Efficacy and safety of PD-1 inhibitor combined with concurrent chemoradiotherapy in locally advanced cervical cancer with pelvic and/or para-aortic lymph node metastases: a retrospective cohort study.

BACKGROUND: The prognosis remains poor after standard chemoradiotherapy in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases. Programmed cell death receptor-1 (PD-1) inhibitors have been recommended as the first-line treatment for recurrent cervical cancer. The efficacy of PD-1 inhibitor combined with concurrent chemoradiotherapy in locally advanced cervical cancer was still uncertain. This study aimed to explore the efficacy and safety of PD-1 inhibitors combined with concurrent chemoradiotherapy in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases. METHODS: This retrospective study included patients with pelvic and/or para-aortic lymph node positive diseases [International Federation of Gynecology and Obstetrics (FIGO) stage IIB-IVA] who had received PD-1 inhibitors plus chemoradiotherapy/radiotherapy between April 1, 2020, and March 31, 2022 at the Hunan Cancer Hospital. The baseline clinicopathological characteristics, treatment, and clinical outcomes were collected. The major clinical outcomes were objective response rate (ORR), progression-free survival (PFS), and treatment-related adverse events (TRAEs). RESULTS: A total of 29 patients were included. The mean age was 55.8 [standard deviation (SD): 8.8] years. Most patients had stage IIIA-IIIB disease (72.4%) and squamous cell carcinoma (93.1%). All patients had lymph node metastases, including 24 (82.8%) with multiple metastases and 11 (37.9%) with para-aortic lymph node metastases. Among the 29 patients, 18 received sintilimab and 11 received camrelizumab concurrently with chemoradiotherapy or radiotherapy. The ORR was 96.6% [95% confidence interval (CI): 0.828, 0.993] at 3 months after radiotherapy (including 15 complete responses and 13 partial responses). At the data cutoff (August 31, 2022), the median follow-up was 14 (range, 5-30) months. The median PFS was not mature. The estimated 1- and 2-year PFS rates were 85.3% (95% CI: 60.1%, 95.2%) and 76.8% (95% CI: 47.0%, 91.2%), respectively. TRAEs of any grade occurred in 27 (93.1%) patients, most commonly as a decrease in white blood counts (82.8%), anemia (58.6%), and fatigue (48.3%). TRAEs of grade 3 or greater occurred in eight (27.6%) patients. There were no treatment-related deaths. CONCLUSIONS: PD-1 inhibitor combined with concurrent chemoradiotherapy showed potential benefit in term of tumor response and PFS in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases.

Relationship between muscular fitness and quality of life as well as psychological distress in radiotherapy patients with cervical cancer. / æŽ¥å—æ”¾å°„æ²»ç–—çš„å®«é¢ˆç™Œæ‚£è€ è‚Œè‚‰é€‚èƒ½ä¸Žç”Ÿæ´»è´¨é‡åŠå¿ƒç†ç—›è‹¦çš„å ³ç³».

OBJECTIVES: Patients with cervical cancer who have received radiotherapy often suffer from systemic muscle volume reduction and quality of life decline due to systemic effects of tumor and side effects of radiotherapy. The purpose of this study was to investigate the status of muscle fitness, quality of life, and psychological pain in patients with cervical cancer who received radiotherapy, and to explore the correlation between muscle fitness, quality of life, and psychological pain. METHODS: A total of 202 cervical cancer patients aged 19-71, who received radiotherapy in Hunan Cancer Hospital from July 2020 to February 2021, were selected by convenience sampling method. Functional Assessment of Cancer Therapy Cervix (FACT-CX) and Distress Thermometer (DT) were used for the survey. The patient's grip strength was assessed by a handgrip meter and compared with that of healthy Chinese women of the same age. The correlation between muscle fitness and quality of life and psychological pain was analyzed. RESULTS: The grip strength of cervical cancer patients receiving radiotherapy was significantly lower than that of healthy Chinese women at the same age (P<0.05). Multiple linear regression analysis showed that there were 4 factors affecting grip strength, including emotional thermometer score, social and family status score, cervical cancer related function score and tumor metastasis (all P<0.05). CONCLUSIONS: The grip strength of patients with cervical cancer undergoing radiotherapy is generally decreased, which is affected by many factors, and is closely related to the quality of life and psychological pain of patients. In the future, dynamic attention should be paid to the changes of grip strength and related functions in patients receiving radiotherapy for cervical cancer, the potential risks in the treatment should be identified early, and targeted intervention should be taken.

Pyroptosis: A New Frontier in Kidney Diseases.

Pyroptosis is a pattern of programmed cell death that significantly differs from apoptosis and autophagy in terms of cell morphology and function. The process of pyroptosis is characterized predominantly by the formation of gasdermin protein family-mediated membrane perforation, cell collapse, and the release of inflammatory factors, including IL-1ß and IL-18. In recent years, with the rise of pyroptosis research, scholars have devoted time to study the mechanism of pyroptosis in kidney-related diseases. Pyroptosis is probably involved in kidney diseases through two pathways: the caspase-1-mediated canonical pathway and the caspase-4/5/11-mediated noncanonical pathway. In addition, some scholars have identified targets for the treatment of kidney-related diseases from the viewpoint of pyroptosis and developed corresponding medicines, which may become a recommendation for prognosis, targeted treatment, and clinical diagnosis of kidney diseases. This paper focuses on the up-to-date advances in the field of pyroptosis, especially on the key pathogenic role of pyroptosis in the development and progression of kidney diseases. It presents a more in-depth understanding of the pathogenesis of kidney diseases and introduces novel therapeutic targets for the prevention and clinical treatment of kidney diseases.

Efficacy and Safety of Tanshinone for Chronic Kidney Disease: A Meta-Analysis.

OBJECTIVE: To systematically evaluate the efficacy and safety of tanshinone for chronic kidney disease (CKD). METHODS: Randomized controlled trials (RCTs) on the treatment of CKD using tanshinone were searched using 4 Chinese databases (China National Knowledge Infrastructure (CNKI), Value In Paper (VIP), Wanfang, and Chinese Biology Medicine (CBM)) and 3 English databases (PubMed, Cochrane Library, and Excerpta Medica Database (Embase)). The results included data on blood urine nitrogen (BUN), serum creatinine (Scr), glomerular filtration rate (GFR), 24 h urine protein, microalbuminuria (mALB), ß2-macroglobulin (ß2-MG), cystatin C (CysC), and safety events. The data were analyzed using Revman 5.3 and Stata 12.0 software. RESULTS: Twenty-one studies were entered into this meta-analysis, which involved 1857 patients including 954 cases from the tanshinone treatment group and 903 cases from the control group. BUN levels in the tanshinone treatment group were significantly reduced compared with the control (standardized mean difference (SMD) = -0.65, 95% confidence interval (CI): -0.81 to -0.49, p < 0.01). In addition, subgroup analysis indicated that tanshinone had a significant effect in reducing Scr levels at 14, 21, and 28 days. Scr levels in the tanshinone treatment group were significantly reduced compared with the control group (SMD = -1.40, 95% CI: -2.09 to -0.71, p < 0.01); subgroup analysis based on treatment time also yielded the same results. GFR in the tanshinone treatment group was better than that in the control group (SMD = 0.83, 95% CI: 0.59 to 1.07, p < 0.01). In terms of urine protein levels, 24 h urine protein level, mALB, and ß2-MG of CKD patients were reduced to some degree compared with controls, and CysC levels in the tanshinone treatment group were also significantly reduced compared with the control group (SMD = -0.24, 95% CI: -0.44 to -0.03, p < 0.05). Safety in the tanshinone treatment group did not differ significantly from that of the control group (risk ratio (RR) = 7.78, 95% CI: 0.99 to 61.05, p > 0.05). CONCLUSION: This meta-analysis showed that tanshinone could control urine protein level in CKD patients, improve kidney function, and delay the evolution of CKD without significant side effects. However, the results were limited and should be interpreted with caution because of the low quality of the included studies. In the future, more rigorous clinical trials need to be conducted to provide sufficient and accurate evidence.

Let-7d microRNA Attenuates 6-OHDA-Induced Injury by Targeting Caspase-3 in MN9D Cells.

Parkinson's disease (PD) mainly results from the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), and the exact underlying mechanisms of the loss of DA neurons in PD remains largely unclear. The results of our previous work showed that let-7d was significantly downregulated in a 6-OHDA-induced cellular model of PD. However, the exact effect of let-7d on DA neural cells was unclear. In MN9D dopaminergic neuronal cells, we used a let-7d mimic and inhibitor to upregulate and downregulate the expression of let-7d, respectively, a cell counting kit to assess cell viability, and a TUNEL staining assay and flow cytometry to examine the cell death rate, and we found that let-7d could negatively regulate 6-OHDA-induced cell injury. Then, we verified that caspase-3 was a target gene of let-7d by using a dual-luciferase reporter system. Furthermore, using caspase-3 siRNA and a caspase-3-overexpression vector (without the 3'UTR) to respectively inhibit and increase the expression of caspase-3, we found that caspase-3 siRNA could reverse the cell injury induced by the let-7d inhibitor and that caspase-3 overexpression could reverse the protective effects of the let-7d mimic on 6-OHDA-induced cell injury. Taken together, these findings strongly suggest that let-7d plays an important role in DA neuronal cell injury and that the effects of let-7d are, at least in part, via the suppression of caspase-3 expression.

The Actin Cytoskeleton Is Involved in Glial Cell Line-Derived Neurotrophic Factor (GDNF)-Induced Ret Translocation into Lipid Rafts in Dopaminergic Neuronal Cells.

Glial cell line-derived neurotrophic factor (GDNF), a potential therapeutic factor for Parkinson's disease (PD), exerts its biological effects through the Ret receptor tyrosine kinase. The redistribution of Ret into lipid rafts substantially influences Ret signaling, but the mechanisms underlying Ret translocation remain unclear. The purpose of our study was to further explore the signaling mechanisms of GDNF and to determine whether the actin cytoskeleton is involved in the GDNF-induced Ret translocation into lipid rafts. In MN9D dopaminergic neuronal cells, we used density gradient centrifugation and immunofluorescence confocal microscopy to separate and visualize lipid rafts, co-immunoprecipitation to analyze protein-protein interactions, and latrunculin B (Lat B) and jasplakinolide (Jas) to disrupt and enhance the polymerization of the actin cytoskeleton, respectively. The results showed that Ret translocated into lipid rafts and coimmunoprecipitated with actin in response to GDNF treatment. After Lat B or Jas treatment, the Ret-F-actin association induced by GDNF was impaired or enhanced respectively and then the levels of Ret translocated into lipid rafts were correspondingly inhibited or promoted. These data indicate that actin polymerization and cytoskeletal remodeling are integral to GDNF-induced cell signaling in dopaminergic cells and define a new role of the actin cytoskeleton in promoting Ret redistribution into lipid rafts.

MiR-218 inhibits HMGB1-mediated autophagy in endometrial carcinoma cells during chemotherapy.

Endometrial carcinoma is the most common gynecological malignancy among women worldwide. Although treatment for EC has improved with the introduction of Paclitaxel (Tax) chemotherapy, the majority of patients will develop resistance to the treatment, leading to poor prognosis. One of the causes of chemoresistance is the increased ability to undergo autophagy. In this study, we identified that miR-218 was significantly down-regulated in Tax-resistant EC cells compared to the non-drug resistant cell lines, and overexpression of miR-218 sensitized paclitaxel resistant EC cells to paclitaxel. Moreover, we demonstrated that miR-218 directly binds to the 3'-UTR of HMGB1 gene. HMGB1 was upregulated in paclitaxel resistant EC cells, it mediated autophagy and contributed to chemotherapy resistance in endometrial carcinoma in vitro. HMGB1-mediated autophagy could be suppressed by miR-218 overexpression in Tax resistant EC cells. In summary, we determined the targeting role of miR-218 to HMGB1 and the regulation of miR-218 on the HMGB1-mediated cell autophagy during chemotherapy resistance in endometrial carcinoma cells. These results reveal novel potential role of miR-218 against chemotherapy resistance during the treatment of endometrial carcinoma.