BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy (RT) following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed. Inverse probability of treatment weighting (IPTW) analysis was performed to address potential confounding factors. The primary focus of our evaluation was to assess the impact of RT on progression-free survival (PFS) and overall survival (OS). RESULTS: After IPTW analysis, 49 patients received durvalumab plus platinum-etoposide (EP) chemotherapy followed by RT (Durva + EP + RT) and 72 patients received immunochemotherapy (Durva + EP). The median OS was 17.2 months vs . 12.3 months (hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.17-0.85, P = 0.020), and the median PFS was 8.9 months vs . 5.9 months (HR: 0.56, 95% CI: 0.32-0.97, P = 0.030) in Durva + EP + RT and Durva + EP groups, respectively. Thoracic radiation therapy (TRT) resulted in longer OS (17.2 months vs . 14.7 months) and PFS (9.1 months vs . 7.2 months) compared to RT directed to other metastatic sites. Among patients with oligo-metastasis, RT also showed significant benefits, with a median OS of 17.4 months vs . 13.7 months and median PFS of 9.8 months vs . 5.9 months compared to no RT. Continuous durvalumab treatment beyond progression (TBP) prolonged OS compared to patients without TBP, in both the Durva + EP + RT (NA vs . 15.8 months, HR: 0.48, 95% CI: 0.14-1.63, P = 0.238) and Durva + EP groups (12.3 months vs . 4.3 months, HR: 0.29, 95% CI: 0.10-0.81, P = 0.018). Grade 3 or 4 adverse events occurred in 13 (26.5%) and 13 (18.1%) patients, respectively, in the two groups; pneumonitis was mostly low-grade. CONCLUSION Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.
Humans ; Small Cell Lung Carcinoma/therapy* ; Retrospective Studies ; Male ; Female ; Middle Aged ; Lung Neoplasms/therapy* ; Aged ; Antibodies, Monoclonal/therapeutic use* ; Adult ; Immunotherapy/methods* ; Aged, 80 and over

The KCNQ potassium channels play a crucial role in modulating neural excitability, and their dysfunction is closely associated with epileptic disorders. While variants in KCNQ2 have been extensively studied, KCNQ3-related disorders have rarely been reported. With advances in next-generation sequencing technologies, an increasing number of cases of KCNQ3-related disorders have been identified. However, the correlation between genotype and phenotype remains poorly understood. In this study, we established a variant library consisting of 24 missense mutations in KCNQ3 and introduced these mutations into three different template types: KCNQ3, KCNQ3-A315T (Q3*), and KCNQ3-KCNQ2 tandem (Q3-Q2). We then analyzed the effects of these mutations on the KCNQ3 channel function using patch-clamp recording. The most informative parameter across all three backgrounds was the current density of the mutant channels. The current density patterns in the Q3* and Q3-Q2 backgrounds were similar, with most mutations resulting in an almost complete loss of function (LOF), they were concentrated in the pore-forming domain of KCNQ3. In contrast, mutations in the voltage-sensing domain or C-terminus did not show significant differences from the wild-type channel. Interestingly, these LOF mutations were typically associated with self-limited familial neonatal epilepsy, while neurodevelopmental disorders (NDD) were more closely associated with mutations that did not significantly differ from the wild-type. V_1/2, another important parameter of the electrophysiological properties, could not be accurately determined in the majority of KCNQ3 mutations due to its nearly complete LOF in the Q3* and Q3-Q2 backgrounds. Intriguingly, the V_1/2 of functional mutations were primarily leftward shifted, indicating a gain-of-function (GOF) effect, which was typically associated with NDD. In addition to previously reported mutations, we identified G553R as a novel GOF mutation. In the co-transfection background, parameters such as V_1/2 could be determined, but the dysfunctional effects of these mutations were mitigated by the co-expression of wild-type KCNQ3 and KCNQ2 subunits, resulting in no significant differences between most mutations and the wild-type channel. Furthermore, we applied KCNQ modulators to reverse the electrophysiological abnormalities caused by KCNQ3 variants. The LOF mutations were reversed by the application of Pynegabine (HN37), a KCNQ opener, while the GOF mutation responded well to Amitriptyline (AMI), a KCNQ inhibitor. These findings provide essential insights into the pathogenic mechanisms underlying KCNQ3-related disorders and may inform clinical decision-making.
KCNQ3 Potassium Channel/genetics* ; Humans ; Mutation, Missense/genetics* ; KCNQ2 Potassium Channel/genetics* ; Patch-Clamp Techniques ; HEK293 Cells ; Animals ; Phenylenediamines/pharmacology* ; Carbamates

Objective:To identify the key genes in the process inhibiting inflammation by overexpression adenovirus-mediated pigment epithelium-derived factor ( PEDF) gene in human monocytic leukemia cells THP1. Methods:Proteomic analysis of THP1 overexpressing adenovirus-mediated PEDF gene was performed.The THP1 cells were divided into GFP and PEDF groups, transfected with GFP and PEDF adenovirus, respectively.The THP1 cells were divided into mannitol group, high glucose group, high glucose+ GFP group, and high glucose+ PEDF group, which were cultured with mannitol for 4 days, anhydrous glucose for 4 days, GFP adenovirus for 3 days, and PEDF adenovirus for 3 days, respectively.The Pedf-/- mice were divided into Pedf-/- group and Pedf-/- diabetes group according to the random table method, with 12 mice in each group.Another 10 C57BL/6 mice were taken as the control group.Mouse retinas were collected for experiments.The mRNA expression levels of differentially expressed genes (DEGs) in retina and THP1 cells were verified by real-time fluorescence quantitative PCR.The DEGs were intersected with the GSE5504 dataset, and the protein-protein interaction (PPI) network was built using the String database.Modules of the PPI were extracted using the Cytoscape software and the MCODE application.Intersections were taken with the Set1 dataset and key genes were found.The expression levels of key genes in THP1 cells and Pedf-/- mice were verified by Western blot.The feeding and operation of experimental animals were in accordance with the regulations of the State Science and Technology Commission on the management of experimental animals and approved by the Animal Management and Use Committee of Tianjin Medical University (No.TTYY2023120217). Results:Through proteomics and bioinformatics analysis, 105 DEGs in the Set1 dataset were screened.The results of real-time PCR showed that the relative expression levels of ARF5, TCF25 and KCTD9 mRNA were significantly higher and the relative expression levels of RNPS1, CSF1R, OGA, IBA57 and MGST2 mRNA were significantly lower in PEDF group than in GFP group, showing statistically significant differences (all at P<0.001).There were significant overall differences in the relative expression levels of down-regulated TCF25, KCTD9 and ARF5 mRNA and up-regulated CSF1R, RNPS1 and IBA57 mRNA among control group, Pedf-/- group and Pedf-/- diabetes group ( F=64.057, 27.561, 37.179, 65.757, 44.024, 34.248; all at P<0.001).Compared with control group, the relative expression levels of TCF25, KCTD9 and ARF5 mRNA were decreased and the relative expression levels of CSF1R and RNPS1 mRNA were increased in Pedf-/- group, showing statistically significant differences (all at P<0.05).Compared with control group, the relative expression levels of TCF25, KCTD9 and ARF5 mRNA were decreased and the relative expression levels of CSF1R, RNPS1 and IBA57 mRNA were increased in Pedf-/- diabetes group, showing statistically significant differences (all at P<0.05).Compared with Pedf-/- group, the relative expression level of TCF25 mRNA was decreased and the relative expression levels of CSF1R, RNPS1 and IBA57 mRNA were increased in Pedf-/- diabetes group, showing statistically significant differences (all at P<0.05).After intersection with the GSE5504 dataset, 20 differential proteins were obtained, which were mainly enriched in positive regulation of gene expression, positive regulation of ERK1 and ERK2 cascade, positive regulation of insulin secretion involved in cell response to glucose stimulation and antigen processing and presentation pathways.The key gene CSF1R was screened by constructing PPI network and MCODE plugin in Cytoscape software.Western blot results showed that the expression levels of CSF1R in high glucose group and high glucose+ GFP group were 1.961±0.085 and 1.000±0.069, which were higher than 1.000±0.072 in mannitol group and 0.469±0.079 in high glucose+ PEDF group, respectively, and the differences were statistically significant ( t=14.940, 8.765; both at P < 0.01).The expression of CSF1R in the retina of Pedf-/- diabetes group was 1.633±0.192, which was higher than 1.000±0.050 in Pedf-/- group, and the difference was statistically significant ( t=5.537, P<0.01). Conclusions:CSF1R may be a key gene and therapeutic target for the inhibition of inflammation by overexpression of adenovirus-mediated PEDF gene in THP1 cell.

Objective To investigate the effects of insulin therapy on the mechanical behavior of solids,characteristics of fluid flow,and bone marrow stromal cells(BMSCs)differentiation in the distal femoral cancellous bone of type 2 diabetic rats under normal activity and vigorous exercise conditions.Methods The finite element models of cancellous bones and fluids in the distal femurs of rats in the control,diabetes,treatment,and placebo groups in 4-week and 8-week insulin treatment experiments under normal activity and vigorous exercise conditions were established based on micro-CT scanning images.The mechanical and cell differentiation parameters of the models in each group were analyzed using the fluid-solid interaction numerical simulation method.Correlations between mechanical,cell differentiation,and microstructural morphology parameters were also analyzed.Results Insulin therapy under normal activity and vigorous exercise conditions improved the solid and fluid mechanical parameters and BMSC differentiation parameters in type 2 diabetic rats.In the 4-week experiment,insulin treatment under normal activity and vigorous exercise conditions increased the differentiation areas of bone in type 2 diabetic rats from 64.024%to 69.372%and from 73.225%to 75.336%,respectively;in the 8-week experiment,insulin treatment under normal activity and vigorous exercise conditions increased the differentiation areas of bone in type 2 diabetic rats from 67.239%to 72.910%and from 76.147%to 78.291%,respectively.Morphological parameters BV/TV,Tb.N,Tb.Th,Tb.Sp,and structure model index were significantly correlated with the differentiation areas of the bone and cartilage(P<0.05).Conclusions Under vigorous exercise conditions,BMSCs on the surface of cancellous bone in the 8-week insulin treatment group were more likely to differentiate into bone tissue.This study is of great significance for further understanding the effects of insulin on the bone under normal activity and vigorous exercise conditions,and provides theoretical guidance for the selection of the insulin therapy cycle and exercise mode in the clinical treatment of type 2 diabetes.

Objective:To analyze the risk factors for asparaginase-associated pancreatitis (AAP) in children with acute lymphoblastic leukemia (ALL) after treatment with pegaspargase and evaluate the predictive value of pediatric sequential organ failure assessment (SOFA) score, pediatric acute pancreatitis severity (PAPS) score, Ranson′s score and pediatric Ministry of Health, Labour and Welfare of Japan (JPN) score for severe AAP.Methods:Cross-sectional study.The clinical data of 328 children with ALL who received pegaspargase treatment in the Department of Pediatric Hematology, Zhujiang Hospital, Southern Medical University from January 2014 to August 2021, as well as their clinical manifestations, laboratory examinations, and imaging examinations were collected.The SOFA score at the time of AAP diagnosis, PAPS score and Ranson′s score at 48 hours after AAP diagnosis, and JPN score at 72 hours after AAP diagnosis were calculated, and their predictive value for severe AAP was evaluated by the receiver operating characteristic (ROC) curve.Results:A total of 6.7%(22/328) of children had AAP, with the median age of 6.62 years.AAP most commonly occurred in the induced remission phase (16/22, 72.7%). Three AAP children were re-exposed to asparaginase, and 2 of them developed a second AAP.Among the 22 AAP children, 16 presented with mild symptoms, and 6 with severe symptoms.The 6 children with severe AAP were all transferred to the Pediatric Intensive Care Unit (PICU). There were no significant differences in gender, white blood cell count at first diagnosis, immunophenotype, risk stratification, and single dose of pegaspargase between the AAP and non-AAP groups.The age at diagnosis of ALL in the AAP group was significantly higher than that in the non-AAP group ( t=2.385, P=0.018). The number of overweight or obese children in the AAP group was also higher than that in the non-AAP group ( χ2=4.507, P=0.034). The areas under the ROC curve of children′s JPN score, SOFA score, Ranson′s score, and PAPS score in predicting severe AAP were 0.919, 0.844, 0.731, and 0.606, respectively.The JPN score ( t=4.174, P=0.001) and the SOFA score ( t=3.181, P=0.005) showed statistically significant differences between mild and severe AAP. Conclusions:AAP is a serious complication in the treatment of ALL with combined pegaspargase and chemotherapy.Older age and overweight or obesity may be the risk factors for AAP.Pediatric JPN and SOFA scores have predictive value for severe AAP.

Radiotherapy (RT) can potentially induce systemic immune responses by initiating immunogenic cell death (ICD) of tumor cells. However, RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases. Herein, we construct multifunctional self-sufficient nanoparticles (MARS) with dual-enzyme activity (GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse. In addition to limiting the Warburg effect to actualize starvation therapy, MARS catalyzes glucose to produce hydrogen peroxide (H₂O₂), which is then used in the Cu⁺-mediated Fenton-like reaction and RT sensitization. RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms, which have a robust ICD impact on mobilizing the immune system. Thus, when MARS is combined with RT, potent systemic antitumor immunity can be generated by activating antigen-presenting cells, promoting dendritic cells maturation, increasing the infiltration of cytotoxic T lymphocytes, and reprogramming the immunosuppressive tumor microenvironment. Furthermore, the synergistic therapy of RT and MARS effectively suppresses local tumor growth, increases mouse longevity, and results in a 90% reduction in lung metastasis and postoperative recurrence. Overall, we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

Objective:To assess the trends in case-fatality rates for acute myocardial infarction (AMI) in China from 2015 to 2019.Methods:This study employed a population-based surveillance. Data from the China Registry of Acute Cardiovascular Event (China RACE) were utilized, including AMI cases reported by Grade Ⅱ and Grade Ⅲ hospitals at the disease surveillance sites across China from January 1 st 2015 to December 31 st 2019. The 28-day mortality outcome for reported AMI events was obtained by linking to the national death certificate registry system. The study analyzed the overall and age-standardized case-fatality rates, as well as their annual percent change (APC), during the study period, stratified by gender, age, and region. Results:The overall 28-day case fatality rate for AMI was 28.97% (22 532/77 764) from 2015 to 2019. The age-standardized case-fatality rate for AMI declined significantly from 37.53% in 2015 to 18.58% in 2019, with an APC of -14.33% ( P=0.018). We observed a significant downward trend in case-fatality rates of AMI in both genders (both P<0.05). Among males, the case-fatality rate decreased more steeply in younger males compared to elder counterparts. The most marked decreases were seen in males aged<35 years and 35 to 44 years, with APC of -27.63% ( P=0.007) and -22.65% ( P=0.004), respectively. In females, we observed a relatively stable decrease in case-fatality across age groups. The age-standardized case-fatality rate of AMI in eastern and central China decreased significantly from 2015 to 2019, with the APC of -19.22% ( P=0.006) and -15.62% ( P=0.032) respectively. However, the age-standardized case-fatality rate of AMI in western China remained stable ( P=0.227). Conclusions:The prognosis of AMI has considerably improved from 2015 to 2019 in China, regardless of ages and gender. Inequality in case-fatality rates among geographic regions highlights the need for targeted strategies in AMI prevention in western regions.

Objective:To investigate the efficacy and safety of the application of microwave ablation assisted clamp-less suture-less nephron sparing surgery technique in the management of cystic renal cell carcinoma.Methods:The data of 21 consecutive patients with cystic renal cell carcinoma who underwent microwave ablation assisted clamp-less suture-less laparoscopic nephron sparing surgery (MACS-LNSS) in Renji Hospital, Shanghai Jiaotong University School of Medicine from January 2017 to December 2020, were retrospectively analyzed. There were 17 males and 4 females with a mean age of (58.0±2.6) years old. There were 19 cases with Eastern Cooperative Oncology Group (ECOG) score 0 and 2 with score 1. The mean diameter of the tumor was (3.6±0.4) cm, and the mean distance from the collecting system was (10.7±0.9) mm with 12 located on the left and 9 on the right side. There were 5 cases of Bosniak Ⅲ with mean CT value (27.6±4.6) HU and 16 of Bosniak Ⅳ and the mean estimated glomerular filtration rate(eGFR) was (84.1±4.1 ) ml/(min·1.73 m 2). The American Society of Anesthesiology (ASA) graded 17 cas as grade 1, 3 cases as grade 2 and 1 cases as grade 3. MACS-LNSS was performed for all patients. The microwave ablation probe was introduced via the laparoscopic trocar and inserted into the tumor. Then all tumors were resected after microwave ablation was performed for 1 to 3 cycles lasting 2 to 5 minutes for each tumour with a power output of 60 to 100 W using an MTC-3C microwave ablation system. Results:MACS-LNSS was successfully performed in 20 cases. Another one converted to conventional laparoscopic partial nephrectomy because of intraoperative bleeding with 14 min renal artery branch clamped. No case converted to open surgery or radical nephrectomy. The mean operative time was (92.0±6.3) min, with a mean estimated blood loss of (60.0±7.2) ml. The mean length of postoperative hospital stay was (2.7±0.1) d. No case required perioperative transfusion. One case with fever and one case with urine leakage were observed postoperatively and recovered after conservative treatment. Pathologic results revealed 18 cases of clear cell carcinoma, 3 of low grade malignant potential multilocular cystic renal cell tumors. The median eGFR at 6 months postoperative was (82.9±3.8) ml/(min·1.73 m 2).No local recurrence and distant metastasis was observed with a mean follow-up of (41.3±1.5)(range from 32 to 58) months. Conclusions:MACS-LNSS which has the advantages of controllable complications is an alternative, safe and feasible technique for cystic renal cell carcinoma less than 7 cm, with regular tumor base, and the distance from the collecting system more than 5 mm.

Objective:To observe the effects of moxibustion on the levels of glucose-6-phosphate dehydrogenase(G6PD)and reduced nicotinamide adenine dinucleotide phosphate(NADPH)in the plasma and spleen and the CD4+T-cell number in the spleen of rats with adjuvant arthritis,thus to explore the mechanism in rheumatoid arthritis(RA)treatment with moxibustion by regulating the CD4+T-cell proliferation through G6PD-mediated pentose phosphate pathway. Methods:Twenty-seven male Sprague-Dawley rats were randomly divided into a blank group,a model group,and a moxibustion group,with 9 rats in each group.Incomplete Freund's adjuvant was used to induce inflammation in the model group and the moxibustion group.The blank group and the model group were not intervened.In the moxibustion group,suspended moxibustion was performed at bilateral Zusanli(ST36),Guanyuan(CV4),and Ashi points for 30 min,once a day for 24 times in total.Hematoxylin-eosin staining was used to evaluate the histopathological changes of rat synovial tissue;the swelling degree of the rat toes was observed by measuring the toe volume;G6PD and NADPH in the spleen and plasma were detected by Western blotting and enzyme-linked immunosorbent assay.Flow cytometry was used to detect the CD4+T-cell number in the spleen. Results:Compared with the blank group,the levels of G6PD and NADPH in the plasma and spleen and the CD4+T-cell number in the spleen were significantly increased in the model group(P<0.01 or P<0.05).Compared with the model group,the NADPH level in the spleen and plasma and the CD4+T-cell number in the spleen in the moxibustion group decreased significantly(P<0.05 or P<0.01),and the G6PD level in the plasma decreased significantly(P<0.05),but there was no significant difference in the G6PD level in the spleen(P>0.05). Conclusion:Moxibustion can regulate immunity and improve joint synovial inflammation in RA.The mechanism may be that the G6PD-mediated pentose phosphate pathway reduces the production of metabolite NAPDH in CD4+T cells,thereby inhibiting the proliferation of naive CD4+T cells.

Objectives:To present the epidemiological characteristics of stroke incidence and stroke-related mortality among the whole population in national cardiovascular disease surveillance areas from 2015 to 2019. Methods:Data of stroke incidence and stroke-related mortality from 2015 to 2019 were collected from the China Registry of Cardiovascular Events(China RACE),which was established in 2014,covering 100 counties(cities,districts)in 31 provinces in China.The Joinpoint model was used to analyze the annual percentage changes(APC)and trends of stroke incidence rate.The age-standardized incidence rate(ASIR)was calculated using the Seventh National Census data as the standard population.With annual reported stroke events and stroke-related deaths,the mortality to incidence ratio(M/I)were examined. Results:From 2015 to 2019,an increase of 9.41%(APC=2.12%,95%CI:1.43%-2.82%,Ptrend<0.01)resulted in the overall stroke crude incidence rate(CIR)of 468.48/100 000 in 2019 among the whole population,with relatively higher in male and in rural area.The more sharply elevating of CIR appeared in males(11.26%[APC=2.53%,95%CI:1.83%-3.24%,Ptrend<0.01])rather than in females(7.26%[APC=1.63%,95%CI:0.81%-2.46%,Ptrend<0.01]).Meanwhile,the general ASIR decreased 7.47%(APC=-1.72%,95%CI:-3.23%--0.20%,Ptrend<0.05),reaching 523.82/100 000 in 2019.The females generally showed significant descending trend(9.56%[APC=-2.27%,95%CI:-3.99%--0.52%,Ptrend<0.05]),as well as more reduction than that in the males(15.82%vs.11.40%)in urban area.The crude incidence rate of stroke increased with age.From 2015 to 2019,the CIR in 45-49 age group increased 12.48%(APC=3.18%,95%CI:1.67%-4.72%,Ptrend<0.01),compared with an reduction of 15.76%(APC=-4.39%,95%CI:-7.63%--1.04%,Ptrend<0.05)in 80-84 age group.Over the monitoring years,the overall M/I was 0.19,with an age-specific U-shaped distribution.The lowest of M/I(0.10)appeared in those aged 50-54 and 55-59,while the highest(0.45)detected in those aged 85 and over.The M/I of all age in urban areas were consistently lower than that in rural areas. Conclusions:Stroke incidence burden increased from 2015-2019 in the national surveillance areas in China,along with the unfavorable geographic diversity and age-specific divergence.Further efforts are required to improve health care covering all ages and regions in China to reduce the incidence of stroke and stroke-related mortality.