Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Objective:To investigate the neuroprotective efficacy of scutellarin(Scu)against cerebral ischemia-reperfusion(CIRI)injury in rats,with a focus on its regulatory mechanisms involving the CX3CL1/CX3CR1-PI3K/AKT signaling axis.Methods:The rat CIRI model was established using Longa's intraluminal suture method.The experimental design comprised four groups(n=15 per group):Sham operation group,CIRI model group,Scu treat-ment(40 mg/kg/d Scu gavage)group,and Scu+LY294002(Scu combined with PI3K inhibitor LY294002)group.Following 4 weeks of intervention,neurological function,pathological changes,and pathway protein expression were evaluated using Longa scoring,TTC staining,HE staining,transmission electron microscopy,immunofluorescence,or Western blot analysis.Results:Compared to the CIRI model group,Scu treatment significantly improved neurological function,reduced cerebral infarct volume and attenuated neuronal damage(P<0.05).Furthermore,Scu downregulat-ed CX3CL1/CX3CR1 expression,increased p-PI3K/PI3K and p-AKT/AKT ratios,elevated Bcl-2/Bax ratio,and de-creased IL-17A expression(P<0.05).These protective effects were partially reversed by LY294002.Conclusion:Scu exerts neuroprotective effects in cerebral CIRI injury by downregulating CX3CL1/CX3CR1 expression and activating the PI3K/AKT pathway,thereby attenuating inflammation and apoptosis.

Objective To explore the necessity,significance,and implementation forms of integrating tumor health sci-ence popularization education and communication practice into clinical undergraduate oncology teaching.Methods Science pop-ularization education was conducted among clinical undergraduate oncology students at Guangzhou Medical University who partici-pated in science communication activities.Before and after the activities,online questionnaires were distributed via Wenjuanxing.Student questionnaires were collected within the deadline,while two different versions of questionnaires were randomly distributed to 30 parents and 20 faculty members involved in oncology teaching to assess their views and attitudes toward the necessity of pub-lic cancer prevention science communication,as well as the integration of science popularization education and communication practice into oncology teaching,and to evaluate its educational significance.Results The analysis of the questionnaires showed that nearly all or the vast majority of students,parents,and teachers highly recognized the necessity of public cancer prevention science education and awareness-raising,as well as the importance of medical students disseminating tumor health knowledge.They also strongly supported the inclusion of science popularization education in oncology teaching.Most students felt that their knowledge level improved significantly after the education sessions.Conclusion The integration of tumor science popularization education and communication practice into oncology teaching is highly necessary and meaningful.It significantly enhances students' health science literacy,sense of mission,and responsibility.It is recommended to incorporate such content into oncolo-gy teaching.

Objective To explore the necessity,significance,and implementation forms of integrating tumor health sci-ence popularization education and communication practice into clinical undergraduate oncology teaching.Methods Science pop-ularization education was conducted among clinical undergraduate oncology students at Guangzhou Medical University who partici-pated in science communication activities.Before and after the activities,online questionnaires were distributed via Wenjuanxing.Student questionnaires were collected within the deadline,while two different versions of questionnaires were randomly distributed to 30 parents and 20 faculty members involved in oncology teaching to assess their views and attitudes toward the necessity of pub-lic cancer prevention science communication,as well as the integration of science popularization education and communication practice into oncology teaching,and to evaluate its educational significance.Results The analysis of the questionnaires showed that nearly all or the vast majority of students,parents,and teachers highly recognized the necessity of public cancer prevention science education and awareness-raising,as well as the importance of medical students disseminating tumor health knowledge.They also strongly supported the inclusion of science popularization education in oncology teaching.Most students felt that their knowledge level improved significantly after the education sessions.Conclusion The integration of tumor science popularization education and communication practice into oncology teaching is highly necessary and meaningful.It significantly enhances students' health science literacy,sense of mission,and responsibility.It is recommended to incorporate such content into oncolo-gy teaching.

Objective The combined entropy weight technique for order preference by similarity to an ideal solution(TOPSIS)and rank sum ratio(RSR)methods were utilized to rate the protective performance of ice hockey helmets,and the effectiveness and influencing factors of the rating system,as well as the relationship between protective performance and purchase price were explored.Methods The linear acceleration data during impact drops of twenty-four ice hockey helmets were collected using a uniaxial accelerometer in a collision test machine after low and ambient temperature treatments.The protective performance of ice hockey helmets was rated using the STAR model combined with the entropy weight TOPSIS and RSR methods.One-way ANOVA or the Kruskal-Wallis H test was employed to assess the differences in protective performance among helmets across different grade groups.The correlation between different indicators was analyzed by Pearson's correlation coefficient.Results The comprehensive protective performance ratings of the CCM TACKS 310,IBX,BAUD,and WARRIORS COVERT RS PRO helmets were classified as poor,whereas the BAUER REAKT 150,HYPERLITE,and REAKT 200 helmets were rated as excellent.The remaining helmets were rated as moderate.There was a moderate to high positive correlation between the ambient temperature STAR(A)and Rowson's STAR values,the comprehensive Ti and low temperature Ti,the comprehensive T,and ambient temperature Ti(P＜0.05).The comprehensive Ti satisfied the homogeneity of variance(P＞0.05)and exhibited significant differences among groups(P＜0.05).Significant differences were found in the low temperature indicators among different groups(P＜0.05),and their weight coefficients ranked among the top three.The ambient temperature indicators were not affected by the protective performance grade(P＞0.05).A weak positive correlation existed between the comprehensive Ti and purchase price(P＜0.05).Conclusions According to the energy absorption test protocol,the combined entropy weight TOPSIS and RSR methods can efficiently rate the comprehensive protective performance of ice hockey helmets.The effectiveness of using low temperature indicators for the comprehensive evaluation and rating of ice hockey helmet protective performance is superior to that of ambient temperature indicators and purchase price.Consumers are advised not to use price as a criterion for evaluating the comprehensive protective performance of ice hockey helmets.

Objective:To investigate the neuroprotective efficacy of scutellarin(Scu)against cerebral ischemia-reperfusion(CIRI)injury in rats,with a focus on its regulatory mechanisms involving the CX3CL1/CX3CR1-PI3K/AKT signaling axis.Methods:The rat CIRI model was established using Longa's intraluminal suture method.The experimental design comprised four groups(n=15 per group):Sham operation group,CIRI model group,Scu treat-ment(40 mg/kg/d Scu gavage)group,and Scu+LY294002(Scu combined with PI3K inhibitor LY294002)group.Following 4 weeks of intervention,neurological function,pathological changes,and pathway protein expression were evaluated using Longa scoring,TTC staining,HE staining,transmission electron microscopy,immunofluorescence,or Western blot analysis.Results:Compared to the CIRI model group,Scu treatment significantly improved neurological function,reduced cerebral infarct volume and attenuated neuronal damage(P<0.05).Furthermore,Scu downregulat-ed CX3CL1/CX3CR1 expression,increased p-PI3K/PI3K and p-AKT/AKT ratios,elevated Bcl-2/Bax ratio,and de-creased IL-17A expression(P<0.05).These protective effects were partially reversed by LY294002.Conclusion:Scu exerts neuroprotective effects in cerebral CIRI injury by downregulating CX3CL1/CX3CR1 expression and activating the PI3K/AKT pathway,thereby attenuating inflammation and apoptosis.

Objective The combined entropy weight technique for order preference by similarity to an ideal solution(TOPSIS)and rank sum ratio(RSR)methods were utilized to rate the protective performance of ice hockey helmets,and the effectiveness and influencing factors of the rating system,as well as the relationship between protective performance and purchase price were explored.Methods The linear acceleration data during impact drops of twenty-four ice hockey helmets were collected using a uniaxial accelerometer in a collision test machine after low and ambient temperature treatments.The protective performance of ice hockey helmets was rated using the STAR model combined with the entropy weight TOPSIS and RSR methods.One-way ANOVA or the Kruskal-Wallis H test was employed to assess the differences in protective performance among helmets across different grade groups.The correlation between different indicators was analyzed by Pearson's correlation coefficient.Results The comprehensive protective performance ratings of the CCM TACKS 310,IBX,BAUD,and WARRIORS COVERT RS PRO helmets were classified as poor,whereas the BAUER REAKT 150,HYPERLITE,and REAKT 200 helmets were rated as excellent.The remaining helmets were rated as moderate.There was a moderate to high positive correlation between the ambient temperature STAR(A)and Rowson's STAR values,the comprehensive Ti and low temperature Ti,the comprehensive T,and ambient temperature Ti(P＜0.05).The comprehensive Ti satisfied the homogeneity of variance(P＞0.05)and exhibited significant differences among groups(P＜0.05).Significant differences were found in the low temperature indicators among different groups(P＜0.05),and their weight coefficients ranked among the top three.The ambient temperature indicators were not affected by the protective performance grade(P＞0.05).A weak positive correlation existed between the comprehensive Ti and purchase price(P＜0.05).Conclusions According to the energy absorption test protocol,the combined entropy weight TOPSIS and RSR methods can efficiently rate the comprehensive protective performance of ice hockey helmets.The effectiveness of using low temperature indicators for the comprehensive evaluation and rating of ice hockey helmet protective performance is superior to that of ambient temperature indicators and purchase price.Consumers are advised not to use price as a criterion for evaluating the comprehensive protective performance of ice hockey helmets.

Objective:To analyze the clinicopathological characteristics of IgG4-related sialadenitis (IgG4-RS).Methods:A total of 40 cases diagnosed with IgG4-RS were collected from the Department of Oral Pathology, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine from January 2019 to December 2022. Among them, there were 26 males and 14 females. The age range was 29-77 years old [(59.4±11.8) years old], with 23 patients being older than 60 years. The lesion site, imaging manifestations, histopathological features, serological test and treatment information of patients were collected. The expression of IgG4 and IgG proteins was detected by immunohistochemistry.Results:Submandibular region swelling was the most common initial symptom of IgG4-RS (38/40, 95.0%). All the patients having serum IgG4 levels> 1.35 g/L. Serum IgG4 levels were significantly increased in patients aged>60 years ( Z=-2.45, P=0.014) and those involving multiple glands ( Z=-2.04, P=0.042). Thirty six cases received major salivary gland biopsy, and all the cases showed dense lymphocyte and plasma cell infiltration. Lymphoid follicle, storiform fibrosis and obliterative phlebitis were seen in 88.9% (32/36), 63.9% (23/36), 30.6% (11/36) of the cases, respectively. Twenty one cases received labial salivary gland biopsy, 66.7% (14/21) showed lymphocyte and plasma cell infiltration, 19.0% (4/21) had lymphoid follicle structures, and 33.3% (7/21) showed no obvious histological abnormalities. No signs of fibrosis or obliterative phlebitis were observed in all labial salivary gland biopsies. And 95.0% (38/40) of cases had IgG4 positive plasma cell>10/HPF, 82.5% (33/40) of cases had IgG4/IgG positive plasma cell ratio>40%. All the patients had a decrease in serum IgG4 levels after glucocorticoid treatment, but only 21.4% (6/28) of cases had reduced to normal levels (≤1.35 g/L), and there were still significant fluctuations in serum IgG4 levels thereafter. Conclusions:IgG4-RS has a predilection for middle-aged and elderly male patients, and serum IgG4 levels are significantly related to the patient′s age and whether multiple glands are involved. Labial salivary gland biopsy cannot replace submandibular gland for histopathological evaluation. It is a common phenomenon that serum IgG4 levels cannot restored to normal levels after glucocorticoid treatment. This study provides certain assistance for clinical and pathological diagnosis of IgG4-RS. This study is beneficial for further understanding IgG4-RS and improving the clinical and pathological diagnosis of the disease.

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

Objective:To study the expression of programmed death ligand-1 (PD-L1) in tumor cells and CD8 +T lymphocytes in tumor infiltrating lymphocytes, and to analyze the correlation of PD-L1 expression with infiltration of CD8 +T lymphocytes and clinicopathologic features in salivary gland lymphoepithelial carcinoma (LEC). Methods:Forty-two cases of primary salivary LECs and 21 cases of secondary salivary LECs were enrolled at the Department of Oral Pathology, Shanghai Ninth People′s Hospital, Shanghai Jiaotong University between 2015 and 2017. The expression of Epstein-Barr (EB) virus, PD-L1 and CD8 was examined using chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) staining. The data were analyzed using SPSS 23.0 software package.Results:EB virus was detected in 61 cases (61/63, 96.8%), including 42 (42/42, 100%) primary LECs and 19 (19/21, 90.5%) secondary LECs. The PD-L1 positive rate (score ≥1) was 97.6% (41/42), and its high-expression rate (score ≥20) was 78.6% (33/42) in primary LECs. The PD-L1 positive rate (score ≥1) was 71.4% (15/21), and its high-expression rate (≥20) was 38.1% (8/21) in secondary LECs. However, the PD-L1 positive rate (score ≥1, P=0.004) and high-expression rate (score ≥20, P=0.001) in primary LECs were higher than those in secondary LECs. There was no difference in the infiltration degree of CD8 +T lymphocytes between primary and secondary LECs. There was a significant correlation between the expression of PD-L1 and CD8 in primary LECs ( P=0.001) and in secondary LECs ( P=0.048), respectively. Conclusions:There is PD-L1 expression in primary and secondary salivary LECs, while the expression rate is higher in primary LECs than secondary LECs. The combination of PD-L1 expression and CD8 +T lymphocytes′ presence suggest that most LEC patients might be responsive to immunotherapy, and primary LECs might be more significantly responsive than secondary LECs.