Miracle-dz/UniFAR-FTUs huggingface dataset:
Ways into Understanding HIF Inhibition

Simple Summary Cancer cells adapt to hypoxia, survive, and grow. To that aim, they engage hypoxia-inducible pathways. These pathways are under intense investigation in search of new therapies to interfere with signaling components to kill cancer cells. Nowadays, new technologies enable more in-depth studies of hypoxia-induced signaling including protein–protein interaction and transcriptional processes, as well as the mode of action of different inhibitors. In this review, we give insight into useful techniques for studying the components of the hypoxia-inducible pathway and current inhibitors. Abstract Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.
Empathy and COVID-19: Study in Professionals and Students of the Social Health Field in Ecuador

Empathy plays a fundamental role in health related occupations. In this study, we analysed empathy levels in professionals (117) and students (170) from various healthcare fields in Ecuador during the COVID-19 pandemic. The Interpersonal Reactivity Index was used in an online survey. The results show high levels of empathy in both groups, influenced by age and gender. The students presented higher levels of personal distress, and their age was negatively correlated to empathy. Additionally, professionals working in physical health scored higher levels of personal distress compared to those in the field of emotional health. COVID-19 has placed social health systems in great stress. Despite this, the personal capacities for empathy of both students and health professionals have not been diminished.
Concentrations and chemical forms of heavy metals in urban soils of Shanghai, China

Abstract The influence of previous irrigation of sewage water from industry and daily life on the concentrations and chemical forms of heavy metals in soils was examined in Xijia Village, Pudong District, Shanghai, China. Soil samples were taken from three regions in the upland fields that varied in distance from the abandoned open canal. To understand the background levels of heavy metals in the agricultural soils in Pudong District, soils under different land use (upland fields, greenhouses and orchards) were sampled as references from four localities with no history of sewage water irrigation. Analyses of total amounts of Cr, Mn, Ni, Cu, Zn, As, Pb, Cd and Hg indicated that the amounts in the soils from the sewage irrigated field were markedly higher than the background levels. In particular, the total amounts of Cd and Zn in the soil at distances of 2 m and 10 m from the canal exceeded the permissible value set by the Chinese Environmental Quality Standard (GB 15618–1995). Although the contamination showed a trend of decreasing with increasing distance from the canal, the total amount of Cd was still higher than the permissible value 20 m from the canal. The chemical forms of Zn and Cd in the soils taken from Xijia Village and the reference upland soils were then evaluated using a sequential extraction method. In the case of the soils 2 m and 10 m from the canal, the highest amounts of Zn and Cd were found to indicate an occlusion in Fe oxides and retention by the clay exchange sites of the soils. Based on these results, it was recommended not to use these sewage irrigated fields in Xijia Village for agricultural purposes unless the necessary remediation measures were taken to lower the heavy metal concentrations to safe levels.
Using an Interaction Parameter in Model-Based Phase I Trials for Combination Treatments? A Simulation Study

There is growing interest in Phase I dose-finding studies studying several doses of more than one agent simultaneously. A number of combination dose-finding designs were recently proposed to guide escalation/de-escalation decisions during the trials. The majority of these proposals are model-based: a parametric combination-toxicity relationship is fitted as data accumulates. Various parameter shapes were considered but the unifying theme for many of these is that typically between 4 and 6 parameters are to be estimated. While more parameters allow for more flexible modelling of the combination-toxicity relationship, this is a challenging estimation problem given the typically small sample size in Phase I trials of between 20 and 60 patients. These concerns gave raise to an ongoing debate whether including more parameters into combination-toxicity model leads to more accurate combination selection. In this work, we extensively study two variants of a 4-parameter logistic model with reduced number of parameters to investigate the effect of modelling assumptions. A framework to calibrate the prior distributions for a given parametric model is proposed to allow for fair comparisons. Via a comprehensive simulation study, we have found that the inclusion of the interaction parameter between two compounds does not provide any benefit in terms of the accuracy of selection, on average, but is found to result in fewer patients allocated to the target combination during the trial.
Mechanisms of Resistance to KRASG12C Inhibitors

Simple Summary KRAS is a gene that is commonly mutated in cancer, especially in pancreatic, lung and colorectal cancers. Despite its importance, scientists have for many years been unable to create a drug that can inhibit function of the KRAS protein. Recently, several drugs have been created that can inhibit the function of KRAS proteins that have a “G12C” mutation. There is hope that these G12C inhibitors will be useful for treating cancer in patients who have this mutation. In this review we discuss the problems that we may encounter with these drugs, especially the development of drug resistance to G12C inhibitors, and the approaches that we could use to overcome this. Abstract KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of “undruggable”. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.
Potentially Modifiable Factors Associated with Adherence to Adjuvant Endocrine Therapy among Breast Cancer Survivors: A Systematic Review

Simple Summary Endocrine therapy taken after primary breast cancer treatment helps prevent breast cancer recurrence. However, many women are unable to adhere to endocrine therapy. This review examines potentially modifiable factors that are associated with endocrine therapy adherence, which might help future efforts to improve endocrine therapy use. Six categories of factors were identified: side effects, attitudes toward endocrine therapy, psychological factors, healthcare provider-related factors, sociocultural factors, and general or quality of life factors. Overall, self-efficacy (i.e., one’s belief in their ability to do something) and positive decisional balance (i.e., one’s belief that the benefits of endocrine therapy outweigh the risks) were the most consistently associated with adherence. They might represent factors worth investigating in future studies seeking to support the adherence of breast cancer survivors. Abstract Adjuvant endocrine therapy (AET) reduces risk of breast cancer recurrence. However, suboptimal adherence and persistence to AET remain important clinical issues. Understanding factors associated with adherence may help inform efforts to improve use of AET as prescribed. The present systematic review examined potentially modifiable factors associated with adherence to AET in accordance with PRISMA guidelines (PROSPERO registration ID: CRD42019124200). All studies were included, whether factors were significantly associated with adherence or results were null. This review also accounted for the frequency with which a potentially modifiable factor was examined and whether univariate or multivariate models were used. This review also examined whether methodological or sample characteristics were associated with the likelihood of a factor being associated with AET adherence. A total of 68 articles were included. Potentially modifiable factors were grouped into six categories: side effects, attitudes toward AET, psychological factors, healthcare provider-related factors, sociocultural factors, and general/quality of life factors. Side effects were less likely to be associated with adherence in studies with retrospective or cross-sectional than prospective designs. Self-efficacy (psychological factor) and positive decisional balance (attitude toward AET) were the only potentially modifiable factors examined ≥10 times and associated with adherence or persistence ≥75% of the time in both univariate and multivariate models. Self-efficacy and decisional balance (i.e., weight of pros vs. cons) were the potentially modifiable factors most consistently associated with adherence, and hence may be worth focusing on as targets for interventions to improve AET adherence among breast cancer survivors.
Temporomandibular Joint Osteoarthritis: Regenerative Treatment by a Stem Cell Containing Advanced Therapy Medicinal Product (ATMP)—An In Vivo Animal Trial

Temporomandibular joint osteoarthritis (TMJ-OA) is a chronic degenerative disease that is often characterized by progressive impairment of the temporomandibular functional unit. The aim of this randomized controlled animal trial was a comparative analysis regarding the chondroregenerative potency of intra-articular stem/stromal cell therapy. Four weeks after combined mechanical and biochemical osteoarthritis induction in 28 rabbits, therapy was initiated by a single intra-articular injection, randomized into the following groups: Group 1: AB Serum (ABS); Group 2: Hyaluronic acid (HA); Group 3: Mesenchymal stromal cells (STx.); Group 4: Mesenchymal stromal cells in hyaluronic acid (HA + STx.). After another 4 weeks, the animals were euthanized, followed by histological examination of the removed joints. The histological analysis showed a significant increase in cartilage thickness in the stromal cell treated groups (HA + STx. vs. ABS, p = 0.028; HA + ST.x vs. HA, p = 0.042; STx. vs. ABS, p = 0.036). Scanning electron microscopy detected a similar heterogeneity of mineralization and tissue porosity in the subchondral zone in all groups. The single intra-articular injection of a stem cell containing, GMP-compliant advanced therapy medicinal product for the treatment of iatrogen induced osteoarthritis of the temporomandibular joint shows a chondroregenerative effect.
Lyophilized Polyvinylpyrrolidone Hydrogel for Culture of Human Oral Mucosa Stem Cells

This work shows the synthesis of a polyvinylpyrrolidone (PVP) hydrogel by heat-activated polymerization and explores the production of hydrogels with an open porous network by lyophilisation to allow the three-dimensional culture of human oral mucosa stem cells (hOMSCs). The swollen hydrogel showed a storage modulus similar to oral mucosa and elastic solid rheological behaviour without sol transition. A comprehensive characterization of porosity by scanning electron microscopy, mercury intrusion porosimetry and nano-computed tomography (with spatial resolution below 1 μm) showed that lyophilisation resulted in the heterogeneous incorporation of closed oval-like pores in the hydrogel with broad size distribution (5 to 180 μm, d50 = 65 μm). Human oral mucosa biopsies were used to isolate hOMSCs, expressing typical markers of mesenchymal stem cells in more than 95% of the cell population. Direct contact cytotoxicity assay demonstrated that PVP hydrogel have no negative effect on cell metabolic activity, allowing the culture of hOMSCs with normal fusiform morphology. Pore connectivity should be improved in future to allow cell growth in the bulk of the PVP hydrogel.
STAT3 Is an Upstream Regulator of Granzyme G in the Maternal-To-Zygotic Transition of Mouse Embryos

The maternal-to-zygotic transition (MZT), which controls maternal signaling to synthesize zygotic gene products, promotes the preimplantation development of mouse zygotes to the two-cell stage. Our previous study reported that mouse granzyme g (Gzmg), a serine-type protease, is required for the MZT. In this study, we further identified the maternal factors that regulate the Gzmg promoter activity in the zygote to the two-cell stage of mouse embryos. A full-length Gzmg promoter from mouse genomic DNA, FL-pGzmg (−1696~+28 nt), was cloned, and four deletion constructs of this Gzmg promoter, Δ1-pGzmg (−1369~+28 nt), Δ2-pGzmg (−939~+28 nt), Δ3-pGzmg (−711~+28 nt) and Δ4-pGzmg (−417~+28 nt), were subsequently generated. Different-sized Gzmg promoters were used to perform promoter assays of mouse zygotes and two-cell stage embryos. The results showed that Δ4-pGzmg promoted the highest expression level of the enhanced green fluorescent protein (EGFP) reporter in the zygotes and two-cell embryos. The data suggested that time-specific transcription factors upregulated Gzmg by binding cis-elements in the −417~+28-nt Gzmg promoter region. According to the results of the promoter assay, the transcription factor binding sites were predicted and analyzed with the JASPAR database, and two transcription factors, signal transducer and activator of transcription 3 (STAT3) and GA-binding protein alpha (GABPα), were identified. Furthermore, STAT3 and GABPα are expressed and located in zygote pronuclei and two-cell nuclei were confirmed by immunofluorescence staining; however, only STAT3 was recruited to the mouse zygote pronuclei and two-cell nuclei injected with the Δ4-pGzmg reporter construct. These data indicated that STAT3 is a maternal transcription factor and may upregulate Gzmg to promote the MZT. Furthermore, treatment with a STAT3 inhibitor, S3I-201, caused mouse embryonic arrest at the zygote and two-cell stages. These results suggest that STAT3, a maternal protein, is a critical transcription factor and regulates Gzmg transcription activity in preimplantation mouse embryos. It plays an important role in the maternal-to-zygotic transition during early embryonic development.
Topological, Mechanical and Biological Properties of Ti6Al4V Scaffolds for Bone Tissue Regeneration Fabricated with Reused Powders via Electron Beam Melting

Cellularized scaffold is emerging as the preferred solution for tissue regeneration and restoration of damaged functionalities. However, the high cost of preclinical studies creates a gap between investigation and the device market for the biomedical industry. In this work, bone-tailored scaffolds based on the Ti6Al4V alloy manufactured by electron beam melting (EBM) technology with reused powder were investigated, aiming to overcome issues connected to the high cost of preclinical studies. Two different elementary unit cell scaffold geometries, namely diamond (DO) and rhombic dodecahedron (RD), were adopted, while surface functionalization was performed by coating scaffolds with single layers of polycaprolactone (PCL) or with mixture of polycaprolactone and 20 wt. % hydroxyapatite (PCL/HA). The mechanical and biological performances of the produced scaffolds were investigated, and the results were compared to software simulation and experimental evidence available in literature. Good mechanical properties and a favorable environment for cell growth were obtained for all combinations of scaffold geometry and surface functionalization. In conclusion, powder recycling provides a viable practice for the biomedical industry to strongly reduce preclinical costs without altering biomechanical performance.
Postponed Dental Appointments Due to Costs Are Associated with Increased Loneliness—Evidence from the Survey of Health, Ageing and Retirement in Europe

As is already well known, demographic changes will presumably lead to a rising number of old aged individuals and loneliness is a tremendous concern in aging populations. Poor health can be a potential consequence of loneliness, as well as a determining factor. Thus, the objective of the current study was to determine whether postponed dental appointments due to costs affect loneliness longitudinally. Focusing on Germany, data from two waves (waves 5 and 6) of the “Survey of Health Ageing, and Retirement in Europe” (SHARE) were analyzed (n = 7703). The three-item loneliness scale (modified version of the revised UCLA Loneliness scale) was used to quantify loneliness. The presence of postponed dental appointments due to costs in the past 12 months (no; yes) served as a key independent variable. Socioeconomic factors as well as health-related factors were adjusted in the longitudinal regression analysis. After adjusting for confounding variables, regression analyses revealed that loneliness increased with decreases in self-rated health among men. Among women, loneliness increased when self-rated health decreased, when fewer chronic diseases and postponed dental appointments due to costs were reported. Among older women, postponed dental appointments due to costs are associated with feelings of loneliness. The study results add evidence that proper dental care (i.e., regular and appropriate visits to the dentist) is vital not only to one’s oral health, but also plays a role in one’s physical and emotional health.
Interrogating Plant-Microbe Interactions with Chemical Tools: Click Chemistry Reagents for Metabolic Labeling and Activity-Based Probes

Continued expansion of the chemical biology toolbox presents many new and diverse opportunities to interrogate the fundamental molecular mechanisms driving complex plant–microbe interactions. This review will examine metabolic labeling with click chemistry reagents and activity-based probes for investigating the impacts of plant-associated microbes on plant growth, metabolism, and immune responses. While the majority of the studies reviewed here used chemical biology approaches to examine the effects of pathogens on plants, chemical biology will also be invaluable in future efforts to investigate mutualistic associations between beneficial microbes and their plant hosts.
Influence of Body Composition on Post-Exercise Parasympathetic Reactivation of Firefighter Recruits

Firefighters have a sustained risk for experiencing a sudden cardiac event after completing a fire call. Heart rate recovery (HRR) can be utilized to characterize autonomic nervous system (ANS) recovery and has been linked to cardiac events. Research suggests that body composition influences post-exercise HRR responses in non-firefighter populations. The purpose of this study was to examine the influence of body mass index (BMI), waist circumference (WC), and percent body fat (BF) on the HRR response of firefighter recruits. BMI (kg·m−2), WC (cm), and BF (%) data from 57 firefighter recruits were collected. HRR (b·min−1) data were collected at completion (HR0), as well as 15 (HR15), 30 (HR30), 45 (HR45), 60 (HR60), 120 (HR120), and 180 (HR180) seconds following a submaximal step test, and commonly utilized clinical HRR indices were calculated (ΔHRR30, ΔHRR60, ΔHRR120, and ΔHRR180). After controlling for sex, linear mixed regression models did not identify significant interactions between body composition (ps > 0.05) and HRR response across time. However, significant (ps < 0.05) indirect semi-partial correlations were identified between BF and ΔHRR30 (rsp = −0.31) and ΔHRR60 (rsp = −0.27), respectively. Reducing overall BF (vs. BMI or WC) should be prioritized to improve the post-exercise ANS recovery of firefighter recruits.
Co-Overexpression of TWIST1-CSF1 Is a Common Event in Metastatic Oral Cancer and Drives Biologically Aggressive Phenotype

Simple Summary There is clinical evidence that ulcerated and inflammatory cell-infiltrated oral cancer is frequently associated with early metastases. Our results from genomic screening in patients with metastatic oral cancer identified specific changes in genes that regulate macrophage chemotaxis and drive tumor progression. This opens up potential therapeutic opportunities toward personalized medicine tailored to manage patients with advanced disease. Abstract Invasive oral squamous cell carcinoma (OSCC) is often ulcerated and heavily infiltrated by pro-inflammatory cells. We conducted a genome-wide profiling of tissues from OSCC patients (early versus advanced stages) with 10 years follow-up. Co-amplification and co-overexpression of TWIST1, a transcriptional activator of epithelial-mesenchymal-transition (EMT), and colony-stimulating factor-1 (CSF1), a major chemotactic agent for tumor-associated macrophages (TAMs), were observed in metastatic OSCC cases. The overexpression of these markers strongly predicted poor patient survival (log-rank test, p = 0.0035 and p = 0.0219). Protein analysis confirmed the enhanced expression of TWIST1 and CSF1 in metastatic tissues. In preclinical models using OSCC cell lines, macrophages, and an in vivo matrigel plug assay, we demonstrated that TWIST1 gene overexpression induces the activation of CSF1 while TWIST1 gene silencing down-regulates CSF1 preventing OSCC invasion. Furthermore, excessive macrophage activation and polarization was observed in co-culture system involving OSCC cells overexpressing TWIST1. In summary, this study provides insight into the cooperation between TWIST1 transcription factor and CSF1 to promote OSCC invasiveness and opens up the potential therapeutic utility of currently developed antibodies and small molecules targeting cancer-associated macrophages.
Advances in negative Poisson's ratio materials

Poisson’s ratio is defined as the lateral contraction strain in a solid divided by the longitudinal extension strain measured in a simple tension experiment. In almost all materials Poisson’s ratio, usually denoted by v, is positive. For isotropic materials (those in which the properties are independent of direction), energy arguments in the theory of elasticity[’] may be used to show that 1 2 v I 112. The relationship between shear modulus G, bulk modulus K, and Poisson’s ratio v for isotropic materials is given by Equation (1).