Miracle-dz/UniFAR-FTUs huggingface dataset:
A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models

These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib. PARP inhibitors are approved for treatment of cancers with BRCA1 or BRCA2 defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG40kDa carrier via a β-eliminative releasable linker. A single injection of the PEG∼TLZ conjugate was as effective as ∼30 daily oral doses of TLZ in growth suppression of homologous recombination-defective tumors in mouse xenografts. These included the KT-10 Wilms' tumor with a PALB2 mutation, the BRCA1-deficient MX-1 triple-negative breast cancer, and the BRCA2-deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type BRCA2. Although the half-life of PEG∼TLZ and released TLZ in the mouse was only ∼1 day, the exposure of released TLZ from a single safe, effective dose of the prodrug exceeded that of oral TLZ given daily over one month. μPET/CT imaging showed high uptake and prolonged retention of an 89Zr-labeled surrogate of PEG∼TLZ in the MX-1 BRCA1-deficient tumor. These data suggest that the long-lasting antitumor effect of the prodrug is due to a combination of its long t1/2, the high exposure of TLZ released from the prodrug, increased tumor sensitivity upon continued exposure, and tumor accumulation. Using pharmacokinetic parameters of TLZ in humans, we designed a long-acting PEG∼TLZ for humans that may be superior in efficacy to daily oral TLZ and would be useful for treatment of PARP inhibitor-sensitive cancers in which oral medications are not tolerated. Significance: These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib.
Asymmetric gene flow causes cascading reproductive isolation

The interplay between hybridization and reproductive isolation is critical to the origin and maintenance of species. Hybridization between species is known to affect reproductive barrier strength. An extension of this relationship is the expectation that asymmetric hybridization and gene flow will have asymmetric effects on reproductive barrier strength. We tested this hypothesis in a pair of morning glory species which exhibit asymmetric gene flow in sympatry from highly selfing Ipomoea lacunosa into mixed mating I. cordatotriloba. Because of the direction of hybridization, we predicted that reproductive barrier strength would change to a greater extent in I. cordatotriloba than I. lacunosa. We tested this prediction by measuring the strength of a barrier to seed set between these species across their ranges. Consistent with our prediction, we found that sympatric I. cordatotriloba was more compatible with range-wide I. lacunosa than allopatric I. cordatotriloba, whereas sympatric and allopatric I. lacunosa were equally compatible with I. cordatotriloba. This difference likely reflects an asymmetric decrease in reproductive barriers in sympatric I. cordatotriloba. We further demonstrated that changes to sympatric I. cordatotriloba have decreased compatibility with allopatric populations. Thus, introgression associated with asymmetric hybridization not only influences between-species isolation but also contributes to isolation within a species in a manner analogous to cascade reinforcement.
PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth

Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. Here, we demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with increased PI3K/Akt activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/Akt activation. Mutation of Y180F strongly attenuated mouse xenograft tumor growth. An accompanying paper demonstrates altered metabolism, mutation incidence, and epigenetic status in these cells, indicating that PGRMC1 phosphorylation strongly influences cancer biology.
Recent advances in the personalized treatment of estrogen receptor-positive breast cancer with tamoxifen: a focus on pharmacogenomics

ABSTRACT Introduction: Tamoxifen is still an important drug in hormone-dependent breast cancer therapy. Personalization of its clinical use beyond hormone receptor positivity could improve the substantial variability of the treatment response. Areas covered: The overview of the current evidence for the treatment personalization using therapeutic drug monitoring, or using genetic biomarkers including CYP2D6 is provided. Although many studies focused on the PK aspects or the impact of CYP2D6 variability the translation into clinical routine is not clearly defined due to the inconsistent clinical outcome data. Expert opinion: We believe that at least the main candidate factors, i.e. CYP2D6 polymorphism, CYP2D6 inhibition, endoxifen serum levels may become important predictors of clinical relevance for tamoxifen treatment personalization in the future. To achieve this aim, however, further research should take into consideration more precise characterization of the disease, epigenetic factors and also utilize an appropriately powered multifactorial approach instead of a single gene evaluating studies.
Improvement of Component Flux Estimating Model for Pervaporation Processes

Separating non-ideal mixtures by pervaporation (hence PV) is a competitive alternative to most traditional methods, such as distillation, which are based on the vapour–liquid equilibrium (VLE). It must be said, in many cases, accurate VLE data are already well known in the literature. They make the method of PV modelling a lot more complicated, and most of the viable models are (semi)empirical and focus on component flux (Ji) estimation. The pervaporation model of Mizsey and Valentinyi, which is based on Rautenbach’s works, is further improved in this work and tested rigorously by statistical means. Until now, this type of exponential modelling was only used for alcohol–water mixtures, but in this work, it was extended to an ethyl acetate–water binary mixture as well. Furthermore, a flowchart of modelling is presented for the first time in the case of an exponential pervaporation model. The results of laboratory-scale experiments were used as the basis of the study and least squares approximation was used to compare them to the different model’s estimations. According to our results, Valentinyi’s model (Model I) and the alternative model (Model III) appear to be the best methods for PV modelling, and there is no significant difference between the models, mainly in organophilic cases. In the case of the permeation component, Model I, which better follows the exponential function, is recommended. It is important to emphasize that our research confirms that the exponential type model seems to be universally feasible for most organic–water binary mixtures. Another novelty of the work is that after PDMS and PVA-based membranes, the accuracy of the semiempirical model for the description of water flux on a PEBA-based membrane was also proved, in the organophilic case.
Genomic Analysis of CTX-M-Group-1-Producing Extraintestinal Pathogenic E. coli (ExPEc) from Patients with Urinary Tract Infections (UTI) from Colombia

Background: The dissemination of the uropathogenic O25b-ST131 Escherichia coli clone constitutes a threat to public health. We aimed to determine the circulation of E. coli strains belonging to O25b:H4-B2-ST131 and the H30-Rx epidemic subclone causing hospital and community-acquired urinary tract infections (UTI) in Colombia. Methods: Twenty-six nonduplicate, CTX-M group-1-producing isolates causing UTI in the hospital and community were selected for this study. Results: Twenty-two E. coli isolates harboring CTX-M-15, one CTX-M-3, and three CTX-M-55 were identified. Multilocus Sequence Typing (MLST) showed a variety of sequence types (STs), among which, ST131, ST405, and ST648 were reported as epidemic clones. All the E. coli ST131 sequences carried CTX-M-15, from which 80% belonged to the O25b:H4-B2 and H30-Rx pandemic subclones and were associated with virulence factors iss, iha, and sat. E. coli isolates (23/26) were resistant to ciprofloxacin and associated with amino acid substitutions in quinolone resistance-determining regions (QRDR). We detected two carbapenem-resistant E. coli isolates, one coproducing CTX-M-15, KPC-2, and NDM-1 while the other presented mutations in ompC. Additionally, one isolate harbored the gene mcr-1. Conclusions: Our study revealed the circulation of the E. coli ST131, O25b:H4-B2-H30-Rx subclone, harboring CTX-M-15, QRDR mutations, and other resistant genes. The association of the H30-Rx subclone with sepsis and rapid dissemination warrants attention from the public health and infections control.
Integrating Biosignals Measurement in Virtual Reality Environments for Anxiety Detection

This paper proposes a protocol for the acquisition and processing of biophysical signals in virtual reality applications, particularly in phobia therapy experiments. This protocol aims to ensure that the measurement and processing phases are performed effectively, to obtain clean data that can be used to estimate the users’ anxiety levels. The protocol has been designed after analyzing the experimental data of seven subjects who have been exposed to heights in a virtual reality environment. The subjects’ level of anxiety has been estimated based on the real-time evaluation of a nonlinear function that has as parameters various features extracted from the biophysical signals. The highest classification accuracy was obtained using a combination of seven heart rate and electrodermal activity features in the time domain and frequency domain.
Controversy over smoking in COVID‐19—A real world experience in New York city

Data are conflicting regarding the impact of tobacco smoking in people with pneumonia due to SARS‐CoV‐2 infection (COVID‐19). We performed a retrospective multicentre cohort study of 9991 consecutive patients hospitalized in a major New York academic center between March 7th and June 5th, 2020 with laboratory‐confirmed COVID‐19. The clinical outcomes assessed included risk of hospitalization, in‐hospital mortality, risk of intensive care unit (ICU) admission, and need for mechanical ventilation among smokers (current and former). Multivariable logistic regression and propensity score models were built to adjust for potential confounders. Among 9991 consecutive patients diagnosed with COVID‐19, 2212 (22.1%) patients were self‐reported smokers (406 current and 1806 former). Current smoking was not associated with an increased risk of hospitalization (propensity score [PS]‐adjusted OR 0.91; p = .46), in‐hospital mortality (PS‐OR 0.77; p = .12), ICU admission (PS‐OR 1.18; p = .37), or intubation (PS‐OR 1.04; p = .85). Similarly, former smoking was not associated with an increased risk of hospitalization (PS‐OR 0.88; p = .11), in‐hospital mortality (PS‐OR 1.03; p = .78), ICU admission (PS‐OR 1.03; p = .95), or intubation (PS‐OR 0.93; p = .57). Furthermore, smoking (current or former) was not associated with an increased risk of hospitalization (PS‐OR 0.85; p = .05), in‐hospital mortality (PS‐OR 0.94; p = .49), ICU admission (PS‐OR 0.86; p = .17), or intubation (PS‐OR 0.79; p = .06). Smoking is a well‐known risk factor associated with greater susceptibility and subsequent increased severity of respiratory infections. In the current COVID‐19 pandemic, smokers may have increased risk and severe pneumonia. In the current COVID‐19 pandemic, smokers are believed to have an increased risk of mortality as well as severe pneumonia. However, in our analysis of real‐world clinical data, smoking was not associated with increased in‐patient mortality in COVID‐19 pneumonia, in accordance with prior reports.
Metabolic risk factors and risk of Covid-19: A systematic review and meta-analysis

Objective Based on the epidemiologic findings of Covid-19 incidence; illness and mortality seem to be associated with metabolic risk factors. This systematic review and meta-analysis aimed to assess the association of metabolic risk factors and risk of Covid-19. Methods This study was designed according to PRISMA guidelines. Two independent researchers searched for the relevant studies using PubMed, Web of Science, Cochrane Library, and Scopus. The search terms developed focusing on two main roots of “Covid-19” and “metabolic risk factors”. All relevant observational, analytical studies, review articles, and a meta-analysis on the adult population were included in this meta-analysis. Meta-analysis was performed using the random effect model for pooling proportions to address heterogeneity among studies. Data were analyzed using STATA package version 11.2, (StataCorp, USA). Results Through a comprehensive systematic search in the targeted databases we found 1124 papers, after running the proses of refining, 13 studies were included in the present meta-analysis. The pooled prevalence of obesity in Covid-19 patients was 29% (95% CI: 14–47%). For Diabetes and Hypertension, these were 22% (95% CI: 12% 33%) and 32% (95% CI: 12% 56%), respectively. There was significant heterogeneity in the estimates of the three pooled prevalence without any significant small-study effects. Such warning points, to some extent, guide physicians and clinicians to better understand the importance of controlling co-morbid risk factors in prioritizing resource allocation and interventions. Conclusion The meta-analysis showed that hypertension is more prevalent than obesity and diabetes in patients with Covid-19 disease. The prevalence of co-morbid metabolic risk factors must be adopted for better management and priority settings of public health vaccination and other required interventions. The results may help to improve services delivery in COVID-19 patients, while helping to develop better policies for prevention and response to COVID-19 and its critical outcomes.
Characterization of the IL-17 and CD4+ Th17 Cells in the Clinical Course of Dengue Virus Infections

The aims of this study were to determine the involvement of interleukin 17 (IL-17) and IL-17-producing cells in dengue pathogenesis. Blood samples from dengue virus (DENV)-infected patients were collected on different days after the onset of symptoms. Patients were classified according to 1997 World Health Organization guidelines. Our study examined 152 blood samples from dengue fever (DF, n = 109) and dengue hemorrhagic fever (DHF, n = 43) patients and 90 blood samples from healthy controls (HC). High serum concentrations of IL-17A and IL-22 were also associated with DHF (IL-17A [DHF vs. DF, p < 0.01; DHF vs. HC, p < 0.0001]; IL-22 [DHF vs. DF, p < 0.05; DHF vs. HC, p < 0.0001]). Moreover, there was a positive correlation between serum levels of IL-17A and IL-23, a key cytokine that promotes IL-17-based immune responses (r = 0.4089, p < 0.0001). Consistent with the IL-17-biased immune response in DHF patients, we performed ex vivo activation of peripheral blood mononuclear cells (PBMCs) from DHF patients and flow cytometry analysis showed a robust IL-17-biased immune response, characterized by a high frequency of CD4+IL-17+ producing cells. Our results suggests IL-17-producing cells and their related cytokines can play a prominent role in this viral disease.
Chironomus riparius Proteome Responses to Spinosad Exposure

The potential of proteome responses as early-warning indicators of insecticide exposure was evaluated using the non-biting midge Chironomus riparius (Meigen) as the model organism. Chironomus riparius larvae were exposed to environmentally relevant concentrations of the neurotoxic pesticide spinosad to uncover molecular events that may provide insights on the long-term individual and population level consequences. The iTRAQ labeling method was performed to quantify protein abundance changes between exposed and non-exposed organisms. Data analysis revealed a general dose-dependent decrease in the abundance of globin proteins as a result of spinosad exposure. Additionally, the downregulation of actin and a larval cuticle protein was also observed after spinosad exposure, which may be related to previously determined C. riparius life-history traits impairment and biochemical responses. Present results suggest that protein profile changes can be used as early warning biomarkers of pesticide exposure and may provide a better mechanistic interpretation of the toxic response of organisms, aiding in the assessment of the ecological effects of environmental contamination. This work also contributes to the understanding of the sublethal effects of insecticides in invertebrates and their molecular targets.
Dietary pattern and risk of endometrioma in Korean women: a case-control study

Objective The aim of this study was to investigate and compare the dietary patterns of Korean women diagnosed with endometrioma or other benign ovarian cysts. Methods A total of 66 patients, comprising 39 patients who were surgically diagnosed with ovarian endometrioma and 27 control patients with other benign ovarian cysts, were included in this case-control study. Trained interviewers identified and interviewed the case patients and controls on the day before the laparoscopic ovarian surgery, using a semiquantitative food frequency questionnaire developed by the Ministry of Health and Welfare of Korea. Statistical analysis was performed using the Wilcoxon sum-rank test for continuous variables and the χ2 test or Fisher’s exact test for categorical variables. Results The calcium intake from daily food consumption was significantly lower in patients with endometrioma than in those with other benign ovarian cysts. The dietary intakes of vitamin D, iron, and zinc were also relatively lower in patients with endometrioma than in patients with other benign ovarian cysts, although they did not reach the statistical significance threshold. Conclusion The risk of endometrioma is significantly associated with a lower dietary intake of calcium. Future studies including a larger number of patients on a nationwide scale are urgently required for further clarification.
Impact of low bone mass and antiresorptive therapy on antibiotic efficacy in a rat model of orthopedic device‐related infection

A significant proportion of orthopedic devices are implanted in osteoporotic patients, but it is currently unclear how estrogen deficiency and/or exposure to antiresorptive bisphosphonates (BPs) influence orthopedic device‐related infection (ODRI), or response to therapy. The aim of this study is to characterize the bone changes resulting from Staphylococcus epidermidis infection in a rodent ODRI model and to determine if ovariectomy (OVX) or BP treatment influences the infection or the success of antibiotic therapy. A sterile or S. epidermidis‐contaminated screw was implanted into the proximal tibia of skeletally mature female Wistar rats (n = 6–9 per group). Bone changes were monitored over 28 days using in vivo micro‐computed tomography scanning. OVX was performed 12 weeks before screw implantation. The BP zoledronic acid (ZOL) was administered 4 days before screw insertion. A combination antibiotic regimen (rifampin plus cefazolin) was administered from Days 7–21. In skeletally healthy animals, S. epidermidis induced marked changes in bone, with peak osteolysis occurring at Day 9 and woven bone deposition and periosteal mineralization from Day 14 onwards. Antibiotic therapy cleared the infection in the majority of animals (2/9 infected) but did not affect bone responses. OVX did not affect the pattern of infection‐induced changes in bone, nor bacterial load, but reduced antibiotic efficacy (5/9 infected). ZOL treatment did not protect from osteolysis in OVX animals, or further affect antibiotic efficacy (5/9 infected) but did significantly increase the bacterial load. This study suggests that both BPs and OVX can influence host responses to bone infections involving S. epidermidis.
Exposure to Zoonotic West Nile Virus in Long-Tailed Macaques and Bats in Peninsular Malaysia

Simple Summary The role of wildlife animals, such as macaques and bats, in the spreading and maintenance of deadly zoonotic pathogens in nature are documented in several studies. The present study substantially highlights the first evidence of West Nile Virus (WNV) infection, a mosquito borne virus in the Malaysian macaques and bats. Of the 81 macaques sampled, 24 of the long-tailed macaques were seropositive to WNV, indicating that they were exposed to the virus in the past. The long-tailed macaques were found in the mangrove forests located in the Central, Southern, and West Peninsular Malaysia. Meanwhile, five out of 41 bats (Lesser Short-nosed Fruit Bats, Lesser Sheath-tailed Bats, and Thai Horseshoe Bats) that were found in the caves from Northern Peninsular Malaysia showed susceptibility to WNV. Therefore, a constant bio surveillance of WNV in the wildlife in Malaysia is a proactive attempt. This study was aligned with the Malaysian government’s mission under the Malaysia Strategy for Emerging Diseases and Public Health Emergencies (MYSED) II (2017–2021) and the Ministry of Health priorities in order to enhance the regional capability to rapidly and accurately survey, detect, diagnose, and report outbreaks of pathogens and diseases of security concern. Abstract The role of wildlife such as wild birds, macaques, and bats in the spreading and maintenance of deadly zoonotic pathogens in nature have been well documented in many parts of the world. One such pathogen is the mosquitoes borne virus, namely the West Nile Virus (WNV). Previous research has shown that 1:7 and 1:6 Malaysian wild birds are WNV antibody and RNA positive, respectively, and bats in North America may not be susceptible to the WNV infection. This study was conducted to determine the status of WNV in Malaysian macaques and bats found in mangrove forests and caves, respectively. Archive sera and oropharyngeal swabs from long-tailed macaques were subjected to the antibody detection using WNV competitive enzyme-linked immunosorbent assay (c-ELISA) and WNV RNA using RT-PCR, respectively, while the archive oropharyngeal and rectal swabs from bats were subjected to RT-PCR without serological analysis due to the unavailability of serum samples. The analysis revealed a WNV seropositivity of 29.63% (24/81) and none of the macaques were positive for WNV RNA. Meanwhile, 12.2% (5/41) of the bats from Pteropodidae, Emballonuridae, and Rhinolophidae families tested positive for WNV RNA. Here, we show a high WNV antibody prevalence in macaques and a moderate WNV RNA in various Malaysian bat species, suggesting that WNV circulates through Malaysian wild animals and Malaysian bat species may be susceptible to the WNV infection.