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Zuo-Huan Meng,1,* Wen-Yuan Ma,1,* Ying Wang,2 Ya-Rong Li,2 Jing Zhang,3 Yin-Fang Liu,4 Xin-Ke Zhao,5,6 Chun-He Da6 1Institute of Traditional Chinese Medicine, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, People’s Republic of China; 2Department of Pharmacy, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, People’s Republic of China; 3Nutrition Department, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, People’s Republic of China; 4Respiratory Medicine, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, People’s Republic of China; 5Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China; 6The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zuo-Huan Meng, Institute of Traditional Chinese Medicine, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, 730900, People’s Republic of China, Tel +8609438813373, Email 441390739@qq.com Chun-He Da, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, 730900, People’s Republic of China, Tel +8609438810612, Email dachunhedch@outlook.comBackground: “Pneumonia Prevention No.1” belongs to ‘traditional Chinese medicine prescription for prevention of viral pneumonia and influenza’ was urgently formulated by Notice on Printing the Novel Coronavirus Diagnosis and Treatment Scheme for COVID-19 (Trial Version 3) and Traditional Chinese Medicine Prevention and Treatment Scheme for COVID-19 in Hubei Province (Trial). Because the prescription drug has the bidirectional regulation function of human immune function, moderate improvement of immune function can effectively resist virus invasion, while excessive immune function will produce immune overresponse. Excessive immune response will aggravate the condition of patients with COVID-19, resulting in the death of severe patients.Methods: Twenty medical workers aged 20– 60 years old, who had no immune disease, no current disease and healthy physical examination, were selected as participants. The participants took Hubei “Pneumonia Prevention No.1” decoction, one dosage each day, twice a day, for 7 consecutive days. With the before-after control method, blood samples were collected from the median cubital veins before and after medication. Immunoglobulin IgA, IgG and IgM were measured by immunoturbidimetry, and T lymphocyte subsets CD3, CD4, CD8 and CD4/CD8 were measured by flow cytometry. The changes of indexes before and after medication were compared with SPPS 13.0 statistical software. The data were expressed by (mean ± standard deviation). T-test was adopted, and P < 0.05 was considered statistically significant (P < 0.05).Results: The results of this study show that in healthy participants, the immunoglobulin and T lymphocyte subsets did not differ significantly before and after drug administration (P > 0.05).Conclusion: Under normal drug administration circumstances, “Pneumonia Prevention No. 1” had no significant regulating effect on the immune system in a healthy population and did not increase the immune system capacity beyond a reasonable range. It is safe to be used as a prophylactic measure in healthy populations.Keywords: “Pneumonia Prevention No. 1”, healthy population, immunoglobulin, T lymphocyte, safe medication

Shih-Lung Cheng,1,2,&ast; Yi-Rong Li,3,&ast; Nicole Huang,4 Chong-Jen Yu,5 Hao-Chien Wang,5 Meng-Chih Lin,6 Kuo-Chin Chiu,7 Wu-Huei Hsu,8 Chiung-Zuei Chen,9 Chau-Chyun Sheu,10,11 Diahn-Warng Perng,12 Sheng-Hao Lin,13 Tsung-Ming Yang,14 Chih-Bin Lin,15 Chew-Teng Kor,16 Ching-Hsiung Lin13,17,18 1Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 220, Taiwan; 2Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli, Taoyuan, 320, Taiwan; 3Changhua Christian Hospital, Thoracic Medicine Research Center, Changhua, 500, Taiwan; 4Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 7Division of Chest, Department of Internal Medicine, Poh-Ai Hospital, Luodong, 265, Taiwan; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 9Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University, College of Medicine and Hospital, Tainan, 701, Taiwan; 10Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan; 11Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 12Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan; 13Department of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan; 14Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, 613, Taiwan; 15Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan; 16Big Data Center, Changhua Christian Hospital, Changhua, Changhua Christian Hospital, Changhua, 500, Taiwan; 17Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; 18Department of Recreation and Holistic Wellness, MingDao University, Changhua, 523, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ching-Hsiung LinDepartment of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, TaiwanTel +886-4-7238595Fax +886-4-7232942Email 47822@cch.org.twBackground: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has also imposed a substantial economic and social burden on the health care system. In Taiwan, a nationwide COPD pay-for-performance (P4P) program was designed to improve the quality of COPD-related care by introducing financial incentives for health care providers and employing a multidisciplinary team to deliver guideline-based, integrated care for patients with COPD, reducing adverse outcomes, especially COPD exacerbation. However, the results of a survey of the effectiveness of the pay-for-performance program in COPD management were inconclusive. To address this knowledge gap, this study evaluated the effectiveness of the COPD P4P program in Taiwan.Methods: This retrospective cohort study used data from Taiwan’s National Health Insurance claims database and nationwide COPD P4P enrollment program records from June 2016 to December 2018. Patients with COPD were classified into P4P and non-P4P groups. Patients in the P4P group were matched at a ratio of 1:1 based on age, gender, region, accreditation level, Charlson Comorbidity Index (CCI), and inhaled medication prescription type to create the non-P4P group. A difference-in-difference analysis was used to evaluate the influence of the P4P program on the likelihood of COPD exacerbation, namely COPD-related emergency department (ED) visit, intensive care unit (ICU) admission, or hospitalization.Results: The final sample of 14,288 patients comprised 7144 in each of the P4P and non-P4P groups. The prevalence of COPD-related ED visits, ICU admissions, and hospitalizations was higher in the P4P group than in the non-P4P group 1 year before enrollment. After enrollment, the P4P group exhibited a greater decrease in the prevalence of COPD-related ED visits and hospitalizations than the non-P4P group (ED visit: − 2.98%, p< 0.05, 95% confidence interval [CI]: − 0.277 to − 0.086; hospitalization: − 1.62%, p< 0.05, 95% CI: − 0.232 to − 0.020), whereas no significant difference was observed between the groups in terms of the changes in the prevalence of COPD-related ICU admissions.Conclusion: The COPD P4P program exerted a positive net effect on reducing the likelihood of COPD exacerbation, namely COPD-related ED visits and hospitalizations. Future studies should examine the long-term cost-effectiveness of the COPD P4P program.Keywords: COPD, pay-for-performance program, guideline-based, comprehensive care, exacerbation, financial incentive

Xiao-Chong Li,1,* Bang-Sheng Wu,1,2,* Yi Jiang,1,2 Jie Li,3 Ze-Fen Wang,3 Chao Ma,1 Yi-Rong Li,4 Jie Yao,5 Xiao-Qing Jin,6 Zhi-Qiang Li1 1Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, People’s Republic of China; 2Second Clinical School, Wuhan University, Wuhan, 430071, Hubei, People’s Republic of China; 3Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, People’s Republic of China; 4Department of Clinical Laboratory, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, People’s Republic of China; 5Department of Biological Repositories, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, People’s Republic of China; 6Emergency Department, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Qing Jin; Zhi-Qiang Li Email redjin@whu.edu.cn; lizhiqiang@whu.edu.cnBackground: Gut microbiota is associated with the progression of brain tumors. However, the alterations in gut microbiota observed during glioma growth and temozolomide (TMZ) therapy remain poorly understood.Methods: C57BL/6 male mice were implanted with GL261 glioma cells. TMZ/sodium carboxymethyl cellulose (SCC) was administered through gavage for five consecutive days (from 8 to 12 days after implantation). Fecal samples were collected before (T0) and on days 7 (T1), 14 (T2), and 28 (T3) after implantation. The gut microbiota was analyzed using 16S ribosomal DNA sequencing followed by absolute and relative quantitation analyses.Results: Nineteen genera were altered during glioma progression with the most dramatic changes in Firmicutes and Bacteroidetes phyla. During glioma growth, Lactobacillus abundance decreased in the early stage (T1) and then gradually increased (T2, T3); Intestinimonas abundance exhibited a persistent increase; Anaerotruncus showed a transient increase (T2) and then a subsequent decrease (T3). Similar longitudinal changes in Intestinimonas and Anaerotruncus abundance were observed in TMZ-treated mice, but the decrease of Anaerotruncus at T3 in the TMZ-treated group was less than that in the vehicle-treated group. No significant change in Lactobacillus was observed after TMZ treatment. Additionally, compared to vehicle control, TMZ treatment led to an enrichment in Akkermansia and Bifidobacterium.Conclusion: Glioma development and progression altered the composition of gut microbiota. Induction of Akkermansia and Bifidobacterium as well as the prevention of the reduction in Anaerotruncus may contribute to the anti-tumor effect of TMZ. This study helps to reveal the association between levels of specific microbial species in the gut and the anti-tumor effect of TMZ.Keywords: glioma, gut microbiota, temozolomide, tumor microenvironment, epigenetics

Yun-Ren Li,1 Kai-Jie Yu,1 Ying-Hsu Chang,2 Po-Hung Lin,1 I-Hung Shao,1 Hung-Cheng Kan,1 Yuan-Cheng Chu,1 Cheng-Keng Chuang,1 See-Tong Pang,1 Chung-Yi Liu2 1Division of Urology, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; 2Department of Urology, New Taipei Municipal Tu Cheng Hospital, Chang Gung Memorial Hospital and Chang Gung University, New Taipei City, TaiwanCorrespondence: Chung-Yi LiuDepartment of Urology, New Taipei Municipal Tu Cheng Hospital, Chang Gung Memorial Hospital and Chang Gung University, No. 6, Sec.2, JinCheng Road, Tucheng District, New Taipei City 236, TaiwanTel +886-2-22630588 ext. 6230Fax +886-2-22732688Email littleteco@gmail.comPurpose: We investigate factors that may contribute individually to bladder recurrence and find out the potential candidate to receive postoperative single dose intravesical chemotherapy.Materials and Methods: A total of 217 patients who were diagnosed with upper tract urothelial carcinoma (UTUC) underwent radical nephroureterectomy (RNU) between 2012 and 2016 in a single hospital. The possible risk factors that may contribute to development of bladder recurrence and overall survival were analysed. In order to find out the relationship between 1st bladder recurrence timing and outcome, we divided the 54 of 56 patients (2 patients with prophylactic intravesical chemotherapy excluded) with bladder recurrence after RNU into 2 groups, using the median time of 1st bladder recurrence and confirmed with the “minimum P-value” approach. The primary endpoint was the development of relapsing high-risk non-muscle invasive bladder cancer (NMIBC). The predictive factors of early recurrence and prognostic factors of survival were also analysed.Results: Among 217 patients with UTUC under RNU, intravesical recurrence occurred in 56 (25.8%) patients after a median follow-up of 35.2 (1.18– 83.34) months. On multivariable analysis, the preoperative ureter manipulation (p=0.009) was a significant predictor for the development of bladder tumours. As for overall survival, renal rein invasion (p=0.017), neutrophil to lymphocyte ratio (p=0.021), and main tumour size (p=0.015) were significant predictors. For 54 patients who developed bladder recurrence, the optimal cut-off point of early recurrence was determined to be 10 months after surgery (p=0.042). Preoperative ureter manipulation (p=0.005) and tumour located both pelvicalyceally and ureterically (P=0.042) were identified as independent factors associated with early recurrence. An end-stage renal disease history and surgical margin positive patient has more late bladder recurrence.Conclusion: Bladder recurrence was common in UTUC after RNU. Early bladder recurrence was associated with more relapsing high-risk NMIBC and preoperative ureter manipulation was identified as an independent factor associated with early recurrence.Keywords: intravesical recurrence, prognosis, radical nephroureterectomy, upper tract urothelial carcinoma

Lu Ding, Yu-Hang Gao, Ye-Ran Li, Yi-Fan Huang, Xin-Yu Wang, Xin Qi Department of Orthopaedic Surgery, The First Hospital of Jilin University, Jilin University, Chang Chun, People’s Republic of ChinaCorrespondence: Xin QiDepartment of Orthopaedic Surgery, The First Hospital of Jilin University, Jilin University, Xinmin St 71, Chang Chun, People’s Republic of ChinaTel +8615843073202Fax +86043181875600Email qixindoc@163.comPurpose: This study was to evaluate the metabolic score for insulin resistance (METS-IR) in female knee osteoarthritis (KOA) patients in a Chinese population. The associations between METS-IR and adipokines, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were investigated.Patients and Methods: This study included 4686 women from the 2011 China Health and Retirement Longitudinal Study (CHARLS) and 108 women who underwent arthroplasty of KOA at a university hospital. The clinical data were collected, and adipokines were evaluated. METS-IR was calculated in the KOA patients and compared with the national baseline. Logistic regression analyses were applied to explore the associations of METS-IR with adipokines, ESR, and CRP.Results: Receiver operating characteristic curve analysis of METS-IR and metabolic syndrome (MetS) in national baseline showed an area under the curve value of 0.851, with sensitivity of 0.777 and specificity of 0.772. The METS-IR of KOA was higher than the national baseline level (40.29 ± 6.98 vs 36.20 ± 8.50, P < 0.01), even after adjusting age. In addition, the METS-IR was higher in patients with KOA who had MetS than in those without metabolic syndrome (nMetS), even after adjusting body mass index (BMI). After adjusting for age and BMI, METS-IR was associated with CRP (OR 1.238, 95% confidence interval (CI) 1.088, 1.409, P < 0.01), ESR (OR 1.124, 95% CI 1.008, 1.254, P = 0.036), plasma leptin (OR 1.123, 95% CI 1.052, 1.199, P < 0.01), plasma resistin (OR 1.134, 95% CI 1.011, 1.271, P = 0.031), and plasma adiponectin (OR 0.865, 95% CI 0.771, 0.971, P = 0.014).Conclusion: METS-IR in female KOA was higher than that of the national baseline. The METS-IR was related to adipokine disorder and inflammatory activity. These findings suggest that METS-IR can be used to evaluate the degree of involvement of MetS in KOA.Keywords: knee osteoarthritis, metabolic syndrome, insulin resistance, metabolic score for insulin resistance

Autosomal-dominant spinocerebellar ataxias constitute a large, heterogeneous group of progressive neurodegenerative diseases with multiple types. To date, classical genetic studies have revealed 31 distinct genetic forms of spinocerebellar ataxias and identified 19 causative genes. Traditional positional cloning strategies, however, have limitations for finding causative genes of rare Mendelian disorders. Here, we used a combined strategy of exome sequencing and linkage analysis to identify a novel spinocerebellar ataxia causative gene, TGM6. We sequenced the whole exome of four patients in a Chinese four-generation spinocerebellar ataxia family and identified a missense mutation, c.1550T-G transition (L517W), in exon 10 of TGM6. This change is at a highly conserved position, is predicted to have a functional impact, and completely cosegregated with the phenotype. The exome results were validated using linkage analysis. The mutation we identified using exome sequencing was located in the same region (20p13-12.2) as that identified by linkage analysis, which cross-validated TGM6 as the causative spinocerebellar ataxia gene in this family. We also showed that the causative gene could be mapped by a combined method of linkage analysis and sequencing of one sample from the family. We further confirmed our finding by identifying another missense mutation c.980A-G transition (D327G) in exon seven of TGM6 in an additional spinocerebellar ataxia family, which also cosegregated with the phenotype. Both mutations were absent in 500 normal unaffected individuals of matched geographical ancestry. The finding of TGM6 as a novel causative gene of spinocerebellar ataxia illustrates whole-exome sequencing of affected individuals from one family as an effective and cost efficient method for mapping genes of rare Mendelian disorders and the use of linkage analysis and exome sequencing for further improving efficiency. [ABSTRACT FROM AUTHOR]

Exposure to radiation oncology (RO), which is a small and highly subspecialized field of oncology, during undergraduate or medical education is often limited. Coupled with reduced elective exposures during the COVID-19 pandemic, unsubstantiated concerns regarding the RO job market have led to a noticeable decline in residency applications and medical students who express an interest in the field. Here, we describe a summer education program piloted in our RO department at a comprehensive cancer center to provide premedical school students (ranging from high school to postbaccalaureate) early exposure to the specialty through clinical shadowing, research opportunities, journal club, and formal didactic lectures. Pre- and postprogram surveys were administered to these students to evaluate the change in knowledge in RO. A total of 8 students participated in the program. We found an increase in understanding of the specialty, high levels of interest in considering RO as a career, and positive feedback regarding the program overall. This study supports the role of early exposure and education in stimulating interest in future medical students to pursue RO as a career. Future efforts are needed to further develop and evaluate these education programs as well as disseminate the program more broadly., Competing Interests: Disclosures Arya Amini receives research support from RefleXion, Varian, and Genentech, and honoraria from AstraZeneca, Sanofi/Regeneron, and Takeda Pharmaceuticals. Yun Rose Li receives research support from NIH (High Risk-High Reward 1 DP5 OD033424-01) and honoraria from RadOnc Questions and participation on a Data Safety Monitoring Board or Advisory Board (City of Hope CPRMC). Artifical intelligence (AI) or AI-assisted technologies were not used in creation or preparation of this work., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

The use of synthetic antigen-presenting cells to activate and expand engineered T cells for the treatment of cancers typically results in therapies that are suboptimal in effectiveness and durability. Here we describe a high-throughput microfluidic system for the fabrication of synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells. Compared with rigid or elastic microspheres, the synthetic viscoelastic T-cell-activating cells (SynVACs) led to substantial enhancements in the expansion of human CD8 + T cells and to the suppression of the formation of regulatory T cells. Notably, activating and expanding chimaeric antigen receptor (CAR) T cells with SynVACs led to a CAR-transduction efficiency of approximately 90% and to substantial increases in T memory stem cells. The engineered CAR T cells eliminated tumour cells in a mouse model of human lymphoma, suppressed tumour growth in mice with human ovarian cancer xenografts, persisted for longer periods and reduced tumour-recurrence risk. Our findings underscore the crucial roles of viscoelasticity in T-cell engineering and highlight the utility of SynVACs in cancer therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Analyze the cancer screening status of the cancer screening program in urban areas in Shaanxi province in 2019-2020. Methods: The early diagnosis and early treatment project for urban cancers carried out high-risk population screening for 5 types of high-incidence malignant tumors (breast cancer, lung cancer, upper gastrointestinal cancer, liver cancer, and colorectal cancer) in urban areas. Three prefecture-level cities in Shaanxi province with a population of over 1 million (Xi'an, Baoji, and Shangluo) were selected, and 4 communities with a relatively good working foundation were selected in each city. The general population aged 45-74 years was surveyed on the principles of informed consent and voluntariness, and high-risk groups identified through the questionnaire were further subjected to free endoscopy, ultrasound, CT, and other clinical screenings. The high-risk rates, screening compliance rates, and positive detection rates of the above 5 types of malignant tumors were analyzed. Results: A total of 19 632 people completed the survey effectively, with the proportion of male participants (40.0%) lower than that of females (60.0%). A total of 10 102 high-risk groups were identified, with an initial screening high-risk rate of 51.5%, and the high-risk rates for the 5 types of cancers were 24.1% for breast cancer, 28.6% for lung cancer, 9.1% for upper gastrointestinal cancer, 4.0% for liver cancer, and 20.0% for colorectal cancer. Among the 14 960 person-time initially assessed as high-risk, 5 129 person-time received clinical screening, with a screening compliance rate of 34.3%. The number of people receiving clinical screening and the screening compliance rates for the 5 types of cancers were 1 192 (41.9%) for breast cancer, 2 081 (37.1%) for lung cancer, 574 (32.0%) for upper gastrointestinal cancer, 404 (51.3%) for liver cancer, and 878 (22.3%) for colorectal cancer, with positive detection numbers and rates of 179 (15.0%) for breast, 289 (13.9%) for lung, 9 (1.6%) for upper gastrointestinal, 14 (3.5%) for suspected liver, and 67 (7.6%) for colorectal, respectively. Conclusion: The cancer screening status of the cancer screening program in urban areas in Shaanxi province is beneficial for the detection of precancerous lesions and early cancer patients, and improving the early diagnosis and treatment rate of patients, but the public participation rate is not high, and the project management model and technical plan need to be further improved.

Oncogenic mutations (such as in KRAS) can dysregulate transcription and replication, leading to transcription-replication conflicts (TRCs). Here, we demonstrate that TRCs are enriched in human pancreatic ductal adenocarcinoma (PDAC) compared to other common solid tumors or normal cells. Several orthogonal approaches demonstrated that TRCs are oncogene dependent. A small interfering RNA (siRNA) screen identified several factors in the base-excision repair (BER) pathway as main regulators of TRCs in PDAC cells. Inhibitors of BER pathway (methoxyamine and CRT) enhanced TRCs. Mechanistically, BER pathway inhibition severely altered RNA polymerase II (RNAPII) and R-loop dynamics at nascent DNA, causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated the ATR-Chk1 pathway. Co-treatment with ATR inhibitor (VX970) and BER inhibitor (methoxyamine) at clinically relevant doses synergistically enhanced DNA damage and reduced cell proliferation in PDAC cells. The study provides mechanistic insights into the regulation of TRCs in PDAC by the BER pathway, which has biologic and therapeutic implications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Though several nomograms exist, machine learning (ML) approaches might improve prediction of pathologic stage in patients with prostate cancer. To develop ML models to predict pathologic stage that outperform existing nomograms that use readily available clinicopathologic variables., Methods: Patients with prostate adenocarcinoma who underwent surgery were identified in the National Cancer Database. Seven ML models were trained to predict organ-confined (OC) disease, extracapsular extension, seminal vesicle invasion (SVI), and lymph node involvement (LNI). Model performance was measured using area under the curve (AUC) on a holdout testing data set. Clinical utility was evaluated using decision curve analysis (DCA). Performance metrics were confirmed on an external validation data set., Results: The ML-based extreme gradient boosted trees model achieved the best performance with an AUC of 0.744, 0.749, 0.816, 0.811 for the OC, ECE, SVI, and LNI models, respectively. The MSK nomograms achieved an AUC of 0.708, 0.742, 0.806, 0.802 for the OC, ECE, SVI, and LNI models, respectively. These models also performed the best on DCA. Findings were consistent on both a holdout internal validation data set as well as an external validation data set., Conclusions: Our ML models better predicted pathologic stage relative to existing nomograms at predicting pathologic stage. Accurate prediction of pathologic stage can help oncologists and patients determine optimal definitive treatment options for patients with prostate cancer., (© 2024 Wiley Periodicals LLC.)

Defoliation is a primary agronomic traits, its variation depends on different plant species or cultivars. The present article assess the leaf morphological responses, oxidative metabolites and enzymatic activities at sheath base of sugarcane cultivars during defoliation stage of plant leaves. The mature leaf sheath of GT47 strongly wrapped to the stem, and no stem was exposed. The upper and lower edges of the immature fusing abscission zone were parallel, and slightly lower browning area (+ 3 to + 7 leaf position). The ROC22 cultivar was monitored highest leaf sheath-based cellulose and lignin content, followed by GT60 and GT47. Peroxidase activity was higher in leaf sheath base edge (ROC22) as compare to other cultivars. The malondialdehyde content was found highest in GT60, followed by ROC22, and GT47. The exo-β-1,4-glucanase/ cellobiohydrolase activity was found highest in the margin of GT47 than lateral and medial axis of ROC22 and GT60. The axis activity increased exponentially, and ROC22 gradually decreased from the periphery of the mid-axis and lower than GT47 and GT60 in the lateral and mid-axis of leaf. In conclusion, the mature leaves are easy to defoliate mainly loose leaf sheaths, large leaf sheath inclination angles, more deformation during the growth period of the abscission zone, early with large cracks, and slow browning process. Leaf sheaths with high fibre and lignin content showed significant hardness and thickness. The sugarcane cultivars showed positive correlation between peroxidase and malondialdehyde content with the browning process at the base of mature leaf sheaths., (© 2024. The Author(s).)

Objective: To analyze long-term prognosis and influencing factors of recurrence in vocal fold leukoplakia treated by endoscopic cordectomy with CO 2 laser. Methods: A retrospective review was conducted on 599 patients with vocal fold leukoplakia [566 males and 33 females, aged 17-84 years (median age 55 years)], undergoing endoscopic cordectomy by CO 2 laser under general anesthesia at the Department of Otorhinolaryngology Head and Neck Surgery of Beijing Tongren Hospital, Capital Medical University, from January 2000 to December 2023. The study analyzed the clinical features, pathological grade, surgical methods, postoperative voice function, recurrence, malignant changes and analyzed the long-term efficacy and and its influencing factors. The patients were followed up for a duration of 6-249 months postoperatively, with a median follow-up time of 48 months. SPSS 20.0 software was used for statistical analysis. Results: Among the 599 patients, the histopathological grades included simple squamous cell hyperplasia in ( n =264, 44.08%), mild dysplasia ( n =96, 16.03%), moderate dysplasia ( n =74, 12.35%), severe dysplasia( n =43, 7.81%), carcinoma in situ( n =35, 5.84%), and carcinoma in situ with microinvasion( n =87, 14.52%). The 3-year and 5-year overall recurrence rates were 12.91% and 16.00%, respectively. In patients with precancerous lesion, 3.91% of recurrences presented with an upgraded pathologic grade and 2.34% evolved into carcinoma. The risk of recurrence was higher in lesions involving the anterior commissure, larger lesions, significant reduction/absence of mucosal waves, neovascularization/suspected neovascularization, and pathology of dysplasia/carcinoma in situ/carcinoma in situ with microinvasion( F =44.76,21.54,11.55,8.78,23.20,respectively, P< 0.05). Additionally, patients with recurrent disease exhibited higher reflux symptom index scores compared to those without recurrence. Exophytic lesion characteristics and the inability to cease smoking postoperatively were identified as independent risk factors for recurrence with an upgraded pathological grade, with odds ratios of 8.675 and 11.380 times greater than those with non-exophytic lesions and successful smoking cessation, respectively. At the 6-months postoperative assessment, patients who underwent subepithelial cordectomy (typeⅠ) demonstrated a statistically significant increase in fundamental frequency ( t =-3.38, P <0.05), and while other voice acoustic parameters were not significantly different.Conversely, those who underwent transmuscular cordectomy (TypeⅢ) exhibited significant alterations in multiple voice acoustic parameters when compared to preoperative values ( P <0.05). Furthermore, postoperative vocal fold adhesions developed in 84 patients with 13 of these individuals requiring surgical intervention for adhesion release. Conclusions: Lesions involving the anterior commissure, larger lesions, pathology of dysplasia/carcinoma in situ/carcinoma in situ with microinfiltration, significant reduction/absence of vocal fold mucosal waves, and neovascularization visible under NBI are indicative of an increased risk of recurrence, whereas exophytic lesions and the inability to cease smoking postoperatively significantly increase the risk of recurrence with elevated pathologic grade. Recovery of postoperative voice quality is procedure-dependent, underscoring the importance of surgical approach selection in the management of vocal fold leukoplakia.

The neuropsychiatric symptoms are common in Wilson's disease (WD) patients. However, it remains unclear about the associated functional brain networks. In this study, source localization-based functional connectivity analysis of close-eye resting-state electroencephalography (EEG) were implemented to assess the characteristics of functional networks in 17 WD patients with neurological involvements and 17 healthy controls (HCs). The weighted phase-lag index (wPLI) was subsequently calculated in source space across five different frequency bands and the resulting connectivity matrix was transformed into a weighted graph whose structure was measured by five graphical analysis indicators, which were finally correlated with clinical scores. Compared to HCs, WD patients revealed disconnected sub-networks in delta, theta and alpha bands. Moreover, WD patients exhibited significantly reduced global clustering coefficients and small-worldness in all five frequency bands. In WD group, the severity of neurological symptoms and structural brain abnormalities were significantly correlated with disrupted functional networks. In conclusion, our study demonstrated that functional network deficits in WD can reflect the severity of their neurological symptoms and structural brain abnormalities. Resting-state EEG may be used as a marker of brain injury in WD., Competing Interests: Declaration of competing interest None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Light-sheet fluorescence microscopy (LSFM) introduces fast scanning of biological phenomena with deep photon penetration and minimal phototoxicity. This advancement represents a significant shift in 3-D imaging of large-scale biological tissues and 4-D (space + time) imaging of small live animals. The large data associated with LSFM requires efficient imaging acquisition and analysis with the use of artificial intelligence (AI)/machine learning (ML) algorithms. To this end, AI/ML-directed LSFM is an emerging area for multi-organ imaging and tumor diagnostics. This review will present the development of LSFM and highlight various LSFM configurations and designs for multi-scale imaging. Optical clearance techniques will be compared for effective reduction in light scattering and optimal deep-tissue imaging. This review will further depict a diverse range of research and translational applications, from small live organisms to multi-organ imaging to tumor diagnosis. In addition, this review will address AI/ML-directed imaging reconstruction, including the application of convolutional neural networks (CNNs) and generative adversarial networks (GANs). In summary, the advancements of LSFM have enabled effective and efficient post-imaging reconstruction and data analyses, underscoring LSFM's contribution to advancing fundamental and translational research., Competing Interests: CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest.

Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin ligase HUWE1 in GNP proliferation. We show that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. Disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB., (© 2024. The Author(s).)

In this study, we have for the first time constructed a ratiometric ECL biosensor for the ultrasensitive detection of microRNAs (miRNAs) using gold nanoparticles (Au NPs) to trigger both the low-potential emission from conjugated polymer poly(9,9-dioctylfluorene-2,7-diyl) dots (PFO Pdots) and the LSPR-ECL effect with sulfur-doped boron nitride quantum dots (S-BN QDs). PFO Pdots were first applied to the Au NPs-modified electrode, followed by covalent binding to capture the hairpin H1. Immediately thereafter, a small amount of miRNA-141 was able to generate a large amount of output DNA (OP) by traversing the target cycle. OP, H3-S-BN QDs, and H4-glucose oxidase (H4-GOD) were then added sequentially to the Au NPs-modified electrode surface, and the hybridization chain reaction (HCR) was initiated. This resulted in the introduction of a large amount of GOD into the system, which catalyzed the in situ formation of the co-reactant hydrogen peroxide (H 2 O 2 ) from the substrate glucose. Due to the electron transfer effect, the production of H 2 O 2 led to the ECL quenching of PFO Pdots. Meanwhile, H 2 O 2 served as a co-reactant of S-BN QDs, resulting in strong ECL emission of S-BN QDs at the cathode. Furthermore, the cathodic ECL intensity of S-BN QDs was further enhanced by an LSPR-ECL mechanism between Au NPs and S-BN QDs. By measuring the ratio of ECL intensities at two excitation potentials, this approach could provide sensitive and reliable detection of miRNA-141 in the range of 0.1 fM ∼10 nM, with a detection limit of 0.1 fM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to investigate the activity and connectivity of cerebral and cerebellar cortices underlying the sensory trick (ST) effects in patients with cervical dystonia (CD), using electroencephalography (EEG)., Methods: We recruited 15 CD patients who exhibited clinically effective ST and 15 healthy controls (HCs) who mimicked the ST maneuver. EEG signals and multiple-channel electromyography (EMG) were recorded simultaneously during resting and acting stages. EEG source analysis and functional connectivity were performed. To account for the effects of sensory processing, we calculated relative power changes as the difference in power spectral density between resting and the maneuver execution., Results: ST induced a decrease in low gamma (30-50 Hz) spectral power in the primary sensory and cerebellar cortices, which remained lower than in HCs during the maintenance period. Compared with HCs, patients exhibited consistently strengthened connectivity within the sensorimotor network during the maintenance period, particularly in the primary sensory-sensorimotor cerebellum connection., Interpretation: The application of ST resulted in altered cortical excitability and functional connectivity regulated by gamma oscillation in CD patients, suggesting that this effect cannot be solely attributed to motor components. The cerebellum may play important roles in mediating the ST effects., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

A Gram-staining-negative, dark pink, rod-shaped, amastigote and cellulose-degrading strain, designated H9 T , was isolated from intestinal contents of Nipponacmea schrenckii. The isolate was able to grow at 4-42 °C (optimum, 25 °C), at pH 6.5-9.0 (optimum, pH 7.0), and with 0.0-11.0% (w/v) NaCl (optimum, 3.0-5.0%). Phylogenetic analysis of the 16S rRNA gene sequence suggested that isolate H9 T belongs to the genus Roseobacter, neighboring Roseobacter insulae YSTF-M11 T , Roseobacter cerasinus AI77 T and Roseobacter ponti MM-7  T , and the pairwise sequence showed the highest similarity of 99.1% to Roseobacter insulae YSTF-M11 T . The major fatty acid was summed feature 8 (C 18:1 ω7c and/or C 18:1 ω6c; 81.08%). The predominant respiratory quinone was Q-10. The polar lipids consisted of phosphatidylcholine, phosphatidylglycerol, an unknown lipid, and a small amount of an unknown phospholipid. The genome of strain H9 T was 5,351,685 bp in length, and the DNA G + C content was 59.8%. The average amino acid identity (AAI), average nucleotide identity (ANI), and digital DNA hybridization (dDDH) values between strain H9 T and closely related strains were 63.4-76.8%, 74.7-78.8%, and 13.4-19.7%, respectively. On the basis of the phenotypic, chemical taxonomic, and phylogenetic data, it is suggested that strain H9 T should represent a novel species in the genus Roseobacter, for which the name Roseobacter weihaiensis sp. nov. is proposed. The type strain is H9 T (= KCTC 82507  T  = MCCC 1K04354 T )., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In a multicenter case-control investigation, we assessed the efficacy of the Electrooculogram Signal Analysis (EOG-SA) method, which integrates attention-related visual evocation, electrooculography, and nonlinear analysis, for distinguishing between intellectual and developmental disabilities (IDD) and typical development (TD) in children. Analyzing 127 participants (63 IDD, 64 TD), we applied nonlinear dynamics for feature extraction. Results indicated EOG-SA's capability to distinguish IDD, with higher template thresholds and Correlation Dimension values correlating with clinical severity. The template threshold proved a robust indicator, with higher values denoting severe IDD. Discriminative metrics showed areas under the curve of 0.91 (template threshold) and 0.85/0.91 (D2), with sensitivities and specificities of 77.6%/95.9% and 93.5%/71.0%, respectively. EOG-SA emerges as a promising tool, offering interpretable neural biomarkers for early and nuanced diagnosis of IDD., (© 2024. The Author(s).)

A novel multidimensional electromagnetic wave-absorbing material was developed by combining carboxylated carbon nanotubes (CNT) with graphene oxide (GO) through multidimensional design, and cobalt/nickel-based metal organic frameworks (Co/Ni-MOF) were subsequently loaded onto the GO surface via its rich functional groups to form the composite absorbing material CNT-rGO-Co/Ni-MOF. Incorporating 25 wt % of CNT-rGO-Co/Ni-MOF into the paraffin matrix led to a remarkable RL min value of -43 dB at 16.4 GHz, with an effective absorbing bandwidth (EAB) exceeding 4 GHz, all within a thickness of just 1.5 mm, showcasing its "lightweight, broadband, and high efficiency" characteristics. The exceptional electromagnetic wave absorption performance was attributed to multi-interface polarization loss, resistance loss, and magnetic medium loss. Furthermore, when incorporating 10 wt % of CNT-rGO-Co/Ni-MOF, the heat release capacity and peak heat release rate of EP/CNT-rGO-Co/Ni-MOF 10 decreased by 59.2 and 52.6%, respectively.

Background: Diabetic cognitive dysfunction (DCD) has attracted increased attention, but its precise mechanism remains to be explored. Oligodendrocytes form myelin sheaths that wrap around axons. Granzyme B (GZMB) can cause axonal degeneration of the central nervous system. However, the role of GZMB in diabetic cognitive dysfunction (DCD) has not been reported. This study aimed to investigate whether GZMB promotes demyelination and participates in DCD by regulating the endoplasmic reticulum stress function of oligodendrocytes., Methods: Streptozotocin was injected intraperitoneally to establish a diabetic model in C57BL/6 mice. The mice were randomly divided into four groups: control group, diabetic group, diabetic + SerpinA3N group, and diabetic + saline treatment group. We performed the Morris water maze test to assess the learning and memory abilities of the mice. An immunofluorescence assay was performed to detect the expression sites of GZMB and OLIG2 in the hippocampal CA1 region. Luxol Fast Blue staining and electron microscopy were performed to detect the myelin number and myelin plate densities. Immunohistochemistry was used to detect the expression levels of MBP and CNPase. Protein blotting was used to assess the expression levels of GZMB, PERK, p-PERK, eIF2α, p-eIF2α, NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 as well as MBP and CNPase., Results: The GZMB inhibitor SerpinA3N reduces escape latency and increases the traversing platforms and residence time in the target area, improving DCD in mice. It also reduces endoplasmic reticulum stress in hippocampal oligodendrocytes and focal prolapse, further promoting MBP and CNPase expression and reducing demyelination., Conclusions: Our findings suggest that inhibition of GZMB activity modulates oligodendrocyte endoplasmic reticulum stress and pyroptosis, reduces demyelination, and ameliorates diabetes-related cognitive impairment., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR)-engineered T cells represent a front-line therapy for cancers. However, the current CAR T cell manufacturing protocols do not adequately reproduce immunological synapse formation. Here, in response to this limitation, we have developed a flexible graphene oxide antigen-presenting platform (GO-APP) that anchors antibodies onto graphene oxide. By decorating anti-CD3 (αCD3) and anti-CD28 (αCD28) on graphene oxide (GO-APP 3/28 ), we achieved remarkable T cell proliferation. In vitro interactions between GO-APP 3/28 and T cells closely mimic the in vivo immunological synapses between antigen-presenting cells and T cells. This immunological synapse mimicry shows a high capacity for stimulating T cell proliferation while preserving their multifunctionality and high potency. Meanwhile, it enhances CAR gene-engineering efficiency, yielding a more than fivefold increase in CAR T cell production compared with the standard protocol. Notably, GO-APP 3/28 stimulated appropriate autocrine interleukin-2 (IL-2) in T cells and overcame the in vitro reliance on external IL-2 supplementation, offering an opportunity to culture T cell-based products independent of IL-2 supplementation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. This research aimed to investigate the role of F13B in HCC and its underlying mechanisms. Through comprehensive bioinformatics analysis of the GSE120123 and The Cancer Genome Atlas (TCGA)-Liver hepatocellular carcinoma (LIHC) datasets, we identified 220 overlapping prognosis-related genes. Eight key genes, including the previously unreported CCDC170 and F13B in HCC, were identified through Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression analysis. F13B emerged as a significant prognostic factor in HCC, warranting further investigation in subsequent analyses. In vitro experiments showed that F13B expression was notably reduced in HCC cell lines and tissues, particularly in Huh-7 and SMMC-7721 cells. Overexpression of F13B inhibited cell invasion, migration, and proliferation, while its knockdown produced the opposite effect. A lactate dehydrogenase (LDH) activity assay in human umbilical vein endothelial cells (HUVECs) demonstrated that F13B overexpression reduced vascular endothelial growth factor (VEGF)-induced cytotoxicity, whereas knockdown increased it. Further analysis revealed that F13B negatively regulates VEGFA expression, affecting HUVEC proliferation. In HUVECs, F13B overexpression reversed VEGF-induced upregulation of key angiogenesis markers, including phospho-VEGF receptor 2 (p-VEGFR2), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), as well as AKT/mTOR signaling proteins, phospho-Akt (p-AKT), and phospho-mTOR (p-mTOR). Additionally, F13B negatively regulated VEGFA and hypoxia-inducible factor 1 A (HIF1A) under hypoxic conditions, counteracting the hypoxia-induced increase in cell viability. These findings suggest that F13B regulates angiogenesis through the HIF-1α/VEGF pathway and plays a crucial role in HCC progression. Our results highlight the potential of F13B as a therapeutic target in HCC, providing novel insights into the molecular mechanisms of HCC and its prognostic significance.