Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

Objective: To investigate how plasma exchange (PE) and double plasma molecular adsorption combined with half-volume plasma exchange (DPMAS + half-volume PE) affect the curative effect and short-term survival rate in liver failure. Methods: Data from 181 cases of liver failure caused by different etiologies from January 1, 2017 to September 31, 2020, were selected. Patients were divided into a PE treatment alone group and a DPMAS + half-dose PE treatment group. The laboratory indicators with different models of artificial liver before and after treatment and the survival rates of 7, 14, 28, and 90 days after discharge were observed in the two groups. Measurement data were analyzed by t-tests and rank sum tests. Categorical data were analyzed by χ (2) test. Results: Non-biological artificial liver therapy with different models improved the liver and coagulation function in the two groups of patients with liver failure (P < 0.05 in PTA% intra-group). The coagulation function was significantly improved in the PE treatment alone group compared with that in the DPMAS + half-dose PE group [PT after treatment: (20.15 ± 0.88) s in the PE treatment alone group, (23.43 ± 1.02) s, t = -2.44, P = 0.016 in the DPMAS+half-dose PE group; PTA: 44.72% ± 1.75% in the PE treatment alone group, 35.62% ± 2.25%, t = 3.215 P = 0.002 in the DPMAS + half-dose PE group]. Bilirubin levels were significantly decreased in the DPMAS+half-dose PE group compared to the PE treatment alone group [total bilirubin after treatment: (255.30 ± 15.64) μmol/L in the PE treatment alone group, (205.46 ± 9.03) μmol/L, t = 2.74, P = 0.07 in the DPMAS + half-dose PE group; direct bilirubin after treatment: (114.74 ± 7.11) μmol/L in the PE treatment alone group, (55.33 ± 3.18) μmol/L, t = 7.54, P < 0.001) in the DPMAS + half-dose PE group]. However, there was no significant effect on leukocytes and neutrophils after treatment with different models of artificial liver (P > 0.05) in the two groups, and platelets decreased after treatment, with no statistically significant difference between the groups (t = -0.15, P = 0.882). The inflammatory indexes of the two groups improved after treatment with different models of artificial liver (P < 0.05], and the 28 and 90 d survival rates were higher in the DPMAS+half-dose PE group than those of the PE treatment alone group (28 d: 60.3% vs. 75.0%, χ (2) = 4.315, P = 0.038; 90 d: 56.2% vs. 72.5%. χ (2) = 10.355 P < 0.001). DPMAS + half-dose PE group plasma saving was 1385 ml compared with PE treatment alone group (Z = -7.608, P < 0.05). Conclusion: Both DPMAS+half-dose PE and PE treatment alone have a certain curative effect on patients with liver failure. In DPMAS+half-dose PE, the 28-day survival rate is superior to PE treatment alone, and it saves plasma consumption and minimizes blood use in clinic.

To explore pathogens in several tick species in endemic areas of Shandong province,unfed ticks and parasitic ones were collected in seven areas of Shandong province during 2021-2022 and morphologically identified.Five common tick-borne pathogens were detected by PCR with universal primers on the tick samples and phylogenetic analysis based on the sequences from positive pathogens were also performed as well.The results showed that the collected tick samples included 2 genera and 4 species,respectively comprising 145 of Haemaphysalis longicornis,2of Hae.concinna,2of Hae.campanulate,and 5 of Rhipicephalus sanguineus.A total of 34 collected ticks were found with spotted fever group Rickettsia infection,with a total positive rate of 22.08%,29 samples carried Anaplasma,with a total infection rate of 18.83%,the total infection rate of Theileria and Borrelia burgdorferi were revealed as 5.84% and 0.65%,respectively,and no positive samples were detected for Borrelia recurrentis.In conclusion,Hae.longicornis was shown as the dominant tick species in the sampling areas in Shandong province,and various pathogens were found harbored in different tick species.Local surveillance and awareness of tick-borne diseases should be strengthened for the purpose of efficient prevention and control measures.

Objective: To evaluate the long-term outcomes, failure patterns and prognostic factors of definitive radiotherapy in patients with cervical esophageal carcinoma (CEC). Methods: We retrospectively reviewed the clinical data of 148 CEC patients who treated with definitive radiotherapy in Cancer Hospital of Chinese Academy of Medical Sciences from January 2001 to December 2017. The median radiation dose was 66 Gy (59.4-70 Gy) and 33.1% of patients received concurrent chemotherapy. The Kaplan-Meier method was used to calculate survival rates. The log rank test was used for survival comparison and univariate prognostic analysis. The Cox model was used for multivariate prognostic analysis. Results: The median follow-up time was 102.6 months. The median survival time, 2- and 5-year overall survival (OS) were 22.7 months, 49.9% and 28.3%. The median, 2- and 5-year progression-free survival were 12.6 months, 35.8% and 25.8%. The 2- and 5-year locoregional recurrence-free survival were 59.1% and 50.8%. The 2- and 5-year distant metastases-free survival were 74.6% and 65.9%. Multivariate analysis showed that EQD(2)>66 Gy was the only independent prognostic indicator for OS (P=0.040). The median survival time and 5-year OS rate significantly improved in patients who received EQD(2)>66 Gy than those who received≤66 Gy (31.2 months vs. 19.2 months, 40.1% vs. 19.1%, P=0.027). A total of 87 patients (58.8%) developed tumor progression. There were 50 (33.8%), 23 (15.5%) and 39 (26.4%) patients developed local, regional recurrence and distant metastases, respectively. Eleven patients (7.4%) underwent salvage surgery, and the laryngeal preservation rate for entire group was 93.9%. Conclusions: Definitive radiotherapy is an effective treatment for cervical esophageal carcinoma with the advantage of larynx preservation. Local recurrence is the major failure pattern. EQD(2)>66 Gy is associated with the improved overall survival.
Humans ; Retrospective Studies ; Esophageal Neoplasms/pathology* ; Carcinoma/drug therapy* ; Prognosis ; Treatment Outcome ; Chemoradiotherapy/methods* ; Radiotherapy Dosage

Objective: To establish a survival prediction model based on the independent prognostic factors of long-term prognosis after laparoscopic liver resection(LLR) for intrahepatic cholangiocarcinoma(ICC). Methods: The clinical and pathological data of 351 consecutive patients with ICC who received radical LLR in 13 Chinese medical centers from August 2010 to May 2021 were collected retrospectively. There were 190 males and 161 females,aged(M(IQR)) 61(14)years(range:23 to 93 years). The total cohort was randomly divided into a training dataset(264 cases) and a validation dataset(87 cases). The patients were followed up by outpatient service or telephone,and the deadline for follow-up was October 2021. Based on the training dataset,the multivariate Cox proportional hazards regression model was used to screen the independent influencing factors of long-term prognosis to construct a Nomogram model. The Nomogram model's discrimination,calibration,and clinical benefit were evaluated through internal and external validation,and an assessment of the overall value of two groups was made through the use of a receiver operating characteristic(ROC) curve. Results: There was no significant difference in clinical and pathological characteristics and long-term survival results between the training and validation datasets(all P>0.05). The multivariate Cox analysis showed that CA19-9,CA125,conversion to laparotomy during laparoscopic surgery,and lymph node metastasis were independent prognostic factors for ICC patients after LLR(all P<0.05). The survival Nomogram was established based on the independent prognostic factors obtained from the above screening. The ROC curve showed that the area under the curve of 1, 3 and 5-year overall survival rates of patients in the training dataset were 0.794(95%CI:0.721 to 0.867),0.728(95%CI:0.618 to 0.839) and 0.799(95%CI:0.670 to 0.928),and those in the validation dataset were 0.787(95%CI:0.660 to 0.915),0.831(95%CI:0.678 to 0.983) and 0.810(95%CI:0.639 to 0.982). Internal and external validation proved that the model exhibited a certain discrimination,calibration,and clinical applicability. Conclusion: The survival Nomogram model based on the independent influencing factors of long-term prognosis after LLR for ICC(including CA19-9,CA125,conversion to laparotomy during laparoscopic surgery,and lymph node metastasis) exhibites a certain differentiation,calibration,and clinical practicability.
Bile Duct Neoplasms/surgery* ; Bile Ducts, Intrahepatic/pathology* ; CA-19-9 Antigen ; Cholangiocarcinoma/diagnosis* ; Female ; Humans ; Laparoscopy ; Lymphatic Metastasis ; Male ; Nomograms ; Prognosis ; Retrospective Studies

ObjectiveTo explore the role of microRNA-99b-5p （miR-99b-5p） in cardiomyocyte hypertrophy and the related mechanism involved. MethodsThe expression of miR-99b-5p in myocardium was detected by real-time quantitative PCR（RT-qPCR）in the myocardium of patients with heart failure（HF）and healthy controls， as well as in the myocardium of mouse model of transverse aortic restriction （TAC）-induced cardiac hypertrophy. Phalloidin-iFluor 647 staining was used to show the size of neonatal mouse ventricular cardiomyocytes（NMVCs）after AngⅡ treatment. MiR-99b-5p expression was determined by RT-qPCR in AngⅡ-treated NMVCs. After transfection with miR-99b-5p mimic， the expression of cardiac hypertrophy-associated genes and Fgf21 in NMVCs was detected by RT-qPCR and Western blot assay， respectively. We identified the interaction between miR-99b-5p and the 3’UTR of Fgf21 mRNA by dual luciferase reporter assay. The recombinant Ffg21 adenovirus（rAd-Fgf21）and rAd-Sod2 were used to infect NMVCs， and the expression of β-MHC， ANP， FGF21 and SOD2 was detected by Western blot assay. We knocked down Fgf21 and Sod2 in NMVCs to investigate the role of FGF21/Sod2 axis in miR-99b-5p-regulated NMVC hypertrophy. ResultsMiR-99b-5p expression was elevated in the myocardium of HF patients and TAC-operated mice， and in AngⅡ-treated NMVCs （P＜0.01， respectively）. MiR-99b-5p promoted the expression of hypertrophy-related genes in NMVCs （P＜0.01）. Results of dual luciferase reporter gene assay revealed the interaction between miR-99b-5p and Fgf21 mRNA. MiR-99b-5p down-regulated the expression of Fgf21 and the down-stream gene of Sod2（ P＜0.01）. Overexpression of FGF21 or SOD2 could inhibit NMVC hypertrophy and effectively reversed the pro-hypertrophy effect of miR-99b-5p on NMVCs （P＜0.05， respectively）. ConclusionMiR-99b-5p is up-regulated in the hypertrophic myocardium and enhances cardiomyocyte hypertrophy via suppressing Fgf21/Sod2 axis.

Surgery is so far the most effective treatment for early-stage non-small cell lung cancer (NSCLC). Since the 1990s, the pathology spectrum of early-stage lung cancer has gradually changed because of the increased detection of ground-glass opacity (GGO). The findings from preoperative thin-section computed tomography are strong predictors for the invasiveness and lymph node involvement of GGO, and limited surgery is believed to be implemented safely for radiological less invasive lesions, which calls into question the dominance of lobectomy. After the JCOG0201 trial establishing the radiologic criteria of pathological noninvasiveness for lung adenocarcinoma, the Japan Clinical Oncology Group (JCOG) and the West Japan Oncology Group (WJOG) have successively carried out a series of prospective imaging-guided trials to investigate the optimal surgical procedure for early-stage lung cancer. JCOG0804, was a single-arm, non-randomized, confirmatory trial to evaluate the efficacy and safety of sublobar resection (wedge resection and segmentectomy) for GGO dominant peripheral lung cancer. The primary end point was 5-year relapse-free survival. JCOG0802/WJOG4607L, was a multicentre, open-label, phase 3, randomized, controlled, non-inferiority trial to investigate if segmentectomy was non-inferior to lobectomy in patients with small-sized peripheral NSCLC. The primary endpoint was 5-year overall survival. JCOG1211 was also a non-randomized confirmatory trial to confirm the efficacy of a segmentectomy for clinical T1N0 lung cancer with dominant GGO. The primary endpoint was 5-year relapse-free survival. The findings of JCOG0804 and JCOG0802, and the primary analysis results of JCOG1211 have been officially published. This article systematically reviewed and interpreted the results of the JCOG lung cancer surgery trial series.
Carcinoma, Non-Small-Cell Lung/surgery* ; Clinical Trials as Topic ; Clinical Trials, Phase III as Topic ; Humans ; Japan ; Lung Neoplasms/surgery* ; Multicenter Studies as Topic ; Prospective Studies ; Randomized Controlled Trials as Topic

AIM: To compare the consistency and feasibility of objective ocular torsion measured with GMPE module-based optical coherence tomography(OCT)and fundus color photography(FCP).METHODS: Patients were enrolled in our strabismus clinic from December 2020 to March 2021, and the objective ocular torsion of the eyes was measured by both GMPE module-based OCT and FCP on the same day. FCP was used to measure the fovea-disc angle(FDA)manually by using the Adobe Photoshop software, while the GMPE module-based OCT software positioned automatically the macula and the center of the optic disc to measure the FDA.RESULTS: Fifty-five patients were included, the FDA measured by OCT was -6.6°±4.5° in the right eye and -8.8°±4.7° in the left eye, respectively; The FDA measured by FCP was -6.6°±4.7° in the right eye and -8.4°±4.1° in the left eye, respectively, with no statistically significant difference between the results of the two methods(Pright eye=0.90, Pleft eye=0.08). In patients with exotropia, the FDA measured by OCT was -5.8°±4.9° in the right eye and -9.1°±4.5° in the left eye, respectively, the FDA measured by FCP was -5.7°±5.0° in the right eye and -8.6°±4.3° in the left eye, respectively,(Pright eye=0.75, Pleft eye=0.15). Similarly, the patients with esotropia, the FDA measured by OCT was -9.0°±7.3° in the right eye and -11.3°±3.5° in the left eye, respectively, while the FDA measured by FCP was -10.0°±7.0° in the right and -10.1°±2.8° in the left eye(Pright eye=0.21, Pleft eye=0.10), respectively. There were no significant differences between the two methods in patients with esotropia or exotropia(P>0.05). The results of both Pearson test and Bland-Altman analysis were highly correlated(rright eye=0.93, rleft eye=0.94, P<0.01). CONCLUSION: GMPE module-based OCT can be used for objective ocular torsion measurement with high reliability and reproducibility, and is a promising clinical alternative to the fundus color photographic method.

Objective: To analyze the efficacy of sinonasal adenoid cystic carcinoma (ACC) with perineural invasion (PNI), and explore the prognostic value of PNI on sinonasal adenoid cystic carcinoma. Methods: The clinical data of 105 patients with sinonasal ACC admitted to Cancer Hospital, Chinese Academy of Medical Sciences from January 2000 to December 2016 were retrospectively reviewed. All patients were restaged according to American Joint Committee on Cancer 8th edition. Follow-up visits were conducted to obtain information of treatment failure and survival outcome. The Log rank test was used for univariate analysis of prognostic factors, and Cox regression model was used for multivariate prognostic analysis. Results: The maxillary sinus (n=59) was the most common primary site, followed by the nasal cavity (n=38). There were 93 patients with stage Ⅲ-Ⅳ. The treatment modalities included surgery alone (n=14), radiotherapy alone (n=13), preoperative radiotherapy plus surgery (n=10), and surgery plus postoperative radiotherapy (n=68). The median follow-up time was 91.8 months, the 5-year local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) rates were 72.6%, 73.0%, 52.9% and 78.0%, respectively. There were 33 patients (31.4%) with PNI-positive. The 5-year DMFS, PFS, and OS rates of PNI-positive group were 53.7%, 29.4% and 56.5%, respectively, which were significantly inferior to those of PNI-negative group (80.8%, 63.0% and 86.8%, respectively, P<0.05), while there was no significant difference in the 5-year LC rate between both groups (64.5% vs 76.5%, P=0.273). The multivariate Cox regression analysis showed PNI was one of the poor prognostic factors of DMFS (HR=3.514, 95%CI: 1.557-7.932), PFS (HR=2.562, 95%CI: 1.349-4.866) and OS (HR=2.605, 95%CI: 1.169-5.806). Among patients with PNI-positive, the 5-year LC, PFS and OS rates of patients received surgery combined with radiotherapy were 84.9%, 41.3% and 72.7%, respectively, which were significantly higher than 23.3%, 10.0% and 26.7% of patients receiving surgery or radiotherapy alone (P<0.05). Conclusion: The presence of PNI increases the risk of distant metastasis in patients with sinonasal ACC. Compared with patients with PNI-negative, the prognosis of patients with PNI-positive is relatively poor, and surgery combined with radiotherapy for PNI-positive sinonasal ACC results in good clinical outcomes.
Carcinoma, Adenoid Cystic/pathology* ; Humans ; Paranasal Sinus Neoplasms/therapy* ; Prognosis ; Proportional Hazards Models ; Retrospective Studies