Efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells for the treatment of complex perianal fistula in Crohn's disease: a pilot study.

OBJECTIVES: The aim of the study was to evaluate the efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells (TH-SC01) for complex perianal fistula in patients with Crohn's disease (CD). METHODS: This was an open-label, single-arm clinical trial conducted at Jinling Hospital. Adult patients with complex treatment-refractory CD perianal fistulas (pfCD) were enrolled and received a single intralesional injection of 120 million TH-SC01 cells. Combined remission was defined as an absence of suppuration through an external orifice, complete re-epithelization, and absence of collections larger than 2 cm measured by magnetic resonance imaging (MRI) at 24 weeks after cell administration. RESULTS: A total of 10 patients were enrolled. Six patients (60.0%) achieved combined remission at 24 weeks. The number of draining fistulas decreased in 9 (90.0%) and 7 (70.0%) patients at weeks 12 and 24, respectively. Significant improvement in Perianal Crohn Disease Activity Index, Pelvic MRI-Based Score, Crohn Disease Activity Index, and quality of life score were observed at 24 weeks. No serious adverse events occurred. The probability of remaining recurrence-free was 70% at week 52. CONCLUSION: The study demonstrated that local injection of TH-SC01 cells might be an effective and safe treatment for complex treatment-refractory pfCD after conventional and/or biological treatments fail (ClinicalTrials.gov ID, NCT04939337). TRIAL REGISTRATION: The study was retrospectively registered on www. CLINICALTRIALS: gov (NCT04939337) on June 25, 2021.

A MODIFIED SURGICAL SEPSIS MODEL SATISFYING SEPSIS-3 AND HAVING HIGH CONSISTENCY OF MORTALITY.

ABSTRACT: Background : Cecal ligation and perforation (CLP) is currently considered the criterion standard model of sepsis; however, there are some deficiencies, such as low clinical relevance, inconsistency in severity grading, and an unknown proportion of CLP animals meeting the requirements of sepsis-3. Methods : Adult rats were randomly divided into the following three groups: modified CLP (M-CLP) group, CLP group, and sham group. The vital organ function of rats was evaluated 24 hours postoperatively by blood pressure, behavioral testing, histopathology, and blood test. Cytokine levels were determined by enzyme-linked immunosorbent assay, and T-cell suppression was assessed by flow cytometry. The stability of the model was evaluated by comparing the survival rates of repeated experiments in all groups from day 1 to day 14. Results : More rats in the M-CLP group met Sepsis-3 criteria than those in the CLP group 24 hours postoperatively (53.1% vs. 21.9%, P = 0.01). Rats in the M-CLP group developed more serious hepatic, pulmonary, and renal dysfunction. Similar to human sepsis, rats in the M-CLP group demonstrated more serious immunosuppression and systemic inflammation compared with the CLP group. In addition, disease development and severity, which was indicated by the stable survival rates of model animals, were more stable in the M-CLP group. Conclusions : More rats could meet Sepsis-3 criteria with this novel surgical procedure, which may reduce the number of animals needed in preclinical sepsis experiments. This stable M-CLP model may contribute to the development of new therapies.

Trend of drug clinical trials in mainland China from 2009 to 2020.

With the development of linnovative regulations on drug clinical trials in mainland China, the quantity and quality of drug clinical trials have gradually improved over the past decade. Based on the information of the clinical trials from the online drug clinical trial registration platform of National Medical Products Administration, we reviewed the data of drug clinical trials in mainland China from 2009 to 2020. A total of 8,593 clinical trials have been conducted during this period. The annual number of clinical trials has been increasing gradually, and peaked in 2017. There were 2,127, 1,051, 1,551, and 156 phases I, II, III, and IV clinical trials respectively. In addition, there were 3,441 bioequivalence studies. Trials for anti-tumor drugs ranked the highest (19.45%), followed by trials of drugs for infections and infestations (12.96%) and those for cardiovascular diseases (9.00%). Meanwhile the number of the clinical trial sites also increased annually. However, there were only 116 and 130 clinical trials of drugs for children and rare diseases respectively. The geographical distribution of the sites was uneven. This mapping review provides an overall look of clinical trials in China, which may be useful for domestic and international sponsors.

Diagnosis and Management of Pediatric Papillary Craniopharyngiomas.

OBJECTIVE: Papillary craniopharyngioma (PCP) was previously believed to occur only in adults. Sporadic pediatric PCP (PPCP) confirmed by detection of BRAF V600E mutation has been reported since 2018, but is often misdiagnosed before being diagnosed definitively. We aimed to evaluate PPCP characteristics and propose diagnostic criteria for prompt diagnosis, seeking to reduce patient morbidity and mortality and reduce costs linked to misdiagnosis. METHODS: This study included 5 patients with PPCPs whose data were retrieved retrospectively from among 1032 patients with craniopharyngiomas admitted to Sanbo Brain Hospital Management Group from March 2017 to May 2021. Patients' demographics, clinical presentation, tumor imaging characteristics, histopathologic results, surgical approaches, and postoperative outcomes were analyzed. RESULTS: PPCP was misdiagnosed intraoperatively as sellar abscess (n = 4) or Rathke cleft cyst (n = 1). Preoperative magnetic resonance imaging showed that all tumors were under the saddle diaphragm, and the cyst wall was enhanced (n = 5). Computed tomography scans showed scattered high-density signs (n = 4). No recurrence was noted after complete resection. Postoperative hypothalamic dysfunction was mild. BRAF V600E mutation was confirmed in all cases by sequencing and immunohistochemistry. Immunohistochemistry showed granulation and inflammation and MPO, CD3, CD20, CD38, CD68, and CD163 were positively expressed. CONCLUSIONS: Misdiagnosis of PPCP is responsible for failed surgical treatment. We propose that prompt diagnosis of PPCP can be achieved if preoperative magnetic resonance images show the tumor under saddle diaphragm with tumor wall enhancement and computed tomography scans show high-density signs scattered in the tumor, which leads to safe, effective tumor resection. Our proposed diagnosis and treatment strategy for PPCP reduces morbidity and mortality.

A Novel Necroptosis-Associated IncRNAs Signature for Prognosis of Head and Neck Squamous Cell Carcinoma.

Purpose: The prognosis of head and neck squamous cell carcinoma (HNSCC) is poor. Necroptosis is a novel programmed form of necrotic cell death. The prognostic value of necroptosis-associated lncRNAs expression in HNSCC has not been explored. Methods: We downloaded mRNA expression data of HNSCC patients from TCGA databases. Prognostic lncRNAs were identified by univariate Cox regression. LASSO was used to establish a model with necroptosis-related lncRNAs. Kaplan-Meier analysis and ROC were applied to verify the model. Finally, functional studies including gene set enrichment analyses, immune microenvironment analysis, and anti-tumor compound IC50 prediction were performed. Results: We identified 1,117 necroptosis-related lncRNAs. The Cox regression showed 55 lncRNAs were associated with patient survival (p < 0.05). The risk model of 24- lncRNAs signature categorized patients into high and low risk groups. The patients in the low-risk group survived longer than the high-risk group (p < 0.001). Validation assays including ROC curve, nomogram and correction curves confirmed the prediction capability of the 24-lncRNA risk mode. Functional studies showed the two patient groups had distinct immunity conditions and IC50. Conclusion: The 24-lncRNA model has potential to guide treatment of HNSCC. Future clinical studies are needed to verify the model.

A Modified Approach with Caval Transection for Supracardiac Total Anomalous Pulmonary Venous Connection: Comparison Between Conventional and Sutureless Surgery in 173 Patients.

The efficacy of primary sutureless repair for supracardiac total anomalous pulmonary venous connection (TAPVC) needs to be confirmed. This study aimed to compare the long-term outcomes between the conventional surgery and the sutureless technique with a modified approach in superior TAPVC. Between January 2008 and December 2018, 173 patients with supracardiac TAPVC underwent surgery either with the conventional procedure (n = 130) or the sutureless repair (n = 43). Multivariate analysis and competing-risk analysis were used to identify risk factors for early death and postoperative pulmonary venous obstruction (PVO), respectively. Among 173 patients who underwent repair of supracardiac TAPVC, 46 (28%) had preoperative PVO, and 22 (12.7%) had postoperative PVO. The sutureless group had a lower postoperative PVO rate compared with the conventional group (p = 0.027). The risk factors for death were age ≤ 28 days [odds ratio (OR), 11.56; 95% confidence interval (CI) 1.33-100.47, p = 0.015], weight ≤ 3 kg (OR 9.57; 95% CI 1.58-58.09, p = 0.009), emergency operation (OR 19.24; 95% CI 3.18-116.35, p = 0.002), cardiopulmonary bypass time (OR 2.16; 95% CI 1.36-3.43, p = 0.003), cross-clamp time (OR 1.73; 95% CI 1.20-2.50, p = 0.022), and duration of ventilation (OR 1.11; 95% CI 1.02-1.21, p = 0.027). Age ≤ 28 days [Hazard Ratio (HR) 1.92; 95% CI 1.92-11.02, p < 0.001] and preoperative PVO (HR 41.70; 95% CI 8.15-213.5, p < 0.001) were associated with postoperative PVO. The sutureless repair is a reliable technique for supracardiac TAPVC. Age ≤ 28 days is associated with 30-day mortality and postoperative PVO.

Generation of an induced pluripotent stem cell line, FJMUUHi001-A, from a hereditary Parkinson's disease patient with homozygous mutation of c.189dupA in PARK7.

PARK7 mutations are accountable for the inherited Parkinson's disease. An induced pluripotent stem cell (iPSC) line FJMUUHi001-A was generated by expressing five reprogramming factors, OCT3/4, SOX2, c-MYC, KLF4 and BCL-XL, in peripheral blood mononuclear cells from a 32-year old patient carrying a homozygous mutation of c.189dupA in PARK7. The iPSCs with a normal karyotype had the abilities to differentiate into three germ layers and expressed pluripotency markers without detectable residual plasmids. The cell line FJMUUHi001-A carrying the truncating protein PARK7 could be a useful tool to help comprehend the function of PARK7 in the iPSCs and differentiated cells from them.

Digestive system manifestations and clinical significance of coronavirus disease 2019: A systematic literature review.

BACKGROUND AND AIM: A worldwide outbreak of coronavirus disease 2019 (COVID-19) has drawn global attention. Several reports have described the gastrointestinal (GI) manifestations in the infected patients. The systematic review was designed to highlight the gaps in our knowledge about the prevalence and clinical significance of GI symptoms in patients with COVID-19. METHODS: We searched PubMed database and Google articles published in both English and Chinese up to June 3, 2020, using search terms "clinical features," "2019 novel coronavirus," "2019-nCoV," "COVID-19," or "SARS-Cov-2." Observational studies, case reports, or letters describing the clinical features or observational studies regarding the detection and/or isolation of severe acute respiratory syndrome coronavirus 2 viruses in stools were included. RESULTS: A total of 22 publications were finally selected. It was reported that GI symptoms occurred in about 3-40.7% of patients. GI manifestations included nausea, diarrhea, anorexia, vomiting, abdominal pain, belching, abdominal distension, and GI hemorrhage. Diarrhea was the most common GI symptom. Infected patients had various degrees of liver dysfunction, and the severity of liver dysfunction was significantly associated with the severity of the disease. Therapy focusing on digestive system like liver supportive therapy or nutrition support or probiotics has been demonstrated to be effective interventions, which greatly improve prognosis. Fecal-oral transmission route is a potential risk for transmission. CONCLUSIONS: GI symptoms are common in COVID-19. Strengthening the recognition on abnormalities in digestive system of patients with COVID-19 is crucial for early identification and timely treatment, especially for those atypical patients. Hygiene protection and keeping the drainpipe free flowing are necessary for everyone.

Prognostic nomogram based on immune scores for laryngeal squamous cell cancer.

PURPOSE: Immune scores have been used as a prognostic factor for various types of cancer. However, the association between immune scores and the prognosis of laryngeal squamous cell cancer (LSCC) has not yet been investigated. This study aimed to explore the prognostic significance of immune scores and construct a clinical nomogram to predict the survival of patients with LSCC. METHODS: The clinicopathological characteristics and immune scores of 102 patients with LSCC were obtained from TCGA database and a nomogram was developed. C-index and calibration curves were applied to assess the performance of the model. RESULTS: Patients with higher immune scores had significantly better overall survival (OS). The prognostic nomogram presented a good performance in survival prediction. CONCLUSIONS: High immune scores are correlated with improved OS in patients with LSCC. In addition, the nomogram developed for this study may assist clinicians in the prognostic evaluation of patients with LSCC.

Mechanical stretching of pulmonary vein stimulates matrix metalloproteinase-9 and transforming growth factor-ß1 through stretch-activated channel/MAPK pathways in pulmonary hypertension due to left heart disease model rats.

Pulmonary hypertension due to left heart disease (PH-LHD) is a momentous pulmonary hypertension disease, and left heart disease is the most familiar cause. Mechanical stretching may be a crucial cause of vascular remodeling. While, the underlining mechanism of mechanical stretching-induced in remodeling of pulmonary vein in the early stage of PH-LHD has not been completely elucidated. In our study, the PH-LHD model rats were successfully constructed. After 25 days, doppler echocardiography and hemodynamic examination were performed. In addition, after treatment, the levels of matrix metalloproteinase-9 (MMP-9) and transforming growth factor-ß1 (TGF-ß1) were determined by ELISA, immunohistochemistry and western blot assays in the pulmonary veins. Moreover, the pathological change of pulmonary tissues was evaluated by H&E staining. Our results uncovered that left ventricular insufficiency and interventricular septal shift could be observed in PH-LHD model rats, and the right ventricular systolic pressure (RVSP) and mean left atrial pressure (mLAP) were also elevated in PH-LHD model rats. Meanwhile, we found that MMP-9 and TGF-ß1 could be highly expressed in PH-LHD model rats. Besides, we revealed that stretch-activated channel (SAC)/mitogen-activated protein kinases (MAPKs) signaling pathway could be involved in the upregulations of MMP-9 and TGF-ß1 mediated by mechanical stretching in pulmonary vein. Therefore, current research revealed that mechanical stretching induced the increasing expressions of MMP-9 and TGF-ß1 in pulmonary vein, which could be mediated by activation of SAC/MAPKs signaling pathway in the early stage of PH-LHD.

Systematic evaluation of therapeutic effects of stem cell transplantation trials for heart diseases in China.

BACKGROUND: To systematically assess the quality of reports of clinical trials of stem cell for heart diseases published in Chinese. METHODS: The quality of reports was assessed according to the CONSORT statement and the Jadad score. The association between the CONSORT scores and the reported therapeutic effects was evaluated. RESULTS: A total of 36 randomized clinical trials were identified, and 1552 patients were included. The mean CONSORT score was 7.06 (SD = 2.99). The proportion of reports with a Jadad score of 3 was 8.33%. The improvement of left ventricular function, myocardial perfusion area, left ventricular diastolic diameter, and cardiac output decreased with the increase in the CONSORT score. CONCLUSIONS: The percentages of high-quality reports published in Chinese on stem cell therapy for heart diseases are low. Although stem cell transplantation seems promising for heart diseases, high-quality studies are needed to verify the conclusions．.

Unrelated cord blood transplantation versus haploidentical transplantation in adult and pediatric patients with hematological malignancies-A meta-analysis and systematic review.

Several clinical trials have compared the safety and efficacy of umbilical cord blood transplantation (UCBT) with haploidentical transplantation (HIT) in patients with hematological malignancies. To obtain more reliable evidence, we performed a systematic review and meta-analysis. Seven studies were included and there was a combined total of 102 children and 1311 adults undergoing UCBT, along with 94 children and 915 adults undergoing HIT. Pooled comparisons of studies of UCBT and HIT in children found that the incidence of chronic graft-versus-host disease (GVHD) and disease-free survival (DFS) at 2 years (RR 0.34, 95% CI (0.03, 4.53), P=0.41; HR 0.51, 95% CI (0.23, 1.09), P=0.08) were not statistically different. For adults, although the incidence of grade II-IV acute GVHD differ (RR 1.17, 95% CI (1.02, 1.34), P=0.02), but it indicates a very small difference between the groups as the RR is barely above 1. On the other hand, although the incidence of grade III-IV acute GVHD did not differ (RR 1.51, 95% CI (0.78, 2.92), P=0.22), but there is a tendency of higher risk for the UCBT. And the incidence of chronic GVHD did not differ (RR 1.05, 95% CI (0.82, 1.34), P=0.71). There was no difference in relapse, non-relapse mortality (NRM) and DFS at 2 years (HR 0.92, 95% CI (0.74, 1.13), P=0.42; HR 0.87, 95% CI (0.49, 1.52) P=0.62 and HR 0.74 95% CI (0.39, 1.43), P=0.37). In conclusion, UCBT and HIT could be considered as equally effective option for adult patients without HLA-matched donors.

Identification of core biomarkers associated with pathogenesis and prognostic outcomes of laryngeal squamous-cell cancer using bioinformatics analysis.

PURPOSE: Despite advances in the treatment of laryngeal squamous-cell carcinoma (LSCC), the survival rate of LSCC remains poor. Thereby, it is urgent to identify novel diagnostic and prognostic biomarkers for LSCC. The study aimed to identify potential core genes associated with the pathogenesis and prognosis of LSCC. METHODS: Differentially expressed genes between LSCC and normal laryngeal tissue samples were screened by an integrated analysis of data from GEO and TCGA databases. Core genes related to the pathogenesis and prognosis of LSCC were identified by employing protein-protein interaction network and Cox proportional hazards model analyses. RESULTS: Ten hub genes (AURKA, AURKB, CDC45, KIF2C, NDC80, EXO1, TYMS, RAD51AP1, ITGA3, and UBE2T) that might be highly related to the pathogenesis of LSCC were identified. An eight-gene prognostic signature consisted of ZG16B, STATH, RTN4R, MSRA, CBX8, SLC5A1, EFNB1 and CNTFR was constructed with a good performance in predicting overall survivals. CONCLUSION: Our findings might shed some new light on the pathogenesis of LSCC and help identify new therapeutic targets of LSCC.

Efficiency of Modified Triple-Branched Stent Graft in Type I Aortic Dissection: Two-Year Follow-up.

BACKGROUND: The efficacy of hemiarch replacement combined with a modified triple-branched stent graft in Debakey type I aortic dissection remains to be confirmed. METHODS: From January 2016 to December 2017, 167 patients with acute Debakey type I aortic dissection underwent hemiarch replacement combined with a modified triple-branched stent graft. The clinical and imaging data were retrospectively analyzed. The early composite endpoint was defined to comprise perioperative mortality, permanent neurologic deficits, and renal failure requiring hemodialysis at discharge. RESULTS: The overall 30-day mortality was 4.2% (7 of 167). The incidence of the composite endpoint was 11.4% (19 of 167). The risk factors for the composite endpoint were malperfusion syndrome (odds ratio 5.17; 95% confidence interval, 1.46 to 18.35; P = .011) and creatine greater than 1.5 mg/dL (odds ratio 5.44; 95% confidence interval, 2.27 to 13.06; P < .001). The overall survival was 94% at 1 year and 92.2% at 2 years during a median follow-up of 20.9 ± 9.6 months. Three patients required distal aorta reintervention. Complete thrombosis in the false lumen of the descending aorta at the level of the pulmonary bifurcation and at the level of the celiac trunk was observed in 98.8% and 10.8% of the patients, respectively. CONCLUSIONS: Hemiarch replacement combined with a modified triple-branched stent graft is a reliable technique for acute Debakey type I aortic dissection as indicated by 2 years of follow-up.

Long non-coding RNA TCONS_00000200 as a non-invasive biomarker in patients with intracranial aneurysm.

We performed long non-coding RNA (lncRNA) microarray assay to identify lncRNAs with differential expression between patients with intracranial aneurysm (IA) and healthy control individuals to evaluate their potential use as biomarkers of IA. Arraystar Human lncRNA Microarray v3.0 was performed to identify differentially expressed lncRNAs and mRNAs in plasma samples (4 ml). lncRNAs with the most pronounced differential expression were used to select gene markers, and results were validated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Plasma levels of TCONS_00000200 (fold change: 2.28) and ENST00000511927 (fold change: 2.50) were significantly higher in IA patients than in healthy individuals (P<0.001), and plasma levels of ENST00000421997 (fold change: 0.45) and ENST00000538202 (fold change: 0.43) were significantly lower in IA patients than in healthy individuals (P<0.001). qRT-PCR confirmed the same trends of up- and down-regulation of these four lncRNAs. A receiver operating characteristic (ROC) curve for TCONS_00000200 showed that the area under the curve (AUC) was 0.963 (95% confidence interval, 0.919-1.000), optimal cut-off point was 0.0081, sensitivity was 90.0%, and specificity was 96.7%. These results indicate that the lncRNA TCONS_00000200 is differentially expressed in the plasma of IA patients and could serve as a biomarker of IA.

Increased perihematomal neuron autophagy and plasma thrombin-antithrombin levels in patients with intracerebral hemorrhage: An observational study.

Animal studies have demonstrated that autophagy was involved in neuronal damage after intracerebral hemorrhage (ICH). Several studies showed thrombin-antithrombin (TAT) plasma levels were elevated in patients with ICH. In this study, we aimed to evaluate if autophagy occurred in patients with ICH; and the relationship between the severity of brain injury and plasma TAT levels.A novel tissue harvesting device was used during hematoma removal surgery to collect loose fragments of tissue surrounding the affected brain area in 27 ICH patients with hematoma volumes of >30 mL in the basal ganglia. Control tissues were obtained from patients who underwent surgery for arteriovenous malformation (n = 25). Transmission electron microscopy (TEM) and immunohistochemistry for autophagy-related proteins were used to evaluate the ultrastructural and morphologic cellular characteristics; and the extent of autophagy in the recovered tissue specimens. Stroke severity was assessed by using the Glasgow Coma Scale (GCS) and the National Institutes of Health Stroke Scale (NIHSS). An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma TAT levels.Transmission electron microscopy showed autophagosomes and autolysosomes exist in neurons surrounding the hematoma, but not in the control tissues. The number of cells containing autophagic vacuoles correlated with the severity of brain injury. Immunohistochemistry showed strong LC3, beclin 1, and cathepsin D staining in ICH tissue specimens. Plasma TAT levels correlated positively with autophagic cells and ICH severity (P < .01).Autophagy was induced in perihematomal neurons after ICH. Autophagy and plasma TAT levels correlated positively with severity of brain injury. These results suggest that autophagy and increased plasma TAT levels may contribute to the secondary damage in ICH patients.

Comparison of the short-term and long-term outcomes of surgical treatment versus endoscopic treatment for early esophageal squamous cell neoplasia larger than 2 cm: a retrospective study.

BACKGROUND: NCCN Guidelines of esophageal cancer recommend that endoscopic therapy is considered "preferred" for patients with limited early-stage disease less than or equal to 2 cm. However, there is currently no definite evidence to support either endoscopic therapy or esophagectomy for early esophageal cancer larger than 2 cm. We aimed to explore the optimal treatment for this condition. METHODS: From January 2010 to June 2016, 116 patients with early esophageal neoplasia [high-grade dysplasia (HGD), lamina propria and muscularis mucosae (T1a) cancer, selected superficial submucosa (T1b) cancer without lymph node metastases] larger than 2 cm and treated either surgically or endoscopically were included. RESULTS: Endoscopic therapy was performed in 69 patients and esophagectomy in 47 patients, respectively. The median follow-up time was 43.8 months in the endoscopic cohort and 49.4 months in the surgical cohort. The overall survival was similar between the two cohorts (97.1% vs. 91.5%, P = 0.18). Survival without readmission for treatment-related complicates was also similar. Minor and severe procedure-related complications occurred more often in the surgical cohort than in the endoscopic cohort (63.8% vs. 43.5% and 8.5% vs. 0 respectively, P < 0.05 for both). Four patients in the endoscopic cohort had to undergo additional esophagectomy and were alive during follow-up. There were no procedure-related deaths in the endoscopic cohort, whereas two deaths occurred in the surgical cohort. Recurrence occurred in nine patients in the endoscopic group (13%): six with local recurrence, one with residual neoplasia and two with metachronous neoplasia. None of them died after repeated endoscopic treatments. CONCLUSIONS: Efficacy was similar between endoscopic therapy and esophagectomy in the treatment of early esophageal squamous cell neoplasia larger than 2 cm and endoscopic therapy was associated with fewer and manageable complications. We recommend endoscopic treatment should be preferred selected for early esophageal neoplasia larger than 2 cm.