow dynamic coastal environments in the North-Eastern Atlantic Region.
A Novel Epitope Quality-Based Immune Escape Mechanism Reveals Patient’s Suitability for Immune Checkpoint Inhibition

Background Immune checkpoint inhibition, especially the blockade of PD-1 and PD-L1, has become one of the most thriving therapeutic approaches in modern oncology. Immune evasion caused by altered tumor epitope processing (so-called processing escapes) may be one way to explain immune checkpoint inhibition therapy failure. In the present study, we aim to demonstrate the effects of processing escapes on immunotherapy outcome in NSCLC patients. Patients and Methods Whole exome sequencing data of 400 NSCLC patients (AdC and SCC) were extracted from the TCGA database. The ICB cohort was composed of primary tumor probes from 48 NSCLC patients treated with nivolumab. Mutations were identified by targeted amplicon-based sequencing including hotspots and whole exomes of 22 genes. The effect of mutations on proteasomal processing was evaluated by deep learning methods previously trained on 1260 known MHC-I ligands. Cox regression modelling was used to determine the influence on overall survival. Results In the TCGA cohort, processing escapes were associated with decreased overall survival (p= 0.0140). In the ICB cohort, patients showing processing escapes in combination with high levels of PD-L1 (n=8/48) also showed significantly decreased overall survival, independently of mutational load or PD-L1 status. Conclusion The concept of altered epitope processing may help to understand immunotherapy failure. Especially when combined with PD-L1 status, this method can be used as a biomarker to identify patients not suitable for immunotherapy.
Sarcopenia Coexisting with High Adiposity Exacerbates Insulin Resistance and Dyslipidemia in Saudi Adult Men

Objective The associations between sarcopenia, adiposity indices and metabolic dysregulation still remain controversial. We aimed to assess and compare insulin resistance and metabolic profile in sarcopenic and non-sarcopenic obese Saudi adult men. Methods This cross sectional study was conducted at the College of Sports Sciences, King Saud University, Riyadh. We recruited 312 Saudi adult male individuals and 288 were finally selected for the study. Body composition analysis and hand grip strength (HGS) were estimated by bioimpedance analysis (BIA) and dynamometer in all subjects, respectively. Fasting blood samples were collected for glucose (FBG), basal insulin (BI) and lipid profile. The subjects were divided into three groups based on the body composition parameters, appendicular lean mass (ALM) and body fat percentage (BF%), into non-obese (NonOb) [Normal ALM+<25 BF%], obese without sarcopenia (ObNonS) [Normal ALM+>25 BF%] and obese with sarcopenia (ObS) [Low ALM+>25 BF%]. Results Obese subjects had significantly higher BI, HOMA-IR and HOMA-β compared to non-obese. Moreover, comparison between two obese groups revealed that both BI and HOMA-IR levels were higher in ObS subjects compared to ObNonS individuals revealing that sarcopenia exacerbates the insulin resistance profile. There was a significant trend of higher resistance and lower sensitivity from non-obese to obesity with sarcopenia. Total cholesterol (TC) and triglycerides (TG) were significantly higher and high density lipoprotein cholesterol (HDL-C) was significantly lower in sarcopenic obese subjects compared to non-sarcopenic obese individuals. The worsening effects were more significant at cutoff point of 7.46 on insulin indices and lipid profile showing that sarcopenia associated with obesity exacerbates the dyslipidemia. Conclusion Our study shows that obesity associated with sarcopenia exhibits significantly greater insulin resistance and dyslipidemia than sarcopenia or obesity per se. Therefore, sarcopenic obesity might be an independent risk factor for metabolic disease progression.
Molecular Mechanisms of TRAF6 Ubiquitination and Activation

Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6) is an E3 ubiquitin ligase catalyzing K63‐linked polyubiquitination of itself and other molecules upon association with upstream effectors possessing a short TRAF Interaction Motif (TIM) peptide. TRAF6 regulates biological processes such as inflammation, innate and adaptive immunity, osteoclastogenesis, and nerve growth. Ectopic expression of TRAF6 is sufficient as a dominant‐positive activator. However, the mechanism by which a TIM activates TRAF6 has been unclear. We now demonstrate that two critical domains of TRAF6, the MATH domain required for TIM binding and the RING‐Zinc for downstream signaling, mutually interact and render the molecule structurally closed and inactive. We propose that TIM engagement disrupts this interaction and that autoubiquitination provides a means of sustaining the open conformation necessary for downstream signaling. However, excessive ubiquitination results in inactivation of TRAF6 by trafficking into subcellular sequestosomes. Furthermore, the inferred cis nature of TRAF autoubiquitination is now demonstrated to act in trans and is regulated via its RING‐Zinc and coiled‐coil domains, providing a new mechanism for TRAF regulation and its ubiquitination target diversity.
Pharmacists’ practices for non-prescribed antibiotic dispensing in Mozambique

Background: Antibiotics are the most frequently used medicines worldwide with most of the countries defining these as prescription-only medicines. Though, dispensing non-prescribed antibiotics represent one of the chief causal factors to the irrational use of antibiotics that paves the way to the development of antimicrobial resistance. Objective: We aimed at describing the practices and the enablers for non-prescribed antibiotic dispensing in Maputo city, Mozambique. Methods: A qualitative study was conducted, between October 2018 and March 2019, in nine private pharmacies randomly selected across Maputo city. Eighteen pharmacists were contacted and seventeen enrolled through snowball sampling. In-depth interviews were conducted, audiotaped, and transcribed verbatim. Transcripts were coded and analysed though thematic analysis with guidelines from Braun and Clark. The Consolidated Criteria for Reporting Qualitative Studies (COREQ) checklist by (Tong, 2007) was performed. Results: Out of seventeen, fifteen pharmacists admitted non-prescribed dispensing of antibiotics. Common antibiotic dispensing practices included; dispensing without prescription, without asking for a brief clinical history of patients, without clear explanation of the appropriate way of administering, without advising on the side effects. Reasons for non-prescribed antibiotic dispensing are linked to patients’ behaviour of demanding for non-prescribed antibiotics, to the patients expectations and beliefs on the healing power of antibiotics, to the physicians’ prescribing practices. Other reasons included the pressure for profits from the pharmacy owners, the fragile law enforcement, and absence of accountability mechanisms. Conclusions: The practices of non-prescribed antibiotic dispensing characterize the ‘daily life’ of the pharmacists. On the one hand, the patient’s demand for antibiotics without valid prescriptions, and pharmacist’s wish to assist based on their role in the pharmacy, the pressure for profits and on the understanding of the larger forces driving the practices of self-medication with antibiotics - rock. On the other hand, pharmacists are aware of the legal status of antibiotics and the public health consequences of their inappropriate dispensing practices and their professional and ethical responsibility for upholding the law - hard place. Highlighting the role of pharmacists and their skills as health promotion professionals is needed to optimizing antibiotic dispensing and better conservancy in Mozambique.
Evidence Supporting the Safety of Pegylated Diethylaminoethyl-Chitosan Polymer as a Nanovector for Gene Therapy Applications

Purpose Diethylaminoethyl-chitosan (DEAE-CH) is a derivative with excellent potential as a delivery vector for gene therapy applications. The aim of this study is to evaluate its toxicological profile for potential future clinical applications. Methods An endotoxin-free chitosan (CH) modified with DEAE, folic acid (FA) and polyethylene glycol (PEG) was used to complex small interfering RNA (siRNA) and form nanoparticles (DEAE12-CH-PEG-FA2/siRNA). Based on the guidelines from the International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), and the Nanotechnology Characterization Laboratory (NCL), we evaluated the effects of the interaction between these nanoparticles and blood components. In vitro screening assays such as hemolysis, hemagglutination, complement activation, platelet aggregation, coagulation times, cytokine production, and reactive species, such as nitric oxide (NO) and reactive oxygen species (ROS), were performed on erythrocytes, plasma, platelets, peripheral blood mononuclear cells (PBMC) and Raw 264.7 macrophages. Moreover, MTS and LDH assays on Raw 264.7 macrophages, PBMC and MG-63 cells were performed. Results Our results show that a targeted theoretical plasma concentration (TPC) of DEAE12-CH-PEG-FA2/siRNA nanoparticles falls within the guidelines’ thresholds: <1% hemolysis, 2.9% platelet aggregation, no complement activation, and no effect on coagulation times. ROS and NO production levels were comparable to controls. Cytokine secretion (TNF-α, IL-6, IL-4, and IL-10) was not affected by nanoparticles except for IL-1β and IL-8. Nanoparticles showed a slight agglutination. Cell viability was >70% for TPC in all cell types, although LDH levels were statistically significant in Raw 264.7 macrophages and PBMC after 24 and 48 h of incubation. Conclusion These DEAE12-CH-PEG-FA2/siRNA nanoparticles fulfill the existing ISO, ASTM and NCL guidelines’ threshold criteria, and their low toxicity and blood biocompatibility warrant further investigation for potential clinical applications.
Vimentin as a target for the treatment of COVID-19

We and others propose vimentin as a possible cellular target for the treatment of COVID-19. This innovative idea is so recent that it requires further attention and debate. The significant role played by vimentin in virus-induced infection however is well established: (1) vimentin has been reported as a co-receptor and/or attachment site for SARS-CoV; (2) vimentin is involved in viral replication in cells; (3) vimentin plays a fundamental role in both the viral infection and the consequent explosive immune-inflammatory response and (4) a lower vimentin expression is associated with the inhibition of epithelial to mesenchymal transition and fibrosis. Moreover, the absence of vimentin in mice makes them resistant to lung injury. Since vimentin has a twofold role in the disease, not only being involved in the viral infection but also in the associated life-threatening lung inflammation, the use of vimentin-targeted drugs may offer a synergistic advantage as compared with other treatments not targeting vimentin. Consequently, we speculate here that drugs which decrease the expression of vimentin can be used for the treatment of patients with COVID-19 and advise that several Food and Drug Administration-approved drugs be immediately tested in clinical trials against SARS-CoV-2, thus broadening therapeutic options for this type of viral infection.
Matrix metalloproteinase-9 increases and Interleukin-10 reduces with increase in body mass index in polycystic ovary syndrome: A cross-sectional study

Abstract Background Obesity, inflammation and alterations in matrix metalloproteinase-9 (MMP-9) and nitric oxide (NO) levels are involved in the development of polycystic ovary syndrome (PCOS). Objective To investigate the relationship of MMP-9, NO and interleukin-10 (IL-10) with the increase in body mass index (BMI) in women with PCOS. Materials and Methods Sixty two infertile PCOS women were included in the study. Serum levels of NO, IL-10 and MMP-9 were assessed in the women with increase in BMI. Results MMP-9 was significantly increased (p = 0.029) and IL-10 (p = 0.015) was significantly reduced in obese PCOS subjects compared to those with lesser BMI. MMP-9 levels positively correlated with the duration of infertility (r = 0.253, p = 0.047) and negatively correlated with NO levels (r = - 0.259, p = 0.042). A significant negative correlation between the interleukin-10 levels and the BMI (r = - 0.272, p = 0.033) was also found in the PCOS subjects. Conclusion MMP-9 levels are increased in obese PCOS women and it is associated with NO levels and the duration of infertility.
Development and Validation of a Model for Predicting Urethral Recurrence in Male Patients with Muscular Invasive Bladder Cancer After Radical Cystectomy Combined with Urinary Diversion

Purpose Radical cystectomy (RC) is the primary treatment strategy for patients with muscular invasive bladder cancer (MIBC). However, the prognosis is poor and tumor recurrence is not rare, in particular, urethral recurrence (UR) in male patients who underwent RC combined with urinary diversion. Here, we have developed and validated a model for predicting UR in these patients. Patients and Methods The development cohort comprised 310 patients who underwent RC combined with urinary diversion at our center between 1 January 2007 and 31 December 2015. Clinicopathologic data of patients were comprehensively recorded. Multivariate Cox proportional hazard regression was used for building a predictive model with regression coefficients and backward stepwise selection applied by utilizing the likelihood ratio test with Akaike’s information criterion as the stopping rule. An independent cohort consisting of 131 consecutive patients treated from 1 January 2016 to 31 December 2017 was used for validation. The performance of this predictive model was assessed with respect to discrimination, calibration, and clinical usefulness. Results The predictors of this model included body mass index, history of transurethral resection of bladder tumor, tumor grade, tumor stage, and concomitant carcinoma in situ. In the validation cohort, the model showed good discrimination with a concordance index of 0.777 (95% CI, 0.618 to 0.937) and calibration. Decision curve analysis also demonstrated the clinical utility of the model. Conclusion The predictive model facilitated postoperative individualized prediction of UR in male patients with MIBC after RC combined with urinary diversion and it may therefore serve to improve follow-up strategies.
IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice

ABSTRACT The metabolic gene isocitrate dehydrogenase 1 (IDH1) is commonly mutated in lower grade glioma (LGG) and secondary glioblastoma (GBM). Regulatory T cells (Tregs) play a significant role in the suppression of antitumor immunity in human glioma. Given the importance of Tregs in the overall framework of designing immune-based therapies, a better understanding on their association with IDH mutational status remains of critical clinical importance. Using multispectral imaging analysis, we compared the incidence of Tregs in IDH-mutant and IDH wild-type glioma from patient tumor samples of LGG. An orthotopic IDH-mutant murine model was generated to evaluate the role of mutant IDH on Treg infiltration by immunohistochemistry. When compared to IDH wild-type controls, Tregs are disproportionally underrepresented in mutant disease, even when taken as a proportion of all infiltrating T cells. Our findings suggest that therapeutic agents targeting Tregs may be more appropriate in modulating the immune response to wild-type disease.
County-level exposures to greenness and associations with COVID-19 incidence and mortality in the United States

Background: COVID-19 is an infectious disease that has killed more than 175,000 people in the US. During a time of social distancing measures and increasing social isolation, green spaces may be a crucial factor to maintain a physically and socially active lifestyle while not increasing risk of infection. Objectives: We evaluated whether greenness is related to COVID-19 incidence and mortality in the United States. Methods: We downloaded data on COVID-19 cases and deaths for each US county up through June 7, 2020, from Johns Hopkins University, Center for Systems Science and Engineering Coronavirus Resource Center. We used April-May 2020 Normalized Difference Vegetation Index (NDVI) data, to represent the greenness exposure during the initial COVID-19 outbreak in the US. We fitted negative binomial mixed models to evaluate associations of NDVI with COVID-19 incidence and mortality, adjusting for potential confounders such as county-level demographics, epidemic stage, and other environmental factors. We evaluated whether the associations were modified by population density, proportion of Black residents, median home value, and issuance of stay-at-home order. Results: An increase of 0.1 in NDVI was associated with a 6% (95% Confidence Interval: 3%, 10%) decrease in COVID-19 incidence rate after adjustment for potential confounders. Associations with COVID-19 incidence were stronger in counties with high population density and high median home values, and in counties with stay-at-home orders. Greenness was not associated with COVID-19 mortality in all counties; however, it was protective in counties with high percentages of Black residents, high median home value, and higher population density. Discussion: Exposures to NDVI had beneficial impacts on county-level incidence of COVID-19 in the US and may have reduced county-level COVID-19 mortality rates, especially in densely populated counties.