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

Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.
Humans ; Acetylation ; Carcinoma, Hepatocellular/genetics* ; Liver Neoplasms/genetics* ; Pyruvate Dehydrogenase Complex/genetics* ; Gene Expression Regulation, Neoplastic ; Animals ; Mice ; Cell Line, Tumor ; Protein Processing, Post-Translational ; Histones/metabolism* ; Disease Progression

Objective:To investigate the clinicopathological, immunohistochemical, and molecular genetic characteristics of microsecretory adenocarcinoma (MSA) of the salivary gland, and to improve the understanding of this rare tumor.Methods:Cases originally diagnosed as MSA at the Department of Oral Pathology, the Ninth People′s Hospital of Shanghai Jiao Tong University School of Medicine were retrospectively collected. The cases of polymorphous adenocarcinoma and adenocarcinoma, not otherwise specified from January 2000 to January 2020 were reviewed to identify potential misdiagnosed MSA cases. Clinicopathological analysis and follow-up of all confirmed MSA cases were performed, and relevant literature was reviewed.Results:A total of 4 MSA cases were identified, including 2 screened from the polymorphous adenocarcinoma cohort. Of the 4 MSA patients, 3 were male and 1 was female, with an average age of 53 years (range, 37-67 years). Three cases occurred in the palate, and one in the buccal region. The clinical manifestation was usually a slow-growing painless mass. Tumors were generally small, with a maximum diameter ranging from 0.7 to 1.8 cm (average, 1.2 cm). Microscopically, the tumor was unencapsulated and showed an infiltrative growth pattern. The tumor cells appeared small in size and showed bland, cubic and flattened cytological features, forming microcystic lumens and glandular tubes. Significant basophilic secretions were seen in the lumens. Between the tumor nests there was fibro-myxoid stroma. Immunohistochemistry showed diffusely or partially positive staining for cytokeratin 7, S-100, SOX-10, p63 and vimentin and negative staining for p40, mammaglobin, and calponin. The proliferation index of Ki-67 was relatively low (1%-3%). Four MSA cases all harbored SS18 gene rearrangement as shown by fluorescence in situ hybridization (FISH), including 2 cases with MEF2C::SS18 fusion gene through RNA-targeted next generation sequencing. All 4 patients underwent surgical resection without any adjuvant treatments. Three patients were followed up for a period of 2 to 203 months. No tumor recurrence, metastasis, or disease-related death was found.Conclusions:Salivary gland MSA is a novel and rare low-grade carcinoma with unique and consistent histological morphology, immunophenotype, and molecular changes. Immunohistochemical staining and SS18 break apart FISH are useful for the diagnosis of the tumor with atypical morphology and high-grade transformation.

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.

Objective:To explore the efficacy and safety of Rasburicase therapy in critically ill children su-ffering from advanced Burkitt′s lymphoma.Methods:A retrospective analysis of children with advanced Burkitt′s lymphoma was admitted to Pediatric Intensive Care Unit, the First Affiliated Hospital of Sun Yat-Sen University, from January 2015 to May 2020 and accepted treatment.According to the uric acid-lowering therapies, patients were divided into 2 groups, namely Rasburicase group (Group R) and traditional treatment group (Group T), to compare the effects of hypouricemic treatment and the prognosis between the 2 groups.Results:Twenty-nine children with advanced Burkitt′s lymphoma were included in this study, with 13 cases (44.83%) of stage Ⅲ and 16 cases (55.17%) of stage Ⅳ.Abdominal mass/ abdominal distension (13 cases, 44.83%) and abdominal pain (7 cases, 24.14%) were the main reasons of initial medical visit attendance.The most common primary tumor site was abdominal/ pelvic cavity (21 cases, 72.41%), followed by head or neck (6 cases, 20.69%). There were 15 cases in Group R and 14 cases in group T. No significant differences in serum creatinine, lactate dehydrogenase and uric acid were detected between the 2 groups (all P>0.05). The proportion of serum uric acid recovery rate of 24 hours and 72 hours after initial treatment in Group R were significantly higher than those in T group (85.71% vs.25.00%, 100.00% vs.25.00%, all P<0.01). Although there were no obvious differences in the incidence of tumor lysis syndrome between the 2 groups (33.33% vs.64.29%, P=0.096), the incidence of acute renal injury, renal replacement therapy requirement, serious complications and the 28 day mortality in Group R were remarkably lower than those in Group T (33.33% vs.85.71%, 13.33% vs.64.29%, 20.00% vs.78.57%, 0 vs.35.71%, all P< 0.05). Conclusions:Rasburicase can effectively reduce the serum uric acid level and decrease the incidence of acute kidney injury and other severe complications, thus improving the prognosis of children experiencing advanced Burkitt′s lymphoma.

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.

【Objective】 To explore the effect of allogeneic platelet gel on hemostasis and repair of vascular anastomoses and wounds in patients with giant aortic aneurysms during surgery. 【Methods】 One adult dose of allogeneic platelets, applied as platelet rich plasma (PRP), was prepared as platelet gel (PG) (about 220 mL) for spraying or smearing at the vascular anastomosis and thoracic wound during the surgery of giant aortic aneurysms. 【Results】 The gel formation was presented about 30 seconds after spraying or smearing with PG on the anastomotic and wound surface. The hemostatic effect is good, with less postoperative drainage fluid from pericardium and mediastinum than usual, and the ICU stay was 4 days. 【Conclusion】 Allogeneic platelets as a source of PRP to prepare PG may be applied to obtain the clotting and healing during surgical operation.

Objective:To investigate the clinical characteristics and prognosis in adult acute myeloid leukemia (AML) patients with FLT3-ITD and CEBPA double-mutated (CEBPAdm) co-mutation.Methods:Clinical data and prognostic factors were retrospectively analyzed in adult AML patients with FLT3-ITD and CEBPAdm co-mutation at The First Affiliated Hospital of Zhengzhou University from January 2016 to September 2018.Results:Among 599 non-acute promyelocytic leukemia (APL) patients, 268 received gene mutation detection, who were divided into 4 groups including 19 FLT3-ITD positive (FLT3-ITD +) and CEBPAdm positive (CEBPAdm +) cases (group A) , 84 FLT3-ITD + and CEBPAdm - cases (group B) , 95 FLT3-ITD - and CEBPAdm + cases (group C) , 70 double negative mutation cases (group D) . Gender, platelet count, FAB classification, induction treatment regimen and fusion gene mutation were comparable among four groups ( P>0.05) , while age onset, peripheral white blood cell (WBC) count, hemoglobin, percentage of blasts in peripheral blood, percentage of blasts in bone marrow, complete remission rate (CR 1 rate) after the first induction chemotherapy, the relapse rate, the median progression-free survival (PFS) time, and median overall survival (OS) time were significantly different between groups ( P<0.05) . When compared in pairs, gender, age onset, hemoglobin, platelet count, FAB classification in group A were not statistically different compared to group B, C and D ( P>0.05) , while patients in group A had higher WBC count, blasts in peripheral blood, minimal residual disease (MRD) in bone marrow. The CR 1 rates of group A, B, C, and D were 50.0%、32.4%、59.8%、39.0% respectively ( P=0.003) , and the relapse rates were 55.6%, 50.0%, 21.1%, 40.0% ( P<0.001) . As to survival, the median OS in each group was 6.25, 3.0, 15.5, 10.5 months respectively ( P<0.001) , and the median PFS was 5.0, 4.0, 10.0, 6.7 months ( P=0.032) . Conclusion:Adult AML patients with FLT3-ITD and CEBPAdm co-mutation have a higher leukemia load and low CR 1 rate, which translates into poor prognosis with high relapse rate and short survival time.

Objectives: This study explored the relationship between weight control and atrial fibrillation (AF) recurrence after catheter ablation in overweight and obese patients. Methods: We prospectively enrolled consecutive 333 overweight and obese patients aged 28 to 87 years old, who underwent catheter ablation for AF in Beijing Anzhen Hospital between October 2015 and February 2016. Data of patients′ characteristics, laboratory examination and treatment were collected at baseline. Each patient was followed up at 3, 6 and 12 months after ablation to collect information on weight, AF recurrence, stroke, major bleeding, hospitalization for cardiovascular reasons and death, etc. Patients were divided into weight controlled group (ΔBMI<-1 kg/m²) and weight uncontrolled group (ΔBMI≥-1 kg/m²), according to the changes in the most recent exposure BMI before AF recurrence in patients with recurrence or the BMI at 12 months′ follow-up in patients without recurrence and the BMI at baseline. Multivariate logistic regression was performed to adjust other known risk factors of AF recurrence and to explore the association between weight control and AF recurrence after catheter ablation. Results: There were 54 patients in weight controlled group and 279 patients in weight uncontrolled group. There were no significant differences in age, gender, education level, left atrial size and history of hypertension between the two groups (all P>0.05). The proportion of patients using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was higher in the weight controlled group (50.0%(27/54) vs. 34.8%(97/279), P=0.034). However, there was no significant difference in the proportion of patients with obesity (33.3% (18/54) vs. 29.7% (83/279)), paroxysmal AF (59.3% (32/54) vs. 56.6% (158/279)) and AF duration less than 5 years (76.9% (40/52) vs. 65.4% (178/272)) between the weight controlled group and the uncontrolled group. During 1-year follow-up after ablation, the recurrence rate of AF was significantly lower in the weight controlled group than that in the weight uncontrolled group (14.8% (8/54) vs. 32.6%(91/279), P=0.009). Multivariable logistic regression analysis shows that weight control is independently associated with a lower postoperative AF recurrence rate (OR=0.40, 95%CI 0.18-0.90, P=0.026). Conclusion Weight control is strongly associated with a lower AF recurrence rate after catheter ablation in overweight and obese patients.

Objectives This study explored the relationship between weight control and atrial fibrillation (AF) recurrence after catheter ablation in overweight and obese patients. Methods We prospectively enrolled consecutive 333 overweight and obese patients aged 28 to 87 years old, who underwent catheter ablation for AF in Beijing Anzhen Hospital between October 2015 and February 2016. Data of patients′ characteristics, laboratory examination and treatment were collected at baseline. Each patient was followed up at 3, 6 and 12 months after ablation to collect information on weight, AF recurrence, stroke, major bleeding, hospitalization for cardiovascular reasons and death, etc. Patients were divided into weight controlled group (ΔBMI<-1 kg/m2) and weight uncontrolled group (ΔBMI≥-1 kg/m2), according to the changes in the most recent exposure BMI before AF recurrence in patients with recurrence or the BMI at 12 months′ follow?up in patients without recurrence and the BMI at baseline. Multivariate logistic regression was performed to adjust other known risk factors of AF recurrence and to explore the association between weight control and AF recurrence after catheter ablation. Results There were 54 patients in weight controlled group and 279 patients in weight uncontrolled group. There were no significant differences in age, gender, education level, left atrial size and history of hypertension between the two groups (all P>0.05). The proportion of patients using angiotensin?converting enzyme inhibitors/angiotensin receptor blockers was higher in the weight controlled group (50.0%(27/54) vs. 34.8%(97/279), P=0.034). However, there was no significant difference in the proportion of patients with obesity (33.3% (18/54) vs. 29.7% (83/279)), paroxysmal AF (59.3% (32/54) vs. 56.6% (158/279)) and AF duration less than 5 years (76.9% (40/52) vs. 65.4% (178/272)) between the weight controlled group and the uncontrolled group. During 1?year follow?up after ablation, the recurrence rate of AF was significantly lower in the weight controlled group than that in the weight uncontrolled group (14.8% (8/54) vs. 32.6%(91/279), P=0.009). Multivariable logistic regression analysis shows that weight control is independently associated with a lower postoperative AF recurrence rate ( OR=0.40, 95%CI 0.18-0.90, P=0.026). Conclusion Weight control is strongly associated with a lower AF recurrence rate after catheter ablation in overweight and obese patients.