Machine Learning Model for Anesthetic Risk Stratification for Gynecologic and Obstetric Patients: A Novel Approach for Early Detection.

BACKGROUND: Preoperative evaluation is important, our study explored the application of machine learning methods for anesthetic risk classification and for the evaluation of the contributions of various factors. To minimize the effects of confounding variables during model training, we used a homogenous group with similar physiological states and ages undergoing similar pelvic organ-related procedures not involving malignancies. OBJECTIVE: Data on women of reproductive age (age = 20-50 years) who underwent gestational or gynecological surgery between January 1, 2017, and December 31, 2021, were obtained from the National Taiwan University Hospital Integrated Medical Database. METHODS: We first performed an exploratory analysis and selected key features. We then performed data preprocessing to acquire relevant features related to preoperative examination. To further enhance predictive performance, we employed the log likelihood ratio algorithm to generate comorbidity patterns. Lastly, we input the processed features into the light gradient boosting machine (LightGBM) model for training and subsequent prediction. RESULTS: A total of 10,892 patients were included. Within this data set, 9893 patients were classified as having low anesthetic risk (American Society of Anesthesiologists physical status score 1-2), and 999 patients were classified as having high anesthetic risk (American Society of Anesthesiologists physical status score > 2). The area under the receiver operating characteristic curve of the LightGBM model was 90.25. CONCLUSIONS: By combining comorbidity information and clinical laboratory data, our methodology based on the LightGBM model provides more accurate predictions for anesthetic risk classification. CLINICALTRIAL: This study was registered with the Research Ethics Committee of the National Taiwan University Hospital with trial number 202204010RINB.

Genomic characterization of Escherichia coli harbor a polyketide synthase ( pks ) island associated with colorectal cancer (CRC) development.

The E. coli strain harboring the polyketide synthase ( Pks) island encodes the genotoxin colibactin, a secondary metabolite reported to have severe implications for human health and for the progression of colorectal cancer. The present study involved whole-genome-wide comparison and phylogenetic analysis of pks harboring E. coli isolates to gain insight into the distribution and evolution of these organism. Fifteen E. coli strains isolated from patients with ulcerative colitis were sequenced, 13 of which harbored pks islands. In addition, 2,654 genomes from the public database were also screened for pks harboring E. coli genomes, 158 of which were pks -positive isolates. Whole-genome-wide comparison and phylogenetic analysis revealed that 171 (158+13) pks -positive isolates belonged to phylogroup B2, and most of the isolates associated to sequence types ST73 and ST95. One isolate from an ulcerative colitis (UC) patient was of the sequence type ST8303. The maximum likelihood tree based on the core genome of pks -positive isolates revealed horizontal gene transfer across sequence types and serotypes. Virulome and resistome analyses revealed the preponderance of virulence genes and a reduced number of antimicrobial genes in Pks -positive isolates. This study strongly contributes to understanding the evolution of pks islands in E. coli .

Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia.

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation.

Protein Binder Toolbox for Studies of Solute Carrier Transporters.

Transporters of the solute carrier superfamily (SLCs) are responsible for the transmembrane traffic of the majority of chemical substances in cells and tissues and are therefore of fundamental biological importance. As is often the case with membrane proteins that can be heavily glycosylated, a lack of reliable high-affinity binders hinders their functional analysis. Purifying and reconstituting transmembrane proteins in their lipidic environments remains challenging and standard approaches to generate binders for multi-transmembrane proteins, such as SLCs, channels or G protein-coupled receptors (GPCRs) are lacking. While generating protein binders to 27 SLCs, we produced full length protein or cell lines as input material for binder generation by selected binder generation platforms. As a result, we obtained 525 binders for 22 SLCs. We validated the binders with a cell-based validation workflow using immunofluorescent and immunoprecipitation methods to process all obtained binders. Finally, we demonstrated the potential applications of the binders that passed our validation pipeline in structural, biochemical, and biological applications using the exemplary protein SLC12A6, an ion transporter relevant in human disease. With this work, we were able to generate easily renewable and highly specific binders against SLCs, which will greatly facilitate the study of this neglected protein family. We hope that the process will serve as blueprint for the generation of binders against the entire superfamily of SLC transporters.

CXCR7 activation evokes the anti-PD-L1 antibody against glioblastoma by remodeling CXCL12-mediated immunity.

The interaction between glioblastoma cells and glioblastoma-associated macrophages (GAMs) influences the immunosuppressive tumor microenvironment, leading to ineffective immunotherapies. We hypothesized that disrupting the communication between tumors and macrophages would enhance the efficacy of immunotherapies. Transcriptomic analysis of recurrent glioblastoma specimens indicated an enhanced neuroinflammatory pathway, with CXCL12 emerging as the top-ranked gene in secretory molecules. Single-cell transcriptome profiling of naïve glioblastoma specimens revealed CXCL12 expression in tumor and myeloid clusters. An analysis of public glioblastoma datasets has confirmed the association of CXCL12 with disease and PD-L1 expression. In vitro studies have demonstrated that exogenous CXCL12 induces pro-tumorigenic characteristics in macrophage-like cells and upregulated PD-L1 expression through NF-κB signaling. We identified CXCR7, an atypical receptor for CXCL12 predominantly present in tumor cells, as a negative regulator of CXCL12 expression by interfering with extracellular signal-regulated kinase activation. CXCR7 knockdown in a glioblastoma mouse model resulted in worse survival outcomes, increased PD-L1 expression in GAMs, and reduced CD8+ T-cell infiltration compared with the control group. Ex vivo T-cell experiments demonstrated enhanced cytotoxicity against tumor cells with a selective CXCR7 agonist, VUF11207, reversing GAM-induced immunosuppression in a glioblastoma cell-macrophage-T-cell co-culture system. Notably, VUF11207 prolonged survival and potentiated the anti-tumor effect of the anti-PD-L1 antibody in glioblastoma-bearing mice. This effect was mitigated by an anti-CD8ß antibody, indicating the synergistic effect of VUF11207. In conclusion, CXCL12 conferred immunosuppression mediated by pro-tumorigenic and PD-L1-expressing GAMs in glioblastoma. Targeted activation of glioblastoma-derived CXCR7 inhibits CXCL12, thereby eliciting anti-tumor immunity and enhancing the efficacy of anti-PD-L1 antibodies.

Calycosin Enhances Heat Shock Related-Proteins in H9c2 Cells to Modulate Survival and Apoptosis against Heat Shock.

Heat shock proteins (HSPs), which function as chaperones, are activated in response to various environmental stressors. In addition to their role in diverse aspects of protein production, HSPs protect against harmful protein-related stressors. Calycosin exhibits numerous beneficial properties. This study aims to explore the protective effects of calycosin in the heart under heat shock and determine its underlying mechanism. H9c2 cells, western blot, TUNEL staining, flow cytometry, and immunofluorescence staining were used. The time-dependent effects of heat shock analyzed using western blot revealed increased HSP expression for up to 2[Formula: see text]h, followed by protein degradation after 4[Formula: see text]h. Hence, a heat shock damage duration of 4[Formula: see text]h was chosen for subsequent investigations. Calycosin administered post-heat shock demonstrated dose-dependent recovery of cell viability. Under heat shock conditions, calycosin prevented the apoptosis of H9c2 cells by upregulating HSPs, suppressing p-JNK, enhancing Bcl-2 activation, and inhibiting cleaved caspase 3. Calycosin also inhibited Fas/FasL expression and activated cell survival markers (p-PI3K, p-ERK, p-Akt), indicating their cytoprotective properties through PI3K/Akt activation and JNK inhibition. TUNEL staining and flow cytometry confirmed that calycosin reduced apoptosis. Moreover, calycosin reversed the inhibitory effects of quercetin on HSF1 and Hsp70 expression, illustrating its role in enhancing Hsp70 expression through HSF1 activation during heat shock. Immunofluorescence staining demonstrated HSF1 translocation to the nucleus following calycosin treatment, emphasizing its cytoprotective effects. In conclusion, calycosin exhibits pronounced protective effects against heat shock-induced damages by modulating HSP expression and regulating key signaling pathways to promote cell survival in H9c2 cells.

Use of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients With Type 2 Diabetes and the Incidence of Retinal Vein Occlusion in Taiwan.

Purpose: The purpose of this study was to evaluate the risk of newly diagnosed retinal vein occlusion (RVO) in patients with type 2 diabetes (T2D) using sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared to dipeptidyl peptidase-4 inhibitors (DPP-4i). Methods: Claims data from the National Health Insurance Research Database of Taiwan were used in this nationwide retrospective cohort study. A target trial emulation framework was applied. Patients with T2D with no prior diagnosis of RVO who had newly commenced treatment with SGLT-2i or DPP-4i between May 1, 2016, and December 31, 2020, were included. Potential systematic differences in baseline characteristics between the paired groups were controlled using stabilized inverse probability of treatment weighting. The outcome of interest was incident RVO. The hazard ratio (HR) for SGLT-2i compared with that of DPP-4i was estimated using a Cox regression model. Results: Data from 123,567 and 578,665 patients receiving SGLT-2i and DPP-4i, respectively, were analyzed. The incidence of RVO was lower in patients newly receiving SGLT-2i (0.59 events per 1000 person-years) compared to those receiving DPP-4i (0.77 events per 1000 person-years) over a mean follow-up of 1.61 years. SGLT-2i users had a significantly lower risk of developing RVO compared with DPP-4i users (HR = 0.76, 95% confidence interval [CI] = 0.59-0.98). In the individual outcome analysis, SGLT-2i use was significantly associated with a lower risk of branch RVO (HR = 0.71, 95% CI = 0.52-0.96), but not central RVO (HR = 0.84, 95% CI = 0.57-1.24). Conclusions: The risk of developing RVO was lower in patients with T2D receiving SGLT-2i compared with that in those receiving DPP-4i.

The Impact of Thallium Exposure in Public Health and Molecular Toxicology: A Comprehensive Review.

This review offers a synthesis of the current understanding of the impact of low-dose thallium (Tl) on public health, specifically emphasizing its diverse effects on various populations and organs. The article integrates insights into the cytotoxic effects, genotoxic potential, and molecular mechanisms of thallium in mammalian cells. Thallium, a non-essential heavy metal present in up to 89 different minerals, has garnered attention due to its adverse effects on human health. As technology and metallurgical industries advance, various forms of thallium, including dust, vapor, and wastewater, can contaminate the environment, extending to the surrounding air, water sources, and soil. Moreover, the metal has been identified in beverages, tobacco, and vegetables, highlighting its pervasive presence in a wide array of food sources. Epidemiological findings underscore associations between thallium exposure and critical health aspects such as kidney function, pregnancy outcomes, smoking-related implications, and potential links to autism spectrum disorder. Thallium primarily exerts cellular toxicity on various tissues through mitochondria-mediated oxidative stress and endoplasmic reticulum stress. This synthesis aims to shed light on the intricate web of thallium exposure and its potential implications for public health, emphasizing the need for vigilant consideration of its risks.

Using a clinical narrative-aware pre-trained language model for predicting emergency department patient disposition and unscheduled return visits.

The increasing prevalence of overcrowding in Emergency Departments (EDs) threatens the effective delivery of urgent healthcare. Mitigation strategies include the deployment of monitoring systems capable of tracking and managing patient disposition to facilitate appropriate and timely care, which subsequently reduces patient revisits, optimizes resource allocation, and enhances patient outcomes. This study used âˆ¼ 250,000 emergency department visit records from Taipei Medical University-Shuang Ho Hospital to develop a natural language processing model using BlueBERT, a biomedical domain-specific pre-trained language model, to predict patient disposition status and unplanned readmissions. Data preprocessing and the integration of both structured and unstructured data were central to our approach. Compared to other models, BlueBERT outperformed due to its pre-training on a diverse range of medical literature, enabling it to better comprehend the specialized terminology, relationships, and context present in ED data. We found that translating Chinese-English clinical narratives into English and textualizing numerical data into categorical representations significantly improved the prediction of patient disposition (AUROC = 0.9014) and 72-hour unscheduled return visits (AUROC = 0.6475). The study concludes that the BlueBERT-based model demonstrated superior prediction capabilities, surpassing the performance of prior patient disposition predictive models, thus offering promising applications in the realm of ED clinical practice.

The Interrelationship of Benefit Finding, Demoralization, and Stigma among Patients with Parkinson's Disease and Their Caregivers.

Parkinson's disease (PD) is a debilitating neurodegenerative disease with a relentlessly progressive course of illness. This study aimed to assess the dyadic dynamics of benefit finding (BF), demoralization, and stigma on the depression severity of PD patients and their caregivers. This study used a cross-sectional design with purposive sampling. In total, 120 PD patients and 120 caregivers were recruited from the neurological ward or neurological outpatient clinic of a medical center in Taiwan from October 2021 to September 2022. PD patients and their caregivers were enrolled and assessed using the Mini International Neuropsychiatric Interview, the Benefit Finding scale, Demoralization Scale, Stigma Subscale of the Explanatory Model Interview Catalogue, and Taiwanese Depression Questionnaire. Among the 120 patients and 120 caregivers that successfully completed the study, 41.7% (N = 50) and 60% (N = 72) were female, respectively. The most common psychiatric diagnoses of both the PD patients (17.5%) and their caregivers (13.3%) were depressive disorders. Using structural equation modeling, we found that the stigma, BF, and demoralization of PD patients might contribute to their depression severity. Demoralization and stigma of PD patients' caregivers might also contribute to the depression severity of PD patients. Caregivers' BF and demoralization were significantly linked with their depression severity. PD patients' BF degree and their caregivers' BF degree had significant interactive effects. Both patients' and their caregivers' stigma levels had significant interactive effects. Clinicians should be aware of and manage these contributing factors between PD patients and their caregivers in order to prevent them from exacerbating each other's depression.

A nursing note-aware deep neural network for predicting mortality risk after hospital discharge.

BACKGROUND: ICU readmissions and post-discharge mortality pose significant challenges. Previous studies used EHRs and machine learning models, but mostly focused on structured data. Nursing records contain crucial unstructured information, but their utilization is challenging. Natural language processing (NLP) can extract structured features from clinical text. This study proposes the Crucial Nursing Description Extractor (CNDE) to predict post-ICU discharge mortality rates and identify high-risk patients for unplanned readmission by analyzing electronic nursing records. OBJECTIVE: Developed a deep neural network (NurnaNet) with the ability to perceive nursing records, combined with a bio-clinical medicine pre-trained language model (BioClinicalBERT) to analyze the electronic health records (EHRs) in the MIMIC III dataset to predict the death of patients within six month and two year risk. DESIGN: A cohort and system development design was used. SETTING(S): Based on data extracted from MIMIC-III, a database of critically ill in the US between 2001 and 2012, the results were analyzed. PARTICIPANTS: We calculated patients' age using admission time and date of birth information from the MIMIC dataset. Patients under 18 or over 89 years old, or who died in the hospital, were excluded. We analyzed 16,973 nursing records from patients' ICU stays. METHODS: We have developed a technology called the Crucial Nursing Description Extractor (CNDE), which extracts key content from text. We use the logarithmic likelihood ratio to extract keywords and combine BioClinicalBERT. We predict the survival of discharged patients after six months and two years and evaluate the performance of the model using precision, recall, the F1-score, the receiver operating characteristic curve (ROC curve), the area under the curve (AUC), and the precision-recall curve (PR curve). RESULTS: The research findings indicate that NurnaNet achieved good F1-scores (0.67030, 0.70874) within six months and two years. Compared to using BioClinicalBERT alone, there was an improvement in performance of 2.05 % and 1.08 % for predictions within six months and two years, respectively. CONCLUSIONS: CNDE can effectively reduce long-form records and extract key content. NurnaNet has a good F1-score in analyzing the data of nursing records, which helps to identify the risk of death of patients after leaving the hospital and adjust the regular follow-up and treatment plan of relevant medical care as soon as possible.

A comparison between intraosseous and intravenous access in patients with out-of-hospital cardiac arrest: A retrospective cohort study.

INTRODUCTION: The optimal vascular access for patients with out-of-hospital cardiac arrest (OHCA) remains controversial. Increasing evidence supports intraosseous (IO) access due to faster medication administration and higher first-attempt success rates compared to intravenous (IV) access. However, the impact on patient outcomes has been inconclusive. METHODS: This retrospective cohort study in Taoyuan City, Taiwan, from January 1, 2019, to December 31, 2022, included patients aged ≥18 years with non-traumatic OHCA resuscitated by emergency medical technician paramedics (EMT-Ps) with either IVs or IOs for final vascular access. The exclusion criteria were cardiac arrest en route to the hospital and resuscitation during the coronavirus pandemic (from May 1, 2022, to October 31, 2022). The primary and secondary outcomes were sustained ROSC (≥2 h) and cerebral performance category (CPC) 1-2, respectively. Univariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CI) for the primary analysis. Multivariable logistic regression was employed, with variables selected based on a p-value of <0.05 in the univariate analysis. The survival benefits of different insertion sites and subgroups like general ambulance teams (with a composition that includes fewer EMT-Ps and limited experience in using IO access) were also analyzed. RESULTS: A total of 2003 patients were enrolled; 1602 received IV access and 401 IO access. The median patient age was 70 years, and most were male (66.6%). Compared to patients receiving IV access, the adjusted odds ratios (aORs) for primary and secondary outcomes in patients with IOs were 0.83 (95% confidence interval [CI], 0.61-1.11; p = 0.20) and 0.96 (95% CI, 0.39-2.40; p = 0.93), respectively. Different insertion sites showed no outcome differences. In the subgroups of females and patients resuscitated by general ambulance teams, the aORs for sustained ROSC were 0.55 (95% CI, 0.33-0.92; p = 0.02) and 0.62 (95% CI, 0.41-0.94; p = 0.02), respectively. CONCLUSIONS: For patients with OHCA resuscitated by EMT-Ps, IO access was comparable to IV access regarding patient outcomes. However, in females and patients resuscitated by general ambulance teams, IV access might be favorable.

Cardiopulmonary functional capacity in Taiwanese children with atrial septal defects.

BACKGROUND: Most existing studies measure atrial septal defect (ASD) outcomes based on morbidity rates such as atrial arrhythmias and heart failure rather than the functional assessment of physical capacity postprocedure. Few studies have evaluated cardiopulmonary function in ASD children. This study represents the largest sample population in the current research, encompassing a total of 122 Taiwanese children with ASD who had undergone treatment, to evaluate cardiopulmonary functional capacity through the implementation of cardiopulmonary exercise testing (CPET), and to investigate whether variations in treatment may impact their cardiopulmonary function. METHODS: This is a retrospective cohort study with the data collected from January 2010 to December 2021. All patients and controls (age-, sex-, and body mass index-matched) underwent CPET and pulmonary function testing. RESULTS: In total, 122 ASD patients (surgically closed ASDs 27, transcatheter-closed ASDs 48, and follow-up unrepaired ASD 47) and 244 healthy controls were recruited. The ASD group exhibited lower peak metabolic equivalent (MET), peak oxygen consumption (VO 2 , p < 0.001), and peak minute ventilation ( p = 0.028) along with MET and VO 2 at the anaerobic threshold (AT) ( p = 0.012) compared to the control group. No statistically significant differences were observed in the pulmonary function test. Among surgically closed, transcatheter closed and unrepaired ASD subgroups, no significant variances were seen in CPET and pulmonary function tests. CONCLUSION: Taiwanese ASD children exhibited diminished exercise capacity and cardiopulmonary performance compared to their healthy counterparts. Differences among specific ASD treatments in cardiopulmonary tests were non-significant.

Genetic analysis of IRF2BPL in a Taiwanese dystonia cohort: The genotype and phenotype correlation.

OBJECTIVE: IRF2BPL mutation has been associated with a rare neurodevelopmental disorder with abnormal movements, including dystonia. However, the role of IRF2BPL in dystonia remains elusive. We aimed to investigate IRF2BPL mutations in a Taiwanese dystonia cohort. METHODS: A total of 300 unrelated patients with molecularly unassigned isolated (n = 256) or combined dystonia (n = 44) were enrolled between January 2015 and July 2023. The IRF2BPL variants were analyzed based on whole exome sequencing. The in silico prediction of the identified potential pathogenic variant was performed to predict its pathogenicity. We also compared the clinical and genetic features to previous literature reports. RESULTS: We identified one adolescent patient carrying a de novo heterozygous pathogenic variant of IRF2BPL, c.379C>T (p.Gln127Ter), who presented with generalized dystonia, developmental regression, and epilepsy (0.33% of our dystonia cohort). This variant resides within the polyglutamine (poly Q) domain before the first PEST sequence block of the IRF2BPL protein, remarkably truncating the protein structure. Combined with other patients with IRF2BPL mutations in the literature (n = 60), patients with variants in the poly Q domain have a higher rate of nonsense mutations (p < 0.001) and epilepsy (p = 0.008) than patients with variants in other domains. Furthermore, as our index patient, carriers with substitutions before the first PEST sequence block have significantly older age of onset (p < 0.01) and higher non-epilepsy symptoms, including generalized dystonia (p = 0.003), and ataxia (p = 0.003). INTERPRETATION: IRF2BPL mutation is a rare cause of dystonia in our population. Mutations in different domains of IRF2BPL exhibit different phenotypes.

Benefit analysis of the auto-verification system of intelligent inspection for microorganisms.

In recent years, the automatic machine for microbial identification and antibiotic susceptibility tests has been introduced into the microbiology laboratory of our hospital, but there are still many steps that need manual operation. The purpose of this study was to establish an auto-verification system for bacterial naming to improve the turnaround time (TAT) and reduce the burden on clinical laboratory technologists. After the basic interpretation of the gram staining results of microorganisms, the appearance of strain growth, etc., the 9 rules were formulated by the laboratory technologists specialized in microbiology for auto-verification of bacterial naming. The results showed that among 70,044 reports, the average pass rate of auto-verification was 68.2%, and the reason for the failure of auto-verification was further evaluated. It was found that the main causes reason the inconsistency between identification results and strain appearance rationality, the normal flora in the respiratory tract and urine that was identified, the identification limitation of the mass spectrometer, and so on. The average TAT for the preliminary report of bacterial naming was 35.2 h before, which was reduced to 31.9 h after auto-verification. In summary, after auto-verification, the laboratory could replace nearly 2/3 of manual verification and issuance of reports, reducing the daily workload of medical laboratory technologists by about 2 h. Moreover, the TAT on the preliminary identification report was reduced by 3.3 h on average, which could provide treatment evidence for clinicians in advance.

A Preliminary Investigation of the Roles of Endometrial Cells in Endometriosis Development via In Vitro and In Vivo Analyses.

Endometriosis is a complex gynecological disease that affects more than 10% of women in their reproductive years. While surgery can provide temporary relief from women's pain, symptoms often return in as many as 75% of cases within two years. Previous literature has contributed to theories about the development of endometriosis; however, the exact pathogenesis and etiology remain elusive. We conducted a preliminary investigation into the influence of primary endometrial cells (ECs) on the development and progression of endometriosis. In vitro studies, they were involved in inducing Lipopolysaccharide (LPS) in rat-isolated primary endometrial cells, which resulted in increased nuclear factor-kappa B (NF-κB) and vascular endothelial growth factor (VEGF) mRNA gene expression (quantitative polymerase chain reaction analysis, qPCR) and protein expression (western blot analysis). Additionally, in vivo studies utilized autogenic and allogeneic transplantations (rat to rat) to investigate endometriosis-like lesion cyst size, body weight, protein levels (immunohistochemistry), and mRNA gene expression. These studies demonstrated that estrogen upregulates the gene and protein regulation of cytoskeletal (CK)-18, transforming growth factor-ß (TGF-ß), VEGF, and tumor necrosis factor (TNF)-α, particularly in the peritoneum. These findings may influence cell proliferation, angiogenesis, fibrosis, and inflammation markers. Consequently, this could exacerbate the occurrence and progression of endometriosis.

The SMAC mimetic GDC-0152 is a direct ABCB1-ATPase activity modulator and BIRC5 expression suppressor in cancer cells.

Upregulation of the multidrug efflux pump ABCB1/MDR1 (P-gp) and the anti-apoptotic protein BIRC5/Survivin promotes multidrug resistance in various human cancers. GDC-0152 is a DIABLO/SMAC mimetic currently being tested in patients with solid tumors. However, it is still unclear whether GDC-0152 is therapeutically applicable for patients with ABCB1-overexpressing multidrug-resistant tumors, and the molecular mechanism of action of GDC-0152 in cancer cells is still incompletely understood. In this study, we found that the potency of GDC-0152 is unaffected by the expression of ABCB1 in cancer cells. Interestingly, through in silico and in vitro analysis, we discovered that GDC-0152 directly modulates the ABCB1-ATPase activity and inhibits ABCB1 multidrug efflux activity at sub-cytotoxic concentrations (i.e., 0.25×IC50 or less). Further investigation revealed that GDC-0152 also decreases BIRC5 expression, induces mitophagy, and lowers intracellular ATP levels in cancer cells at low cytotoxic concentrations (i.e., 0.5×IC50). Co-treatment with GDC-0152 restored the sensitivity to the known ABCB1 substrates, including paclitaxel, vincristine, and YM155 in ABCB1-expressing multidrug-resistant cancer cells, and it also restored the sensitivity to tamoxifen in BIRC5-overexpressing tamoxifen-resistant breast cancer cells in vitro. Moreover, co-treatment with GDC-0152 restored and potentiated the anticancer effects of paclitaxel in ABCB1 and BIRC5 co-expressing xenograft tumors in vivo. In conclusion, GDC-0152 has the potential for use in the management of cancer patients with ABCB1 and BIRC5-related drug resistance. The findings of our study provide essential information to physicians for designing a more patient-specific GDC-0152 clinical trial program in the future.

Applying machine learning to assess the morphology of sculpted teeth.

Background/purpose: Producing tooth crowns through dental technology is a basic function of dentistry. The morphology of tooth crowns is the most important parameter for evaluating its acceptability. The procedures were divided into four steps: tooth collection, scanning skills, use of mathematical methods and software, and machine learning calculation. Materials and methods: Dental plaster rods were prepared. The effective data collected were to classify 121 teeth (15th tooth position), 342 teeth (16th tooth position), 69 teeth (21st tooth position), and 89 teeth (43rd tooth position), for a total of 621 teeth. The procedures are divided into four steps: tooth collection, scanning skills, use of mathematical methods and software, and machine learning calculation. Results: The area under the curve (AUC) value was 0, 0.5, and 0.72 in this study. The precision rate and recall rate of micro-averaging/macro-averaging were 0.75/0.73 and 0.75/0.72. If we took a newly carved tooth picture into the program, the current effectiveness of machine learning was about 70%-75% to evaluate the quality of tooth morphology. Through the calculation and analysis of the two different concepts of micro-average/macro-average and AUC, similar values could be obtained. Conclusion: This study established a set of procedures that can judge the quality of hand-carved plaster sticks and teeth, and the accuracy rate is about 70%-75%. It is expected that this process can be used to assist dental technicians in judging the pros and cons of hand-carved plaster sticks and teeth, so as to help dental technicians to learn the tooth morphology more effectively.

Conserved molecular chaperone PrsA stimulates protective immunity against group A Streptococcus.

Group A Streptococcus (GAS) is a significant human pathogen that poses a global health concern. However, the development of a GAS vaccine has been challenging due to the multitude of diverse M-types and the risk of triggering cross-reactive immune responses. Our previous research has identified a critical role of PrsA1 and PrsA2, surface post-translational molecular chaperone proteins, in maintaining GAS proteome homeostasis and virulence traits. In this study, we aimed to further explore the potential of PrsA1 and PrsA2 as vaccine candidates for preventing GAS infection. We found that PrsA1 and PrsA2 are highly conserved among GAS isolates, demonstrating minimal amino acid variation. Antibodies specifically targeting PrsA1/A2 showed no cross-reactivity with human heart proteins and effectively enhanced neutrophil opsonophagocytic killing of various GAS serotypes. Additionally, passive transfer of PrsA1/A2-specific antibodies conferred protective immunity in infected mice. Compared to alum, immunization with CFA-adjuvanted PrsA1/A2 induced higher levels of Th1-associated IgG isotypes and complement activation and provided approximately 70% protection against invasive GAS challenge. These findings highlight the potential of PrsA1 and PrsA2 as universal vaccine candidates for the development of an effective GAS vaccine.