Risk factors analysis and construction of predictive models for acute kidney injury in overweight patients receiving vancomycin treatment.

BACKGROUND: Vancomycin induced acute kidney injury (VI-AKI) is one of its serious adverse reactions. The purpose of this study is to discuss the risk factors for VI-AKI in overweight patients and construct a clinical prediction model based on the results of the analysis. METHODS: Multivariable logistic regression analysis was used to identify risk factors for VI-AKI and constructed nomogram models. The performance of the nomogram was evaluated based on the area under the receiver operating characteristic curve (AUC), calibration curves and decision curve analysis (DCA). RESULT: Cancer (OR 4.186, 95% CI 1.473-11.896), vancomycin trough concentration >20.0 µg/mL (OR 6.251, 95% CI 2.275-17.180), concomitant furosemide (OR 2.722, 95% CI 1.071-6.919) and vasoactive agent (OR 2.824, 95% CI 1.086-7.340) were independent risk factors for VI-AKI. The AUC of the nomogram validation cohorts were 0.807 (95% CI 0.785-0.846). The calibration curve revealed that the predicted outcome was in agreement with the actual observations. Finally, the DCA curves showed that the nomogram had a good clinical applicability value. CONCLUSION: There are four independent risk factors for the occurrence of VI-AKI in overweight patients, and the nomogram prediction model has good predictive ability, which can provide reference for clinical decision-making.

Association Between the Oxidative Balance Score and Endometriosis: A Population-Based Study.

Purpose: To investigate the association between the oxidative balance score (OBS) and endometriosis. Methods: This cross-sectional study used four cycles of the National Health and Nutrition Examination Survey (NHANES) (1999-2000, 2001-2002, 2003-2004, and 2005-2006). OBS involved 16 dietary nutrients and 4 lifestyle factors, including 5 pro-oxidants and 15 anti-oxidants. According to weighted quartiles, the OBS was divided into four categories: < 12.54, 12.54-18.70, 18.71-24.68, and > 24.68. Endometriosis was diagnosed based on a question from the reproductive health questionnaire. Weighted multivariate logistic analysis was used to investigate the association between OBS and endometriosis. Subgroup analysis was performed based on menstrual regularity and female hormone use. Results: A total of 5095 women were included, with 1140 (22.37%), 1232 (24.18%), 1224 (24.02%), and 1499 (29.42%) women in the OBS < 12.54, of 12.54-18.70, of 18.71-24.68, and > 24.68 categories, respectively. After adjusting age, race, family poverty-to-income ratio (PIR), education level, uterine fibroids, menstrual regularity, oophorectomy, female hormone use, hypertension, dyslipidemia, and steroid drug, a high OBS (> 24.68) was found to be associated with lower odds of endometriosis [odds ratio (OR) = 0.70, 95% confidence interval (CI): 0.50-0.97, P = 0.033] compared to a low OBS (< 12.54). The similar result was also found in women with irregular menstruation (OR = 0.58, 95% CI: 0.37-0.91, P = 0.020) and with female hormone use (OR = 0.71, 95% CI: 0.52-0.98, P = 0.037). Conclusion: A high OBS was associated with lower odds of endometriosis, especially in women with irregular menstruation and female hormone use.

Neutrophils Recruited by NKX2-1 Suppression via Activation of CXCLs/CXCR2 Axis Promote Lung Adenocarcinoma Progression.

NK2 Homeobox 1 (NKX2-1) is a well-characterized pathological marker that delineates lung adenocarcinoma (LUAD) progression. The advancement of LUAD is influenced by the immune tumor microenvironment through paracrine signaling. However, the involvement of NKX2-1 in modeling the tumor immune microenvironment is still unclear. Here, the downregulation of NKX2-1 is observed in high-grade LUAD. Meanwhile, single-cell RNA sequencing and Visium in situ capturing profiling revealed the recruitment and infiltration of neutrophils in orthotopic syngeneic tumors exhibiting strong cell-cell communication through the activation of CXCLs/CXCR2 signaling. The depletion of NKX2-1 triggered the expression and secretion of CXCL1, CXCL2, CXCL3, and CXCL5 in LUAD cells. Chemokine secretion is analyzed by chemokine array and validated by qRT-PCR. ATAC-seq revealed the restrictive regulation of NKX2-1 on the promoters of CXCL1, CXCL2, and CXCL5 genes. This phenomenon led to increased tumor growth, and conversely, tumor growth decreased when inhibited by the CXCR2 antagonist SB225002. This study unveils how NKX2-1 modulates the infiltration of tumor-promoting neutrophils by inhibiting CXCLs/CXCR2-dependent mechanisms. Hence, targeting CXCR2 in NKX2-1-low tumors is a potential antitumor therapy that may improve LUAD patient outcomes.

Anesthesia for cesarean delivery and subsequent depression: A nationwide retrospective cohort study.

BACKGROUND: Postpartum depression is a major psychiatric disorder associated with maternal suicide and child developmental disturbances. In this study, we aimed to investigate whether general anesthesia for cesarean delivery is associated with a higher rate of new-onset depression after delivery than neuraxial anesthesia. METHODS: This is a nationwide retrospective cohort study using data retrieved from the National Health Insurance Research Database between 2014 and 2018. Women who had cesarean delivery under general or neuraxial anesthesia were enrolled. After 1:4 propensity score matching, there were 4544 and 18,176 women under the general and neuraxial anesthesia groups, respectively. The primary outcome was new-onset depression diagnosed after delivery in a time-to-event analysis setting. RESULTS: After propensity-score matching, the rate of new-onset depression diagnosed within 1 year was 1.10 % (50/4488) and 0.86 % (157/18176) after cesarean delivery under general and neuraxial anesthesia, respectively. For depression diagnosed within 90 days of delivery, significant difference between the two groups was noted (0.51 % vs. 0.30 %, P = 0.031). In the time-to-event analysis with Cox regression model, women who delivered under general anesthesia were associated with significantly higher risk of postpartum depression within 90 days (Hazard ratio [HR], 1.71; 95 % CI, 1.05-2.79) compared with those under neuraxial anesthesia. LIMITATIONS: The observational design only allows asserting association, rather than establishing causality between exposure and outcomes. CONCLUSIONS: Women who underwent cesarean delivery under general anesthesia had a higher risk of subsequent depression within 90 days than those under neuraxial anesthesia. Early screening for depressive disorders might facilitate timely management.

Unplanned emergency department visits within 90 days of hip hemiarthroplasty for osteoporotic femoral neck fractures: Reasons, risks, and mortalities.

Objectives: Bipolar hemiarthroplasty is commonly performed to treat displaced femoral neck fractures in osteoporotic patients. This study aimed to assess the occurrence and outcomes of unplanned return visits to the emergency department (ED) within 90 days following bipolar hemiarthroplasty for displaced femoral neck fractures. Methods: The clinical data of 1322 consecutive patients who underwent bipolar hemiarthroplasty for osteoporotic femoral neck fractures at a tertiary medical center were analyzed. Data from the patients' electronic medical records, including demographic information, comorbidities, and operative details, were collected. The risk factors and mortality rates were analyzed. Results: Within 90 days after surgery, 19.9% of patients returned to the ED. Surgery-related reasons accounted for 20.2% of the patient's returns. Older age, a high Charlson comorbidity index score, chronic kidney disease, and a history of cancer were identified as significant risk factors for unplanned ED visits. Patients with uncemented implants had a significantly greater risk of returning to the ED due to periprosthetic fractures than did those with cemented implants (P = 0.04). Patients who returned to the ED within 90 days had an almost fivefold greater 1-year mortality rate (15.2% vs 3.1%, P < 0.001) and a greater overall mortality rate (26.2% vs 10.5%, P < 0.001). Conclusions: This study highlights the importance of identifying risk factors for unplanned ED visits after bipolar hemiarthroplasty, which may contribute to a better prognosis. Consideration should be given to the use of cemented implants for hemiarthroplasty, as uncemented implants are associated with a greater risk of periprosthetic fractures.

Fabrication of Stable Liquid-like Wetting Buckled Surfaces as Bioinspired Antibiofouling Coatings by Using Silicon-Containing Block Copolymers.

Inspired by animals with a slippery epidermis, durable slippery antibiofouling coatings with liquid-like wetting buckled surfaces are successfully constructed in this study by combining dynamic-interfacial-release-induced buckling with self-assembled silicon-containing diblock copolymer (diBCP). The core diBCP material is polystyrene-block-poly(dimethylsiloxane) (PS-b-PDMS). Because silicon-containing polymers with intrinsic characters of low surface energy, they easily flow over and cover a surface after it has undergone controlled thermal treatment, generating a slippery wetting layer on which can eliminate polar interactions with biomolecules. Additionally, microbuckled patterns result in curved surfaces, which offer fewer points at which organisms can attach to the surface. Different from traditional slippery liquid-infused porous surfaces, the proposed liquid-like PDMS wetting layer, chemically bonded with PS, is stable and slippery but does not flow away. PS-b-PDMS diBCPs with various PDMS volume fractions are studied to compare the influence of PDMS segment length on antibiofouling performance. The surface characteristics of the diBCPs─ease of processing, transparency, and antibiofouling, anti-icing, and self-cleaning abilities─are examined under various conditions. Being able to fabricate ecofriendly silicon-based lubricant layers without needing to use fluorinated compounds and costly material precursors is an advantage in industrial practice.

Recent methodological advances in federated learning for healthcare.

For healthcare datasets, it is often impossible to combine data samples from multiple sites due to ethical, privacy, or logistical concerns. Federated learning allows for the utilization of powerful machine learning algorithms without requiring the pooling of data. Healthcare data have many simultaneous challenges, such as highly siloed data, class imbalance, missing data, distribution shifts, and non-standardized variables, that require new methodologies to address. Federated learning adds significant methodological complexity to conventional centralized machine learning, requiring distributed optimization, communication between nodes, aggregation of models, and redistribution of models. In this systematic review, we consider all papers on Scopus published between January 2015 and February 2023 that describe new federated learning methodologies for addressing challenges with healthcare data. We reviewed 89 papers meeting these criteria. Significant systemic issues were identified throughout the literature, compromising many methodologies reviewed. We give detailed recommendations to help improve methodology development for federated learning in healthcare.

Evaluation of the Stereochemistry of Staphyloferrin A for Developing Staphylococcus-specific Targeting Conjugates.

Bacteria in the genus Staphylococcus are pathogenic and harmful to humans. Alarmingly, some Staphylococcus, such as methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) have spread worldwide and become notoriously resistant to antibiotics, threatening and concerning public health. Hence, the development of new Staphylococcus-targeting diagnostic and therapeutic agents is urgent. Here, we chose the S. aureus-secreted siderophore staphyloferrin A (SA) as a guiding unit. We developed a series of Staphyloferrin A conjugates (SA conjugates) and showed the specific targeting ability to Staphylococcus bacteria. Furthermore, among the structural factors we evaluated, the stereo-chemistry of the amino acid backbone of SA conjugates is essential to efficiently target Staphylococci. Finally, we demonstrated that fluorescent Staphyloferrin A probes (SA-FL probes) could specifically target Staphylococci in complex bacterial mixtures.

Correlations of factors associated with job values, job stress and job satisfaction among hospital nursing assistants.

AIM: To investigate the correlation between job values, job stress, and job satisfaction among nursing assistants in a hospital setting. DESIGN: A cross-sectional study. METHODS: Data were collected from nursing assistants working in a regional hospital and a medical center in Northern Taiwan. A self-rated structured questionnaire was used to collect data on participants' demographic characteristics, job values, job stress, and job satisfaction. Descriptive statistics, t test, one-way analysis of variance, Pearson's correlation coefficient, and stepwise regression were used for data analysis. RESULTS: A total of 135 questionnaires were distributed; of them, 132 were returned, resulting in a response rate of 97.8%. The average age of the participants was 57.08 ± 5.86 years, with the majority being female, high school educated, and married. Most participants (70%) had >5 years of experience in working as nursing assistants. The average job satisfaction score of was 63.63, indicating a moderate level of job satisfaction. Job satisfaction exhibited a significantly positive correlation with job values but a significantly negative correlation with job stress. Job value was negatively correlated with job stress. Stepwise regression revealed that job values significantly explained the variance in job satisfaction among hospital nursing assistants. CONCLUSIONS: Nursing assistants are integral to clinical practice. To enhance their job satisfaction and professional development, health-care institutions and policymakers should implement strategies such as providing continual training, offering recognition and rewards to enhance sense of accomplishment. PATIENT OR PUBLIC CONTRIBUTION: This study involves no patient or public contribution.

Hypothyroidism following carbon monoxide poisoning: An epidemiological study supported by animal experiments.

Previous studies have suggested a possible association between carbon monoxide poisoning (COP) and hypothyroidism, but the evidence is limited. Therefore, the aim of this study was to further investigate this relationship. Using data from the Taiwan National Health Research Database, we identified 32,162 COP patients and matched with 96,486 non-COP patients by age and index date for an epidemiological study. The risk of hypothyroidism was compared between the two cohorts until 2018. Independent predictors of hypothyroidism were analyzed using competing risk analysis. An animal study was also conducted to support the findings. COP patients had an increased risk of hypothyroidism compared to non-COP patients in the overall analysis (adjusted hazard ratio [AHR]= 3.88; 95 % confidence interval [CI]: 3.27-4.60) and in stratified analyses by age, sex, and comorbidities. The increase in the overall risk persisted even after more than six years of follow-up (AHR= 4.19; 95 % CI: 3.18-5.53). Independent predictors of hypothyroidism, in addition to COP, included age ≥65 years, female sex, hyperlipidemia, and mental disorder. The animal study showed damages in the hypothalamus, pituitary gland, and thyroid, as well as altered hormone levels 28 days after COP exposure. The epidemiological results showed an increased risk of hypothyroidism in COP patients, which was further supported by the animal study. These findings suggest the need for close monitoring of thyroid function in COP patients, especially in those who are age ≥65 years, female, and have hyperlipidemia or mental disorder.

Spatiotemporal analysis and seasonality of tuberculosis in Pudong New Area of Shanghai, China, 2014-2023.

BACKGROUND: Spatiotemporal analysis is a vital method that plays an indispensable role in monitoring epidemiological changes in diseases and identifying high-risk clusters. However, there is still a blank space in the spatial and temporal distribution of tuberculosis (TB) incidence rate in Pudong New Area, Shanghai. Consequently, it is crucial to comprehend the spatiotemporal distribution of TB in this district, this will guide the prevention and control of TB in the district. METHODS: Our research used Geographic Information System (GIS) visualization, spatial autocorrelation analysis, and space-time scan analysis to analyze the TB incidence reported in the Pudong New Area of Shanghai from 2014 to 2023, and described the spatiotemporal clustering and seasonal hot spot distribution of TB incidence. RESULTS: From 2014 to 2023, the incidence of TB in the Pudong New Area decreased, and the mortality was at a low level. The incidence of TB in different towns/streets has declined. The spatial autocorrelation analysis revealed that the incidence of TB was spatially clustered in 2014, 2016-2018, and 2022, with the highest clusters in 2014 and 2022. The high clustering area was mainly concentrated in the northeast. The space-time scan analysis indicated that the most likely cluster was located in 12 towns/streets, with a period of 2014-2018 and a radiation radius of 15.74 km. The heat map showed that there was a correlation between TB incidence and seasonal variations. CONCLUSIONS: From 2014 to 2023, the incidence of TB in the Pudong New Area of Shanghai declined, but there were spatiotemporal clusters and seasonal correlations in the incidence area. Local departments should formulate corresponding intervention measures, especially in high-clustering areas, to achieve accurate prevention and control of TB within the most effective time and scope.

Valorization of broiler edible byproducts: a chicken-liver hydrolysate with hepatoprotection against binge drinking.

Over 10,000 metric-ton broiler livers are produced annually in Taiwan. Concerning unpleasant odor and healthy issue, broiler livers are not attractive to consumers. Although the patented chicken-liver hydrolysates (CLHs) through pepsin digestion possess several biofunctionalities, there is no study on hepatoprotection of CLH-based formula capsule (GBHP01) against binge drinking (Whiskey, 50% Alc./Vol.). GBHP01 led to an accelerated blood-alcohol clearance in rats, as evidenced by lowering blood-alcohol increment within 0 to 4 h, increasing blood-alcohol decrement within 4 to 8 h, and smaller blood alcohol concentration areas under the curve (BAC AUC) in the 8-h period (p < 0.05). The ameliorative effects of GBHP01 against binge drinking in rats over 6 wk were attributed to accelerated alcohol metabolism by further increasing alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities while downregulating cytochrome P450 2E1 (CYP2E1) protein expression, elevating antioxidant capacity, decreasing zonula occludens-1 (ZO-1) protein decrement and serum endotoxin, and reducing inflammation related protein levels, that is, toll-like receptor 4 (TLR4) and mitogen-activated protein kinase (MAPK), and proinflammatory cytokines. The development of CLH supplements could not only enhance the added value of broiler livers through nutraceutical development but also offer a strategy to maximize the utilization of poultry processing residues, as shown in this study.

Direct Excitation Transfer in Plasmonic Metal-Chalcopyrite-Hybrids: Insights from Single Particle Line Shape Analysis.

Hybrid nanomaterials containing both noble metal and semiconductor building blocks provide an engineerable platform for realizing direct or indirect charge and energy transfer for enhanced plasmonic photoconversion and photocatalysis. In this work, silver nanoparticles (AgNPs) and chalcopyrite (CuFeS2) nanocrystals (NCs) are combined into a AgNP@CuFeS2 hybrid structure comprising NCs embedded in a self-assembled lipid coating around the AgNP core. In AgNP@CuFeS2 hybrid structures, both metallic and semiconductor NCs support quasistatic resonances. To characterize the interactions between these resonances and their effect on potential charge and energy transfer, direct interfacial excitation transfer between the AgNP core and surrounding CuFeS2 NCs is probed through single particle line shape analysis and supporting electromagnetic simulations. These studies reveal that CuFeS2 NCs localized in the evanescent field of the central AgNP induce a broadening of the metal NP line shape that peaks when an energetic match between the AgNP and CuFeS2 NC resonances maximizes direct energy transfer. Dimers of AgNPs whose resonances exhibit poor energetic overlap with the CuFeS2 NC quasistatic resonance yield much weaker line shape broadening in a control experiment, corroborating the existence of resonant energy transfer in the AgNP@CuFeS2 hybrid. Resonant coupling between the metallic and semiconductor building blocks in the investigated hybrid architecture provides a mechanism for utilizing the large optical cross-section of the central AgNP to enhance the generation of reactive charge carriers in the surrounding semiconductor NCs for potential applications in photocatalysis.

Immunomodulation in Endometriosis: Investigating the interrelationship between VISTA expression and Escherichia.Shigella-Associated metabolites.

AIMS: Endometriosis is characterized by an abnormal immune microenvironment. Despite the extensive use of immune therapies, the application of immune checkpoint inhibitors in endometriosis lacks confidence due to the instability of preclinical research data. This study aims to elucidate the regulation of the immune inhibitory checkpoint VISTA and its effects on T cells from the perspective of microbiota and metabolism. MAIN METHODS: We divided endometriosis patients into high and low groups based on the expression levels of VISTA in lesion tissues. We collected peritoneal fluid samples from these two groups and performed 16 s RNA sequencing and metabolomics analysis to investigate microbial diversity and differential metabolites. Through combined analysis, we identified microbial-associated metabolites and validated their correlation with VISTA and CD8 + T cells using ELISA and immunofluorescence. In vitro experiments were conducted to confirm the regulatory relationship among these factors. KEY FINDINGS: Our findings revealed a distinct correlation between VISTA expression and the microbial colony Escherichia.Shigella. Moreover, we identified the metabolites LTD4-d5 and 2-n-Propylthiazolidine-4-carboxylic acid as being associated with both Escherichia.Shigella and VISTA expression. In vitro experiments confirmed the inhibitory effects of these metabolites on VISTA expression, while they demonstrated a positive regulation of CD8 + T cell infiltration into endometriotic lesions. SIGNIFICANCE: This study reveals the connection between microbial diversity, metabolites, and VISTA expression in the immune microenvironment of endometriosis, providing potential targets for therapeutic interventions.

Peripheral blood cells RNA-seq identifies differentially expressed gene network linked to lymphocyte subsets alterations and active lupus nephritis associated with declines in renal function.

Background: The aim of this study was to investigate whether quantitative changes in lymphocyte subsets and gene expression in peripheral blood (PB) cells are related to the clinical manifestations and pathogenesis of lupus nephritis (LN). Methods: We enrolled 95 pediatric-onset SLE patients with renal involvement who presented with 450 clinical episodes suspicious for LN flare. Percentages of lymphocyte subsets at each episode were determined. We stratified 55 of 95 patients as high or low subset group according to the median percentage of each lymphocyte subset and the association with changes in the eGFR (ΔeGFR) were analyzed. Peripheral blood bulk RNA-seq to identify differentially expressed genes (DEGs) in 9 active LN vs. 9 inactive LN patients and the DEG-derived network was constructed by Ingenuity Pathway Analysis (IPA). Results: The mean ΔeGFR of low NK-low memory CD4+ T-high naive CD4+ T group (31.01 mL/min/1.73 m2) was significantly greater than that of high NK-high memory CD4+ T-low naive CD4+ T group (11.83 mL/min/1.73 m2; P = 0.0175). Kaplan-Meier analysis showed that the median time for ΔeGFR decline to mean ΔeGFR is approximately 10 years for high NK-high memory CD4+ T-low naive CD4+ T group and approximately 5 years for low NK-low memory CD4+ T-high naive CD4+ T group (log-rank test P = 0.0294). Conclusions: Our study highlighted important connections between DEG-derived network, lymphocyte subset composition, and disease status of LN and GN. A novel scoring system based on lymphocyte subset proportions effectively stratified patients into groups with differential risks for declining renal function.

TCL1A-expressing B cells are critical for tertiary lymphoid structure formation and the prognosis of oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a malignant tumor with a poor prognosis. Traditional treatments have limited effectiveness. Regulation of the immune response represents a promising new approach for OSCC treatment. B cells are among the most abundant immune cells in OSCC. However, the role of B cells in OSCC treatment has not been fully elucidated. METHODS: Single-cell RNA sequencing analysis of 13 tissues and 8 adjacent normal tissues from OSCC patients was performed to explore differences in B-cell gene expression between OSCC tissues and normal tissues. We further investigated the relationship between differentially expressed genes and the immune response to OSCC. We utilized tissue microarray data for 146 OSCC clinical samples and RNA sequencing data of 359 OSCC samples from The Cancer Genome Atlas (TCGA) to investigate the role of T-cell leukemia 1 A (TCL1A) in OSCC prognosis. Multiplex immunohistochemistry (mIHC) was employed to investigate the spatial distribution of TCL1A in OSCC tissues. We then investigated the effect of TCL1A on B-cell proliferation and trogocytosis. Finally, lentiviral transduction was performed to induce TCL1A overexpression in B lymphoblastoid cell lines (BLCLs) to verify the function of TCL1A. RESULTS: Our findings revealed that TCL1A was predominantly expressed in B cells and was associated with a better prognosis in OSCC patients. Additionally, we found that TCL1A-expressing B cells are located at the periphery of lymphatic follicles and are associated with tertiary lymphoid structures (TLS) formation in OSCC. Mechanistically, upregulation of TCL1A promoted the trogocytosis of B cells on dendritic cells by mediating the upregulation of CR2, thereby improving antigen-presenting ability. Moreover, the upregulation of TCL1A expression promoted the proliferation of B cells. CONCLUSION: This study revealed the role of B-cell TCL1A expression in TLS formation and its effect on OSCC prognosis. These findings highlight TCL1A as a novel target for OSCC immunotherapy.

Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs.

BACKGROUND: Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known. METHODS: A typical von Hippel-Lindau tumor suppressor (VHL)-PROTAC 14C-A947 (BRM degrader)-was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing. Bile duct-cannulated (BDC) rats allowed the elucidation of in vivo clearance pathways. Distribution kinetics was evaluated in the tissues and tumors of mice to support PK-PD correlation. In vitro studies enabled the evaluation of cell uptake mechanisms and cell retention properties. RESULTS: Here, we show that A947 quickly distributes into rat tissues after IV dosing, where it accumulates and is retained in tissues such as the lung and liver although it undergoes fast clearance from circulation. Similar uptake/retention kinetics enable tumor growth inhibition over 2-3 weeks in a lung cancer model. A947 quickly excretes in the bile of rats. Solute carrier (SLC) transporters are involved in hepatocyte uptake of PROTACs. Sustained BRM protein degradation is seen after extensive washout that supports prolonged cell retention of A947 in NCI-H1944 cells. A947 tissue exposure and pharmacodynamics are inversely correlated in tumors. CONCLUSIONS: Plasma sampling for VHL-PROTAC does not represent the tissue concentrations necessary for efficacy. Understanding of tissue uptake and retention could enable less frequent IV administration to be used for therapeutic dosing.

Proteolysis-targeting chimeras (PROTACs) are a type of potential cancer medicine designed to target proteins primarily present in tumours. There is limited data on how it is absorbed, distributed, metabolised and excreted from tissues. Here, we studied the tissue distribution of synthetic PROTAC molecules labelled with radioactivity following intravenous injection in rodent models. We find that PROTAC can rapidly distribute to target tumour tissues and its prolonged retention within the tumour cells can contribute to prevention of further tumour growth, as demonstrated in the lung cancer model. These findings suggest the evaluation of PROTAC therapeutic effectiveness directly from tumour tissues provides more relevant assessment than sampling from blood circulation, which may have implications for a reduction in intravenous dosing.

Automated detection and classification of concealed objects using infrared thermography and convolutional neural networks.

This paper presents a study on the effectiveness of a convolutional neural network (CNN) in classifying infrared images for security scanning. Infrared thermography was explored as a non-invasive security scanner for stand-off and walk-through concealed object detection. Heat generated by human subjects radiates off the clothing surface, allowing detection by an infrared camera. However, infrared lacks in penetration capability compared to longer electromagnetic waves, leading to less obvious visuals on the clothing surface. ResNet-50 was used as the CNN model to automate the classification process of thermal images. The ImageNet database was used to pre-train the model, which was further fine-tuned using infrared images obtained from experiments. Four image pre-processing approaches were explored, i.e., raw infrared image, subject cropped region-of-interest (ROI) image, K-means, and Fuzzy-c clustered images. All these approaches were evaluated using the receiver operating characteristic curve on an internal holdout set, with an area-under-the-curve of 0.8923, 0.9256, 0.9485, and 0.9669 for the raw image, ROI cropped, K-means, and Fuzzy-c models, respectively. The CNN models trained using various image pre-processing approaches suggest that the prediction performance can be improved by the removal of non-decision relevant information and the visual highlighting of features.

Assessment of the feasibility of human amniotic membrane stem cell-derived cardiomyocytes in vitro.

Myocardial infarction (MI) is a leading cause of death worldwide, resulting in extensive loss of cardiomyocytes and subsequent heart failure. Inducing cardiac differentiation of stem cells is a potential approach for myocardial regeneration therapy to improve post-MI prognosis. Mesenchymal stem cells (MSCs) have several advantages, including immune privilege and multipotent differentiation potential. This study aimed to explore the feasibility of chemically inducing human amniotic membrane MSCs (hAMSCs) to differentiate into cardiomyocytes in vitro. Human amniotic membrane (AM) samples were obtained from routine cesarean sections at Far Eastern Memorial Hospital. The isolated cells exhibited spindle-shaped morphology and expressed surface antigens CD73, CD90, CD105, and CD44, while lacking expression of CD19, CD11b, CD19, CD45, and HLA-DR. The SSEA-1, SSEA-3, and SSEA-4 markers were also positive, and the cells displayed the ability for tri-lineage differentiation into adipocytes, chondrocytes, and osteoblasts. The expression levels of MLC2v, Nkx2.5, and MyoD were analyzed using qPCR after applying various protocols for chemical induction, including BMP4, ActivinA, 5-azacytidine, CHIR99021, and IWP2 on hAMSCs. The group treated with 5 ng/ml BMP4, 10 ng/ml Activin A, 10 µM 5-azacytidine, 7.5 µM CHIR99021, and 5 µM IWP 2 expressed the highest levels of these genes. Furthermore, immunofluorescence staining demonstrated the expression of α-actinin and Troponin T in this group. In conclusion, this study demonstrated that hAMSCs can be chemically induced to differentiate into cardiomyocyte-like cells in vitro. However, to improve the functionality of the differentiated cells, further investigation of inductive protocols and regimens is needed.