Objective To systematically analyze the research hotspots and development trends of drug resistance mechanisms in renal cell carcinoma(RCC),and to provide a reference for research in this field.Methods The literature related to drug resistance in treatment of RCC was obtained from Web of Science core collection.CiteSpace software was used for keyword clustering and trend analysis,and VOSviewer software was used for keyword co-occurrence network analysis.Results In total,1 392 literature were incorporated,including 736 regarding targeted therapy,158 in immunotherapy,and 369 in chemotherapy.The overall research trend in this field was on the rise,in which the research on targeted therapy resistance occupies a dominant position,and immunotherapy resistance was a new research direction.Key words in this field were focused on molecular mechanisms of drug resistance,potential signaling pathways,combination therapy,indicators,and novel therapy.The evolution of keywords and theme words suggests that the research tendency of RCC targeted therapy resistance in recent years focuses on the exploration of new mechanisms of drug resistance and the application of multi-target drugs.The research trend of immunotherapy resistance highlights combination therapy,tumor microenvironment,and metastasis correlation.The research trend of chemotherapy resistance focused on pharmacokinetic-related factors,multidrug resistance genes.Conclusion To provide references for researchers to accurately grasp the research status and development trend of drug resistance in RCC.

Objective To investigate the protective effect of Guanxinning(GXN)tablet on dilated cardiomyopathy(DCM),and to explore its effect and mechanism in pyroptosis of cardiomyocytes via the NLRP3/ASC/Caspase-1 pathway.Methods Rats were divided into GXN low-dose,GXN high-dose,digoxin,model control,and normal control groups.The DCM model was induced by multiple intraperitoneal injections of 17.5 mg/kg doxorubicin(DOX).The drug was administered at the same time as the model was established for 10 weeks.After the last administration,echocardiography was used to assess cardiac function indexes.After sacrificing the rats,serum was collected to measure IL-1β and IL-18 levels.RT-PCR was used to detect mRNA expression of NLRP3,ASC,Caspase-1,NF-κB,TXNIP,IL-1β,and IL-18.Immunohistochemistry and immunofluorescence staining and Western Blot were used to assess NLRP3,ASC,Caspase-1,IL-1β,and IL-18,GSDMD and GSDMD-NT protein,and TUNEL staining result.Changes in the microstructure of cardiomyocytes were observed by transmission electron microscopy.Results Compared with the normal control group,IVSs,IVSd,LVPWs,FS,SV,EF,and HR of the model control group were significantly reduced,LVIDs,ESV,and serum IL-1β and IL-18 were significantly increased,NLRP3,ASC,Caspase-1,NF-κB,TXNIP,IL-1β and IL-18 mRNA expression was significantly increased,and NLRP3,ASC,Caspase-1,IL-1β,IL-18 and GSDMD-NT protein expression and the TUNEL staining area were increased significantly,and the microstructure of cardiomyocytes changed significantly.Compared with the model control group,GXN significantly increased IVSs,SV,FS,EF,and HR,significantly reduced LVIDs,ESV,and the serum levels of IL-1β and IL-18,and reduced NLRP3,ASC,Caspase-1,NF-κB,TXNIP,IL-1β,and IL-18 mRNA expression,NLRP3,ASC,Caspase-1,IL-1β,IL-18 and GSDMD-NT protein expression,and the TUNEL staining area.Additionally,the microstructure was improved significantly.Conclusions GXN alleviates cardiomyocyte pyroptosis in rats with DCM by inhibiting the NLRP3/ASC/Caspase-1 pathway.

Objective To study the effects and mechanisms of Smilax glabra flavonoids(SGF)on myocardial hypertrophy and cardiac inflammation induced by isoproterenol(ISO)in mice.Methods C57/6J mice were randomly divided into a normal group,ISO model group(1.25 mg/(kg·d)),SGF low-dose group(50 mg/(kg·d)),and SGF high-dose group(100 mg/(kg·d)).The SGF groups were given prophylactic SGF for 7 days before modeling,then subcutaneous ISO injection was given to each group,and echocardiography was performed after continuous injection for 7 days.Serum was separated from orbital blood,and the NT-proBNP and inflammatory factor(IL-1β,IL-6,and TNF-α)contents of the blood were detected.Myocardial specimens were collected,and pathological changes to myocardial tissue were observed.Myocardial ROS levels were detected by DHE staining.The mRNA levels of heart-related hypertrophy genes and changes in the expression of key proteins in the inflammatory pathway of NLRP3/Caspase-1/IL-18 in myocardial tissue were detected.Results SGF prophylactic administration decreased IVSd,IVSs,and EF in echocardiography and increased LVIDs,LVIDd,and LVESV.The IL-1 β,IL-6,TNF-α,and NT-proBNP contents of blood decreased,and the mRNA expression levels of the heart-related hypertrophy genes for ANP,BNP,and β-MHC were subdued.The increase in myocardial ROS levels was also inhibited.The protein expression of NLRP3,Caspase-1(p20),and IL-18,which are key factors in the NLRP3/caspase-l/IL-18 inflammatory pathway,was down-regulated in myocardial tissue.The hypertrophy and disordered arrangement of cardiomyocytes were improved,the increase in fibroblast numbers outside myocardial fibers was reduced,and the infiltration of inflammatory cells and fibrosis of myocardial tissue were alleviated.Conclusions SGF can improve ISO-induced myocardial hypertrophy and cardiac inflammation in mice and may act through the NLRP3/Caspase-1/IL-18 inflammatory pathway.

Objective:To evaluate the safety and efficacy of tumor-treating fields (TTFields) and chemoradiation in patients with high-grade glioblastoma.Methods:Clinical data of 38 patients admitted to the Jiangsu Cancer Hospital from September 2021 to May 2023 who were diagnosed with high-grade glioblastoma (36 cases of World Health Organization grade Ⅳ and 2 cases of grade Ⅲ) were retrospectively analyzed. All patients received TTFields combined with concurrent chemoradiation after surgery. Response assessment in neuro-oncology (RANO) criteria was used to evaluate the glioma responses as tumor remission, stable or progression. Common terminology criteria for adverse events v5.0 and TTFields related skin adverse reaction (dAE) criteria were used to evaluate the adverse events. Treatment compliance was assessed by data on the NovoTTF-200A therapeutic device, calculated as a percentage of daily TTFields usage time. Survival analysis was estimated by the Kaplan-Meier method and compared by the log-rank test.Results:The median duration of treatment with TTFields in 38 patients was 20 h (rang: 2.4-22.6 h), and the median treatment compliance was 83% (range: 10%-94%). After 42 days of TTFields combined with concurrent chemoradiation, 12 patients who underwent complete tumor resection were assessed as stable according to RANO criteria. Among the 26 patients who underwent partial tumor resection, 23 (88%) were evaluated as disease remission according to RANO criteria. The 7-, 10-, 13-month progression-free survival rate was 81.0%、64.0%、49.5%, repectively. The common adverse events included grade 1 (45%) and grade 2 (8%) dAE, without grade 3-4 dAE. Typical presentations included contact dermatitis, blisters, lesions or ulcers, and abscesses. The median follow-up time was 10.0 months (range: 1.6-21.3 months). At follow-up as of July 2023, 26 of the 38 patients were stable and 12 had disease progression (8 died).Conclusion:The preliminary results show that TTFields combined with chemoradiation is effective, safe and reliable treatment for high-grade glioblastoma.

OBJECTIVE To mine the cardiovascular safety signal of relugolix， and provide a reference for the listing of this drug in China and future clinical safety drug evaluation. METHODS The adverse event （AE） report data of relugolix， as the primary or secondary suspected drug， was collected from the FDA Adverse Event Reporting System （FAERS） from the first quarter of 2021 to the third quarter of 2023. The reporting odds ratio （ROR） method was used for data mining. The AEs in the FAERS database were identified and coded using preferred terms （PT） stated in version 24.0 of the Medical Dictionary for Drug Regulatory Activities （MedDRA）. The AEs of the target drug were identified by the narrow standardized MedDRA query （SMQ） terms and high-level term （HLT）. Sensitivity analysis was conducted using AEs suspected to be primarily or secondarily related to relugolix or related to drug interaction and concomitant drug， and broad SMQ terms. RESULTS A total of 4 354 relugolix-related AE reports were extracted. In the primary analysis， nine SMQ terms were analyzed， involving 2 positive signals such as dyslipidemia and hyperglycemia/new onset diabetes mellitus. Eleven HLTs were analyzed， and three positive signals were detected for three terms including cholesterol analyses， triglyceride analyses and hyperglycemia conditions （non-alternative analysis）. Sensitivity analysis results indicated the reliability of the study findings. CONCLUSIONS Relugolix may induce risk signals related to high blood lipids and high blood glucose， but no moderate risk signals such as hypertension， heart disease， and stroke are found. During relugolix treatment in clinical practice， attention must be paid to hyperlipidemia and hyperglycemia-related AE.

Background and objective Invasive mucinous adenocarcinoma(IMA)was a rare and specific type of lung adenocarcinoma,which was often characterized by fewer lymphatic metastases.Therefore,it was difficult to evaluate the prognosis of these tumors based on the existing tumor-node-metastasis(TNM)staging.So,this study aimed to develop Nomo-grams to predict outcomes of patients with pathologic N0 in resected IMA.Methods According to the inclusion criteria and exclusion criteria,IMA patients with pathologic N0 in The Affiliated Lihuili Hospital of Ningbo University(training cohort,n=78)and Ningbo No.2 Hospital(validation cohort,n=66)were reviewed between July 2012 and May 2017.The prognostic value of the clinicopathological features in the training cohort was analyzed and prognostic prediction models were established,and the performances of models were evaluated.Finally,the validation cohort data was put in for external validation.Results Univariate analysis showed that pneumonic type,larger tumor size,mixed mucinous/non-mucinous component,and higher overall stage were significant influence factors of 5-year progression-free survival(PFS)and overall survival(OS).Multivariate analysis further indicated that type of imaging,tumor size,mucinous component were the independent prognostic factors for poor 5-year PFS and OS.Moreover,the 5-year PFS and OS rates were 62.82％and 75.64％,respectively.In subgroups,the sur-vival analysis also showed that the pneumonic type and mixed mucinous/non-mucinous patients had significantly poorer 5-year PFS and OS compared with solitary type and pure mucinous patients,respectively.The C-index of Nomograms with 5-year PFS and OS were 0.815(95％CI:0.741-0.889)and 0.767(95％CI:0.669-0.865).The calibration curve and decision curve analysis(DCA)of both models showed good predictive performances in both cohorts.Conclusion The Nomograms based on clinicopathological characteristics in a certain extent,can be used as an effective prognostic tool for patients with pathologic N0 after IMA resection.

Objective:To investigate the iodine content in drinking water of residents in Henan Province, and clarify the distribution characteristics of water iodine in Henan Province.Methods:In 2017, in all counties (cities and districts, hereinafter referred to as counties) of Henan Province, taking township (town, subdistrict office, hereinafter referred to as township) as the unit to carry out an investigation of iodine content in drinking water; and in the township with water iodine content of 10 μg/L or more, taking administrative village (neighborhood committee, hereinafter referred to as the administrative village) as the unit to carry out the drinking water iodine content investigation. Supplementary investigation was conducted from 2018 to 2020 in administrative villages where water iodine levels had never been tested or had not been tested after replacing water sources. At least 25 ml water samples were collected at each sampling site, and the water iodine content was determined by cerous sulfate catalytic spectrophotometry.Results:From 2017 to 2020, the median water iodine in Henan Province was 8.20 μg/L. A total of 50 124 administrative villages in 2 465 townships, 160 counties and 18 provincial-level cities were investigated for iodine content in drinking water, of which 65.5% (32 807/50 124) of the administrative villages had a median water iodine < 40 μg/L, belonging to iodine deficiency area; 16.9% (8 473/50 124) of the administrative villages had a median water iodine of 40-100 μg/L, suitable for iodine; and 17.6% (8 844/50 124) of the administrative villages had a median water iodine > 100 μg/L, belonging to water source high iodine area.Conclusions:Henan Province as a whole is at the state of iodine deficiency in the external environment. Most administrative villages are iodine deficiency areas. There are certain proportion of water source areas with high iodine and areas with suitable iodine.

Objective:To learn about the progress of prevention and control of drinking-water-borne endemic arsenic poisoning in Henan Province, and provide scientific basis for achieving the goal of eliminating high arsenic hazards as scheduled.Methods:From July to August 2019, in accordance with the requirements of the National Monitoring Program for Drinking-water-borne Endemic Arsenic Poisoning, a general survey was carried out in 26 high-arsenic villages in 6 counties of Henan Province to investigate the water improvement situation and the operation of water improvement projects, and the arsenic content in drinking water of households was measured, meanwhile, the arsenic poisoning status of permanent residents in high-arsenic villages was investigated.Results:All 26 villages with high arsenic content in the province had undergone water improvement, with a water improvement rate of 100.00%. A total of 18 water improvement projects were investigated in 26 high-arsenic villages, all of which were operating normally. Twenty-six water samples were collected, and the arsenic content in the household water was < 0.01 mg/L, which met the sanitary standards for drinking water. No patient of endemic arsenic poisoning was found during the survey.Conclusion:In Henan Province, the drinking-water-borne endemic arsenic poisoning has been effectively controlled, and the prevention and control achievements should continue to be consolidated in the future.

Objective:To investigate the epidemic situation of drinking water-borne endemic fluorosis in Henan Province, evaluate the effectiveness of prevention and control measures, and provide a basis for formulating further prevention and control policies.Methods:From April to November 2021, a census of all diseased villages registered in 112 drinking water-borne endemic fluorosis counties (cities, districts, hereinafter referred to as counties) of 17 provincial-level cities and 9 provincial-level counties (cities) in Henan Province was conducted to collect the basic information of diseased counties and villages. The content of fluoride in drinking water and the prevalence of dental fluorosis in children aged 8 - 12 years old were measured on a village by village basis.Results:By the end of 2021, drinking water-borne endemic fluorosis was prevalent in 112 diseased counties in Henan Province, involving 17 450 diseased villages. Among them, 17 433 villages had implemented measures to reduce fluoride and improve water quality, with a water improvement rate of 99.90% (17 433/17 450). There were 14 920 villages with qualified water, and the qualified rate of water fluoride was 85.50% (14 920/17 450). There were a total of 4 232 water improvement projects in all diseased villages, with a normal operation rate of 97.09% (4 109/4 232) and a qualified rate of 93.03% (3 937/4 232) for water fluoride in the projects. The total detection rate of dental fluorosis in children in the province was 9.64% (39 391/408 584), with moderate to severe dental fluorosis accounted for 8.08% (3 182/39 391), the dental fluorosis index was 0.18. The prevalence of fluorosis was negative.Conclusions:In 2021, the prevalence of drinking water-borne endemic fluorosis is widespread in Henan Province, and measures to reduce fluoride and improve water quality in diseased villages have been basically implemented. However, the fluoride content of water in some villages still does not meet the standard, and some water improvement projects cannot operate normally throughout the year. In the future, it is necessary to address the above issues one by one and consolidate the achievements in prevention and control of drinking water-borne endemic fluorosis.

Objective:To design a method to introduce random six-dimensional setup error (6D-SE) into the intensity-modulated radiotherapy (IMRT) planning for rectal cancer and evaluate its dosimetric effect.Methods:A total of 21 IMRT plans for patients with rectal cancer were randomly selected as reference plans [2 Gy per fraction for a total of 50 Gy; a 5 mm uniform margin around the clinical target volume (CTV) was taken as the planning target volume (PTV)]. For each fraction of the reference plan, a randomly generated 6D-SE was introduced by adjusting the geometrical parameters of the radiation field, and the dose was recalculated. The overall dose distribution with 6D-SE was obtained by adding up the dose of each fraction. A treatment simulation program that could complete the above workflow was developed using the Varian Eclipse scripting API (ESAPI). 6D-SEs that obey two preset distributions [distribution 1: translational error obey N(0, 4 2), and rotational error obey N(0, 2 2); distribution 2: translational error obey N(0, 2 2), and rotational error obey N(0, 1 2)] were introduced into the reference plans, and the dosimetric effects were assessed. Results:When the reference plans, error distribution 1, and error distribution 2 were applied, the Dmin values of the CTV were (49.4±0.41), (47.56±0.76), and (49.17±0.64) Gy, respectively; the D98% values of the CTV were (50.23±0.07), (49.98±0.10), and (50.27±0.09) Gy, respectively; the D98% values of the primary target area (the kernel part of the target area, excluding the margins) were (50.25±0.08), (50.42±0.13), and (50.33±0.10) Gy, respectively; the D98% values of the marginal area were (50.22±0.10), (49.88±0.11), and (50.26±0.10) Gy, respectively. In addition, compared with the result of the reference plans, the result of errors 1 and 2 showed no significant changes in the mean dose of the bladder and femoral heads ( P>0.05), despite slight decreases in the conformity index of the dose distribution with limited clinical significance. Conclusion:The proposed method and the treatment simulation program developed thereupon can introduce the 6D-SE obeying different distributions into the IMRT plans for rectal cancer on demand and provide overall dosimetric changes.