Search

Qian-Er Wen,1 Liang Li,1 Rui-Qi Feng,1 De-Hui Li,2 Chang Qiao,1 Xiao-Song Xu,3 Yan-Jing Zhang2 1Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, People’s Republic of China; 2Oncology Department II, The First Affiliated Hospital of Hebei University of Chinese Medicine (Hebei Province Hospital of Chinese Medicine), Key Laboratory of Integrated Chinese and Western Medicine for Gastroenterology Research, Shijiazhuang, Hebei Province, People’s Republic of China; 3Scientific research Center, The First Affiliated Hospital of Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, People’s Republic of ChinaCorrespondence: De-Hui Li; Yan-Jing Zhang, Email 258289951@qq.com; yanjing198107@163.comAbstract: Breast cancer is one of the most common malignant tumors in women in the world, and its incidence is increasing year by year, which seriously threatens the physical and mental health of women. Triple negative breast cancer (TNBC) is a special molecular type of breast cancer in which estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 are negative. Compared with other molecular types of breast cancer, triple-negative breast cancer (TNBC) has high aggressiveness and metastasis, high recurrence rate, lack of effective therapeutic targets, and usually poor clinical treatment effect. Chemotherapy was the main therapeutic means used in the past. With the advent of the immune era, immunotherapy has made a lot of progress in the treatment of triple-negative breast cancer (TNBC), bringing new therapeutic hope for the treatment of triple-negative breast cancer. This review combines the results of cutting-edge medical research, mainly summarizes the research progress of immunotherapy, and summarizes the main treatment methods of triple-negative breast cancer (TNBC) immunotherapy, including immune checkpoint inhibitors, tumor vaccines, adoptive immunotherapy and the application of traditional Chinese and western medicine. It provides a new idea for the treatment of triple negative breast cancer (TNBC).Keywords: breast cancer, triple negative breast cancer, immunotherapy, immune checkpoint inhibitors, tumor vaccine, adoptive immunotherapy

Hao Chen,1,2,&ast; Qing Ma,3,&ast; Bo Du,1 Yan Huang,1 Shi-Guang Zhu,1 Sheng-Li Li,4 De-Qin Geng,1 Xing-Shun Xu2,5,6 1Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215000, People’s Republic of China; 3Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China; 4Department of Medical Records and Statistics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China; 5Institute of Neuroscience, Soochow University, Suzhou, 215000, People’s Republic of China; 6Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: De-Qin Geng, Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, People’s Republic of China, Tel +86 18052268197, Email gengdeqingdq@outlook.com Xing-Shun Xu, Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215000, People’s Republic of China, Tel +86 13915411326, Email xuxingshunxxs@126.comObjective: The present study aims to analysis the mental health of high-risk health care workers (HHCWs) and low-risk HCWs (LHCWs) who were respectively exposed to COVID-19 wards and non-COVID-19 wards by following up on mental disorders in HCWs in China for 6 months.Methods: A multi-psychological assessment questionnaire was used to follow up on the psychological status of HCWs in the Affiliated Hospital of Xuzhou Medical University in Xuzhou City (a non-core epidemic area) at 6 months after the first evaluation conducted during the COVID-19 epidemic. Based on the risk of exposure to COVID-19 patients, the HCWs were divided into two groups: high-risk HCWs, who worked in COVID-19 wards, and low-risk HCWs, who worked in non-COVID-19 wards.Results: A total of 198 HCWs participated in the study, and 168 questionnaires were selected for evaluation. Among them, 93 (55.4%) were in the HHCW group and 75 (44.5%) were in the LHCW group. Significant differences were observed in salary, profession, and altruistic behavior between the two groups (P < 0.05). There were no significant differences in the anxiety, depression, insomnia, or posttraumatic stress disorder (PTSD) scores between the two groups. Logistic regression revealed that work stress was a major joint risk factor for mental disorders in HCWs. Among all the HCWs, a total of 58 voluntarily participated in psychotherapy; the analysis showed a significant decrease in anxiety, depression, PTSD, work stress, and work risk after attending psychotherapy. There were also significant differences in positive and negative coping styles before and after psychotherapy.Conclusion: In the present follow-up, work stress was the major contributing factor to mental disorders in HCWs. Psychotherapy is helpful in terms of stress management and should be provided to first-line COVID-19 HCWs.Keywords: COVID-19, anxiety, depression, posttraumatic stress disorder, insomnia, work stress

Sheng Zhang,1 Xiang Shang Xu,1 Jie Xi Yang,1 Jian Hui Guo,1 Teng Fei Chao,2 YiXin Tong1 1Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Background: Axl is a receptor tyrosine kinase that is involved in many pathological conditions and carcinogenesis. Gas6 is the major ligand of Axl. Activation of Gas6/Axl pathway is essential for cancer development. However, its prognostic significance in solid tumors remains unclear. Therefore, we performed this meta-analysis to elucidate the prognostic impact of Axl.Methods: Published studies on Axl or Gas6 expression and overall survival (OS) and/or disease-free survival (DFS) were searched from databases. The outcome measurement is hazard ratio (HR) for OS or DFS related to Axl/Gas6 expression. Meta-analysis was performed using RevMan. The pooled HR was calculated by fixed-/random-effect models.Results: A total of 3,344 patients from 25 studies were included. The results of meta-analysis showed that Axl overexpression was correlated with shorter OS (HR: 2.03, p

Xue-miao Tang,1,2,* Hao Chen,2,3,* Qing Li,1,2 Yiling Song,2,3 Shuping Zhang,2,3 Xiao-Shuan Xu,4 Yiwei Xu,5,6 Shulin Chen2,3 1Department of Ultrasound and Electrocardiogram, 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 3Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, 4School of Laboratory Medicine, Guangdong Medical University, 5Department of Clinical Laboratory, The Cancer Hospital of Shantou University Medical College, 6The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Guangdong, China *These authors contributed equally to this work Objective: The cardiac safety of cetuximab and panitumumab, particularly as single agents, has not been investigated extensively. This trial was designed to specifically evaluate the cardiac safety of cetuximab and panitumumab as single therapy in Chinese chemotherapy-refractory metastatic colorectal cancer (mCRC) patients.Patients and methods: Sixty-one patients received cetuximab at an initial dose of 400 mg/m2 intravenously over 120 minutes on day 1 (week 1), followed by a maintenance dose of 250 mg/m2 intravenously over 60 minutes on day 1 of each 7-day cycle. Forty-three patients received panitumumab at a dose of 6 mg/kg intravenously every 14 days. Routine laboratory tests and electrocardiogram (ECG) were performed at baseline, during therapy and after the treatment (4th and 10th months). The incidence of elevation of troponin I ultra (TNI Ultra), abnormal ECGs, cardiac events and noncardiac adverse events (AEs) were recorded and analyzed.Results: The incidence of elevation of TNI Ultra between the two groups had no significance (p=0.681), and TNI Ultra+ was observed more frequently in patients with metastases to more than three organs and they received fourth or above lines of chemotherapy. The most frequent abnormal ECG manifestations were nonspecific ST changes and QTc prolongation in the two groups. At 10 months after treatment, most of the abnormal ECG manifestations were reversed. The most common cardiac AEs of cetuximab and panitumumab included palpitations, dyspnea, chest pain and arrhythmias requiring treatment. Most of the events were mild and transient. The incidence of cardiac AEs had no significant difference between the two groups. Rash was still the most common noncardiac AE in both groups.Conclusion: Cetuximab and panitumumab showed favorable cardiac safety as single agents for Chinese chemotherapy-refractory mCRC patients. But monitoring for cardiac AEs is still necessary throughout the entire treatment process. Keywords: cetuximab, panitumumab, targeted therapy, colorectal cancer, toxicity, cardiac safety

Qing Pang, Jian-Bin Bi, Zhi-Xin Wang, Xin-Sen Xu, Kai Qu, Run-Chen Miao, Wei Chen, Yan-Yan Zhou, Chang Liu Department of Hepatobiliary Surgery, the First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Shaanxi Province, People’s Republic of China Background: Several hepatic cirrhosis-derived noninvasive models have been developed to predict the incidence and outcomes of hepatocellular carcinoma (HCC). We aimed to investigate the prognostic significance of the two novel established cirrhosis-associated models based on gamma-glutamyl transpeptidase (GGT) and platelets in hepatitis B-associated HCC. Methods: We retrospectively evaluated 182 HCC patients with positive hepatitis B surface antigen who received radical therapy at a single institution between 2002 and 2012. Laboratory data prior to operation were collected to calculate the GGT to platelets ratio (GPR) and the S-index. Predictive factors associated with overall survival and recurrence-free survival were assessed using log-rank test and multivariate Cox analysis. Additional analyses were performed after patients were stratified based on cirrhosis status, tumor size, therapy methods, and so forth, to investigate the prognostic significance in different subgroups. Results: During a median follow-up time of 45.0 months, a total of 88 (48.4%) patients died and 79 (43.4%) patients recurred. The cut-off points for GPR and S-index in predicting death were determined to be 0.76 and 0.56, respectively. Compared with patients with a lower GPR, those with GPR ≥0.76 had a higher probability of cirrhosis and a larger tumor (both P

AIM OF THE STUDY: Cerebralcare Granule (CG) is a Chinese herb compound preparation that has been used for treatment of cerebrovascular related diseases. However, the effect of post-treatment with CG on ischemia and reperfusion (I/R) induced cerebral injury is so far unclear. MATERIALS AND METHODS: In present study, cerebral global I/R was induced in Mongolian gerbils by clamping bilateral carotid arteries for 30 min followed by reperfusion for 5 days, and CG (0.4 g/kg or 0.8 g/kg) was administrated 3h after the initiation of reperfusion. RESULTS: Post-treatment with CG for 5 days attenuated the I/R-induced production of hydrogen peroxide in, leukocyte adhesion to, and albumin leakage from cerebral microvessels, and, meanwhile, protected neuron from death, reduced the number of caspase-3- and Bax-positive cells, and increased Bcl-2-positive cells in hippocampal CA1 region. CONCLUSION: The results suggest that CG given after initiation of reperfusion is able to ameliorate cerebral microvascular dysfunction and hippocampal CA1 neuron damage caused by I/R. [ABSTRACT FROM AUTHOR]

Compared with young liver donors, aged liver donors are more susceptible to ischemia-reperfusion injury (IRI) following transplantation, which may be related to excessive inflammatory response and macrophage dysfunction, but the specific mechanism is unclear. Macrophage scavenger receptor 1 (MSR1) is a member of the scavenger receptor family, and plays an important regulatory role in inflammation response and macrophage function regulation. But its role in IRI following aged-donor liver transplantation is still unclear. This study demonstrates that MSR1 expression is decreased in macrophages from aged donor livers, inhibiting their efferocytosis and pro-resolving polarisation. Decreased MSR1 is responsible for the more severe IRI suffered by aged donor livers. Overexpression of MSR1 using F4/80-labeled AAV 9 improved intrahepatic macrophage efferocytosis and promoted pro-resolving polarisation, ultimately ameliorating IRI following aged-donor liver transplantation. In vitro co-culture experiments further showed that overexpression of MSR1 promoted an increase in calcium concentration, which further activated the PI3K-AKT-GSK3β pathway, and induced the upregulation of β-catenin. Overall, MSR1-dependent efferocytosis promoted the pro-resolving polarisation of macrophages through the PI3K-AKT-GSK3β pathway-induced up-regulating of β-catenin leading to improved IRI following aged-donor liver transplantation., 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. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Inc.)

Circulating tumor DNA (ctDNA) provides valuable tumor-related information without invasive biopsies, yet consensus is lacking on optimal parameters for predicting clinical outcomes. Utilizing longitudinal ctDNA data from the large phase 3 IMpower150 study (NCT02366143) of atezolizumab in combination with chemotherapy with or without bevacizumab in patients with stage IV non-squamous Non-Small Cell Lung Cancer (NSCLC), here we report that post-treatment ctDNA response correlates significantly with radiographic response. However, only modest concordance is identified, revealing that ctDNA response is likely not a surrogate for radiographic response; both provide distinct information. Various ctDNA metrics, especially early ctDNA nadirs, emerge as primary predictors for progression-free survival and overall survival, potentially better assessing long-term benefits for chemoimmunotherapy in NSCLC. Integrating radiographic and ctDNA assessments enhances prediction of survival outcomes. We also identify optimal cutoff values for risk stratification and key assessment timepoints, notably Weeks 6-9, for insights into clinical outcomes. Overall, our identified optimal ctDNA parameters can enhance the prediction of clinical outcomes, refine trial designs, and inform therapeutic decisions for first-line NSCLC patients., (© 2024. The Author(s).)

Background: We aim to compare the prognostic value of organ-specific dynamics with the sum of the longest diameter (SLD) dynamics in patients with metastatic colorectal cancer (mCRC)., Methods: All datasets are accessible in Project Data Sphere, an open-access platform. The tumor growth inhibition models developed based on organ-level SLD and SLD were used to estimate the organ-specific tumor growth rates (KGs) and SLD KG. The early tumor shrinkage (ETS) from baseline to the first measurement after treatment was also evaluated. The relationship between organ-specific dynamics, SLD dynamics, and survival outcomes (overall survival, OS; progression-free survival, PFS) was quantified using Kaplan-Meier analysis and Cox regression., Results: This study included 3687 patients from 6 phase III mCRC trials. The liver emerged as the most frequent metastatic site (2901, 78.7 %), with variable KGs across different organs in individual patients (liver 0.0243 > lung 0.0202 > lymph node 0.0127 > other 0.0118 [week -1 ]). Notably, the dynamics for different organs did not equally contribute to predicting survival outcomes. In liver metastasis cases, liver KG proved to be a superior prognostic indicator for OS and surpasses the predictive performance of SLD, (C-index, liver KG 0.610 vs SLD KG 0.606). A similar result can be found for PFS. Moreover, liver ETS also outperforms SLD ETS in predicting survival. Cox regression analysis confirmed liver KG is the most significant variable in survival prediction., Conclusions: In mCRC patients with liver metastasis, liver dynamics is the primary prognostic indicator for both PFS and OS. In future drug development for mCRC, greater emphasis should be directed towards understanding the dynamics of liver metastasis development., Competing Interests: Declaration of Competing Interest Manish Gupta, Yan Summer Feng, and Xu Steven Xu are employees of Genmab Inc., Princeton, NJ, USA. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Mitigating inflammation associated with the foreign body response (FBR) remains a significant challenge in enhancing the performance of implantable medical devices. Current anti-inflammatory approaches aim to suppress implant fibrosis, the major outcome of the FBR, but also inadvertently inhibit beneficial immune signalling necessary for tissue healing and vascularization. In a previous study, we demonstrated the feasibility of 'selective' immunosuppression targeting the NLRP3 inflammasome using the small molecule inhibitor MCC950, leading to reduced implant fibrosis without compromising healing and leading to enhanced vascularization. However, the clinical potential of MCC950 is severely limited due to its failure to pass Phase I clinical safety trials. This has triggered substantial efforts to develop safer analogues of NLRP3 inhibitors. Dapansutrile (OLT1177) is emerging as a leading candidate amongst current NLRP3 inhibitors, demonstrating both safety and effectiveness in a growing number of clinical indications and Phase 2 trials. While the anti-inflammatory effects of OLT1177 have been shown, validation of these effects in the context of implanted materials and the FBR have not yet been demonstrated. In this study, we show OLT1177 possesses beneficial effects on key cell types which drive FBR outcomes, including macrophages, fibroblasts, and smooth muscle cells. Evaluation of OLT1177 in a 28 day subcutaneous implantation model showed OLT1177 reduced fibrotic capsule formation while promoting implant vascularization. Mechanistic studies revealed that this occurred through activation of early pro-angiogenic markers while suppressing late-stage anti-angiogenic markers. These findings establish OLT1177 as a promising therapeutic approach for mitigating implant fibrosis while supporting vascularisation, suggesting a highly promising selective immunosuppressive strategy for the FBR warranting further research to explore its optimal integration into medical materials and devices.

Cl - activated peroxymonosulfate (PMS) oxidation technology can effectively degrade pollutants, but the generation of chlorinated disinfection byproducts (DBPs) limits the application of this technology in water treatment. In this study, a method of nanobubbles (NBs) synergistic Cl - /PMS system was designed to try to improve this technology. The results showed the synergistic effects of NBs/Cl - /PMS were significant and universal while its upgrade rate was from 12.89% to 34.97%. Moreover, the synergistic effects can be further improved by increasing the concentration and Zeta potential of NBs. The main synergistic effects of NBs/Cl - /PMS system were due to the electrostatic attraction of negatively charged NBs to Na + from NaCl, K + from PMS, and H + from phenol, which acted as a "bridge" between Cl - and HSO 5 - as well as phenol and Cl - /HSO 5 - , increasing active substance concentration. In addition, the addition of NBs completely changed the oxidation system of Cl - /PMS from one that increases environmental toxicity to one that reduces it. The reason was that the electrostatic attraction of NBs changed the active sites and degradation pathway of phenol, greatly reducing the production of highly toxic DBPs. This study developed a novel environmentally friendly oxidation technology, which provides an effective strategy to reduce the generation of DBPs in the Cl - /PMS system., 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.)

Background: The NOD-like receptor protein 3 (NLRP3) mediated pyroptosis of macrophages is closely associated with liver ischemia reperfusion injury (IRI). As a covalent inhibitor of NLRP3, Oridonin (Ori), has strong anti-inflammasome effect, but its effect and mechanisms for liver IRI are still unknown., Methods: Mice and liver macrophages were treated with Ori, respectively. Co-IP and LC-MS/MS analysis of the interaction between PKM2 and NLRP3 in macrophages. Liver damage was detected using H&E staining. Pyroptosis was detected by WB, TEM, and ELISA., Results: Ori ameliorated liver macrophage pyroptosis and liver IRI. Mechanistically, Ori inhibited the interaction between pyruvate kinase M2 isoform (PKM2) and NLRP3 in hypoxia/reoxygenation（H/R）-induced macrophages, while the inhibition of PKM2/NLRP3 reduced liver macrophage pyroptosis and liver IRI., Conclusion: Ori exerted protective effects on liver IRI via suppressing PKM2/NLRP3-mediated liver macrophage pyroptosis, which might become a potential therapeutic target in the clinic., 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 Inc. All rights reserved.)

Introduction: Cervical cancer (CC) ranks as the fourth most prevalent malignant tumor among women worldwide, and is the fourth leading cause of cancer-related mortality. GuiErBai (GEB), a compound preparation developed by our research team, is derived from the ancient Chinese medicine of the Miao nationality and is comprised of podophyllotoxin (PTOX), imperatorin, isoimperatorin, and A. dahurica alkaloids. These individual components have demonstrated notable efficacy in tumor treatment. However, the specific anti-tumor effect of the compound Chinese medicine GEB in the context of CC has yet to be validated. Methods: HeLa and SiHa cell lines were utilized for in vitro experiments and treated with 5 mg/mL and 10 mg/mL GEB concentrations, respectively. The cell cycle changes after GEB treatment were assessed using flow cytometry. Transmission electron microscopy was employed to observe autophagic bodies and apoptotic bodies, while MDC staining evaluated the occurrence of autophagy. CCK-8 was used to observe the effect of GEB on cell proliferation, and Transwell assays assessed cell migration and invasion. Western blotting detected cell cycle and apoptosis-related protein expression, along with the expression level of autophagy-related protein LC3I/II. Changes in ROS and mitochondrial membrane potential in cervical cancer cells following GEB treatment were determined using ROS detection and mitochondrial membrane potential detection kits. For the in vivo experiment, a nude mouse model of cervical cancer transplantation based on HeLa cells was established. Experimental animals were divided into negative control, positive control, high-dose GEB (10 mg/mL), and low-dose GEB (5 mg/mL) groups. Results: In HeLa and SiHa cell lines, the G0/G1 phase of tumor cells significantly decreased ( p < 0.001), while the G2/M phase increased notably ( p < 0.001) following various GEB treatments. Electron microscopy showed GEB promoted apoptotic body and autophagosome formation in both cell lines. Compared to untreated HeLa and SiHa cells, GEB-treated cells exhibited significantly reduced caspase3 protein expression, and substantially increased autophagy-related protein LC3I/II expression. GEB treatment significantly reduced migration and invasion capabilities in both cell lines ( p < 0.001), while ROS content and mitochondrial membrane potential were significantly elevated ( p < 0.001). GEB effectively inhibited cervical cancer cell proliferation, with the optimal concentration being 10 mg/mL. A successful nude mouse model of cervical cancer transplantation was established using HeLa cells. Post-GEB treatment, the tumor volume and weight in nude mice significantly decreased ( p < 0.001), with diminished expression of CD34, VEGF, and caspase3 proteins in tumor tissues. Discussion: GEB exhibits a robust antitumor effect against cervical cancer, both in vitro and in vivo , in a concentration-dependent manner, by regulating autophagy and apoptosis of tumor cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qin, Peng, Xu, Zhang, Tian, Wan, Pu, Li, Wu, Zheng and Xu.)

Purpose: To use modern machine learning approaches to enhance and automate the feature extraction from the longitudinal circulating tumor DNA (ctDNA) data and to improve the prediction of survival and disease progression, risk stratification, and treatment strategies for patients with 1L non-small cell lung cancer (NSCLC)., Materials and Methods: Using IMpower150 trial data on patients with untreated metastatic NSCLC treated with atezolizumab and chemotherapies, we developed a machine learning algorithm to extract predictive features from ctDNA kinetics, improving survival and progression prediction. We analyzed kinetic data from 17 ctDNA summary markers, including cell-free DNA concentration, allele frequency, tumor molecules in plasma, and mutation counts., Results: Three hundred and ninety-eight patients with ctDNA data (206 in training and 192 in validation) were analyzed. Our models outperformed existing workflow using conventional temporal ctDNA features, raising overall survival (OS) concordance index to 0.72 and 0.71 from 0.67 and 0.63 for C3D1 and C4D1, respectively, and substantially improving progression-free survival (PFS) to approximately 0.65 from the previous 0.54-0.58, a 12%-20% increase. Additionally, they enhanced risk stratification for patients with NSCLC, achieving clear OS and PFS separation. Distinct patterns of ctDNA kinetic characteristics (eg, baseline ctDNA markers, depth of ctDNA responses, and timing of ctDNA clearance, etc) were revealed across the risk groups. Rapid and complete ctDNA clearance appears essential for long-term clinical benefit., Conclusion: Our machine learning approach offers a novel tool for analyzing ctDNA kinetics, extracting critical features from longitudinal data, improving our understanding of the link between ctDNA kinetics and progression/mortality risks, and optimizing personalized immunotherapies for 1L NSCLC.

Background: Mechanical thrombectomy (MT) is an effective treatment for patients with acute ischemic stroke due to large vessel occlusion. However, some elderly patients with recanalization have a very poor outcome, including vegetative state and mortality. This study evaluated predictors of very poor outcome at 3 months in older patients with stroke undergoing MT treatment., Methods: We retrospectively collected data from consecutive stroke patients ≥80 years old undergoing MT between April 2018 and January 2021. A very poor outcome was defined as a modified Rankin Scale (mRS) score of 5 or 6 at 3-month follow-up. Multiple logistic regression analysis was performed to identify the predictors of very poor outcome at 3 months., Results: The study enrolled 62 patients with a median age of 85.5 years (interquartile range: 82.0-89.0). Of patients, 35 (56.5%) had a very poor outcome at 3-month follow-up. Multiple logistic regression analysis identified female sex (odds ratio = 3.592, 95% confidence interval 1.047-12.319, P = 0.042) and stroke-associated pneumonia (odds ratio = 6.103, 95% CI 1.541-24.174, P = 0.010) as independent predictors of very poor outcome., Conclusions: In elderly stroke patients undergoing MT treatment, female sex and stroke-associated pneumonia were independent predictors of very poor outcome at 3 months., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The intent of this perspective is to share the recommendations of the International Consortium for Innovation and Quality in Pharmaceutical Development Metabolite Bioanalysis Working Group on the fit-for-purpose metabolite bioanalysis in support of drug development and registration. This report summarizes the considerations for the trigger, timing, and rigor of bioanalysis in the various assessments to address unique challenges due to metabolites, with respect to efficacy and safety, which may arise during drug development from investigational new drug (IND) enabling studies, and phase I, phase II, and phase III clinical trials to regulatory submission. The recommended approaches ensure that important drug metabolites are identified in a timely manner and properly characterized for efficient drug development., (© 2023 Novartis. AbbVie Inc. Incyte Corporation et al. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Many soft biclustering algorithms have been developed and applied to various biological and biomedical data analyses. However, few mutually exclusive (hard) biclustering algorithms have been proposed, which could better identify disease or molecular subtypes with survival significance based on genomic or transcriptomic data. In this study, we developed a novel mutually exclusive spectral biclustering (MESBC) algorithm based on spectral method to detect mutually exclusive biclusters. MESBC simultaneously detects relevant features (genes) and corresponding conditions (patients) subgroups and, therefore, automatically uses the signature features for each subtype to perform the clustering. Extensive simulations revealed that MESBC provided superior accuracy in detecting pre-specified biclusters compared with the non-negative matrix factorization (NMF) and Dhillon's algorithm, particularly in very noisy data. Further analysis of the algorithm on real datasets obtained from the TCGA database showed that MESBC provided more accurate (i.e., smaller p-value) overall survival prediction in patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cancers when compared to the existing, gold-standard subtypes for lung cancers (integrative clustering). Furthermore, MESBC detected several genes with significant prognostic value in both LUAD and LUSC patients. External validation on an independent, unseen GEO dataset of LUAD showed that MESBC-derived clusters based on TCGA data still exhibited clear biclustering patterns and consistent, outstanding prognostic predictability, demonstrating robust generalizability of MESBC. Therefore, MESBC could potentially be used as a risk stratification tool to optimize the treatment for the patient, improve the selection of patients for clinical trials, and contribute to the development of novel therapeutic agents., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Min Yuan reports financial support was provided by Natural Science Foundation of Anhui Province. Min Yuan reports financial support was provided by National Science Foundation of China., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Pretreatment serum lactate dehydrogenase (LDH) levels have been associated with poor prognosis in several types of cancer, including metastatic colorectal cancer (mCRC). However, very few models link survival to longitudinal LDH measured repeatedly over time during treatment. We investigated the prognostic value of on-treatment LDH dynamics in mCRC. Using data from two large phase III studies (2L and 3L+ mCRC settings, n = 824 and 210, respectively), we found that integrating longitudinal LDH data with baseline risk factors significantly improved survival prediction. Current LDH values performed best, enhancing discrimination ability (area under the receiver operating characteristic curve) by 4.5~15.4% and prediction accuracy (Brier score) by 3.9~15.0% compared with baseline variables. Combining all longitudinal LDH markers further improved predictive performance. After controlling for baseline covariates and other longitudinal LDH indicators, current LDH levels remained a significant risk factor in mCRC, increasing mortality risk by over 90% (P < 0.001) in 2L patients and 60-70% (P < 0.01) in 3L+ patients per unit increment in current log (LDH). Machine-learning techniques, like functional principal component analysis (FPCA), extracted informative features from longitudinal LDH data, capturing over 99% of variability and allowing prediction of survival. Unsupervised clustering based on the extracted FPCA features stratified patients into three groups with distinct LDH dynamics and survival outcomes. Hence, our approaches offer a valuable and cost-effective way for risk stratification and improves survival prediction in mCRC using LDH trajectories., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Synthetic lethality is a phenomenon wherein the simultaneous deficiency of two or more genes results in cell death, while the deficiency of any individual gene does not lead to cell death. In recent years, synthetic lethality has emerged as a significant topic in the field of targeted cancer therapy, with certain drugs based on this concept exhibiting promising outcomes in clinical trials. Nevertheless, the presence of tumor heterogeneity and the intricate DNA repair mechanisms pose challenges to the effective implementation of synthetic lethality. This review aims to explore the concepts, development, and ethical quandaries surrounding synthetic lethality. Additionally, it will provide an in-depth analysis of the clinical application and underlying mechanism of synthetic lethality., 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Recent research on few-shot fine-grained image classification (FSFG) has predominantly focused on extracting discriminative features. The limited attention paid to the role of loss functions has resulted in weaker preservation of similarity relationships between query and support instances, thereby potentially limiting the performance of FSFG. In this regard, we analyze the limitations of widely adopted cross-entropy loss and introduce a novel Angular ISotonic (AIS) loss. The AIS loss introduces an angular margin to constrain the prototypes to maintain a certain distance from a pre-set threshold. It guides the model to converge more stably, learn clearer boundaries among highly similar classes, and achieve higher accuracy faster with limited instances. Moreover, to better accommodate the feature requirements of the AIS loss and fully exploit its potential in FSFG, we propose a Multi-Layer Integration (MLI) network that captures object features from multiple perspectives to provide more comprehensive and informative representations of the input images. Extensive experiments demonstrate the effectiveness of our proposed method on four standard fine-grained benchmarks. Codes are available at: https://github.com/Legenddddd/AIS-MLI.

Purpose: To apply deep learning algorithms to histopathology images, construct image-based subtypes independent of known clinical and molecular classifications for glioblastoma, and produce novel insights into molecular and immune characteristics of the glioblastoma tumor microenvironment., Materials and Methods: Using whole-slide hematoxylin and eosin images from 214 patients with glioblastoma in The Cancer Genome Atlas (TCGA), a fine-tuned convolutional neural network model extracted deep learning features. Biclustering was used to identify subtypes and image feature modules. Prognostic value of image subtypes was assessed via Cox regression on survival outcomes and validated with 189 samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) data set. Morphological, molecular, and immune characteristics of glioblastoma image subtypes were analyzed., Results: Four distinct subtypes and modules (imClust1-4) were identified for the TCGA patients with glioblastoma on the basis of the image feature data. The glioblastoma image subtypes were significantly associated with overall survival (OS; P = .028) and progression-free survival ( P = .003). Apparent association was also observed for disease-specific survival ( P = .096). imClust2 had the best prognosis for all three survival end points (eg, after 25 months, imClust2 had >7% surviving patients than the other subtypes). Examination of OS in the external validation using the unseen CPTAC data set showed consistent patterns. Multivariable Cox analyses confirmed that the image subtypes carry unique prognostic information independent of known clinical and molecular predictors. Molecular and immune profiling revealed distinct immune compositions of the tumor microenvironment in different image subtypes and may provide biologic explanations for the patterns in patients' outcomes., Conclusion: Our image-based subtype classification on the basis of deep learning models is a novel tool to refine risk stratification in cancers. The image subtypes detected for glioblastoma represent a promising prognostic biomarker with distinct molecular and immune characteristics and may facilitate developing novel, individualized immunotherapies for glioblastoma.

In digital pathology tasks, transformers have achieved state-of-the-art results, surpassing convolutional neural networks (CNNs). However, transformers are usually complex and resource intensive. This study developed a novel and efficient digital pathology classifier called DPSeq to predict cancer biomarkers through fine-tuning a sequencer architecture integrating horizontal and vertical bidirectional long short-term memory networks. Using hematoxylin and eosin-stained histopathologic images of colorectal cancer from two international data sets (The Cancer Genome Atlas and Molecular and Cellular Oncology), the predictive performance of DPSeq was evaluated in a series of experiments. DPSeq demonstrated exceptional performance for predicting key biomarkers in colorectal cancer (microsatellite instability status, hypermutation, CpG island methylator phenotype status, BRAF mutation, TP53 mutation, and chromosomal instability), outperforming most published state-of-the-art classifiers in a within-cohort internal validation and a cross-cohort external validation. In addition, under the same experimental conditions using the same set of training and testing data sets, DPSeq surpassed four CNNs (ResNet18, ResNet50, MobileNetV2, and EfficientNet) and two transformer (Vision Transformer and Swin Transformer) models, achieving the highest area under the receiver operating characteristic curve and area under the precision-recall curve values in predicting microsatellite instability status, BRAF mutation, and CpG island methylator phenotype status. Furthermore, DPSeq required less time for both training and prediction because of its simple architecture. Therefore, DPSeq appears to be the preferred choice over transformer and CNN models for predicting cancer biomarkers., Competing Interests: Disclosure Statement X.S.X. is an employee of Genmab, Inc. Genmab did not provide any funding for this study., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat stress (CSDS) attenuates the excitatory output of the claustrum (CLA) to the prelimbic cortex (PL) through the dynorphin/κ-opioid receptor (KOR) signaling, being critical for depression-related behaviors in male mice. The CSDS preferentially impairs the excitatory output from the CLA onto the parvalbumin (PV) of the PL, leading to PL micronetwork dysfunction by disinhibiting pyramidal neurons (PNs). Optogenetic activation or inhibition of this circuit suppresses or promotes depressive-like behaviors, which is reversed by chemogenetic inhibition or activation of the PV neurons. Notably, manipulating the dynorphin/KOR signaling in the CLA-PL projecting terminals controls depressive-like behaviors that is suppressed or promoted by optogenetic activation or inhibition of CLA-PL circuit. Thus, this study reveals both mechanism of the stress etiology of depression and possibly therapeutic interventions by targeting CLA-PL circuit., (© 2023. The Author(s).)

Small molecules that bind to the pocket targeted by a peptide, termed capsid assembly inhibitor (CAI), have shown antiviral effects with unique mechanisms of action. We report the discovery of two natural compounds, sennoside A (SA) and sennoside B (SB), derived from medicinal plants that bind to this pocket in the C-terminal domain of capsid (CA CTD). Both SA and SB were identified via a drug-screening campaign that utilized a time-resolved fluorescence resonance energy transfer assay. They inhibited the HIV-1 CA CTD/CAI interaction at sub-micromolar concentrations of 0.18 μM and 0.08 μM, respectively. Mutation of key residues (including Tyr 169, Leu 211, Asn 183, and Glu 187) in the CA CTD decreased their binding affinity to the CA monomer, from 1.35-fold to 4.17-fold. Furthermore, both compounds induced CA assembly in vitro and bound directly to the CA hexamer, suggesting that they interact with CA beyond the CA CTD. Molecular docking showed that both compounds were bound to the N-terminal domain (NTD)/CTD interface between adjacent protomers within the CA hexamer. SA established a hydrogen-bonding network with residues N57, V59, Q63, K70, and N74 of CA1-NTD and Q179 of CA2-CTD. SB formed hydrogen bonds with the N53, N70, and N74 residues of CA1-NTD, and the A177and Q179 residues of CA2-CTD. Both compounds, acting as glue, can bring αH4 in the NTD and αH9 in the CTD of the NTD/CTD interface close to each other. Collectively, our research indicates that SA and SB, which enhance CA assembly, could serve as novel chemical tools to identify agents that modulate HIV-1 CA assembly. These natural compounds may potentially lead to the development of new antiviral therapies with unique mechanisms of action., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Xu, Zhou and Fu.)

Objective: To investigate the clinical characteristics, cytogenetics, molecular biology, treatment, and prognosis of patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) secondary to malignancies. Methods: The clinical data of 86 patients with t-MDS/AML in West China Hospital of Sichuan University between January 2010 and April 2023 were retrospectively analyzed. The clinical characteristics, primary tumor types, and tumor-related therapies were analyzed. Results: The study enrolled a total of 86 patients with t-MDS/AML, including 67 patients with t-AML, including 1 patient with M(0), 6 with M(1), 27 with M(2), 9 with M(3), 12 with M(4), 10 with M(5), 1 with M(6), and 1 with M(7). Sixty-two patients could be genetically stratified, with a median overall survival (OS) of 36 (95% CI 22-52) months for 20 (29.9%) patients in the low-risk group and 6 (95% CI 3-9) months for 10 (14.9%) in the intermediate-risk group. The median OS time was 8 (95% CI 1-15) months in 32 (47.8%) patients in the high-risk group. For patients with non-acute promyelocytic leukemia (APL) and AML, the median OS of the low-risk group was 27 (95% CI 18-36) months, which was significantly longer than that of the non-low-risk group ( χ (2)=5.534, P =0.019). All 9 APL cases were treated according to the initial treatment, and the median OS was not reached, and the 1-, 2-, and 3-year OS rates were 100.0%, (75.0±6.2) %, and (75.0±6.2) % respectively. Of the 58 patients with non-APL t-AML (89.7%), 52 received chemotherapy, and 16 achieved complete remission (30.8%) after the first induction chemotherapy. The 1-, 2-, and 3-year OS rates of the non-APL t-AML group were (42.0 ± 6.6) %, (22.9±5.7) %, and (13.4±4.7) %, respectively. The median OS of patients who achieved remission was 24 (95% CI 18-30) months, and the median OS of those who did not achieve remission was 6 (95% CI 3-9) months ( χ (2)=10.170, P =0.001). Bone marrow CR was achieved in 7 (53.8%) of 13 patients treated with vineclar-containing chemotherapy, with a median OS of 12 (95% CI 9-15) months, which was not significantly different from that of vineclar-containing chemotherapy ( χ (2)=0.600, P =0.437). In 19 patients with t-MDS, the 1-, 2-, and 3-year OS rates were (46.8±11.6) %, (17.5±9.1) %, and (11.7±9.1) % with a median OS of 12 (95% CI 7-17) months, which was not significantly different from that in t-AML ( χ (2)=0.232, P =0.630) . Conclusions: Breast cancer, bowel cancer, and other primary tumors are common in patients with t-MDS/AML, which have a higher risk of adverse genetics. Patients with APL had a high induction remission rate and a good long-term prognosis, whereas patients without APL had a low remission rate and a poor long-term prognosis.

It has been hypothesized that the biodynamic responses of the human finger tissues to vibration are among the major stimuli that cause vibration health effects. Furthermore, the finger contact pressure can alter these effects. It is difficult to test these hypotheses using human subjects or existing animal models. The objective of this study was to develop a new rat-tail vibration model to investigate the combined effects of vibration and contact pressure and to identify their relationships with the biodynamic responses. Physically, the new exposure system was developed by adding a loading device to an existing rat-tail model. An analytical model of the rat-tail exposure system was proposed and used to formulate the methods for quantifying the biodynamic responses. A series of tests with six tails dissected from rat cadavers were conducted to test and evaluate the new model. The experimental and modeling results demonstrate that the new model behaves as predicted. Unlike the previous model, the vibration strain and stress of the rat tail does not depend primarily on the vibration response of the tail itself but on that of the loading device. This makes it possible to quantify and control the biodynamic responses conveniently and reliably by measuring the loading device response. This study also identified the basic characteristics of the tail biodynamic responses in the exposure system, which can be used to help design the experiments for studying vibration biological effects.

This study was envisaged to identify a strain of bacteria isolated from the gill of mandarin fish. Identification and characterization of the bacterial strain were performed using morphological characteristics, growth temperature, physiological and biochemical tests, antibiotic sensitivity tests, artificial infection tests, and 16S rRNA gene sequencing homology analysis. The results showed that the bacterium was Gram-negative, with flagella at the end and the side. The bacterium exhibited a light brownish-gray colony on the Luria-Bertani culture and white colony on the blood agar plate without hemolytic ring. Normal growth was achieved at 42°C, and growth could be delayed in 7% NaCl broth medium. By homology comparison and analysis, the phylogenetic tree was constructed using MEGA7.0, and the bacterium was preliminarily identified as Achromobacter . The antibiotic sensitivity test showed that the strain was sensitive to piperacillin, carbenicillin, cefoperazone, cefazolin, ofloxacin, gentamicin, kanamycin, amikacin, neomycin, erythromycin, minocycline, doxycycline, polymyxin B, tetracycline, chloramphenicol, and other drugs. However, it was resistant to penicillin, ampicillin, oxacillin, ceftriaxone, cefradine, cefalexin, cefuroxime sodium, ciprofloxacin, norfloxacin, vancomycin, compound sulfamethoxazole, clindamycin, medimycin, and furazolidone., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter.)

Objective: To observe the effects of herbal cake separated moxibustion on macrophage effector molecule T-cell immunoglobulin and mucin-domain containing-4 (Tim-4) and ubiquitination of programmed cell death protein 1 (PD-1) in rabbits with immunosuppression, and to explore the possible mechanism on herbal cake separated moxibustion in improving immunosuppression., Methods: Thirty-two big-ear white rabbits were randomly divided into a normal group, a model group, a moxa stick moxibustion group and a herbal cake separated moxibustion group, 8 rabbits in each group. Except the normal group, the immunosuppression model was established by intraperitoneal injection of cyclophosphamide of60 mg/kg in the other 3 groups. "Shenque" (CV 8), "Shenshu" (BL 23), "Zusanli" (ST 36), etc. were selected in both the moxa stick moxibustion group and the herbal cake separated moxibustion group. Moxa stick moxibustion was applied in the moxa stick moxibustion group, one cone at each acupoint; herbal cake separated moxibustion was applied in the herbal cake separated moxibustion group, 5 cones at each acupoint. The intervention was given once every other day for 10 times in both groups. Leukocyte content in peripheral blood was detected by blood cell analyzer; the positive expression of PD-1 in CD + 4 T lymphocytes, CD + 8 T lymphocytes and CD + 68 macrophages in peripheral blood was measured by flow cytometry, the serum levels of interleukin 2 (IL-2), CD 8 , CD 68 and Tim-4 were detected by ELISA, and the expression of Tim-4 and F-box only protein 38 (FBXO38) in the liver and spleen tissues was measured by immunohistochemistry., Results: Compared with the normal group, in the model group, white blood cell count (WBC) and percentage of neutrophils (NEU%) were decreased while percentage of lymphocyte (LYM%) was increased ( P <0.01) in peripheral blood; the positive expression rates of PD-1 in CD + 4 T lymphocytes, CD + 8 T lymphocytes and CD + 68 macrophages in peripheral blood were increased ( P <0.01); the serum levels of IL-2, CD 68 and Tim-4 were increased ( P <0.01), the serum level of CD 8 was decreased ( P <0.01); the average optical density (AOD) of Tim-4 in the liver tissue and FBXO38 in the liver and spleen tissues was increased ( P <0.01). Compared with the model group, in the moxa stick moxibustion group and the herbal cake separated moxibustion group, WBC and NEU% were increased ( P <0.01); the positive expression rates of PD-1 in CD + 4 T lymphocytes, CD + 8 T lymphocytes and CD + 68 macrophages in peripheral blood were decreased ( P <0.01); the serum levels of IL-2, CD 68 and Tim-4 were decreased ( P <0.01), the serum levels of CD 8 were increased ( P <0.01); the AOD of Tim-4 and FBXO38 in the liver tissue and FBXO38 in the spleen tissue was decreased ( P <0.01, P <0.05). Compared with the moxa stick moxibustion group, in the herbal cake separated moxibustion group, the positive expression rate of PD-1 in CD + 68 macrophages in peripheral blood was increased ( P <0.05); serum level of Tim-4 was increased ( P <0.01); AOD of Tim-4 in the liver tissue was decreased ( P <0.05)., Conclusion: Herbal cake separated moxibustion can improve immunosuppression by regulating the expression of macrophage effector molecule Tim-4 and the FBXO38 mediated ubiquitination of PD-1, Tim-4 may be one of the specific indexes of immunomodulation involving with herbal cake separated moxibustion.

Several studies have demonstrated that adhering to the Dietary Approaches to Stop Hypertension (DASH) diet may result in decreased blood pressure levels and hypertension risk. This may be an effect of a reduction in central obesity. In the current study, we explored the mediation role of multiple anthropometric measurements in association with DASH score and hypertension risk, and we investigated potential common micro/macro nutrients that react with the obesity-reduction mechanism. Our study used data from the National Health and Nutrition Examination Survey (NHANES). Important demographic variables, such as gender, race, age, marital status, education attainment, poverty income ratio, and lifestyle habits such as smoking, alcohol drinking, and physical activity were collected. Various anthropometric measurements, including weight, waist circumference, body mass index (BMI), and waist-to-height ratio (WHtR) were also obtained from the official website. The nutrient intake of 8224 adults was quantified through a combination of interviews and laboratory tests. We conducted stepwise regression to filter the most important anthropometric measurements and performed a multiple mediation analysis to test whether the selected anthropometric measurements had mediation effects on the total effect of the DASH diet on hypertension. Random forest models were conducted to identify nutrient subsets associated with the DASH score and anthropometric measurements. Finally, associations between common nutrients and DASH score, anthropometric measurements, and risk of hypertension were respectively evaluated by a logistic regression model adjusting for possible confounders. Our study revealed that BMI and WHtR acted as full mediators between DASH score and high blood pressure levels. Together, they accounted for more than 45% of the variation in hypertension. Interestingly, WHtR was found to be the strongest mediator, explaining approximate 80% of the mediating effect. Furthermore, we identified a group of three commonly consumed nutrients (sodium, potassium, and octadecatrienoic acid) that had opposing effects on DASH score and anthropometric measurements. These nutrients were also found to be associated with hypertension in the same way as BMI and WHtR in univariate regression models. The most important among these nutrients was sodium, which was negatively correlated with the DASH score (β = -0.53, 95% CI = -0.56~-0.50, p < 0.001) and had a positive association with BMI (β = 0.04, 95% CI = 0.01~0.07, p = 0.02), WHtR (β = 0.06, 95% CI = 0.03~0.09, p < 0.001), and hypertension (OR = 1.09, 95% CI = 1.01~1.19, p = 0.037). Our investigation revealed that the WHtR exerts a greater mediating effect than BMI on the correlation between the DASH diet and hypertension. Notably, we identified a plausible nutrient intake pathway involving sodium, potassium, and octadecatrienoic acid. Our findings suggested that lifestyle modifications that emphasize the reduction of central obesity and the attainment of a well-balanced micro/macro nutrient profile, such as the DASH diet, could potentially be efficacious in managing hypertension.

Background and Objective: The designs of first-in-human (FIH) studies in oncology (e.g., 3 + 3 dose escalation design) usually do not provide a sufficient sample size to determine the dose-response relationship for efficacy. This study aimed to assess the feasibility of using monoclonal antibody (mAb) clearance as a biomarker for efficacy to facilitate the identification of potentially efficacious doses across cancer types and drug targets., Methods: We performed electronic searches of the Drugs@FDA website, the European Medicines Agency website, and PubMed to identify reports of FIH trials of approved mAbs in oncology. The clearance, half-life, and overall response rate (ORR) data for the mAbs at different dose levels were extracted., Results: Twenty-five approved mAbs were included in this study. As expected, due to the small sample sizes in FIH studies, there was no clear dose-response for ORR. However, we found a clear negative association between mAb clearance and ORR across tumors/drug targets, and a clear negative dose-clearance relationship, with clearance decreasing and saturated at high dose levels. The approved mAb doses (1-25 mg/kg) are approximately 2-fold the saturation doses (1-10 mg/kg). The associated clearance values at the approved doses vary across different cancers and drug targets (0.17-1.56 L/day), while tend to be similar within a disease/drug target. Anti-CD20 mAbs for B-cell lymphomas show a higher clearance (~ 1 L/day) than other cancers and targets (e.g., ~ 0.3 L/day for anti-PD-1)., Conclusions: Clearance of mAbs can be a tumor/drug target-agnostic biomarker for potential anti-tumor activity as clearance decreases with increasing ORR. Our findings shed important insights into target clearance values that may lead to desired efficacy for different cancers and drug targets, which can be used to guide dose selection for the future development of mAbs during FIH oncology studies., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Many artificial intelligence models have been developed to predict clinically relevant biomarkers for colorectal cancer (CRC), including microsatellite instability (MSI). However, existing deep learning networks require large training datasets, which are often hard to obtain. In this study, based on the latest Hierarchical Vision Transformer using Shifted Windows (Swin Transformer [Swin-T]), we developed an efficient workflow to predict biomarkers in CRC (MSI, hypermutation, chromosomal instability, CpG island methylator phenotype, and BRAF and TP53 mutation) that required relatively small datasets. Our Swin-T workflow substantially achieved the state-of-the-art (SOTA) predictive performance in an intra-study cross-validation experiment on the Cancer Genome Atlas colon and rectal cancer dataset (TCGA-CRC-DX). It also demonstrated excellent generalizability in cross-study external validation and delivered a SOTA area under the receiver operating characteristic curve (AUROC) of 0.90 for MSI, using the Molecular and Cellular Oncology dataset for training (N = 1,065) and the TCGA-CRC-DX (N = 462) for testing. A similar performance (AUROC = 0.91) was reported in a recent study, using ~8,000 training samples (ResNet18) on the same testing dataset. Swin-T was extremely efficient when using small training datasets and exhibited robust predictive performance with 200-500 training samples. Our findings indicate that Swin-T could be 5-10 times more efficient than existing algorithms for MSI prediction based on ResNet18 and ShuffleNet. Furthermore, the Swin-T models demonstrated their capability in accurately predicting MSI and BRAF mutation status, which could exclude and therefore reduce samples before subsequent standard testing in a cascading diagnostic workflow, in turn reducing turnaround time and costs., (© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Self-attention mechanism-based algorithms are attractive in digital pathology due to their interpretability, but suffer from computation complexity. This paper presents a novel, lightweight Attention-based Multiple Instance Mutation Learning (AMIML) model to allow small-scale attention operations for predicting gene mutations. Compared to the standard self-attention model, AMIML reduces the number of model parameters by approximately 70%. Using data for 24 clinically relevant genes from four cancer cohorts in TCGA studies (UCEC, BRCA, GBM, and KIRC), we compare AMIML with a standard self-attention model, five other deep learning models, and four traditional machine learning models. The results show that AMIML has excellent robustness and outperforms all the baseline algorithms in the vast majority of the tested genes. Conversely, the performance of the reference deep learning and machine learning models vary across different genes, and produce suboptimal prediction for certain genes. Furthermore, with the flexible and interpretable attention-based pooling mechanism, AMIML can further zero in and detect predictive image patches., 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. Steven Xu is an employee of Genmab, Inc. Genmab did not provide any funding for this study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To explore the repair methods of complex facial defect wounds involving paranasal sinuses and their clinical effectiveness. Methods: A retrospective observational study was conducted. From January 2020 to May 2022, 5 patients admitted to the Department of Burns and Plastic Surgery of Xiangya Hospital of Central South University and 4 patients admitted to the Department of Burns and Plastic Surgery of Chenzhou First People's Hospital with complex facial defect wounds involving paranasal sinuses met the inclusion criteria, including 6 males and 3 females, aged 35-69 years, including 4 patients with titanium mesh exposure combined with paranasal sinuses injury and 5 patients with tumor involving paranasal sinuses. After an adequate assessment of the damage by a multiple discipline team, titanium mesh removal, paranasal sinus debridement, and paranasal sinus mucosa removal were performed in patients with exposed titanium mesh, and radical tumor resection was performed in patients with tumors, with postoperative skin and soft tissue defects areas of 5.0 cm×2.5 cm to 18.0 cm×7.0 cm, anterior paranasal sinus wall defects/absence areas of 3 cm×2 cm to 6 cm×4 cm, and sinus cavity depths of 1 to 4 cm. Depending on the perforator course of the descending branch of the lateral circumflex femoral artery, the anterolateral femoral chimeric flap or anterolateral femoral myocutaneous flap (with flap area of 9 cm×4 cm to 19 cm×8 cm, muscle size of 5 cm×3 cm×3 cm to 11 cm×6 cm×3 cm) was transplanted to repair the defect, and the donor site wound was sutured directly. The type of tissue flap transplanted, the blood vessel of the recipient area, and the vascular anastomosis way during the operation, the recovery of the donor and recipient areas and the occurrence of complications after operation were observed. The appearance and blood supply of the recipient area and the recurrence of ulcers and tumors were followed up. Results: The anterolateral femoral myocutaneous flap transplantation was performed in 6 patients, and the anterolateral femoral chimeric flap transplantation was performed in 3 patients. The blood vessels in recipient areas were facial arteries and veins in 3 cases and superficial temporal arteries and veins in 6 cases. The superficial temporal arteries and veins were bridged with blood vessels in tissue flaps by flow-through way in 2 patients, and end-to-end anastomosis of blood vessels in donor and recipient areas was performed in 7 patients. After operation, all the tissue flaps survived, and the facial defect wounds were well repaired without cerebrospinal fluid leakage or paranasal sinus secretion leakage, no intracranial infection occurred, and the wounds in donor areas were healed well. Follow-up of 6-35 months after operation showed that all the patients had good blood supply in the recipient area, and the shape was acceptable; 4 patients with exposed titanium mesh had no recurrence of ulceration, and 5 patients with tumor had no local tumor recurrence or metastasis. Conclusions: Based on an adequate assessment of the extent of paranasal sinuses involved in the facial wound and the nature of the defect, good clinical effects can be achieved by using the anterolateral femoral muscle flap or the anterolateral femoral chimeric flap transplantation to repair complex facial defect wounds with open paranasal sinuses.

The capsid protein (CA), an essential component of human immunodeficiency virus type 1 (HIV-1), represents an appealing target for antivirals. Small molecules targeting the CAI-binding cavity in the C-terminal domain of HIV-1 CA (CA CTD) confer potent antiviral activities. In this study, we report that a small molecule, protoporphyrin IX (PPIX), targets the HIV-1 CA by binding to this pocket. PPIX was identified via in vitro drug screening, using a homogeneous and time-resolved fluorescence-based assay. CA multimerization and a biolayer interferometry (BLI) assay showed that PPIX promoted CA multimerization and bound directly to CA. The binding model of PPIX to CA CTD revealed that PPIX forms hydrogen bonds with the L211and E212 residues in the CA CTD. Moreover, the BLI assay demonstrated that this compound preferentially binds to the CA hexamer versus the monomer. The superposition of the CAI CTD-PPIX complex and the hexameric CA structure suggests that PPIX binds to the interface formed by the NTD and the CTD between adjacent protomers in the CA hexamer via the T72 and E212 residues, serving as a glue to enhance the multimerization of CA. Taken together, our studies demonstrate that PPIX, a hexamer-targeted CA assembly enhancer, should be a new chemical probe for the discovery of modulators of the HIV-1 capsid assembly. IMPORTANCE CA and its assembled viral core play essential roles in distinct steps during HIV-1 replication, including reverse transcription, integration, nuclear entry, virus assembly, and maturation through CA-CA or CA-host factor interactions. These functions of CA are fundamental for HIV-1 pathogenesis, making it an appealing target for antiviral therapy. In the present study, we identified protoporphyrin IX (PPIX) as a candidate CA modulator that can promote CA assembly and prefers binding the CA hexamer versus the monomer. PPIX, like a glue, bound at the interfaces between CA subunits to accelerate CA multimerization. Therefore, PPIX could be used as a new lead for a CA modulator, and it holds potential research applications.

Objective: To quantitatively evaluate the clinical effect of platelet-rich plasma(PRP) intra-articular injection for early and middle stage knee osteoarthritis(KOA) treatment by 3.0T MRI T2 mapping sequence. Methods: Clinical data of 26 patients with early or middle stage KOA who received treatment from April to December 2021 at Department of Orthopaedic Surgery,the Second Affiliated Hospital,Zhengzhou University were retrospectively analyzed. In total, 8 patients were male and 18 were female,with age of (66.4±12.0)years(range:51 to 94 years). Four patients were bilateral KOA and 22 patients were unilateral KOA.All patients received PRP intra-articular injection. Patients underwent 3.0T MRI T2 mapping sequence scanning pre-treatment,3-month-after and 6-month-after treatment respectively. Those were used to measure and compare T2 values of medial and lateral femoral articular surface and patellofemoral articular surface. Visual analogue scale(VAS) and Western Ontario and McMaster Osteoarthritis Index (WOMAC) score were recorded and evaluated. The results were analyzed using repeated measure ANOVA followed by Bonferroni multiple comparison test.The correlation between WOMAC scores and T2 values at pre-treatment and 6 months post-treatment was analyzed using Pearson correlation test. Results: After treatment, the patients' International Cartilage Regeneration＆Joint Preservation Society(ICRS) classification were partly improved(one case improved from grade Ⅲ to grade Ⅱ, one case improved from grade Ⅱ to grade Ⅰ),and all patients generally improved after treatment in clinical symptoms. Compared with pre-treatment,VAS and WOMAC scores of grade Ⅰ,Ⅱ,and Ⅲ of 6-month after treatment were declined significantly(all P <0.05).The T2 values of articular cartilage declined to varying degrees(the decrease in T2 values was about 2.06 ms in grade Ⅰ, 2.66 ms in grade Ⅱ, and 3.72 ms in grade Ⅲ).Three-month (VAS:4.8±1.3,WOMAC:21.5±4.0) and 6-month (VAS:4.2±1.4,WOMAC:17.2±2.9) after treatment, the VAS and WOMAC score were significantly higher than those before treatment (VAS:6.0±1.2, WOMAC:29.0±2.3) ( F =48.846, F =346.746;both P <0.01). Multiple comparisons showed a statistically significant difference between pre-treatment and post-treatment VAS ( P <0.01) and it also was significantly different between 3-month and 6-month post-treatment ( P <0.01).At 3- and 6-month after treatment,WOMAC scores were significantly different from before treatment.And it also was significantly different between 3-month and 6-month post-treatment ( P <0.01).There was a statistically significant improvement in T2 values of patellofemoral articular surface, medial and lateral femoral articular surface at pre-treatment((44.64±4.02)ms,(44.17±3.64)ms and(43.53±3.91)ms) and 3-month ((43.19±3.91)ms,(43.24±3.34)ms and (42.47±3.80)ms), 6-month ((41.49±3.64)ms,(41.83±3.15)ms and (41.10±3.42)ms) after treatment( F =148.845, F =73.657, F =86.268;all P <0.01).The results of the multiple comparisons showed a statistically significant difference in the T2 values of medial and lateral femoral articular surface and patellofemoral articular surface at each time point(all P <0.01).The Pearson correlation analysis suggested that the WOMAC score at pre-treatment was positively correlated with the medial condyle ( r =0.856, P <0.01) and the patellofemoral joint surface T2 values ( r =0.840, P <0.01);The WOMAC score at 6-month post-treatment was positively correlated with the medial condyle ( r =0.731, P <0.01) and the patellofemoral joint surface T2 values ( r =0.691, P <0.01). Conclusions: In the treatment of early and mid-stage KOA,MRI T2 mapping sequences are able to indicate the integrity of cartilage morphology and quantitatively evaluate cartilage repair. PRP has a good therapeutic effect on cartilage repair and reconstruction.

Deep learning models are increasingly being used to interpret whole-slide images (WSIs) in digital pathology and to predict genetic mutations. Currently, it is commonly assumed that tumor regions have most of the predictive power. However, it is reasonable to assume that other tissues from the tumor microenvironment may also provide important predictive information. In this paper, we propose an unsupervised clustering-based multiple-instance deep learning model for the prediction of genetic mutations using WSIs of three cancer types obtained from The Cancer Genome Atlas. Our proposed model facilitates the identification of spatial regions related to specific gene mutations and exclusion of patches that lack predictive information through the use of unsupervised clustering. This results in a more accurate prediction of gene mutations when compared with models using all image patches on WSIs and two recently published algorithms for all three different cancer types evaluated in this study. In addition, our study validates the hypothesis that the prediction of gene mutations solely based on tumor regions on WSI slides may not always provide the best performance. Other tissue types in the tumor microenvironment could provide a better prediction ability than tumor tissues alone. These results highlight the heterogeneity in the tumor microenvironment and the importance of identification of predictive image patches in digital pathology prediction tasks., (© 2022 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

The most common complications after pancreaticoduodenectomy include pancreatic fistula, biliary fistula, delayed gastric emptying, bleeding, and abdominal infection. Although advances in surgery have led to a significant decrease in perioperative mortality in recent years, the risk of complications after pancreaticoduodenectomy remains. Thus, prevention and treatment of various complications are important to improve the prognosis of patients.

Findings from epidemiological studies suggest that occupational exposure to whole-body vibration (WBV) may increase the risk of miscarriage and contribute to a reduction in fertility rates in both men and women. However, workers exposed to WBV may also be exposed to other risk factors that contribute to reproductive dysfunction. The goal of this experiment was to examine the effects of WBV on reproductive physiology in a rat model. Male and female rats were exposed to WBV at the resonant frequency of the torso (31.5 Hz, 0.3 g amplitude) for 4 hr/day for 10 days. WBV exposure resulted in a significant reduction in number of developing follicles, and decrease in circulating estradiol concentrations, ovarian luteinizing hormone receptor protein levels, and marked changes in transcript levels for several factors involved in follicular development, cell cycle, and steroidogenesis. In males, WBV resulted in a significant reduction in spermatids and circulating prolactin levels, elevation in number of males having higher circulating testosterone concentrations, and marked alterations in levels of transcripts associated with oxidative stress, inflammation, and factors involved in regulating the cell cycle. Based upon these findings data indicate that occupational exposure to WBV contributes to adverse alterations in reproductive physiology in both genders that may lead to reduction in fertility.

Background: Red blood cell distribution width (RDW) is considered to be related to coronary heart disease and heart failure and all-cause mortality, but its relationship with acute ischemic stroke is still unclear. In this study, we aimed to explore the relationship between RDW and the stroke severity and functional outcomes of ischemic stroke., Methods: We retrospectively reviewed patients with acute ischemic stroke between September 2016 and January 2020. Demographic, clinical, stroke complications, laboratory data, and treatment were collected for all patients. Stroke severity and functional outcomes were evaluated by NIHSS score, modified Rankin Scale (mRS), and Barthel Index (BI) at 3 months. Furthermore, multiple logistic regression analysis was used to assess the relationship between RDW and stroke severity and functional outcomes., Results: A total of 629 patients with acute ischemic stroke were included and were categorized into four groups according to the quartiles of RDW (< 12.4, 12.4-12.9, 13.0-13.4, > 13.4). After multivariable analysis, higher RDW was directly associated with moderate to severe stroke (OR 2.21, 95% CI, 1.30-3.75, P = 0.003), mRS score of 3-6 at 3 months (OR 1.86, 95% CI, 1.02-3.41, P = 0.044), and BI score below 85 at 3 months (OR 2.27, 95% CI, 1.25-4.12, P = 0.007) in patients with ischemic stroke., Conclusion: Our results demonstrate that RDW is associated with stroke severity and unfavorable functional outcomes at 3 months in patients with ischemic stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xue, Zhang, Zhang, Zhu, Xu and Yue.)

Objective: To observe the effect of herbal cake-separated moxibustion (HCSM) on serum lactic acid (BLA) level and AMPK/PGC-1α signaling pathway in the quadriceps femoris in chronic fatigue syndrome (CFS) rats, so as to explore its mechanisms underlying improvement of CFS., Methods: According to the random number table, 50 SD rats were divided into blank control, model, HCSM, sham HCSM and medication (herbal medicine gavage) groups, with 10 rats in each group. The CFS model was established by using chronic restraint and exhaustive swimming, alternately, once daily for 21 days. The herbal cake was made of Xiaoyao Powder (Mental Ease Powder, composed of [Danggui ( Radix Angelicae Sinensis ), Baishao ( Radix Paeoniae Alba ), Chaihu ( Radix Bupleuri ), Fuling ( Poria ), Baizhu ( Rhizoma Atractylodis, Macrocephalae ), etc.]. The HCSM was applied to "Shenque" (CV8), "Guanyuan "(CV4), bilateral "Zusanli" (ST36) and "Qimen" (LR14), 5 moxa-cones for each acupoint, once daily for 10 days. For sham HCSM, the excipient was instead of herbal cake, and the same 5 moxa-cones was given as the HCSM group. Rats of the medication group received gavage of Xiaoyao Powder suspension (60 mg·kg -1 ), once daily for 10 days. The open field test and tail suspension test were conducted for determining the animals' locomotor activity. The blood sample was taken from the abdominal aorta under anesthesia for assaying the levels of serum BLA, chemokine ligand CXCL9 and β-endorphin (EP) by ELISA. Bilateral quadriceps femoris were sampled for observing histopathological changes after staining with conventional H.E. technique, and for detecting the expression levels of phosphorylated AMP-activated protein kinase (p-AMPK) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) by using immunohistochemistry., Results: Compared with the blank control group, the number of rearing and horizontal grid-crossing times, struggling times of tail suspension test were significantly decreased ( P <0.05), and the immobility time was obviously prolonged ( P <0.05) in the model group. Compared with the model group, both HCSM and medication groups had a significant increase of rearing, horizontal grid-crossing times and struggling times ( P <0.05), and the immobility time had a significant decrease ( P <0.05). But there were no significant differences in the total movement distance among the 5 groups ( P >0.05), and in the 5 indexes of behavioral measurements between the HCSM and medication groups ( P >0.05). The sham HCSM could also evidently increase the struggling times and reduce the immobility time ( P <0.05). The contents of serum BLA, CXCL9 and β-EP were obviously higher in the model group than in the blank control group ( P <0.05), as well as remarkably lower in the HCSM and medication groups than in the model group ( P <0.05). Whereas the expression levels of muscular p-AMPK and PGC-1α were considerably lower in the model group than in the blank control group ( P <0.05), and significantly increased in both HCSM and medication groups relevant to the model group ( P <0.05). Compared with the sham HCSM group, the contents of BLA, CXCL9 and β-EP in serum of the HCSM group and contents of CXCL9, β-EP in medication group were significantly decreased ( P <0.05), and the protein expressions of p-AMPK and PGC-1α in quadriceps femoris in both HCSM and medication groups were significantly increased ( P <0.05). H.E. staining showed smaller intercellular space, uneven cytoplasmic staining in some muscle fibers, nucleus pyknosis and condensation, and inflammatory cell infiltration in the model group, which was milder in both HCSM and medication groups., Conclusion: HCSM can mitigate the stress behavioral state in CFS rats, which may be related with its functions in lowering the levels of serum BLA, CXCL9 and β-EP, and activating AMPK/PGC-1α signaling pathway (balancing energy metabolism) in the quadriceps femoris.

Recently, supervised cross-modal hashing has attracted much attention and achieved promising performance. To learn hash functions and binary codes, most methods globally exploit the supervised information, for example, preserving an at-least-one pairwise similarity into hash codes or reconstructing the label matrix with binary codes. However, due to the hardness of the discrete optimization problem, they are usually time consuming on large-scale datasets. In addition, they neglect the class correlation in supervised information. From another point of view, they only explore the global similarity of data but overlook the local similarity hidden in the data distribution. To address these issues, we present an efficient supervised cross-modal hashing method, that is, fast cross-modal hashing (FCMH). It leverages not only global similarity information but also the local similarity in a group. Specifically, training samples are partitioned into groups; thereafter, the local similarity in each group is extracted. Moreover, the class correlation in labels is also exploited and embedded into the learning of binary codes. In addition, to solve the discrete optimization problem, we further propose an efficient discrete optimization algorithm with a well-designed group updating scheme, making its computational complexity linear to the size of the training set. In light of this, it is more efficient and scalable to large-scale datasets. Extensive experiments on three benchmark datasets demonstrate that FCMH outperforms some state-of-the-art cross-modal hashing approaches in terms of both retrieval accuracy and learning efficiency.

Purpose: Most of Stage II/III colorectal cancer (CRC) patients can be cured by surgery alone, and only certain CRC patients benefit from adjuvant chemotherapy. Risk stratification based on deep-learning from haematoxylin and eosin (H&E) images has been postulated as a potential predictive biomarker for benefit from adjuvant chemotherapy. However, very limited success has been achieved in using biomarkers, including deep-learning-based markers, to facilitate the decision for adjuvant chemotherapy despite recent advances of artificial intelligence., Methods: We trained and internally validated CRCNet using 780 Stage II/III CRC patients from Molecular and Cellular Oncology. Independent external validation of the model was performed using 337 Stage II/III CRC patients from The Cancer Genome Atlas (TCGA)., Results: CRCNet stratified the patients into high, medium, and low-risk subgroups. Multivariate Cox regression analyses confirmed that CRCNet risk groups are statistically significant after adjusting for existing risk factors. The high-risk subgroup significantly benefits from adjuvant chemotherapy. A hazard ratio (chemo-treated vs untreated) of 0.2 (95% Confidence Interval (CI), 0.05-0.65; P = 0.009) and 0.6 (95% CI 0.42-0.98; P = 0.038) are observed in the TCGA and MCO Fluorouracil-treated patients, respectively. Conversely, no significant benefit from chemotherapy is observed in the low- and medium-risk groups (P = 0.2-1)., Conclusion: The retrospective analysis provides further evidence that H&E image-based biomarkers may potentially be of great use in delivering treatments following surgery for Stage II/III CRC, improving patient survival, and avoiding unnecessary treatment and associated toxicity, and warrants further validation on other datasets and prospective confirmation in clinical trials., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)