Pan-cancer analysis of heterogeneity of tumor mutational burden and genomic mutation under treatment pressure.

BACKGROUND: High tumor mutational burden (TMB) is one of the widely researched predictive biomarkers of immune checkpoint inhibitors and has been shown to be closely related with response to immunotherapy in multiple cancer types. However, for patients who have failed conventional therapy and are about to undergo immunotherapy, there is no consensus recommendation on the timing of tumor sampling for TMB analysis, and the effects of different therapies on TMB have not been clarified. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure. PATIENTS AND METHODS: We retrospectively collected the available genomic and therapeutic information from 8051 samples across 15 tumor types (>50 samples/tumor) found in 30 published studies and investigated the distribution and heterogeneity of TMB under treatment across diverse cohorts. RESULTS: This integrated analysis has shown anticancer treatments increased TMB. Significant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-naïve TMB, including breast, prostate, and pediatric cancers. For different cancer therapies, chemotherapy was prone to be correlated with an increased TMB in most cancer types. Meanwhile, the fraction of the TMB-high category of breast, prostate, and bladder cancers and glioma increased significantly after chemotherapy. Several actionable genes including ERS1 and NF1 in breast cancer, as well as some prognostic markers including TERT in bladder cancer and IDH1 in glioma, were significantly changed in post-chemotherapy tumors compared to treatment-naïve tumors. CONCLUSION: Our study reveals the heterogeneity of TMB under treatment across diverse cancer types and provides evidences that chemotherapy was associated with increases in TMB as well as the fraction of TMB-high category, suggesting that resampling tumor tissues for calculating post-chemotherapy TMB could be a better option for predicting the response to immunotherapy, especially for tumors with initially low TMB.

[Auxiliary diagnostic value of T cells spot test of Mycobacterium tuberculosis infection for pulmonary and extra-pulmonary tuberculosis among the elderly].

OBJECTIVE: To evaluate the auxiliary diagnostic value of T cells spot test of Mycobacterium tuberculosis infection (T-SPOT.TB) for pulmonary and extra-pulmonary tuberculosis among the elderly. METHODS: A total of 173 elderly patients at ages of 60 years and older and with suspected tuberculosis that were admitted to People's Hospital of Xinjiang Uygur Autonomous Region during the period from October 2022 through February 2024 were enrolled, and all patients underwent T-SPOT.TB, acid fast staining and GeneXpert MTB/RIF tests. The etiological tests of MTB served as a gold standard, and the diagnostic values of T-SPOT.TB, acid fast staining and GeneXpert MTB/RIF tests for pulmonary and extra-pulmonary tuberculosis were compared among the elderly patients. RESULTS: Of the 173 elderly patients suspected of tuberculosis, there were 44 patients definitely diagnosed with pulmonary tuberculosis, 30 cases with extra-pulmonary tuberculosis, and 99 cases without tuberculosis. The sensitivities of T-SPOT.TB, acid fast staining and GeneXpert MTB/RIF tests were 86.5%, 27.0% and 54.1% for diagnosis of tuberculosis. The sensitivities of T-SPOT.TB were 86.4% and 86.7% for diagnosis of pulmonary tuberculosis and extra-pulmonary tuberculosis, with an 80.8% specificity for diagnosis of tuberculosis. The sensitivities of GeneXpert MTB/RIF were 56.8% and 50.0% for diagnosis of pulmonary tuberculosis and extra-pulmonary tuberculosis, with a 100.0% specificity each, and the sensitivities of acid fast staining were 31.8% and 20.0% for diagnosis of pulmonary tuberculosis and extra-pulmonary tuberculosis, with a 100.0% specificity each. In addition, the areas under the receiver operating characteristic curve were 0.836, 0.635 and 0.770 for diagnosis of tuberculosis with T-SPOT.TB, acid fast staining and GeneXpert MTB/RIF tests among the elderly patients, respectively. CONCLUSIONS: T-SPOT.TB has a high auxiliary diagnostic value for both pulmonary and extra-pulmonary tuberculosis among elderly patients.

[Intraperitoneal chemotherapy for colorectal cancer peritoneal metastasis].

Peritoneal metastasis is one of the common site of colorectal cancer metastasis and associated with a poor prognosis. The core strategy for colorectal cancer peritoneal metastasis primarily revolves around a comprehensive treatment approach with cytoreductive surgery and systemic chemotherapy as the mainstay, supplemented by intraperitoneal chemotherapy. As an important supplement to treatment, intraperitoneal chemotherapy has broad application prospects. The main modalities are hyperthermic intraperitoneal chemotherapy (HIPEC), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), early postoperative intraperitoneal chemotherapy (EPIC), sequential postoperative intraperitoneal chemotherapy (SPIC), normothermic intraperitoneal chemotherapy (NIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). To promote the standardized application of intraperitoneal chemotherapy, further research on the mechanisms underlying peritoneal metastasis of colorectal cancer, selection of effective intraperitoneal chemotherapy agents, determination of optimal timing and administration protocols, exploration of the feasibility of sequential intraperitoneal chemotherapy and conduction of valuable basic and clinical research are currently needed. This paper will review the development and origins of intraperitoneal chemotherapy, treatment modalities, as well as the current application status and prospects of various treatment approaches in the context of peritoneal metastasis of colorectal cancer.

Computer-aided drug discovery strategies for novel therapeutics for prostate cancer leveraging next-generating sequencing data.

INTRODUCTION: Prostate cancer (PC) is the most common malignancy and accounts for a significant proportion of cancer deaths among men. Although initial therapy success can often be observed in patients diagnosed with localized PC, many patients eventually develop disease recurrence and metastasis. Without effective treatments, patients with aggressive PC display very poor survival. To curb the current high mortality rate, many investigations have been carried out to identify efficacious therapeutics. Compared to de novo drug designs, computational methods have been widely employed to offer actionable drug predictions in a fast and cost-efficient way. Particularly, powered by an increasing availability of next-generation sequencing molecular profiles from PC patients, computer-aided approaches can be tailored to screen for candidate drugs. AREAS COVERED: Herein, the authors review the recent advances in computational methods for drug discovery utilizing molecular profiles from PC patients. Given the uniqueness in PC therapeutic needs, they discuss in detail the drug discovery goals of these studies, highlighting their translational values for clinically impactful drug nomination. EXPERT OPINION: Evolving molecular profiling techniques may enable new perspectives for computer-aided approaches to offer drug candidates for different tumor microenvironments. With ongoing efforts to incorporate new compounds into large-scale high-throughput screens, the authors envision continued expansion of drug candidate pools.

Mortality associated with polymyalgia rheumatica in the United States in the 1999-2020 period: a multiple-cause-of-death study.

OBJECTIVE: Multicause-of-death methods were used to analyze mortality and leading causes of death associated with polymyalgia rheumatica (PMR) in the United States from 1999 to 2020. MATERIALS AND METHODS: We analyzed mortality data from the Centers for Disease Control and Prevention (CDC) Data analysis system and selected death certificates that listed PMR as the cause of death based on the International Statistical Classification of Diseases and Related Health Problems (ICD-10) category code. Relevant mortality rates, number of deaths and historical trends were analyzed. The number of PMR-related deaths and age-standardized mortality rate (ASMR) trend charts were made using Excel 2010 version and trend lines were added. RESULTS: Over the last 22 years, the total number of PMR-related deaths in the United States was 15,421 women (89.8%), a ratio of about 1:9 men to women. When PMR is listed as the underlying cause of death, the ASMR for women and men (per 100,000 people) is approximately 1.8-5.1:1, and when it is listed as the non-underlying cause of death, it is 1.8-3.3:1. PMR deaths are more frequent in individuals aged 70 years and above, with patients aged 80 years and above being most affected. Among different ethnicities, the highest number of deaths was found in Caucasians, followed by Black or African American. When it comes to causes of death, heart disease still ranks first, followed by cancer. In addition, we also found that when PMR combined with malignant tumors as a multiple cause of death, the number of female deaths was higher than that of male deaths, the overall number of deaths of both showed an upward trend, and the overall ASMR of both showed a downward trend. CONCLUSIONS: In the past 22 years, we have observed a low mortality rate of PMR in the United States. However, for patients with PMR, especially elderly women, medical workers should be vigilant and pay attention to whether they are combined with other complications, such as malignant neoplasms, and make timely diagnosis and treatment to further reduce the mortality rate of patients with PMR.

Integration of Computational Pipeline to Streamline Efficacious Drug Nomination and Biomarker Discovery in Glioblastoma.

Glioblastoma multiforme (GBM) is the deadliest, most heterogeneous, and most common brain cancer in adults. Not only is there an urgent need to identify efficacious therapeutics, but there is also a great need to pair these therapeutics with biomarkers that can help tailor treatment to the right patient populations. We built patient drug response models by integrating patient tumor transcriptome data with high-throughput cell line drug screening data as well as Bayesian networks to infer relationships between patient gene expression and drug response. Through these discovery pipelines, we identified agents of interest for GBM to be effective across five independent patient cohorts and in a mouse avatar model: among them are a number of MEK inhibitors (MEKis). We also predicted phosphoglycerate dehydrogenase enzyme (PHGDH) gene expression levels to be causally associated with MEKi efficacy, where knockdown of this gene increased tumor sensitivity to MEKi and overexpression led to MEKi resistance. Overall, our work demonstrated the power of integrating computational approaches. In doing so, we quickly nominated several drugs with varying known mechanisms of action that can efficaciously target GBM. By simultaneously identifying biomarkers with these drugs, we also provide tools to select the right patient populations for subsequent evaluation.

Computational Modeling to Identify Drugs Targeting Metastatic Castration-Resistant Prostate Cancer Characterized by Heightened Glycolysis.

Metastatic castration-resistant prostate cancer (mCRPC) remains a deadly disease due to a lack of efficacious treatments. The reprogramming of cancer metabolism toward elevated glycolysis is a hallmark of mCRPC. Our goal is to identify therapeutics specifically associated with high glycolysis. Here, we established a computational framework to identify new pharmacological agents for mCRPC with heightened glycolysis activity under a tumor microenvironment, followed by in vitro validation. First, using our established computational tool, OncoPredict, we imputed the likelihood of drug responses to approximately 1900 agents in each mCRPC tumor from two large clinical patient cohorts. We selected drugs with predicted sensitivity highly correlated with glycolysis scores. In total, 77 drugs predicted to be more sensitive in high glycolysis mCRPC tumors were identified. These drugs represent diverse mechanisms of action. Three of the candidates, ivermectin, CNF2024, and P276-00, were selected for subsequent vitro validation based on the highest measured drug responses associated with glycolysis/OXPHOS in pan-cancer cell lines. By decreasing the input glucose level in culture media to mimic the mCRPC tumor microenvironments, we induced a high-glycolysis condition in PC3 cells and validated the projected higher sensitivity of all three drugs under this condition (p < 0.0001 for all drugs). For biomarker discovery, ivermectin and P276-00 were predicted to be more sensitive to mCRPC tumors with low androgen receptor activities and high glycolysis activities (AR(low)Gly(high)). In addition, we integrated a protein-protein interaction network and topological methods to identify biomarkers for these drug candidates. EEF1B2 and CCNA2 were identified as key biomarkers for ivermectin and CNF2024, respectively, through multiple independent biomarker nomination pipelines. In conclusion, this study offers new efficacious therapeutics beyond traditional androgen-deprivation therapies by precisely targeting mCRPC with high glycolysis.

Integration of Pan-Cancer Cell Line and Single-Cell Transcriptomic Profiles Enables Inference of Therapeutic Vulnerabilities in Heterogeneous Tumors.

Single-cell RNA sequencing (scRNA-seq) greatly advanced the understanding of intratumoral heterogeneity by identifying distinct cancer cell subpopulations. However, translating biological differences into treatment strategies is challenging due to a lack of tools to facilitate efficient drug discovery that tackles heterogeneous tumors. Developing such approaches requires accurate prediction of drug response at the single-cell level to offer therapeutic options to specific cell subpopulations. Here, we developed a transparent computational framework (nicknamed scIDUC) to predict therapeutic efficacies on an individual cell basis by integrating single-cell transcriptomic profiles with large, data-rich pan-cancer cell line screening data sets. This method achieved high accuracy in separating cells into their correct cellular drug response statuses. In three distinct prospective tests covering different diseases (rhabdomyosarcoma, pancreatic ductal adenocarcinoma, and castration-resistant prostate cancer), the predicted results using scIDUC were accurate and mirrored biological expectations. In the first two tests, the framework identified drugs for cell subpopulations that were resistant to standard-of-care (SOC) therapies due to intrinsic resistance or tumor microenvironmental effects, and the results showed high consistency with experimental findings from the original studies. In the third test using newly generated SOC therapy-resistant cell lines, scIDUC identified efficacious drugs for the resistant line, and the predictions were validated with in vitro experiments. Together, this study demonstrates the potential of scIDUC to quickly translate scRNA-seq data into drug responses for individual cells, displaying the potential as a tool to improve the treatment of heterogenous tumors. SIGNIFICANCE: A versatile method that infers cell-level drug response in scRNA-seq data facilitates the development of therapeutic strategies to target heterogeneous subpopulations within a tumor and address issues such as treatment failure and resistance.

[Exploration and practice of novel models of cellular therapy and hematopoietic stem cell transplantation].

Hematopoietic stem cell transplantation provides an effective cure for various hematological diseases, especially malignant hematological diseases, its treatment system has been continuously optimized, the source of donors has been expanding, the indications have been expanding, and the therapeutic effect has also made breakthroughs to a certain extent. At present, the status of hematopoietic stem cell transplantation technology in most hematological diseases is still unshakable, but the recurrence of the primary disease and complications related to hematopoietic stem cell transplantation are still two major clinical challenges that affect the long-term survival and quality of life of patients. Cell therapy represented by chimeric antigen receptor T (CAR-T) has made breakthrough progress in the treatment of refractory/recurrent B-cell malignancies. Compared with traditional drugs, cell therapy has unique in vivo metabolic characteristics, relying on immune specific recognition and the repair ability of stem cells. It is currently emerging in the treatment of blood tumors and the management of transplant complications. Multiple clinical studies have preliminarily demonstrated a new diagnostic and therapeutic model combining cell therapy with hematopoietic stem cell transplantation.

[Safety and efficacy of donor-derived chimeric antigen receptor T-cell therapy in patients with relapsed B-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation].

Objective: To investigated the safety and efficacy of donor-derived CD19+ or sequential CD19+ CD22+ chimeric antigen receptor T-cell (CAR-T) therapy in patients with B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: The data of 22 patients with B-ALL who relapsed after allo-HSCT and who underwent donor-derived CAR-T therapy at the Zhujiang Hospital of Southern Medical University and the 920th Hospital of Joint Logistics Support Force of the People's Liberation Army of China from September 2015 to December 2022 were retrospectively analyzed. The primary endpoint was overall survival (OS), and the secondary endpoints were event-free survival (EFS), complete remission (CR) rate, and Grade 3-4 adverse events. Results: A total of 81.82% (n=18) of the 22 patients achieved minimal residual disease-negative CR after CAR-T infusion. The median follow-up time was 1037 (95% CI 546-1509) days, and the median OS and EFS were 287 (95% CI 132-441) days and 212 (95% CI 120-303) days, respectively. The 6-month OS and EFS rates were 67.90% (95% CI 48.30%-84.50%) and 58.70% (95% CI 37.92%-79.48%), respectively, and the 1-year OS and EFS rates were 41.10% (95% CI 19.15%-63.05%) and 34.30% (95% CI 13.92%-54.68%), respectively. Grade 1-2 cytokine release syndrome occurred in 36.36% (n=8) of the patients, and grade 3-4 occurred in 13.64% of the patients (n=3). Grade 2 and 4 graft-versus-host disease occurred in two patients. Conclusion: Donor-derived CAR-T therapy is safe and effective in patients with relapsed B-ALL after allo-HSCT.

[Evaluation of differences in quality of life in patients with chronic graft-versus-host disease].

Objective: To evaluate the status of, differences in, and factors influencing quality of life (QoL) in patients with chronic graft-versus-host disease (GVHD). Methods: From September 2021 to February 2023, a cross-sectional study of 140 patients with chronic GVHD was conducted at our center. Symptom burden was assessed by the Lee Symptomatology Scale (LSS), and QoL was assessed by the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36) (version 1) and five-level EuroQoL five-dimensional questionnaire (EQ-5D-5L). Results: Data from 140 respondents, including 32 (22.9%) with mild chronic GVHD, 87 (62.1%) with moderate chronic GVHD, and 21 (15.0%) with severe chronic GVHD, were analyzed. Of the respondents, 61.4% were male, and the median transplantation age was 34 (15-68) years. The primary diagnoses were acute myeloid leukemia (50.0%), acute lymphoblastic leukemia (20.0%), and myelodysplastic syndrome (15.0%). The common chronic GVHD-affected organs included the skin in 74 patients (52.9%), the eyes in 57 patients (40.7%), and the liver in 50 patients (35.7%). Among the whole cohort, the eye (20.48±23.75), psychological (16.13±17.00), and oral (13.66±20.55) scores were highest in the LSS group. The physiological function (36.07±11.13), social function (36.10±10.68), and role-emotional functioning (38.36±11.88) scores were lowest in the SF-36 group. The EQ-5D index was 0.764. The total LSS scores for mild, moderate, and severe chronic GVHD were 6.51±6.15, 10.07±5.61, and 20.90±10.09, respectively. The SF-36 physical component scores (PCSs) were 43.12±6.38, 40.73±7.14, and 36.97±6.97, respectively, and the mental component scores (MCSs) were 43.00±8.47, 38.90±9.52, and 28.96±9.63, respectively. The EQ-5D values were 0.810±0.124, 0.762±0.179, and 0.702±0.198, respectively. The multivariate analysis showed that the overall symptom burden (ß=-0.517), oral symptom burden (ß=-0.456), National Institute of Health (NIH) criteria for the eyes (ß=-0.376), and nutrition-related symptom burden (ß=-0.211) were significantly negatively correlated with the PCS. The NIH score (ß=-0.260) was negatively correlated with the MCS score. Oral symptom burden (ß=-0.400), joint/fascia NIH criteria (ß=-0.332), number of involved systems (ß=-0.253), overall NIH criteria (ß=-0.205), and number of immunosuppressants taken (ß=-0.171) were significantly negatively correlated with the EQ-5D score (all P<0.05). Medium to strong correlations were found between the EQ-5D score and the SF-36 score (|r|=0.384-0.571, P<0.001). Conclusions: The QoL of patients with chronic GVHD is impaired, and the more severe the disease, the poorer the QoL. Overall symptom burden, severity of eyes, and oral symptom burden were the most important factors affecting QoL.

Prospects of targeting JAK/STAT signal transduction pathways for vasculitis.

Vasculitis is the inflammation of blood vessels caused by autoimmunity and/or autoinflammation, and its etiology and pathogenesis remain largely unknown. The Janus kinase (JAK) and Signal transduction Transcription Activator (STAT) signal transduction pathways are a group of molecules involved in the major pathways by which many cytokines exert and integrate their functions, and their dysregulation has been implicated in the pathogenesis of a variety of autoimmune diseases. However, current data supporting the role of the JAK/STAT pathway in the development of vasculitis is limited. In terms of treatment, glucocorticoids and immunosuppressants have been the standard therapy. However, because of the huge burden of treatment side effects, people have long waited for new treatment options. JAK inhibitors reduce the production of multiple cytokines and inhibit inflammation by targeting the JAK/STAT pathway, and have the advantage of rapidly acting in oral formulations, reducing glucocorticoid dependence and associated adverse events, especially in refractory cases. Therefore, JAK inhibitors are expected to be a promising drug for the treatment of vasculitis.

[Clinical characteristics of hospitalized children with respiratory syncytial virus infection and risk prediction of severe illness during the post-COVID-19 era in Kunming].

Objective: To compare the epidemiological and clinical characteristics of hospitalized children with respiratory syncytial virus (RSV) infection in Kunming among the pre-and post-COVID-19 era, and to establish a prediction model for severe RSV infection in children during the post-COVID-19 period. Methods: This was a retrospective study. Clinical and laboratory data were collected from 959 children hospitalized with RSV infection in the Department of Pulmonary and Critical Care Medicine at Kunming Children's Hospital during January to December 2019 and January to December 2023. Patients admitted in 2019 were defined as the pre-COVID-19 group, while those admitted in 2023 were classified as the post-COVID-19 group. Epidemiological and clinical characteristics were compared between the two groups. Subsequently, comparison of the clinical severity among the two groups was performed based on propensity score matching (PSM). Furthermore, the subjects in the post-COVID-19 group were divided into severe and non-severe groups based on clinical severity. Chi-square test and Mann-Whitney U test were used for pairwise comparison between groups, and multivariate Logistic regression was applied for the identification of independent risk factors and construction of the prediction model. The receiver operating characteristic (ROC) curve and calibration curve were employed to evaluate the predictive performance of this model. Results: Among the 959 children hospitalized with RSV infection, there were 555 males and 404 females, with an onset age of 15.4 (7.3, 28.5) months. Of which, there were 331 cases in the pre-COVID-19 group and 628 cases in the post-COVID-19 group. The peak period of RSV hospitalization in the post-COVID-19 group were from May to October 2023, and the monthly number of inpatients for each of these months were as follows: 72 cases (11.5%), 98 cases (15.6%), 128 cases (20.4%), 101 cases (16.1%), 65 cases (10.4%), and 61 cases (9.7%), respectively. After PSM for general data, 267 cases were matched in each group. The proportion of wheezing in the post-COVID-19 group was lower than that in the pre-COVID-19 group (109 cases (40.8%) vs. 161 cases (60.3%), χ2=20.26, P<0.001), while the incidences of fever, tachypnea, seizures, severe case, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein and interleukin-6 levels were all higher than those in the pre-COVID-19 group (146 cases (54.7%) vs. 119 cases (44.6%), 117 cases (43.8%) vs. 89 cases (33.3%), 37 cases (13.9%) vs. 14 cases (5.2%), 69 cases (25.8%) vs. 45 cases (16.9%), 3.6 (1.9, 6.4) vs. 2.3 (1.8, 4.6), 9.9 (7.1, 15.2) vs. 7.8 (4.5, 13.9) mg/L, 20.5 (15.7, 30.4) vs. 17.2 (11.0, 26.9) ng/L, χ2=5.46, 6.36, 11.47, 6.42, Z=4.13, 3.06, 2.96, all P<0.05). There were 252 cases and 107 cases with co-infection in the post-and pre-COVID-19 groups, respectively. The proportion of triple and quadruple infection in the post-COVID-19 group was higher than that in the pre-COVID-19 group (59 cases (23.4%) vs. 13 cases (12.1%), 30 cases (11.9%) vs. 5 cases (4.7%), χ2=5.94, 4.46, both P<0.05). Among the 252 cases with co-infection in post-COVID-19 group, the most prevalent pathogens involving in co-infections, in order, were Mycoplasma pneumoniae 56 cases (22.2%), Influenza A virus 53 cases (21.0%), Rhinovirus 48 cases (19.0%), Parainfluenza virus 35 cases (13.9%), and Adenovirus 28 cases (11.1%).The result of multivariate Logistic regression showed that age (OR=0.70, 95%CI 0.62-0.78, P<0.001), underlying diseases (OR=10.03, 95%CI 4.10-24.55, P<0.001), premature birth (OR=6.78, 95%CI 3.53-13.04, P<0.001), NLR (OR=1.85, 95%CI 1.09-3.15, P=0.023), and co-infection (OR=1.28, 95%CI 1.18-1.38, P<0.001) were independently associated with the development of severe RSV infection in the post-COVID-19 group. The ROC curve of the prediction model integrating the above five factors indicated an area under the curve of 0.85 (95%CI 0.80-0.89, P<0.001), with an optimal cutoff of 0.21, a sensitivity of 0.83 and a specificity of 0.80. The calibration curve showed that the predicted probability in this model did not differ significantly from the actual probability (P=0.319). Conclusions: In the post-COVID-19 era in Kunming, the peak in pediatric hospitalizations for RSV infection was from May to October, with declined incidence of wheezing and increased incidence of fever, tachypnea, seizures, severe cases, and rates of triple and quadruple co-infections. Age, underlying diseases, premature birth, NLR, and co-infection were identified as independent risk factors for severe RSV infection in the post-COVID-19 period. In this study, a risk prediction model for severe pediatric RSV infection was established, which had a good predictive performance.

[Impact of hyperoxia on the phenotype of pulmonary artery smooth muscle cells].

Objective: To investigate the influence of varied oxygen (O2) concentration environments on the phenotypic transformation of pulmonary artery smooth muscle cells (PASMC) and the mechanism of pulmonary hypertension. Methods: Primary rat PASMC were isolated and cultured through the process of enzymatic digestion. Following identification, the stable passaged PASMC were subjected to a 6-hour incubation in sealed containers with normal O2 content (group C) and relative O2 content comprising 55% (group H55), 75% (group H75), and 95% (group H95). mRNA and protein expression of α-Actin (α-SMA), smooth muscle 22α (SM22α), osteopontin (OPN), and matrix metalloproteinase-2 (MMP-2) were measured using real-time quantitative PCR and western blot analysis. Results: The H55 group displayed no significant difference from the C group in terms of mRNA and relative protein expression levels for α-SMA, SM22α, OPN, and MMP-2 (all P>0.05). On the other hand, groups H75 and H95 exhibited a reduction in mRNA and relative protein expression of α-SMA and SM22α, along with an increase in mRNA and relative protein expression of OPN and MMP-2 when compared with both the C and H55 groups (all P<0.05). The H95 group showed a higher relative mRNA expression of MMP-2 as compared to the H75 group (P<0.05). Conclusions: Oxygen concentration environments of 75% or higher can serve as the foundation for the pathogenesis of pulmonary hypertension, essentially by inducing a phenotypic transformation in PASMC towards adopting a robust secretory function. This induction is contingent upon the concentration of oxygen present.

[Application effect of a dual release system of androgen and its antagonist in the repair of full-thickness burn wounds in mice].

Objective: To explore the optimal ratio of dihydrotestosterone and hydroxyflutamide (hereinafter referred to as DH), construct a dual release system of androgen and its antagonist, and analyze the application effect of this system in the repair of full-thickness burn wounds in mice. Methods: This study was an experimental study. The HaCaT cells were divided into blank group (without drug culture), low baseline group, medium baseline group, and high baseline group according to the random number table (the same grouping method below), and the last three groups of cells were cultured by adding three different ratios of DH. Under a medium ratio, the mass of dihydrotestosterone in the three baseline groups from low to high was 1.4, 2.8, and 4.0 µg, respectively, and the mass of hydroxyflutamide was 1.2, 1.6, and 2.0 µg, respectively. On this basis, under a small ratio, the mass of dihydrotestosterone was reduced by half and the mass of hydroxyflutamide was increased by half; under a large ratio, the mass of dihydrotestosterone was increased by half and the mass of hydroxyflutamide was reduced by half. After culture of 2 days, the cell proliferation level was detected by cell counting kit 8 (n=4). Sixteen 6-8-week-old male BALB/c mice were used to establish a full-thickness burn wound on the back and divided into blank group, small ratio group, medium ratio group, and large ratio group, with 4 mice in each group. On post injury day (PID) 7, normal saline containing different ratios of DH was locally dropped to the wounds of mice in the last three groups of mice (the total mass of DH in the three ratio groups from small to large was 127.5, 165.0, and 202.5 µg, respectively, and the mass ratios of dihydrotestosterone to hydroxyflutamide (hereinafter referred to as drug mass ratio) were 8∶9, 8∶3, and 8∶1, respectively), afterwards, the administration was repeated every 48 hours until PID 27; normal saline was dropped to the wound of mice in blank group at the aforementioned time points. The wound healing status on PID 0 (immediately), 7, 14, 21, and 28 was observed, and the wound healing rates on PID 7, 14, 21, and 28 were calculated (n=4). On PID 28, the wound tissue was taken, which was stained with hematoxylin and eosin for observing re-epithelialization and with Masson for observing collagen fibers, and the proportion of collagen fibers was analyzed (n=3). Twenty 6-8-week-old male BALB/c mice were used to establish a full-thickness burn wound on the back and divided into ordinary scaffold group, small proportion scaffold group, medium proportion scaffold group, and large proportion scaffold group (with 5 mice in each group). On PID 7, the wound was continuously dressed with a polycaprolactone scaffold without drug and a polycaprolactone scaffold containing DH with a drug mass ratio of 1∶3, 1∶1, or 3∶1 (i.e. the dual release system of androgen and its antagonist, with total mass of DH being about 1.7 mg) prepared by using electrospinning technology until the end of the experiment. Histopathological analyses of tissue (n=3) at the same time points as those in the previous animal experiment were performed. On PID 7 and 14, the wound exudates were collected and the relative abundance of bacterial communities was analyzed using 16S ribosomal RNA high-throughput sequencing (n=3). Results: After culture of 2 days, under a small ratio, the proliferation levels of HaCaT cells in low baseline group and high baseline group were significantly higher than the level in blank group (P<0.05). As the time after injury prolonged, the wounds of all four groups of mice continued to shrink. On PID 14, the wound healing rate of mice in large ratio group was 72.5% (61.7%, 75.1%), which was close to 53.3% (49.5%, 64.4%) in blank group (P>0.05); the wound healing rates of mice in small and medium ratio groups were 74.2% (71.0%, 84.2%) and 70.4% (65.1%, 74.4%), respectively, which were significantly higher than the rate in blank group (with both Z values being -2.31, P<0.05). On PID 21, the wound healing rate of mice in small ratio group was significantly higher than that in blank group (Z=-2.31, P<0.05). On PID 28, the wounds of mice in the three ratio groups were completely re-epithelialized and the epidermis was thicker than that in blank group; compared with that in blank group, the collagen fiber content in the wound tissue of mice in the three ratio groups was higher and arranged more orderly, and the proportions of collagen fibers in the wound tissue of mice in small and large ratio groups were significantly increased (P<0.05). On PID 28, the wounds of mice in ordinary scaffold group were partially epithelialized, while the wounds of mice in the three proportion scaffold groups were almost completely epithelialized. Among them, the wounds of mice in small proportion scaffold group had the thickest epidermis. The proportion of collagen fibers in the wound tissue of mice in small proportion scaffold group was significantly increased compared with that in ordinary scaffold group (P<0.05). On PID 7, the bacterial communities with high relative abundance in the wound exudation of mice in the four groups included bacteria of Corynebacterium, Staphylococcus, and Rhodococcus. On PID 14, the bacterial communities with high relative abundance in the wound exudation of mice in the four groups included bacteria of Stenotrophomonas, Rhodococcus, and Staphylococcus, and the number of bacterial species in the wound exudation of mice in the three proportion scaffold groups was more than that in ordinary scaffold group. Conclusions: When the drug mass ratio is relatively small, DH has the effect of promoting the proliferation of HaCaT cells. The ratio of 8∶9 is the optimal mass ratio of dihydrotestosterone to hydroxyflutamide, and DH with this mass ratio can promote re-epithelialization and collagen deposition of full-thickness burn wounds in mice, and promote wound healing. The constructed dual release system of androgen and its antagonist with DH in a 1∶3 drug mass ratio contributes to the re-epithelialization and collagen deposition of the full-thickness burn wounds in mice, and can improve the diversity of wound microbiota.

A Web Application for Predicting Drug Combination Efficacy Using Monotherapy Data and IDACombo.

We recently reported a computational method (IDACombo) designed to predict the efficacy of cancer drug combinations using monotherapy response data and the assumptions of independent drug action. Given the strong agreement between IDACombo predictions and measured drug combination efficacy in vitro and in clinical trials, we believe IDACombo can be of immediate use to researchers who are working to develop novel drug combinations. While we previously released our method as an R package, we have now created an R Shiny application to allow researchers without programming experience to easily utilize this method. The app provides a graphical interface which enables users to easily generate efficacy predictions with IDACombo using provided data from several high-throughput cell line screens or using custom, user-provided data.

Sex-related differences in delayed doxorubicin-induced cardiac dysfunction in C57BL/6 mice.

Cancer survivors may experience long-term cardiovascular complications due to chemotherapeutic drugs such as doxorubicin (DOX). The exact mechanism of delayed DOX-induced cardiotoxicity has not been fully elucidated. Sex is an important risk factor for DOX-induced cardiotoxicity. In the current study, we identified sex differences in delayed DOX-induced cardiotoxicity and determined the underlying molecular determinants of the observed sexual dimorphism. Five-week-old male and female mice were administered intraperitoneal injections of DOX (4 mg/kg/week) or saline for 6 weeks. Echocardiography was performed 5 weeks after the last dose of DOX to evaluate cardiac function. Thereafter, mice were sacrificed and gene expression of markers of apoptosis, senescence, and inflammation was measured by PCR in hearts and livers. Proteomic profiling of the heart from both sexes was conducted to determine differentially expressed proteins (DEPs). Only DOX-treated male, but not female, mice demonstrated cardiac dysfunction, cardiac atrophy, and upregulated cardiac expression of Nppb and Myh7. No sex-related differences were observed in DOX-induced expression of most apoptotic, senescence, and pro-inflammatory markers. However, the gene expression of Trp53 was significantly reduced in hearts of DOX-treated female mice only. The anti-inflammatory marker Il-10 was significantly reduced in hearts of DOX-treated male mice only, while the pro-inflammatory marker Il-1α was significantly reduced in livers of DOX-treated female mice only. Gene expression of Tnf-α was reduced in hearts of both DOX-treated male and female mice. Proteomic analysis identified several DEPs after DOX treatment in a sex-specific manner, including anti-inflammatory acute phase proteins. This is the first study to assess sex-specific proteomic changes in a mouse model of delayed DOX-induced cardiotoxicity. Our proteomic analysis identified several sexually dimorphic DEPs, many of which are associated with the anti-inflammatory marker Il-10.

The safety and feasibility of same-day discharge for the management of patients undergoing pulmonary lobectomy.

OBJECTIVES: Is same-day discharge mode safe and feasible for thoracoscopic lobectomy? This study assesses the safety and feasibility of same-day discharge for patients undergoing thoracoscopic lobectomy. METHODS: We conducted a prospective cohort study from January to December 2022, all patients undergoing thoracoscopic lobectomy were screened for eligibility, and participating eligible patients were separated into a same-day discharge lobectomy (SDDL) group and an inpatient lobectomy (InpL) group based upon length of stay. All discharged patients underwent 30-day postoperative follow-up performed by a team of medical professionals. In addition, eligible patients that underwent thoracoscopic lobectomy from January to December 2021 were included in the historical lobectomy (HisL) group. RESULTS: Of the 52 patients that met the eligibility criteria for same-day discharge, 17 were discharged within 24 h after surgery. In the SDDL group, of whom 1 (5.9%) underwent emergency treatment and readmission within 30 days after surgery due to a pulmonary infection, no patients experienced complications such as reoperation, air leakage, atelectasis, chylothorax, or blood transfusion events during the follow-up period. No differences in overall postoperative complication rates were detected between the SDDL and InpL groups (P>0.05), there was a non-significantly higher rate of readmission and emergency visits in the SDDL group relative to the other two groups (P>0.05). CONCLUSIONS: These results emphasize the safety and feasibility of same-day discharge for patients undergoing thoracoscopic lobectomy, it may further revolutionize the general approach to the hospitalization of thoracoscopic lobectomy patients.