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 feasibility and safety of intracardiac echocardiography(ICE)combined with total three-dimensional(T3D)technique in zero-fluoroscopy individualized transseptal puncture.Methods:A total of 112 patients with atrial fibrillation who underwent radiofrequency ablation in Yongchuan Hospital Affiliated to Chongqing Medical University from April 2021 to March 2024 were enrolled,and according to the method for transseptal puncture,they were randomly divided into ICE+T3D group with 56 patients and ICE group with 56 patients.The two groups were analyzed in terms of baseline data,time to atrial reconstruc-tion,time to coronary sinus electrode placement,frequency of ICE probe adjustment during transseptal puncture,duration of transsep-tal puncture,pretreatment time before ablation,incidence rate of complications,and the duration and dosage of X-ray exposure.Results:There were no significant differences in baseline data between the two groups.Compared with the ICE group,the ICE+T3D group had a significantly lower frequency of ICE probe adjustment during transseptal puncture(1.70±0.63 vs.5.34±1.71,P<0.001)and the duration of transseptal puncture(3.66±1.09 min vs.4.90±1.92 min,P<0.001).Compared with the ICE group,the ICE+T3D group had significantly longer time to atrial reconstruction(22.44±3.13 min vs.12.34±2.12 min,P<0.001)and pretreatment time be-fore ablation(49.41±3.52 min vs.37.65±4.04 min,P<0.001).In the ICE+T3D group,43(76.8%)patients achieved zero radiation during pretreatment before ablation,and 13 patients received X-ray due to the difficulty in catheter placement;compared with the ICE group,the ICE+T3D group had a significantly shorter duration of X-ray exposure(1.68±0.72 min vs.3.14±1.95 min,P=0.010)and a significantly lower dosage of X-ray exposure(6.28±2.78 mGy vs.23.85±21.32 mGy,P=0.004).During the stage of transseptal punc-ture,all patients in the ICE+T3D group achieved zero radiation,while 45 patients(80.4%)in the ICE patients received X-ray.In terms of complications,there were no life-threatening complications such as cardiac tamponade,perforation of the aorta by mistake,and embolization in either group,while there was one case(1.8%)of vascular complications in each group.Conclusions:ICE combined with T3D after integration and improvement is a safe and reliable procedure for zero-fluoroscopy individualized transseptal puncture.

Objective:To investigate the effects of Zhuanggu Zhitong Capsules on JNK signaling molecules and their phosphorylated proteins in postmenopausal osteoporosis model female mice.Methods:The rats were divided into sham-operation group, blank group, model group, positive drug group, and Zhuanggu Zhitong Capsules group according to the random number table method, with 10 rats in each group. The model group, the positive drug group and the Zhuanggu Zhitong Capsules group were prepared by bilateral ovarian detomy to prepare a female mouse model of postmenopausal osteoporosis. The positive drug group was given 0.9 mg/kg of alendronate sodium, the Zhuanggu Zhitong Capsules group was given was Zhuanggu Zhitong Capsules 1.944 g/kg for gavage, and the blank group, sham-operation group, and model group were given the same volume of normal saline for gavage, once a day for a total of 13 weeks. Rat vaginal exfoliated cells were stained with Wright's staining; serum Omentin-1 and 25(OH)D 3 levels were determined by ELISA; renal tissue and femoral structure were observed by HE staining; JNK and p-JNK protein expressions were detected by immunohistochemical staining; JNK mRNA levels were detected by PCR. Results:Compared with the model group, the serum levels of 25(OH)D3 and Omentin-1 in the Zhuanggu Zhitong Capsules group and the positive drug group increased ( P<0.01), the mean gray values of JNK and p-JNK protein in bone and kidney tissues decreased ( P<0.01), and the mRNA levels of JNK in bone and kidney tissues decreased ( P<0.01). Conclusion:Zhuanggu Zhitong Capsules can effectively improve the bone microstructure of postmenopausal osteoporotic rats, and its mechanism may be related to the regulation of JNK signaling pathway.

BACKGROUND:Mn can participate in oxidation-reduction reactions in various organisms.For example,as a metal-assisted group in superoxide dismutase 2,Mn plays a role in helping to remove reactive oxygen species.Therefore,the development of novel anti-oxidative stress materials containing Mn has become a research focus in recent years.OBJECTIVE:To investigate the protective effect of Mn bioceramic powder material on oxidative stress damage to chondrocytes by reducing the reactive oxygen species pathway.METHODS:Bioceramic powders containing Mn were prepared by molten salt method.Primary mouse chondrocytes were isolated and cultured.Bioceramic powder containing 0,0.15,and 0.30 mg/mL of Mn was added into H2O2 solution.The H2O2 clearance rate was detected after incubation without light.The passage 2 to passage 4 chondrocytes were co-cultured with complete media containing Mn-containing bioceramic powder with different mass concentrations(0,0.15,and 0.30 mg/mL).Cell viability was detected by cell live/dead staining.The passage 2-4 chondrocytes(or cartilage tissue)were divided into four groups for intervention:Complete culture medium was added to the blank control group.The H2O2 group was added and cultured with complete medium containing H2O2.H2O2+low mass concentration Mn powder group was cultured by adding H2O2+0.15 mg/mL Mn-containing bioceramic powder.The complete medium containing H2O2+0.30 mg/mL Mn-containing bioceramic powder was added to the H2O2+high mass concentration Mn powder group.Viability of chondrocytes was detected by CCK-8 assay.Generation of reactive oxygen species of chondrocytes was detected by 2,7-dichlorofluorescein diacetate probe.Expression of chondrocyte-related factors was detected by qRT-PCR.The tissue structure and function of cartilage were detected by toluidine blue staining.RESULTS AND CONCLUSION:(1)Both doses of Mn-containing bioceramic powders could significantly remove H2O2 in vitro,and they were concentration dependent.The results of cell live/death staining showed that 0.15 mg/mL bioceramic powder containing Mn had chondrocyte safety,and 0.30 mg/mL bioceramic powder containing Mn had chondrocytotoxicity.(2)The results of CCK-8 assay showed that the two mass concentrations of Mn-containing bioceramic powders could significantly reduce the inhibitory effect of H2O2 on chondrocyte viability,and inhibit the generation of reactive oxygen species induced by H2O2 in chondrocytes in a mass concentration dependent manner.Both kinds of Mn-containing bioceramic powders could reverse the H2O2-induced increase of mRNA expression of a disintegrin and metalloproteinase with thrombospondin motifs-5 and decrease of proteoglycan mRNA expression in chondrocytes.(3)Toluidine blue staining results showed that both concentrations of Mn-containing bioceramic powder could protect the integrity of cartilage tissue structure under oxidative stress,and 0.30 mg/mL of Mn-containing bioceramic powder could also reduce the functional damage of cartilage tissue.(4)The results indicate that the Mn-containing bioceramic powder can protect chondrocytes under oxidative stress by clearing reactive oxygen species,maintaining the extracellular matrix homeostasis.However,0.30 mg/mL Mn-containing bioceramic powder has certain chondrocytotoxicity,so 0.15 mg/mL Mn-containing bioceramic powder is preferred for follow-up studies.

BACKGROUND:Mn can participate in oxidation-reduction reactions in various organisms.For example,as a metal-assisted group in superoxide dismutase 2,Mn plays a role in helping to remove reactive oxygen species.Therefore,the development of novel anti-oxidative stress materials containing Mn has become a research focus in recent years.OBJECTIVE:To investigate the protective effect of Mn bioceramic powder material on oxidative stress damage to chondrocytes by reducing the reactive oxygen species pathway.METHODS:Bioceramic powders containing Mn were prepared by molten salt method.Primary mouse chondrocytes were isolated and cultured.Bioceramic powder containing 0,0.15,and 0.30 mg/mL of Mn was added into H2O2 solution.The H2O2 clearance rate was detected after incubation without light.The passage 2 to passage 4 chondrocytes were co-cultured with complete media containing Mn-containing bioceramic powder with different mass concentrations(0,0.15,and 0.30 mg/mL).Cell viability was detected by cell live/dead staining.The passage 2-4 chondrocytes(or cartilage tissue)were divided into four groups for intervention:Complete culture medium was added to the blank control group.The H2O2 group was added and cultured with complete medium containing H2O2.H2O2+low mass concentration Mn powder group was cultured by adding H2O2+0.15 mg/mL Mn-containing bioceramic powder.The complete medium containing H2O2+0.30 mg/mL Mn-containing bioceramic powder was added to the H2O2+high mass concentration Mn powder group.Viability of chondrocytes was detected by CCK-8 assay.Generation of reactive oxygen species of chondrocytes was detected by 2,7-dichlorofluorescein diacetate probe.Expression of chondrocyte-related factors was detected by qRT-PCR.The tissue structure and function of cartilage were detected by toluidine blue staining.RESULTS AND CONCLUSION:(1)Both doses of Mn-containing bioceramic powders could significantly remove H2O2 in vitro,and they were concentration dependent.The results of cell live/death staining showed that 0.15 mg/mL bioceramic powder containing Mn had chondrocyte safety,and 0.30 mg/mL bioceramic powder containing Mn had chondrocytotoxicity.(2)The results of CCK-8 assay showed that the two mass concentrations of Mn-containing bioceramic powders could significantly reduce the inhibitory effect of H2O2 on chondrocyte viability,and inhibit the generation of reactive oxygen species induced by H2O2 in chondrocytes in a mass concentration dependent manner.Both kinds of Mn-containing bioceramic powders could reverse the H2O2-induced increase of mRNA expression of a disintegrin and metalloproteinase with thrombospondin motifs-5 and decrease of proteoglycan mRNA expression in chondrocytes.(3)Toluidine blue staining results showed that both concentrations of Mn-containing bioceramic powder could protect the integrity of cartilage tissue structure under oxidative stress,and 0.30 mg/mL of Mn-containing bioceramic powder could also reduce the functional damage of cartilage tissue.(4)The results indicate that the Mn-containing bioceramic powder can protect chondrocytes under oxidative stress by clearing reactive oxygen species,maintaining the extracellular matrix homeostasis.However,0.30 mg/mL Mn-containing bioceramic powder has certain chondrocytotoxicity,so 0.15 mg/mL Mn-containing bioceramic powder is preferred for follow-up studies.

BACKGROUND: Legg-Calvé-Perthes disease (LCPD) is still a refractory disease in children’s orthopedics. With the introduction of the concept of ‘‘osteoimmunology’’, the immune-inflammatory mechanisms between bone and immune system have become a research focus of LCPD. However, few studies have reported on the pathological role of inflammation-related receptors such as toll-like receptors (TLRs) as well as immune cells such as macrophages in LCPD. This study was for investigating the mechanism of TLR4 signaling pathway on the direction of macrophage polarization and the repair of avascular necrosis of femoral epiphysis in LCPD. METHODS: With GSE57614 and GSE74089, differentially expressed genes were screened. Through enrichment analysis and protein–protein interaction network, the functions of TLR4 were explored. Furthermore, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), hematoxylin & eosin (H&E) staining, micro-CT, tartrate-resistant acid phosphatase (TRAP) dyeing and western blotting were performed for determining the influences of TAK-242 (a TLR4 inhibitor) on the repair of avascular necrosis of femoral epiphysis in rat models. RESULTS: Totally 40 co-expression genes were screened as well as enriched in TLR4 signaling pathway. Immunohistochemistry and ELISA analyses certified that TLR4 facilitated macrophage polarization toward the M1 phenotype and prevented macrophage polarization toward the M2 phenotype. Besides, the results of H&E and TRAP staining, micro-CT, and western blotting showed that TAK-242 can inhibit osteoclastogenesis and promote osteogenesis. CONCLUSION Inhibition of TLR4 signaling pathway accelerated the repair of avascular necrosis of femoral epiphysis by regulating macrophage polarization in LCPD.

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 explore the diagnostic value of CD4 cell count and IL-6/IL-10 ratio in combination for the diagnosis of AIDS complicated with Pneumocystis pneumonia. Methods A total of 100 AIDS patients with pneumocystis pneumonia admitted to the Nanchong Central Hospital from January 2018 to May 2019 were enrolled in the AIDS pneumonia group, 100 AIDS patients were enrolled in the AIDS group, and 100 healthy subjects were included in the control group. The number of CD4+T cells in serum was detected by flow cytometry, and the expression levels of IL-6 and IL-10 in serum were detected by enzyme-linked immunosorbent assay. The AUC of receiver operating characteristic curve (ROC) was used to analyze the CD4 cell count and the diagnostic significance of IL-6/IL-10 detection in AIDS with pneumocystis pneumonia. Results The number of CD4 cells in the serum of AIDS patients with Pneumocystis pneumonia was significantly lower than that of AIDS patients and healthy subjects (t=28.31, P<0.0001; t=36.90, P<0.0001), but the ratio of IL-6/IL-10 was higher than that of AIDS patients and healthy individuals (t=7.184, P<0.0001; t=19.03, P<0.0001). The sensitivity of CD4 cell count and IL-6/IL-10 ratio in the diagnosis of AIDS patients with Pneumocystis pneumonia was 92.00%, the specificity was 88.00%, and the accuracy was 89.33%. Conclusion The detection of CD4 cell count and IL-6/IL-10 ratio can be used as a potential marker for the diagnosis of AIDS with Pneumocystis pneumonia.

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.