Management and Mechanisms of Diarrhea Induced by Tyrosine Kinase Inhibitors in Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer.

Breast cancer has the highest incidence among female malignancies, significantly impacting women's health. Recently, numerous HER2-targeted therapies have achieved excellent clinical outcomes. Currently, anti-HER2 drugs are divided into three main categories: monoclonal antibodies, small-molecule tyrosine kinase inhibitors, and antibody-coupled drugs (ADCs). The main toxic side effects of small molecule TKI-based therapy are diarrhea, hand-foot syndrome, rash, nausea, and vomiting. Diarrhea is a potential predictor of tumor response, affecting up to 95% of cancer patients treated with TKIs. Severe gastrointestinal toxicity can result in the need for dose reductions and treatment interruptions. This not only compromises the efficacy of TKIs but also deteriorates human nutrition and quality of life. The majority of individuals develop diarrhea within 7 days of starting treatment, with approximately 30% developing grade 3 or higher diarrhea within 2-3 days of starting treatment. The severity of diarrhea typically correlates with the dosage of most TKIs. Current prevention and management strategies are primarily empirical, focusing on symptom alleviation rather than addressing the toxicological mechanisms underlying TKI-induced diarrhea. Consequently, anti-diarrheal drugs are often less effective in managing this condition in cancer patients receiving TKIs. Moreover, our understanding of the toxicological mechanisms responsible for such diarrhea remains limited, underscoring the urgent need to identify these mechanisms in order to develop effective anti-diarrheal medications tailored to this specific context. This review aims to elucidate management approaches and mechanisms for diarrhea induced by TKIs during HER2-positive breast cance.

Breast cancer has the highest incidence among female malignancies, significantly impacting women's health. In recent years, numerous HER2-targeted therapies have been developed, including lapatinib, neratinib, tucatinib, and pyrotinib. However, second-generation tyrosine kinase inhibitors (TKIs) often cause severe gastrointestinal toxicity, necessitating dose reduction and treatment interruption. This not only compromises the efficacy of TKIs but also deteriorates nutritional status and quality of life. Diarrhea is a potential predictor of tumor response and is the second most common adverse event, affecting up to 95% of cancer patients treated with TKIs. Approximately 30% of these patients experience grade 3 or higher diarrhea within just 2-3 days of initiating TKI treatment. The severity of diarrhea typically correlates with the dosage of most TKIs. Current prevention and management strategies are primarily empirical, focusing on symptom alleviation rather than addressing the toxicological mechanisms underlying TKI-induced diarrhea. Consequently, anti-diarrheal drugs are often less effective in managing this condition in cancer patients receiving TKIs. Moreover, our understanding of the toxicological mechanisms responsible for such diarrhea remains limited, underscoring the urgent need to identify these mechanisms to develop effective antidiarrheal medications tailored for this specific context. This review aims to elucidate management approaches for diarrhea induced by HER2 tyrosine kinase inhibitors during breast cancer treatment.

Optimizing the affinity selection mass spectrometry workflow for efficient identification and ranking of potent USP1 inhibitors.

An optimized Affinity Selection-Mass Spectrometry (AS-MS) workflow has been developed for the efficient identification of potent USP1 inhibitors. USP1 was immobilized on agarose beads, ensuring low small molecule retention, efficient protein capture, and protein stability. The binding affinity of 49 compounds to USP1 was evaluated using the optimized AS-MS method, calculating binding index (BI) values for each compound. Biochemical inhibition assays validated the AS-MS results, revealing a potential correlation between higher BI values and lower IC50 values. This optimized workflow enables rapid identification of high-quality USP1 inhibitor hits, facilitating structure-activity relationship studies and accelerating the discovery of potential cancer therapeutics.

RT-RPA-PfAgo detection platform for one-tube simultaneous typing diagnosis of human respiratory syncytial virus.

Human respiratory syncytial virus (HRSV) is the most prevalent pathogen contributing to acute respiratory tract infections (ARTI) in infants and young children and can lead to significant financial and medical costs. Here, we developed a simultaneous, dual-gene and ultrasensitive detection system for typing HRSV within 60 minutes that needs only minimum laboratory support. Briefly, multiplex integrating reverse transcription-recombinase polymerase amplification (RT-RPA) was performed with viral RNA extracted from nasopharyngeal swabs as a template for the amplification of the specific regions of subtypes A (HRSVA) and B (HRSVB) of HRSV. Next, the Pyrococcus furiosus Argonaute (PfAgo) protein utilizes small 5'-phosphorylated DNA guides to cleave target sequences and produce fluorophore signals (FAM and ROX). Compared with the traditional gold standard (RT-qPCR) and direct immunofluorescence assay (DFA), this method has the additional advantages of easy operation, efficiency and sensitivity, with a limit of detection (LOD) of 1 copy/µL. In terms of clinical sample validation, the diagnostic accuracy of the method for determining the HRSVA and HRSVB infection was greater than 95%. This technique provides a reliable point-of-care (POC) testing for the diagnosis of HRSV-induced ARTI in children and for outbreak management, especially in resource-limited settings.

A narrative review: research progress of adjuvant intensive endocrine therapy for early breast cancer.

Background and Objective: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) is the most prevalent subtype of all BCs. The primary treatment modality is endocrine therapy (ET). Traditional adjuvant ET for early-stage breast cancer (EBC) has undergone extensive exploration and is relatively well-established. However, patients at high risk of recurrence may still experience early relapse, necessitating consideration of intensified adjuvant ET to reduce recurrence risk. The objective of this narrative review is to examine various strategies for intensifying adjuvant ET in EBC, thoroughly analyze key clinical studies, and summarize the most effective treatment approaches supported by current evidence-based medicine. Furthermore, it addresses unresolved challenges that necessitate further refinement and investigation. Methods: As of March 2024, a comprehensive literature search, compilation, and analysis were conducted across PubMed, Baidu Scholar, ClinicalTrials.gov, and relevant academic conferences. Key Content and Findings: There are numerous methods to intensify adjuvant ET: (I) combining ovarian function suppression (OFS) to reduce estrogen levels in the body and induce a state of artificial menopause to enhance the efficacy of ET; (II) individual extension of the duration of ET based on patients' varying risks of recurrence, with high-risk patients covering two peak recurrence periods; (III) the addition of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) can significantly extend invasive disease-free survival and reduce the risk of recurrence, serving as the main intensive treatment for high-risk patients; (IV) combination with bone-modifying drugs (BMD) can significantly reduce rates of bone metastasis and slightly enhance prognosis but is not commonly used in adjuvant settings; (V) combined with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, current studies only show a trend towards benefit in HR+ patients with germline BRCA1/2 mutations; more data are still needed to support its clinical benefit. This narrative review examines various strategies for intensifying adjuvant ET in EBC, critically evaluates key clinical studies, and summarizes the most effective treatment approaches supported by current evidence-based medicine. Furthermore, it addresses unresolved challenges that necessitate further refinement and investigation. Conclusions: In the context where traditional adjuvant ET is relatively well-established, the emergence of novel ET has notably addressed issues of endocrine resistance more effectively. Various intensified adjuvant ET has shown potential in further reducing recurrence risk among high-risk patients. However, additional research and time are essential to determine the optimal approaches for intensified adjuvant ET.

Increased ONECUT2 induced by Helicobacter pylori promotes gastric cancer cell stemness via an AKT-related pathway.

Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/ß-catenin phosphorylation. AKT/ß-catenin phosphorylation facilitates ß-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and ß-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/ß-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.

Global incidence and mortality trends of gastric cancer and predicted mortality of gastric cancer by 2035.

OBJECTIVE: To study the historical global incidence and mortality trends of gastric cancer and predicted mortality of gastric cancer by 2035. METHODS: Incidence data were retrieved from the Cancer Incidence in Five Continents (CI5) volumes I-XI, and mortality data were obtained from the latest update of the World Health Organization (WHO) mortality database. We used join-point regression analysis to examine historical incidence and mortality trends and used the package NORDPRED in R to predict the number of deaths and mortality rates by 2035 by country and sex. RESULTS: More than 1,089,000 new cases of gastric cancer and 769,000 related deaths were reported in 2020. The average annual percent change (AAPC) in the incidence of gastric cancer from 2003 to 2012 among the male population, South Korea, Japan, Malta, Canada, Cyprus, and Switzerland showed an increasing trend (P > 0.05); among the female population, Canada [AAPC, 1.2; (95%Cl, 0.5-2), P < 0.05] showed an increasing trend; and South Korea, Ecuador, Thailand, and Cyprus showed an increasing trend (P > 0.05). AAPC in the mortality of gastric cancer from 2006 to 2015 among the male population, Thailand [3.5 (95%cl, 1.6-5.4), P < 0.05] showed an increasing trend; Malta Island, New Zealand, Turkey, Switzerland, and Cyprus had an increasing trend (P > 0.05); among the male population aged 20-44, Thailand [AAPC, 3.4; (95%cl, 1.3-5.4), P < 0.05] showed an increasing trend; Norway, New Zealand, The Netherlands, Slovakia, France, Colombia, Lithuania, and the USA showed an increasing trend (P > 0.05). It is predicted that the mortality rate in Slovenia and France's female population will show an increasing trend by 2035. It is predicted that the absolute number of deaths in the Israeli male population and in Chile, France, and Canada female population will increase by 2035. CONCLUSION: In the past decade, the incidence and mortality of gastric cancer have shown a decreasing trend; however, there are still some countries showing an increasing trend, especially among populations younger than 45 years. Although mortality in most countries is predicted to decline by 2035, the absolute number of deaths due to gastric cancer may further increase due to population growth.

Discovering Potential Mechanisms of Intervertebral Disc Disease Using Systematic Mendelian Randomization of Human Circulating Immunocytomics.

BACKGROUND: Although intervertebral disc degeneration (IVDD) is a critical factor in many spine-related diseases and has an extremely high prevalence in the aging population, the potential pathogenesis remains to be clarified entirely. Immune cells have been found to perform an essential function during the onset and progression of IVDD in recent years. Therefore, we explored the association between immune cell characteristics and IVDD through Mendelian randomization (MR) analysis and further delved into the mediating role of potential metabolites. METHODS: Based on the MR analysis, the association of 731 immune cell phenotypes and 1400 metabolites on IVDD were assessed. Single nucleotide polymorphisms were closely associated the expression levels of immune cell characteristics and the concentrations of metabolites and have been used as instrumental variables for deducing them as risk factors or protective factors for IVDD. In addition, mediation analyses have been performed to identify potential metabolite mediators between immune cell characteristics and IVDD. RESULTS: MR analysis identified 27 immune cell phenotypes and 79 metabolites significantly associated with IVDD. In addition, mediation analysis was performed by selecting the immune cell phenotype that most significantly increased the risk of IVDD - CD86 on monocytes. A total of 4 metabolite-mediated mediation relationships were revealed (3 b-hydroxy-5-cholenoic acid, X-22509, N-acetyl-L-glutamine, and N2-acetyl, N6, N6-dimethyllysine). CONCLUSIONS: The findings of this analysis identified underlying association between immune cell phenotypes, metabolite, and IVDD that may serve as predictive and prognostic clinical biomarkers and benefit IVDD pathogenesis research.

Penfluridol regulates p62 / Keap1 / Nrf2 signaling pathway to induce ferroptosis in osteosarcoma cells.

The cure rate for patients with osteosarcoma (OS) has stagnated over the past few decades. Penfluridol, a first-generation antipsychotic, has demonstrated to prevent lung and esophageal malignancies from proliferation and metastasis. However, the effect of penfluridol on OS and its underlying molecular mechanism remains unclear. This study revealed that penfluridol effectively inhibited cell proliferation and migration, and induced G2/M phase arrest in OS cells. In addition, penfluridol treatment was found to increased reactive oxygen species (ROS) levels in OS cells. Combined with the RNA-Seq results, the anti-OS effect of penfluridol was hypothesized to be attributed to the induction of ferroptosis. Western blot results showed that penfluridol promoted intracellular Fe2+ concentration, membrane lipid peroxidation, and decreased intracellular GSH level to induce ferroptosis. Further studies showed that p62/Keap1/Nrf2 signaling pathway was implicated in penfluridol-induced ferroptosis in OS cells. Overexpression of p62 effectively reversed penfluridol-induced ferroptosis. In vivo, penfluridol effectively inhibited proliferation and prolonged survival in xenograft tumor model. Therefore, penfluridol is a promising drug targeting OS in the future.

Enhancing pediatric asthma management through multifaceted health education.

BACKGROUND: Pediatric asthma is a significant public health issue that impacts the quality of life of children globally. Traditional management approaches focus on symptom control and medication adherence but often overlook the comprehensive educational needs of patients and their families. A multifaceted health education approach may offer a more holistic strategy in managing pediatric asthma, especially in outpatient settings. AIM: To evaluate the efficacy of a comprehensive health education strategy in improving disease management, medication adherence, and quality of life among children with asthma in outpatient settings. METHODS: In total, 100 pediatric patients with severe asthma were enrolled from January 2021 to November 2022 and randomly allocated to a control group (n = 50) or an observation group (n = 50). The control group received standard nursing care, including basic nursing interventions and health education upon admission. In contrast, the observation group was exposed to a broad spectrum of health education methodologies, including internet-based hospital systems, social media channels, one-on-one verbal education, informational brochures, slide presentations, telephone check-ins, animated videos, and illustrated health education manuals. Data on asthma management knowledge, symptom control, quality of life [St. George's Respiratory Questionnaire (SGRQ)], treatment adherence, and nursing satisfaction were collected and analyzed. RESULTS: The scores of the observation group in knowledge areas, such as medication, home care, disease understanding, symptom management, prevention strategies, and nutritional guidance, were significantly higher than those of the control group (P < 0.05). In addition, the observation group exhibited greater symptom control, improved quality of life based on their SGRQ scores, and higher treatment adherence post-intervention (P < 0.05). Nursing satisfaction was also rated higher in the observation group across all evaluated areas (P < 0.05). CONCLUSION: Implementing a diversified health education approach in pediatric asthma management significantly enhances disease understanding, symptom management, and treatment adherence, leading to improved quality of life for affected children. These findings underscore the importance of multifaceted clinical health education in augmenting disease awareness and facilitating continuous improvements in asthma control rates, highlighting the potential benefits of incorporating comprehensive educational strategies into pediatric asthma care protocols.

Development and validation of prediction model for fall accidents among chronic kidney disease in the community.

Background: The population with chronic kidney disease (CKD) has significantly heightened risk of fall accidents. The aim of this study was to develop a validated risk prediction model for fall accidents among CKD in the community. Methods: Participants with CKD from the China Health and Retirement Longitudinal Study (CHARLS) were included. The study cohort underwent a random split into a training set and a validation set at a ratio of 70 to 30%. Logistic regression and LASSO regression analyses were applied to screen variables for optimal predictors in the model. A predictive model was then constructed and visually represented in a nomogram. Subsequently, the predictive performance was assessed through ROC curves, calibration curves, and decision curve analysis. Result: A total of 911 participants were included, and the prevalence of fall accidents was 30.0% (242/911). Fall down experience, BMI, mobility, dominant handgrip, and depression were chosen as predictor factors to formulate the predictive model, visually represented in a nomogram. The AUC value of the predictive model was 0.724 (95% CI 0.679-0.769). Calibration curves and DCA indicated that the model exhibited good predictive performance. Conclusion: In this study, we constructed a predictive model to assess the risk of falls among individuals with CKD in the community, demonstrating good predictive capability.

Development of a risk prediction model for radiation dermatitis following proton radiotherapy in head and neck cancer using ensemble machine learning.

PURPOSE: This study aims to develop an ensemble machine learning-based (EML-based) risk prediction model for radiation dermatitis (RD) in patients with head and neck cancer undergoing proton radiotherapy, with the goal of achieving superior predictive performance compared to traditional models. MATERIALS AND METHODS: Data from 57 head and neck cancer patients treated with intensity-modulated proton therapy at Kaohsiung Chang Gung Memorial Hospital were analyzed. The study incorporated 11 clinical and 9 dosimetric parameters. Pearson's correlation was used to eliminate highly correlated variables, followed by feature selection via LASSO to focus on potential RD predictors. Model training involved traditional logistic regression (LR) and advanced ensemble methods such as Random Forest and XGBoost, which were optimized through hyperparameter tuning. RESULTS: Feature selection identified six key predictors, including smoking history and specific dosimetric parameters. Ensemble machine learning models, particularly XGBoost, demonstrated superior performance, achieving the highest AUC of 0.890. Feature importance was assessed using SHAP (SHapley Additive exPlanations) values, which underscored the relevance of various clinical and dosimetric factors in predicting RD. CONCLUSION: The study confirms that EML methods, especially XGBoost with its boosting algorithm, provide superior predictive accuracy, enhanced feature selection, and improved data handling compared to traditional LR. While LR offers greater interpretability, the precision and broader applicability of EML make it more suitable for complex medical prediction tasks, such as predicting radiation dermatitis. Given these advantages, EML is highly recommended for further research and application in clinical settings.

Impact of Postoperative Bracing Following Spinal Fusion for Degenerative Lumbar Conditions: An Updated Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: There is a lack of consensus on the use of postoperative bracing for lumbar degenerative conditions. Spine surgeons typically determine whether to apply postoperative braces based primarily on clinical experience rather than robust, evidence-based medical data. Thus, the present study sought to assess the impact of postoperative bracing on clinical outcomes, complications, and fusion rates following lumbar fusion surgery in patients with degenerative spinal conditions. METHODS: Only randomized controlled studies published between January 1990 and 20 October 2023 were included in this meta-analysis. The primary outcome measures consisted of pre- and postoperative assessments of the Oswestry Disability Index (ODI) and visual analog scale (VAS) scores. Improvements in VAS and ODI scores were analyzed in the early postoperative period (1 month after operation) and at final follow-up, respectively. The analysis also encompassed fusion rates and complications. RESULTS: Five studies with 362 patients were included in the present meta-analysis. In the early postoperative period, the brace group showed a relatively better improvement in ODI scores compared with the no-brace group (19.47 vs 18.18), although this difference was not statistically significant (P = 0.34). Similarly, during the late postoperative period, the brace group demonstrated a slightly greater improvement in VAS scores in comparison to the no-brace group (4.05 vs 3.84), but this difference did not reach statistical significance (P = 0.30). The complication rate was relatively lower in the brace group compared with the no-brace group (14.9% vs 17.4%), although there was no statistical difference between the 2 groups (P = 0.83). Importantly, there were no substantial differences in fusion rates between patients with or without braces. CONCLUSION: The present meta-analysis revealed that the implementation of a brace following lumbar fusion surgery did not yield substantial differences in terms of postoperative pain relief, functional recovery, complication rates, or fusion rates when compared with cases where no brace was employed. CLINICAL RELEVANCE: This meta-analysis provides valuable insights into the clinical impact of postoperative bracing following lumbar fusion surgery for degenerative spinal conditions.

Miniature computational spectrometer with a plasmonic nanoparticles-in-cavity microfilter array.

Optical spectrometers are essential tools for analysing light‒matter interactions, but conventional spectrometers can be complicated and bulky. Recently, efforts have been made to develop miniaturized spectrometers. However, it is challenging to overcome the trade-off between miniaturizing size and retaining performance. Here, we present a complementary metal oxide semiconductor image sensor-based miniature computational spectrometer using a plasmonic nanoparticles-in-cavity microfilter array. Size-controlled silver nanoparticles are directly printed into cavity-length-varying Fabry‒Pérot microcavities, which leverage strong coupling between the localized surface plasmon resonance of the silver nanoparticles and the Fabry‒Pérot microcavity to regulate the transmission spectra and realize large-scale arrayed spectrum-disparate microfilters. Supported by a machine learning-based training process, the miniature computational spectrometer uses artificial intelligence and was demonstrated to measure visible-light spectra at subnanometre resolution. The high scalability of the technological approaches shown here may facilitate the development of high-performance miniature optical spectrometers for extensive applications.

Cytotoxicity effect and transcriptome analysis of PCV3-infected cells revealed potential viral pathogenic mechanisms.

Porcine circovirus type 3 (PCV3) has become an important pathogen in the global swine industry and poses a threat to pig health, but its pathogenic mechanism remains unknown. In this study, we constructed an innovative, linear infectious clone of PCV3 for rescuing the virus, and explored the transcriptome of infected cells to gain insights into its pathogenic mechanisms. Subsequently, an in vivo experiment was conducted to evaluate the pathogenicity of the rescued virus in pig. PCV3 nucleic acid was distributed across various organs, indicating systemic circulation via the bloodstream and viremia. Immunohistochemical staining also revealed a significant presence of PCV3 antigens in the spleen, lungs, and lymph nodes, indicating that PCV3 had tropism for these organs. Transcriptome analysis of infected ST cells revealed differential expression of genes associated with apoptosis, immune responses, and cellular metabolism. Notably, upregulation of genes related to the hypoxia-inducible factor-1 pathway, glycolysis, and the AGE/RAGE pathway suggests activation of inflammatory responses, ultimately leading to onset of disease. These findings have expanded our understanding of PCV3 pathogenesis, and the interplay between PCV3 and host factors.

Does glial lipid dysregulation alter sleep in Alzheimer's and Parkinson's disease?

In this opinion article, we discuss potential connections between sleep disturbances observed in Alzheimer's disease (AD) and Parkinson's disease (PD) and the dysregulation of lipids in the brain. Research using Drosophila has highlighted the role of glial-mediated lipid metabolism in sleep and diurnal rhythms. Relevant to AD, the formation of lipid droplets in glia, which occurs in response to elevated neuronal reactive oxygen species (ROS), is required for sleep. In disease models, this process is disrupted, arguing a connection to sleep dysregulation. Relevant to PD, the degradation of neuronally synthesized glucosylceramides by glia requires glucocerebrosidase (GBA, a PD-associated risk factor) and this regulates sleep. Loss of GBA in glia causes an accumulation of glucosylceramides and neurodegeneration. Overall, research primarily using Drosophila has highlighted how dysregulation of glial lipid metabolism may underlie sleep disturbances in neurodegenerative diseases.

Unbiasing Enhanced Sampling on a High-Dimensional Free Energy Surface with a Deep Generative Model.

Biased enhanced sampling methods that utilize collective variables (CVs) are powerful tools for sampling conformational ensembles. Due to their large intrinsic dimensions, efficiently generating conformational ensembles for complex systems requires enhanced sampling on high-dimensional free energy surfaces. While temperature-accelerated molecular dynamics (TAMD) can trivially adopt many CVs in a simulation, unbiasing the simulation to generate unbiased conformational ensembles requires accurate modeling of a high-dimensional CV probability distribution, which is challenging for traditional density estimation techniques. Here we propose an unbiasing method based on the score-based diffusion model, a deep generative learning method that excels in density estimation across complex data landscapes. We demonstrate that this unbiasing approach, tested on multiple TAMD simulations, significantly outperforms traditional unbiasing methods and can generate accurate unbiased conformational ensembles. With the proposed approach, TAMD can adopt CVs that focus on improving sampling efficiency and the proposed unbiasing method enables accurate evaluation of ensemble averages of important chemical features.

Roles of DJ41_1407 and DJ41_1408 in Acinetobacter baumannii ATCC19606 Virulence and Antibiotic Response.

Acinetobacter baumannii is a major cause of nosocomial infections, and its highly adaptive nature and broad range of antibiotic resistance enable it to persist in hospital environments. A. baumannii often employs two-component systems (TCSs) to regulate adaptive responses and virulence-related traits. This study describes a previously uncharacterized TCS in the A. baumannii ATCC19606 strain, consisting of a transcriptional sensor, DJ41_1407, and its regulator, DJ41_1408, located adjacent to GacA of the GacSA TCS. Markerless mutagenesis was performed to construct DJ41_1407 and DJ41_1408 single and double mutants. DJ41_1408 was found to upregulate 49 genes and downregulate 43 genes, most of which were associated with carbon metabolism and other metabolic pathways, such as benzoate degradation. MEME analysis revealed a putative binding box for DJ41_1408, 5'TGTAAATRATTAYCAWTWAT3'. Colony size, motility, biofilm-forming ability, virulence, and antibiotic resistance of DJ41_1407 and DJ41_1408 single and double mutant strains were assessed against wild type. DJ41_1407 was found to enhance motility, while DJ41_1408 was found to upregulate biofilm-forming ability, and may also modulate antibiotic response. Both DJ41_1407 and DJ41_1408 suppressed virulence, based on results from a G. mellonella infection assay. These results showcase a novel A. baumannii TCS involved in metabolism, with effects on motility, biofilm-forming ability, virulence, and antibiotic response.

Comparative outcomes of obese and non-obese patients with lumbar disc herniation receiving full endoscopic transforaminal discectomy: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the impact of full endoscopic transforaminal discectomy (FETD) on clinical outcomes and complications in both obese and non-obese patients presenting with lumbar disc herniation (LDH). METHODS: A systematic search of relevant literature was conducted across various primary databases until November 18, 2023. Operative time and hospitalization were evaluated. Clinical outcomes included preoperative and postoperative assessments of the Oswestry Disability Index (ODI) and visual analogue scale (VAS) scores, conducted to delineate improvements at 3 months postoperatively and during the final follow-up, respectively. Complications were also documented. RESULTS: Four retrospective studies meeting inclusion criteria provided a collective cohort of 258 patients. Obese patients undergoing FETD experienced significantly longer operative times compared to non-obese counterparts (P = 0.0003). Conversely, no statistically significant differences (P > 0.05) were observed in hospitalization duration, improvement of VAS for back and leg pain scores at 3 months postoperatively and final follow-up, improvement of ODI at 3 months postoperatively and final follow-up. Furthermore, the overall rate of postoperative complications was higher in the obese group (P = 0.02). The obese group demonstrated a total incidence of complications of 17.17%, notably higher than the lower rate of 9.43% observed in the non-obese group. CONCLUSION: The utilization of FETD for managing LDH in individuals with obesity is associated with prolonged operative times and a higher total complication rate compared to their non-obese counterparts. Nevertheless, it remains a safe and effective surgical intervention for treating herniated lumbar discs in the context of obesity.

The safety and efficacy of neoadjuvant immunochemotherapy following laparoscopic gastrectomy for gastric cancer: a multicentre real-world clinical study.

BACKGROUND: The safety and efficacy of neoadjuvant immunochemotherapy (nICT) for locally advanced gastric cancer (LAGC) remain controversial. METHODS: Patients with LAGC who received either nICT or neoadjuvant chemotherapy (nCT) at 3 tertiary referral teaching hospitals in China between January 2016 and October 2022 were analyzed. After propensity-score matching (PSM), comparing the radiological response, pathological response rate, perioperative outcomes, and early recurrence between the two groups. RESULTS: After PSM, 585 patients were included, with 195 and 390 patients comprising the nICT and nCT groups, respectively. The nICT group exhibited a higher objective response rate (79.5% vs. 59.0%; P <0.001), pathological complete response rate (14.36% vs. 6.41%; P =0.002) and major pathological response rate (39.49% vs. 26.15%; P =0.001) compared with the nCT group. The incidence of surgical complications (17.44% vs. 16.15%, P =0.694) and the proportion of perioperative textbook outcomes (80.0% vs. 81.0%; P =0.767) were similar in both groups. The nICT group had a significantly lower proportion of early recurrence than the nCT group (29.7% vs. 40.8%; P =0.047). Furthermore, the multivariable logistic analysis revealed that immunotherapy was an independent protective factor against early recurrence [odds ratio 0.62 (95% CI 0.41-0.92); P =0.018]. No significant difference was found in neoadjuvant therapy drug toxicity between the two groups (51.79% vs. 45.38%; P =0.143). CONCLUSIONS: Compared with nCT, nICT is safe and effective, which significantly enhanced objective and pathological response rates and reduced the risk for early recurrence among patients with LAGC. TRIAL REGISTRATION: Clinical Trials.gov.

The safety, feasibility, and oncological outcomes of laparoscopic completion total gastrectomy for remnant gastric cancer: a prospective study with 3-year follow-up (FUGES-004 study).

BACKGROUND: The efficacy of laparoscopic completion total gastrectomy (LCTG) for remnant gastric cancer (RGC) remains controversial. METHODS: The primary outcome was postoperative morbidity within 30 days after surgery. Secondary outcomes included 3-year disease-free survival (DFS), 3-year overall survival (OS), and recurrence. Inverse probability treatment weighted (IPTW) was used to balance the baseline between LCTG and OCTG. RESULTS: Final analysis included 46 patients with RGC who underwent LCTG at the FJMUUH between June 2016 and June 2020. The historical control group comprised of 160 patients who underwent open completion total gastrectomy (OCTG) in the six tertiary teaching hospitals from CRGC-01 study. After IPTW, no significant difference was observed between the LCTG and OCTG groups in terms of incidence (LCTG vs. OCTG: 28.0 vs. 35.0%, P =0.379) or severity of complications within 30 days after surgery. Compared with OCTG, LCTG resulted in better short-term outcomes and faster postoperative recovery. However, the textbook outcome rate was comparable between the two groups (45.9 vs. 32.8%, P =0.107). Additionally, the 3-year DFS and 3-year OS of LCTG were comparable to those of OCTG (DFS: log-rank P =0.173; OS: log-rank P =0.319). No significant differences in recurrence type, mean recurrence time, or 3-year cumulative hazard of recurrence were observed between the two groups (all P >0.05). Subgroup analyses and concurrent comparisons demonstrated similar trends. CONCLUSIONS: This prospective study suggested that LCTG was noninferior to OCTG in both short-term and long-term outcomes. In experienced centers, LCTG may be considered as a viable treatment option for RGC.