Myocardial fibrosis (MF) is a common pathological hallmark of cardiovascular diseases, reflecting shared mechanisms in their progression. However, the lack of reliable MF models that accurately mimic its pathogenesis has hindered drug discovery, highlighting the urgent need for more effective therapeutic agents. Herein, a novel contractile three-dimensional (3D) myocardial tissue model integrating cardiomyocytes, cardiac-fibroblasts, and bone marrow-derived macrophages in collagen hydrogel was developed to simulate the fibrotic changes of cardiovascular disease, and facilitate the screening of anti-MF compounds. The 3D myocardial tissue model exhibited precise, visualizable, and quantifiable contractile characteristics under hypoxia and drug interventions. 76 compounds extracted from the resins of Toxicodendron vernicifluum, a traditional Chinese medicine with clear clinical benefits for fibrotic diseases, were screened for anti-fibrotic activity. Using an in vitro 3D oxygen-glucose deprivation (OGD)-treated myocardial tissue model instead of a two-dimensional transforming growth factor-β treated cardiac-fibroblasts model, two candidates including LQ-40 and SQ-3 exert impressive anti-MF activity, which was further validated in left anterior descending coronary artery ligation-induced MF mouse model. The current results demonstrate the feasibility and advantage of the novel contractile 3D tissue model with multi-cell types in discovering candidates for MF, further stressing the great potential of regulating macrophages in the treatment of MF.

Objective:To further improve the understanding of paroxysmal nocturnal hemoglobinuria (PNH), we retrospectively analyzed and summarized the clinical characteristics, treatment status, and survival status of patients with PNH in Zhejiang Province.Methods:This study included 289 patients with PNH who visited 20 hospitals in Zhejiang Province. Their clinical characteristics, comorbidity, laboratory test results, and medications were analyzed and summarized.Results:Among the 289 patients with PNH, 148 males and 141 females, with a median onset age of 45 (16-87) years and a peak onset age of 20-49 years (57.8% ). The median lactic dehydrogenase (LDH) level was 1 142 (604-1 925) U/L. Classified by type, 70.9% (166/234) were classical, 24.4% (57/234) were PNH/bone marrow failure (BMF), and 4.7% (11/234) were subclinical. The main clinical manifestations included fatigue or weakness (80.8%, 235/289), dizziness (73.4%, 212/289), darkened urine color (66.2%, 179/272), and jaundice (46.2%, 126/270). Common comorbidities were hemoglobinuria (58.7% ), renal dysfunction (17.6% ), and thrombosis (15.0% ). Moreover, 82.3% of the patients received glucocorticoid therapy, 70.9% required blood transfusion, 30.7% used immunosuppressive agents, 13.8% received anticoagulant therapy, and 6.3% received allogeneic hematopoietic stem cell transplantation. The 10-year overall survival (OS) rate was 84.4% (95% CI 78.0% -91.3% ) . Conclusion:Patients with PNH are more common in young and middle-aged people, with a similar incidence rate between men and women. Common clinical manifestations include fatigue, hemoglobinuria, jaundice, renal dysfunction, and recurrent thrombosis. The 10-year OS of this group is similar to reports from other centers in China.

Objective:To evaluate the efficacy and safety of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS) .Methods:A total of 409 MDS patients from 45 hospitals in Zhejiang province who received at least four consecutive cycles of HMA monotherapy as initial therapy were enrolled to evaluate the efficacy and safety of HMA. Mann-Whitney U or Chi-square tests were used to compare the differences in the clinical data. Logistic regression and Cox regression were used to analyze the factors affecting efficacy and survival. Kaplan-Meier was used for survival analysis. Results:Patients received HMA treatment for a median of 6 cycles (range, 4-25 cycles) . The complete remission (CR) rate was 33.98% and the overall response rate (ORR) was 77.02%. Multivariate analysis revealed that complex karyotype ( P=0.02, OR=0.39, 95% CI 0.18-0.84) was an independent favorable factor for CR rate. TP53 mutation ( P=0.02, OR=0.22, 95% CI 0.06-0.77) was a predictive factor for a higher ORR. The median OS for the HMA-treated patients was 25.67 (95% CI 21.14-30.19) months. HMA response ( P=0.036, HR=0.47, 95% CI 0.23-0.95) was an independent favorable prognostic factor, whereas complex karyotype ( P=0.024, HR=2.14, 95% CI 1.10-4.15) , leukemia transformation ( P<0.001, HR=2.839, 95% CI 1.64-4.92) , and TP53 mutation ( P=0.012, HR=2.19, 95% CI 1.19-4.07) were independent adverse prognostic factors. There was no significant difference in efficacy and survival between the reduced and standard doses of HMA. The CR rate and ORR of MDS patients treated with decitabine and azacitidine were not significantly different. The median OS of patients treated with decitabine was longer compared with that of patients treated with azacitidine (29.53 months vs 20.17 months, P=0.007) . The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Conclusion:Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.

Objective    To study the clinical results of Mini Maze procedure in atrial fibrillation patients with impaired left ventricular systolic function. Methods    From June 2010 to December 2017, 86 atrial fibrillation patients with impaired left ventricular systolic function received Mini Maze procedure including 54 males and 32 females, with an average age of 60.7±5.9 years. Among them, 12 were with paroxysmal, 27 were with persistent and 47 were with long-standing persistent atrial fibrillation. The mean atrial fibrillation duration was 6.5±4.8 years. CHA2DS2-VASc score was 2.2±1.1. The mean diameter of left atrium was 46.9±3.8 mm. The mean diameter of left ventricle was 51.7±4.6 mm. The preoperative ejection fraction was 42.2%±4.7%. All patients received Mini Maze procedure after general anesthesia. The ablation included 3 annular ablations and 3 linear ablations. The left atrial appendage was excised by Endo-Gia. Ablation of Marshall ligament and epicardial autonomic ganglions were made by an ablation pen. Results    Eighty-six patients successfully completed the procedure without transition to thoracotomy. There was no death during the perioperative period. Seventy-seven patients (89.5%) maintained sinus rhythm at discharge. Eighty patients were followed up for 27.2±12.1 months and 72 patients maintained sinus rhythm. The overall postoperative left ventricular ejection fraction was 47.1%±6.2%. The ejection fraction of the postoperative sinus rhythm group was 48.2%±5.8%, and the ejection fraction of the non-sinus group was 41.6%±5.8% (P<0.05). Multivariate regression analysis showed a left atrial diameter (HR=1.485, 95%CI 1.157-1.906, P<0.05) and an increase in ejection fraction over 10% (HR=18.800, 95%CI 1.674-189.289, P<0.05) were closely related to postoperative recurrence. Kaplan-Meier curve analysis showed that the recurrence rate of atrial fibrillation was significantly lower in patients with an increase in postoperative ejection fraction over 10% (P<0.05). Conclusion    Mini Maze procedure is safe and effective in the treatment of atrial fibrillation patients with left ventricular systolic dysfunction, which helps to improve left ventricular function to prevent the vicious circle of atrial fibrillation and heart failure.

Objective To determine the effects of resecting the lower half of left stellate ganglion (LSG) on fast ventricular rate (VR) in persistent atrial fibrillation (AF) and its mechanism. Methods Twelve mature healthy male beagle dogs (15–25 kg) were studied. They were randomly divided into two groups (an experimental group and a control group, 6 dogs in each group). The control group were merely performed with rapid left atrial pacing to induce persistent AF. The experimental group were disposed with rapid left atrial pacing and received resection of the lower half of LSG after the persistent AF was documented. Simultaneously the ventricular rates were monitored separately before anesthesia, after anesthesia, 30 minutes and one month after LSG resection. The forward passing effective refractory period (ERP) of the canine atrioventricular node (AVN) was also measured. Results Each dog was documented with persistent AF after 3–6 weeks’ left atrial pacing. After resecting the lower half of LSG for 30 minutes (the control group was only observed for 30 minutes without LSG resection), the average VR of the control group attained 144.5±4.2 beats/min, while that of the experimental group was 121.5±8.7 beats/min (P<0.001). After resecting the lower half of LSG for one month (the control group was observed for one month without LSG resection), the average VR of the control group was 139.2±5.6 beats/min, while that of the experimental group was 106.5±4.9 beats/min (P<0.001). Meantime, the forward passing ERP of AVN of the experimental group was significantly prolonged than that of the control group (265.6±7.8 msvs.251.1±4.6 ms, P=0.003). Conclusion Resection of the lower half of LSG is efficient in reducing VR in canines with persistent AF, one of the mechanisms of which may be prolonging the forward passing ERP of AVN.

Objective: To evaluate the efficacy of Mei mini maze procedure for treating atrial fibrillation (AF) patients with previously failed catheter ablation. Methods: Between August 2010 and May 2016, 48 AF (8 proximal AF, 15 persistent AF and 25 long-standing persistent AF) patients (29 males, 19 females, mean age: (62.5±7.3) years old) with previously 1-3 failed catheter ablation results were treated with Mei mini maze procedure in our department. Under thoracoscopic assistance, the procedure was performed through three ports on left chest wall, pulmonary vein isolation and ablations of the roof and posterior wall of left atrium was made by bipolar radiofrequency ablation. Ganglionic plexus ablation was made by the ablation pen. Left atrial appendage was excluded. Patients were followed at outpatient clinic and per telephone. Electrocardiogram, CT and echocardiography examinations were performed at 1, 3, 6 and 12 months post operation. The success rate of the procedure was analyzed by Kaplan-Meier curves and evaluated by the log-rank test. Results: Mean AF history was (8.1±6.3) years and left atria dimension was (44.1±6.2) mm in this patient cohort. All procedures were performed successfully in these 48 patients. Pericardial adhesions were dissected in 21 patients. Durations of the procedures were (142.3±35.6) minutes.There were no serious complications. The hospital stay was (9.3±1.8) days. Sinus rhythm was documented in 44 patients (91.7%) at discharge. The mean follow-up duration was (28.0±17.2) months. Thirty-eight patients (82.6%) were in sinus rhythm. There was no stroke, thrombus in the left atrium and stenosis of pulmonary vein during the follow-up. Sinus rhythm was achieved in 7 out of 8 paroxysmal AF patients, in 31 out of 38 non-paroxysmal AF patients, and in 13 out of 15 persistent AF patients. Kaplan-Meier curve showed that the success rate in the long-standing persistent AF group was lower than in the other two groups, but there was no statistical difference. Conclusions Mei mini maze procedure has a high success rate for AF patients with previously failed catheter ablation history, which could completely isolate the bilateral pulmonary vein and left atrial posterior wall with good quality and integrity of ablation line, and left atrial appendage is also resected during the procedure.

Objective To investigate the diagnostic and prognostic value of serum soluble CD163 (sCD163 )and the positive rate of membrane -bound CD163 (mCD163 )in peripheral blood mononuclear cells (PBMC)in children with infection -associated hemophagocytic syndrome (IAHS).Methods Between July 2012 and June 2016,26 pediatric patients with IAHS (IAHS group)and 28 pediatric patients with sepsis(sepsis group)admitted to Children′s Hospital Affiliated to Shanghai Jiaotong University were selected,and 20 healthy children were taken as healthy control group. Sandwich enzyme linked immunosorbent assay was used to detect serum sCD163 .The population of circulating mCD163 positive monocytes was determined by using flow cytometry.Receiver operating characteristic (ROC)curves were used to evaluate the diagnostic and prognostic values of sCD163 and mCD163 in children with IAHS compared with the diagnos-tic and prognostic values of plasma ferritin,and so on.Results The serum levels of sCD163 in patients of IAHS group, sepsis group and healthy control group were (1264 ±538)mg/L,(862 ±332)mg/L,(610 ±316)mg/L,respective-ly.And the population of mCD163 -positive PBMC in patients of IAHS group,sepsis group and healthy control group was (88.3 ±9.7)%,(68.5 ±18.3)%,(28.9 ±5.2)%,respectively.Both serum sCD163 and the population of mCD163 -positive PBMC were significantly higher in IAHS group compared with those of sepsis group (t =2.031 ,P =0.048;t =3.191 ,P =0.002,respectively).The serum sCD163 and population of mCD163 -positive PBMC in sepsis group were higher than controls (t =3.848,P =0.002;t =4.049,P =0.000,respectively).Moreover,the areas under the ROC curve (AUC)for the mCD163 ,sCD163 ,were 0.853(P =0.013),0.762(P =0.004),0.755(P =0.049),respec-tively.mCD163 at a cutoff of 83.7% had a high diagnosis sensitivity (81 .8%)and specificity (72.4%).The optimal cutoff values of sCD163 and ferritin for predicting IAHS was 888 mg/L (sensitivity 66.7% and specificity 63.3%)and 2880 μg/L (sensitivity 80.0% and specificity 54.5%).In addition,the serum level of sCD163 and the population of mCD163 -positive PBMCs were significantly increased in acute phase and decreased in recovery phase[(1553 ±542) mg/L vs.(866 ±92)mg/L,(91 .0 ±6.4)% vs.(79.0 ±4.6)%,t =2.450,χ2 =3.419,P =0.036,0.007]in IAHS group.Furthermore,subgroup analysis indicated that the serum level of sCD163 and the population of mCD163 -positive PBMCs were significantly higher in dead patients than those in survived patients [(1748.91 ±518.17)mg/L vs. (909.69 ±171 .35)mg/L,t =3.070,P =0.011 ;(93.50 ±8.42)% vs.(77.30 ±3.28)%,χ2 =3.005,P =0.024, respectively].Conclusion Serum sCD163 and the population of mCD163 -positive PMSCs are specific and validity bio-markers for early diagnosis of IAHS,which also are associated with treatment response assessment and prognostic analy-sis in IAHS.

Background: Voltage-gated sodium channel 1.5 (Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β (ER-β) expression in non-metastatic colon cancer patients receiving radical resection. Methods: A total of 269 consecutive patients with pathologically confirmed stages Ⅰ–Ⅲ colon cancer who under-went radical resection were selected. Nav1.5 and ER-β expression was detected by using immunohistochemistry (IHC) on tissue microarray constructed from paraffin-embedded specimens. IHC score was determined according to the percentage and intensity of positively stained cells. Statistical analysis was performed with the X-tile method, k coef-ficient, Chi square test or Fisher's exact test, logistic regression, log-rank test, and Cox proportional hazards models. Results: We found that Nav1.5 was commonly expressed in tumor tissues with higher mean IHC score as compared with matched tumor-adjacent normal tissues (5.1 ± 3.5 vs. 3.5 ± 2.7, P < 0.001). The high expression of Nav1.5 in colon cancer tissues was associated with high preoperative carcinoembryonic antigen level [odds ratio (OR) = 2.980;95% confidential interval (CI) 1.163–7.632; P = 0.023] and high ER-β expression (OR = 2.808; 95% CI 1.243–6.343;P = 0.013). Log-rank test results showed that high Nav1.5 expression contributed to a low 5-year disease-free survival (DFS) rate in colon cancer patients (77.2% vs. 92.1%, P = 0.048), especially in patients with high ER-β expression tumor (76.2% vs. 91.3%, P = 0.032). Analysis with Cox proportional hazards model demonstrated that high Nav1.5 expression [hazard ratio (HR) = 2.738; 95% CI 1.100–6.819; P = 0.030] and lymph node metastasis (HR = 2.633; 95% CI 1.632–4.248; P < 0.001) were prognostic factors for unfavorable DFS in colon cancer patients. Conclusions: High expression of Nav1.5 was associated with high expression of ER-β and indicated unfavorable oncologic prognosis in patients with non-metastatic colon cancer.

OBJECTIVETo explore the clinicopathological characteristics, efficacy, and prognostic factors for patients with rectal gastrointestinal stromal tumor(GIST).

METHODSClinicopathological and follow-up data of 61 patients with rectal GIST in our department from January 1990 to October 2012 were analyzed retrospectively and pathology specimens were reviewed. Kaplan-Meier method was used to calculate the survival. Univariate analysis and multivariate analysis were performed to investigate the influencing factors of prognosis with Log-rank test and Cox regression model.

RESULTSThere were 42 male and 19 female patients with a median age of 59 years old. Eighteen cases(29.5%) were confirmed preoperatively as GIST by biopsy and 46 cases were diagnosed as GIST by first pathological examination. Fifteen cases(24.6%) were revised as GIST after re-examination of specimes among whom 14 cases had been diagnosed as leiomyoma or sarcoma, and 1 as neurolemmoma. Tumor location was above peritoneal reflection in 12 cases(19.7%) and below peritoneal reflection in 49(80.3%). Fifty-two patients underwent surgery, including 21 extended resections(lymph nodes clearance and combined organs resection simultaneously) and 31 local resections(tumor rejection or partial resection of rectal wall). Eleven patients received preoperative imatinib(400 mg/d). Forty-one cases received imatinib therapy after operation or biopsy diagnosis, including 25 cases who received palliative treatment for postoperative recurrence. Median follow-up time was 55(6 to 391) months and follow-up longer than 2 years was carried out in 46 patients. Overall survival rates of 1-, 2-, 3- , 5-year were 98%, 95.6%, 86.0% and 73.7% respectively. There were no significant differences between local resection group(96.4%, 92%, 83.3% and 77.3%) and extended resection group (100%, 94.7%, 89.50% and 82.6%)(χ(2)=0.004, P=0.947). Univariate analysis showed that survival was only associated with recurrence and metastasis (χ(2)=4.292, P=0.038). Multivariate Cox analysis showed postoperative survival was not associated with any factors(all P>0.05). The 3-year survival rate of patients with postoperative recurrence or metastasis receiving imatinib therapy was better as compared to those who did not received imatinib(82.7% vs. 71.4%).

CONCLUSIONSRectal GIST are more common in the lower rectum. Surgery is the main treatment for rectal GIST. Local complete resection is the mainstay treatment. Extensive resection and lymph node clearance may not improve survival. Imatinib can improve the prognosis of patients with recurrence or metastasis.

Benzamides ; Female ; Gastrointestinal Stromal Tumors ; therapy ; Humans ; Imatinib Mesylate ; Male ; Neoplasm Recurrence, Local ; Piperazines ; Prognosis ; Pyrimidines ; Rectal Neoplasms ; pathology ; therapy ; Retrospective Studies ; Survival Rate

Objective To explore the clinicopathological characteristics, efficacy, and prognostic factors for patients with rectal gastrointestinal stromal tumor (GIST). Methods Clinicopathological and follow-up data of 61 patients with rectal GIST in our department from January 1990 to Oc tober 2012 were analyzed retrospectively and pathology specimens were reviewed. Kaplan-Meier method was used to calculate the survival. Univariate analysis and multivariate analysis were performed to investigate the influencing factors of prognosis with Log-rank test and Cox regression model. Results There were 42 male and 19 female patients with a median age of 59 years old. Eighteen cases (29.5%) were confirmed preoperatively as GIST by biopsy and 46 cases were diagnosed as GIST by first pathological examination. Fifteen cases (24.6%) were revised as GIST after re-examination of specimes among whom 14 cases had been diagnosed as leiomyoma or sarcoma, and 1 as neurolemmoma. Tumor location was above peritoneal reflection in 12 cases (19.7%) and below peritoneal reflection in 49 (80.3%). Fifty-two patients underwent surgery, including 21 extended resections(lymph nodes clearance and combined organs resection simultaneously) and 31 local resections (tumor rejection or partial resection of rectal wall). Eleven patients received preoperative imatinib(400 mg/d). Forty-one cases received imatinib therapy after operation or biopsy diagnosis, including 25 cases who received palliative treatment for postoperative recurrence. Median follow-up time was 55 (6 to 391) months and follow-up longer than 2 years was carried out in 46 patients. Overall survival rates of 1-, 2-, 3-, 5-year were 98%, 95.6%, 86.0%and 73.7%respectively. There were no significant differences between local resection group (96.4%, 92%, 83.3%and 77.3%) and extended resection group (100%, 94.7%, 89.50%and 82.6%) (χ2=0.004, P=0.947). Univariate analysis showed that survival was only associated with recurrence and metastasis (χ2=4.292, P=0.038). Multivariate Cox analysis showed postoperative survival was not associated with any factors (all P>0.05). The 3-year survival rate of patients with postoperative recurrence or metastasis receiving imatinib therapy was better as compared to those who did not received imatinib (82.7%vs. 71.4%). Conclusions Rectal GIST are more common in the lower rectum. Surgery is the main treatment for rectal GIST. Local complete resection is the mainstay treatment. Extensive resection and lymph node clearance may not improve survival. Imatinib can improve the prognosis of patients with recurrence or metastasis.