[Prognostic significance of textbook outcome in advanced gastric patients who underwent neoadjuvant chemotherapy followed by surgical resection].

Objective: To investigate the risk factors and prognostic value of the textbook outcome (TO) in patients with advanced gastric cancer (AGC) who underwent neoadjuvant chemotherapy followed by surgical resection. Methods: This is a retrospective cohort study. A total of 253 patients with AGC who underwent neoadjuvant chemotherapy combined with gastrectomy and D2 lymphadenectomy in the Department of Gastric Surgery, Fujian Medical University Union Hospital from January 2010 to December 2019 were retrospectively included. There were 195 males and 58 females, aged (60.3±10.0) years (range: 27 to 75 years). The patients were then divided into the TO group (n=168) and the non-TO group (n=85). Multivariate Logistic regression was used to analyze the independent predictors of TO. Univariate and multivariate Cox analysis were used to analyze independent prognosis factors for overall survival (OS) and disease-free survival (DFS). Propensity score matching was performed to balance the TO and non-TO groups, and the Kaplan-Meier method was used to calculate survival rates and draw survival curves. Results: Among the 253 patients, 168 patients (66.4%) achieved TO. The Eastern Cooperative Oncology Group score (OR=0.488, 95%CI: 0.278 to 0.856, P=0.012) and ypN stage (OR=0.626, 95%CI:0.488 to 0.805, P<0.01) were independently predictive of TO. Multivariate analysis revealed that TO was an independent risk factor for both OS (HR=0.662, 95%CI: 0.457 to 0.959,P=0.029) and DFS (HR=0.687, 95%CI: 0.483 to 0.976, P=0.036). After matching, the 5-year OS rate (42.2% vs. 27.8%) and the 5-year DFS rate (37.5% vs. 27.8%) were significantly higher in the TO group than in the non-TO group (both P<0.05). Furthermore, patients in the non-TO group benefited significantly from postoperative chemotherapy (both P<0.05), but those in the TO group did not (both P>0.05). Conclusion: TO is an independent prognosis factor in patients undergoing neoadjuvant chemotherapy and surgery for AGC and is associated with postoperative chemotherapy benefits.

[Efficacy of vertical control by using mini-implant anchorage in maxillary posterior buccal area for Angle class â ¡ extraction patients].

OBJECTIVE: To investigate the efficacy of vertical control by using conventional mini-implant anchorage in maxillary posterior buccal area for Angle class Ⅱ extraction patients. METHODS: Twenty-eight Angle class Ⅱ patients [9 males, 19 females, and age (22.6±2.8) years] were selected in this study. All of these patients were treated by using straight wire appliance with 4 premolars extraction and 2 mini-implant anchorage in maxillary posterior buccal area. In this study, the self-control method was used to measure and analyze the lateral radiographs taken before and after orthodontic treatment in each case, the main cephalometric analysis items were related to vertical changes. The digitized lateral radiographs were imported into Dolphin Imaging Software (version 11.5: Dolphin Imaging and Management Solutions, Chatsworth, California, USA), and marked points were traced. Each marked point was confirmed by two orthodontists. The same orthodontist performed measurement on the lateral radiographs over a period of time. All measurement items were required to be measured 3 times, and the average value was taken as the final measurement result. RESULTS: Analysis of the cephalometric radiographs showed that, for vertical measurements after treatment, the differences of the following measurements were highly statistically significant (P < 0.001): SN-MP decreased by (1.40±1.45) degrees on average, FMA decreased by (1.58±1.32) degrees on average, the back-to-front height ratio (S-Go/N-Me) decreased by 1.42%±1.43% on average, Y-axis angle decreased by (1.03±0.99) degrees on average, face angle increases by (1.37±1.05) degree on average; The following measurements were statistically significant (P < 0.05): the average depression of the upper molars was (0.68±1.40) mm, and the average depression of the upper anterior teeth was (1.07±1.55) mm. The outcomes indicated that there was a certain degree of upper molar depression after the treatment, which produced a certain degree of counterclockwise rotation of the mandibular plane, resulting in a positive effect on the improvement of the profile. CONCLUSION: The conventional micro-implant anchorage in maxillary posterior buccal area has a certain vertical control ability, and can give rise to a certain counterclockwise rotation of the mandible, which would improve the profile of Angle Class Ⅱ patients.

[Establishment of a mutation prediction model for evaluating the efficacy of immunotherapy in renal carcinoma].

OBJECTIVE: To establish a mutation prediction model for efficacy assessment, the genomic sequencing data of renal cancer patients from the MSKCC (Memorial Sloan Kettering Cancer Center) pan-cancer immunotherapy cohort was used. METHODS: The genomic sequencing data of 121 clear cell renal cell carcinoma patients treated with immune checkpoint inhibitors (ICI) in the MSKCC pan-cancer immunotherapy cohort were obtained from cBioPortal database (http://www.cbioportal.org/) and they were analyzed by univariate and multivariate Cox regression analysis to identify mutated genes associated with ICI treatment efficacy, and we constructed a comprehensive prediction model for drug efficacy of ICI based on mutated genes using nomogram. Survival analysis and time-dependent receiver operator characteristic curves were performed to assess the prognostic value of the model. Transcriptome and genomic sequencing data of 538 renal cell carcinoma patients were obtained from the TCGA database (https://portal.gdc.cancer.gov/). Gene set enrichment analysis was used to identify the potential functions of the mutated genes enrolled in the nomogram. RESULTS: We used multivariate Cox regression analysis and identified mutations in PBRM1 and ARID1A were associated with treatment outcomes in the patients with renal cancer in the MSKCC pan-cancer immunotherapy cohort. Based on this, we established an efficacy prediction model including age, gender, treatment type, tumor mutational burden (TMB), PBRM1 and ARID1A mutation status (HR=4.33, 95%CI: 1.42-13.23, P=0.01, 1-year survival AUC=0.700, 2-year survival AUC=0.825, 3-year survival AUC=0.776). The validation (HR=2.72, 95%CI: 1.12-6.64, P=0.027, 1-year survival AUC=0.694, 2-year survival AUC=0.709, 3-year survival AUC=0.609) and combination (HR=2.20, 95%CI: 1.14-4.26, P=0.019, 1-year survival AUC=0.613, 2-year survival AUC=0.687, 3-year survival AUC=0.526) sets confirmed these results. Gene set enrichment analysis indicated that PBRM1 was involved in positive regulation of epithelial cell differentiation, regulation of the T cell differentiation and regulation of humoral immune response. In addition, ARID1A was involved in regulation of the T cell activation, positive regulation of T cell mediated cyto-toxicity and positive regulation of immune effector process. CONCLUSION: PBRM1 and ARID1A mutations can be used as potential biomarkers for the evaluation of renal cancer immunotherapy efficacy. The efficacy prediction model established based on the mutation status of the above two genes can be used to screen renal cancer patients who are more suitable for ICI immunotherapy.

[Analysis of characteristics and trends of randomized controlled trials of gastric cancer between 2000 and 2019].

Objectives: To analyze the current development status of gastric cancer (GC) randomized controlled trials (RCT) between 2000 and 2019, and to review the basic characteristics of published RCT. Methods: ClinicalTrials.gov was searched for phase 3 or 4 RCT conducted between January 2000 and December 2019 with the keyword "gastric cancer", and the development trend of different types of RCT during different time periods was described. Basic features of registered RCT such as intervention, study area, single-center or multicenter, sample size, and funding were presented. PubMed and Scopus databases were searched to judge the publication status of studies completed until June 2016. The adequacy of the report was estimated by the Consolidated Standards of Reporting Trials (CONSORT) checklist. Design flaws were evaluated by Cochrane tool and/or whether a systematic literature review was cited. The data was analyzed by χ2 test or Fisher exact test. Results: There were 262 RCT including in the present study. The number of GC-RCT registered on ClinicalTrials.gov had been on the rise from 1 case in 2000 to 30 cases in 2015. The proportion of RCT associated with targeted therapy or immunotherapy increased from 0 during 2000-2004 to 37.1% (36/97) during2015-2019. The RCT registered in Asia was 191 cases, while that in non-Asia region was 71 cases. The proportion of multi-center RCT from non-Asia was higher than that from Asia (70.4% (50/71) vs. 50.3% (96/191), χ²=8.527, P=0.003). The proportion of RCT published was 59.1% (81/137). Among the published RCT, 65 (80.2%) studies were reported adequately, but 63 (77.8%) studies had avoidable design limitations. Conclusions: Targeted therapy and immunotherapy have become research hotspots in the treatment of GC. At present, there are inadequate multicenter RCT in Asia, and the publication rate of RCT is low. A considerable number of published RCT are reported inadequately and have avoidable design flaws.

[Analysis of characteristics and trends of randomized controlled trials of gastric cancer between 2000 and 2019].

Objectives: To analyze the current development status of gastric cancer (GC) randomized controlled trials (RCT) between 2000 and 2019, and to review the basic characteristics of published RCT. Methods: ClinicalTrials.gov was searched for phase 3 or 4 RCT conducted between January 2000 and December 2019 with the keyword "gastric cancer", and the development trend of different types of RCT during different time periods was described. Basic features of registered RCT such as intervention, study area, single-center or multicenter, sample size, and funding were presented. PubMed and Scopus databases were searched to judge the publication status of studies completed until June 2016. The adequacy of the report was estimated by the Consolidated Standards of Reporting Trials (CONSORT) checklist. Design flaws were evaluated by Cochrane tool and/or whether a systematic literature review was cited. The data was analyzed by χ2 test or Fisher exact test. Results: There were 262 RCT including in the present study. The number of GC-RCT registered on ClinicalTrials.gov had been on the rise from 1 case in 2000 to 30 cases in 2015. The proportion of RCT associated with targeted therapy or immunotherapy increased from 0 during 2000-2004 to 37.1% (36/97) during 2015-2019. The RCT registered in Asia was 191 cases, while that in non-Asia region was 71 cases. The proportion of multi-center RCT from non-Asia was higher than that from Asia (70.4% (50/71) vs. 50.3% (96/191), χ²=8.527, P=0.003). The proportion of RCT published was 59.1% (81/137). Among the published RCT, 65 (80.2%) studies were reported adequately, but 63 (77.8%) studies had avoidable design limitations. Conclusions: Targeted therapy and immunotherapy have become research hotspots in the treatment of GC. At present, there are inadequate multicenter RCT in Asia, and the publication rate of RCT is low. A considerable number of published RCT are reported inadequately and have avoidable design flaws.

[Effect of splenic hilar lymphadenectomy on locally advanced Siewert type â ¡ and â ¢ adenocarcinoma of esophagogastric junction with a tumor diameter ≥4 cm: a five-year survival analysis].

Objective: To examine the long term outcome of splenic hilar lymphadenectomy (SHL) for locally advanced Siewert type Ⅱ and Ⅲ adenocarcinoma of esophagogastric junction (AEG) with a tumor diameter ≥4 cm. Methods: A total of 489 locally advanced Siewert type Ⅱ and Ⅲ AEG patients with a tumor diameter ≥4 cm who underwent radical resection from January 2010 to April 2016 were included. There were 383 males and 106 females. There were 225 patients aged≥65 years and 264 patients aged <65 years. SHL was conducted in 270 patients(SHL group). Wilcoxon rank-sum test or χ2 test were conducted for inter-group comparison. Cox proportional hazard regression was used to analyze the long term outcome of SHL and the prognosis factors of overall survival. Kaplan-Meier curve was drawn finally. The results of survival analysis were verified by Log-rank test. Results: Followed-up to April 2021,the median follow-up time was 78.0 months (range: 74.0 to 85.0 months), the follow-up rate was 95.5%(467/489). The splenic hilar lymphnode metastasis rate of the SHL group was 12.6% (34/270). Younger patients (<65 years old), less complications, higher proportion of patients received adjuvant chemotherapy were demonstrated in the SHL group (χ2: 5.644 to 6.744, all P<0.05). Multivariate analysis showed that SHL was the independent prognosis factor of overall survival for patients with Siewert type Ⅱ and Ⅲ AEG and a tumor diameter≥4 cm (HR=0.68, 95%CI: 0.52 to 0.88, P=0.004) along with preoperative CA19-9, pathological T stage, pathological N stage, adjuvant chemotherapy and postoperative complication. Further subgroup analysis demonstrated that the SHL group had better 5-year overall survival than non-SHL group (62.4% vs. 39.2%, χ2=17.983, P=0.006) in Siewert type Ⅲ AEG rather than in Siewert type Ⅱ AEG(57.3% vs. 53.7%, χ2=3.031, P=0.805). Conclusion: In experienced center, splenic hilar lymphadenectomy can improve the prognosis of Siewert type Ⅲ AEG with a tumor diameter ≥4 cm.

Analysis of long non-coding RNA expression profiles in disuse osteoporosis using microarray and bioinformatics.

Disuse osteoporosis (DOP) is one of the major consequences of long space flights. DOP also occurs in patients with spinal cord injuries and prolonged bedridden states that can have a severe impact on human health. Bone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that play an important role in bone homeostasis. Long non-coding RNAs (lncRNAs) are involved in regulating osteogenic differentiation of BMSCs, and their abnormal expression might lead to the formation of orthopedic diseases. However, the specific mechanism of DOP has not yet been elucidated. All sequencing data were obtained from Gene Expression Omnibus (GEO) datasets. The limma package of R was applied to identify DEmRNAs and DElncRNAs. Pearson correlation coefficients (PCC) between DElncRNADEmRNA expression levels were calculated. Functional annotation was performed for DEmRNAs coexpressed with DElncRNAs. In addition, the Cytohubba plug-in in Cytoscape was applied to determine the top 10 hub genes. Finally, connectivity map (CMap) analysis was used to identify potential therapeutic drugs for DOP. The gene expression data, GSE100930 and GSE17696, were retrieved from the GEO database. A total of 2,212 differentially expressed mRNAs (DEmRNAs) and 22 differentially expressed lncRNAs (DElncRNAs) were obtained. Gene ontology (GO) functional terms, Kyoto Encyclopedia of Genes, and Genomes (KEGG) pathway enrichment analysis reveal 30 significant GO terms and 13 significant pathways. A coding-non-coding gene co-expression (CNC) network was constructed to study the potential role of hub-DElncRNAs and their co-expressed DEmRNAs in DOP. The lncRNAs, GSNAS1, SNHG12, and EPB41LA4A-AS1, were significant in the CNC network and potential regulators of DOP development. Three bioactive compounds (scoulerine, kinetin riboside, dexanabinol) with potential therapeutic significance for DOP were obtained through the Connectivity Map (CMAP) analysis. Our study revealed a new mechanism for a lineage shift of bone marrow mesenchymal stem cells under microgravity, and linked the function of protein-coding mRNAs with ncRNAs, which may contribute to the development of new therapies for DOP.

Adjuvant chemotherapy for patients with gastric neuroendocrine carcinomas or mixed adenoneuroendocrine carcinomas.

BACKGROUND: The aim of this study was to evaluate whether adjuvant chemotherapy is associated with improved survival in patients with resectable gastric neuroendocrine carcinomas (G-NECs) or mixed adenoneuroendocrine carcinomas (G-MANECs). METHODS: The study included patients with G-NECs or G-MANECs who underwent surgery in one of 21 centres in China between 2004 and 2016. Propensity score matching analysis was used to reduce selection bias, and overall survival (OS) in different treatment groups was estimated by the Kaplan-Meier method. RESULTS: In total, 804 patients with resectable G-NECs or G-MANECs were included, of whom 490 (60·9 per cent) received adjuvant chemotherapy. After propensity score matching, OS in the chemotherapy group was similar to that in the no-chemotherapy group. Among patients with G-NECs, survival in the fluorouracil (5-FU)-based chemotherapy group and the non-5-FU-based chemotherapy group was similar to that in the no-chemotherapy group. Similarly, etoposide plus cisplatin or irinotecan plus cisplatin was not associated with better OS in patients with G-NECs. Among patients with G-MANECs, OS in the non-5-FU-based chemotherapy group was worse than that in the no-chemotherapy group. Patients with G-MANECs did not have better OS when platinum-based chemotherapy was used. CONCLUSION: There was no survival benefit in patients who received adjuvant chemotherapy for G-NECs or G-MANECs.

ANTECEDENTES: El objetivo de este estudio fue evaluar si la quimioterapia adyuvante mejoraba la supervivencia en pacientes con carcinomas gástricos resecables neuroendocrinos (gastric neuroendocrine carcinomas, G-NECs) y carcinomas adenoneuroendocrinos mixtos (mixed adenoneuroendocrine carcinomas, G-MANECs). MÉTODOS: Se incluyeron pacientes con G-NECs y G-MANECs tratados quirúrgicamente en 21 centros en China entre 2004 y 2016. Se utilizó un análisis de emparejamiento por puntaje de propensión para reducir el sesgo de selección y el método de Kaplan-Meier para estimar la supervivencia global (overall survival, OS) de los pacientes en los diferentes grupos de tratamiento. RESULTADOS: En total, se incluyeron en el estudio 804 pacientes con G-NECs y G-MANECs resecables y 490 pacientes (60,9%) recibieron quimioterapia adyuvante. Después del emparejamiento por puntaje de propensión, la OS del grupo con quimioterapia fue similar a la del grupo sin quimioterapia. En los pacientes con G-NECs, la supervivencia en los grupos con quimioterapia basada en 5-FU (fluorouracilo) y de quimioterapia sin 5-FU fue similar a la del grupo sin quimioterapia. Asimismo, la combinación de etopósido y cisplatino o de irinotecán y cisplatino no se asoció con una mejor OS en pacientes con G-NECs. En pacientes con G-MANECs, la OS del grupo con quimioterapia sin 5-FU fue peor que la del grupo sin quimioterapia. Los pacientes con G-MANECs no presentaron una mejor OS cuando se administró quimioterapia basada en platinos. CONCLUSIÓN: La administración de quimioterapia adyuvante en pacientes con G-NECs y G-MANECs no mejoró la supervivencia.

Development and validation of a staging system for gastric adenocarcinoma after neoadjuvant chemotherapy and gastrectomy with D2 lymphadenectomy.

BACKGROUND: Neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy is commonly used for patients with locally advanced gastric adenocarcinoma. The eighth AJCC ypTNM staging system was validated based on patients undergoing more limited lymphadenectomy (less than D2). The aim of this study was to develop a system for accurate staging of patients with locally advanced gastric adenocarcinoma who receive neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy. METHODS: A modified system of ypTNM was developed, based on overall survival (OS) of patients receiving neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy at Memorial Sloan Kettering Cancer Center, and validated using data from an international cohort of patients who had similar treatment. RESULTS: Of 325 patients in the derivation cohort, 33 (10·2 per cent) had ypT0 N0/+ tumours, which are not classifiable under the AJCC system. The 5-year OS rate for modified ypTNM stages I, II, IIIA and IIIB was 89, 71, 42·3 and 10 per cent respectively, compared with 82, 65·2 and 24·1 for AJCC stages I, II and III respectively. The concordance index (0·730 versus 0·709), estimated area under the curve (0·765 versus 0·740) and time-dependent receiver operating characteristic (ROC) curve throughout the observation period were all superior for modified ypTNM staging. For the validation cohort of 186 patients, the modified system was again better at separating patients into prognostic groups for OS. CONCLUSION: The modified ypTNM staging system improves the accuracy of OS prediction for patients treated with neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy.

[Analysis of single-nucleotide polymorphism of Sonic hedgehog signaling pathway in non-syndromic cleft lip and/or palate in the Chinese population].

OBJECTIVE: To study the relationship between Sonic hedgehog (Shh) associated single-nucleotide polymorphism (SNP) and non-syndromic cleft lip and/or palate (NSCL/P), and to explore the risk factors of cleft lip and/or palate. Many studies suggest that the pathogenesis of NSCL/P could be related to genes that control early development, in which the Shh signaling pathway plays an important role. METHODS: Peripheral blood was collected from 197 individuals (100 patients with NSCL/P and 97 healthy controls). Haploview software was used for haplotype analysis and Tag SNP were selected, based on the population data of Han Chinese in Beijing of the international human genome haplotype mapping project. A total of 27 SNP were selected for the 4 candidate genes of SHH, PTCH1, SMO and GLI2 in the Shh signaling pathway. The genotypes of 27 SNP were detected and analyzed by Sequenom mass spectrometry. The data were analyzed by chi-squared test and an unconditional Logistic regression model. RESULTS: The selected SNP basically covered the potential functional SNP of the target genes, and its minimum allele frequency (MAF) was >0.05: GLI2 73.5%, PTCH1 91.0%, SMO 100.0%, and SHH 75.0%. It was found that the genotype frequency of SNP (rs12674259) located in SMO gene and SNP (rs2066836) located in PTCH1 gene were significantly different between the NSCL/P group and the control group. Linkage disequilibrium was also found on 3 chromosomes (chromosomes 2, 7 and 9) where the 4 candidate genes were located. However, in the analysis of linkage imbalance haplotype, there was no significant difference between the disease group and the control group. CONCLUSION: In China, NSCL/P is the most common congenital disease in orofacial region. However, as it is a multigenic disease and could be affected by multiple factors, such as the external environment, the etiology of NSCL/P has not been clearly defined. This study indicates that Shh signaling pathway is involved in the occurrence of NSCL/P, and some special SNP of key genes in this pathway are related to cleft lip and/or palate, which provides a new direction for the etiology research of NSCL/P and may provide help for the early screening and risk prediction of NSCL/P.

[Electrocardiogram characteristics of patients with ventricular arrhythmia originating from the distal great cardiac vein].

Objective: To explore the electrocardiographic characteristics of patients with idiopathic ventricular arrhythmias (VAs) originating from different portions of distal great cardiac veins (DGCV). Methods: The study included 49 patients underwent successful RFCA of premature ventricular complex(PVCs)/ventricular tachycardia(VT) from different portions of the DGCV in our department from July 2009 to March 2016. The surface 12-lead electrocardiogram (ECG) and intraventricular ablation mapping features were analyzed. Patients were divided into four groups according to the mapping and ablation results: DGCV1(10 patients), DGCV2 (13 patients), proximalanterior interventricular vein (PAIV, 17 patients)and extend distal great cardiac vein (EDGCV, 9 patients). We analyzed the similarities and differences between surface 12-lead ECG of patients with PVCs/VT from different portions of DGCV, and compared with random chosen 290 patients with PVCs/VT from ventricular outflow tract and adjacent structure. Results: A positive R wave in inferior leads, a negative QS morphology in lead aVL and aVR were found among all groups. The different characteristics of surface 12-lead ECG of VAs originating from DGCV were as follows: (1)EDGCV patients demonstrated a positive R or r wave on lead Ⅰ(6/9) while a negative rS or qr wave was evidenced in other three groups (39/40). (2)A positive R pattern on lead V(1), V(5)-V(6) (11/13) was presented in patients of DGCV2 group; R (without S or s) wave on V(1) (9/10), RS or Rs wave on V(5)-V(6) were found in DGCV1 group; RS or rS wave was seen on lead V(1), R(without S)wave in lead V(5)-V(6) (25/26) were found in EDGCV and PAIV group and the amplification of R wave in EDGCV was higher than V(1) of PAIV group.(3)Precordial lead transition zone was in front of V(1) for DGCV1 and DGCV2 groups (23/23), within V(1)-V(3) for EDGCV group, but on V(2) or within V(2)-V(3) for PAIV group.(4)Patients of DGCV1 and DGCV2 demonstrated a longer Pseudo delta wave time(PdW), intrinsicoid deflection time (IDT), significantly larger maximum deflection index (MDI) than those in PAIV and EDGCV groups (P<0.001). (5)The different characteristics of surface 12-lead ECG between VAs originating from DGCV and those from ventricular outflow tract and adjacent structure were as follows: ① The ECG features were similar between PVIA and LCC group, both demonstrated a rs wave on the lead Ⅰ, rS wave on V(1)-V(2) and R wave on V(5)-V(6); ②The ECG features were similar betweenEDGCV and RCC group, both presented with R or r wave on the lead Ⅰ, the QRS wave of precordial leads was similar as PAIV and LCC groups; ③A R wave on the lead V(1), V(5)-V(6) was found in group DGCV2, and ILCC; ④Similar to the group Endo-MAA, patients in DGCV1 group also demonstrated a R wave on the lead V(1) and a Rs wave on V(5)-V(6). Conclusion: A positive R wave in inferior leads, a negative QS morphology in lead aVL and aVR are seen in all patients, but different electrocardiographic characteristics of PVC/VT originating from the different portions of the DGCV are presented on lead Ⅰ and V(1)-V(6).

Focus on the Novel Cardiovascular Drug LZC696: from Evidence to Clinical Consideration.

LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is comprised of the angiotensin receptor blocker valsartan and the neprilysin inhibitor pro-drug sacubitril (AHU377). After oral administration, AHU377 is rapidly metabolized to the active neprilysin inhibitor LBQ657. LCZ696 exerts its effects of diuresis, natriuresis, vasodilation and aldosterone secretion inhibition through simultaneous renin-angiotensin-aldosterone system (RAAS) blockade and natriuretic peptides system (NPS) enhancement. Powerful evidence including PARAMETER and PRARDIGM-HF trials have shown that LCZ696 outperforms RAAS inhibition in treating patients with hypertension and heart failure with reduced ejection fraction (HFrEF), and is well tolerated. In addition, accumulating evidence also suggests its potential use in heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), post-myocardium infarction (post-MI) and stroke. Both the FDA and CHMP have approved LCZ696 for treatment of HFrEF. Despite all this, some special issues (e.g. use in specific subgroups, adverse events, contraindications and cost-effectiveness analysis) should be considered before its implementation in clinical practice.

[NELL-1: a novel highly efficient and specific growth factor].

Regeneration of bone tissue, as well as other tissues, requires involvement and interaction of cells, scaffolds and relevant growth factors, among which growth factors play a crucial role in maintaining the stability of microenvironment. Nel-like-type 1 molecule (NELL-1), a novel growth factor in tissue engineering, has been studied intensively in recent years. Researches mainly covered gene and protein structure and their expression profiling, biological function, molecular mechanisms and disease relevance. NELL-1 expressed in embryonic tissue is essential for growth and development of bone tissue. NELL-1 presents excellent abilities of inducing bone and cartilage regeneration,especially with high specificity to chondrocyte lineage. Compared with classic osteogenic growth factor bone morphogenetic protein 2 (BMP-2), the process of osteogenesis interacted with NELL-1 exhibits stronger specificity, higher bone density and fewerside effects. Furthermore, a recent study shows synergistic effects of NELL-1 and BMP-2. NELL-1 enhances the osteogenic reaction induced by BMP-2 of cells and notably declines inflammation response caused by BMP-2. This review evaluates the current research progress of the function and application of NELL-1 by the systematic method of evidence-based medicine.

[Surgical outcomes after laparoscopy-assisted distal gastrectomy and open distal gastrectomy for patients with advanced gastric cancer: a case-control study using a propensity score method].

Objective: To investigate the surgical outcomes after the laparoscopy-assisted distal gastrectomy (LADG) for patients with advanced gastric cancer. Methods: The data of 213 patients who underwent LADG and 213 treated by open distal gastrectomy (ODG) were selected using the propensity score matching method from a prospectively constructed database of 641 patients who underwent radical distal gastrectomy between January 2005 and June 2012 in Department of Gastric Surgery, Fujian Medical University Union Hospital. The baseline characteristics and surgical outcomes were compared using a paired t-test or the Wilcoxon signed ranks test for continuous variables. The cumulative survival rates were compared using the Kaplan-Meier method and log-rank test. Results: Among all patients, there were significant differences in tumor location, digestive tract reconstruction, histologic type, pT stage, and pTNM stage between LADG and ODG group (P<0.05). After propensity score matching, patient distributions were closely balanced. There was no significant difference in clinicopathologic characteristics between the two groups (P>0.05). Regarding perioperative characteristics, the time to first flatus, and time to resumption of diet, did not differ between the two groups (P>0.05), while there were significant differences in the operation time (t=-11.28, P=0.000), blood loss (t=-5.674, P=0.000), number of dissected lymph nodes (t=4.727, P=0.000), and post-operative hospital stay (t=-2.193, P=0.038). LADG group has less morbidity than ODG group (χ2=4.777, P=0.029). Multivariate analysis revealed that the laparoscopic surgery (RR=0.392, P=0.009) was the protected factor for determining postoperative complications. There was no significant difference in the cumulative survival rate at total and each UICC stage between the two groups, either (P>0.05). Conclusion: LADG is an oncological safe minimally invasive procedure for advanced gastric cancer yields comparable oncological outcomes with ODG.

Protection from vascular endothelial dysfunction in acute glycemic load-induced primary hypertension by vitamin C and E.

This study aimed to investigate the influence of acute glycemic load on vascular endothelial function in patients with hypertension and to evaluate the protective effect of vitamins C and E during the acute glycemic phase. We randomly selected 39 hypertensive patients and 21 normal subjects and divided them into 3 groups: 75 g oral glucose (glycemic load group), 75 g glucose+0.9 g vitamin C (VC group), 75 g glucose+2 g vitamin C+0.8 g vitamin E (VC+VE group). Extravascular color Doppler ultrasound was used to detect brachial artery flow-mediated vasodilation at 0, 1, 2, and 3 h, and, at the same time, serum anti-oxidant products were measured. Basic endothelial functions in patients with hypertension were decreased in the glycemic load group (9.48±3.33 versus 13.09±6.78%, P<0.05), and was even more depressed in the hypertensive group (9.48±3.33 versus 14.20±6.48%, P<0.05). Antioxidant vitamins played a dose-dependent protective role on acute damage of endothelial function due to glycemic load. Acute high blood sugar damaged vascular endothelial functions, especially in hypertensive patients, but this effect can be reversed by large doses of vitamin C and E.

First Report of Lettuce Chlorotic Leaf Rot Disease Caused by Phytoplasma in China.

Lettuce (Lactuca sativa) as annual or biennial crop is an important vegetable in China. The lettuce variety Feiqiao, which is extensively cultivated in autumn and winter, is grown for its stem and is a characteristic species bred in Yong'an City. Since October 2005, a new disease of lettuce has been observed sporadically in the fields. Initially, chlorotic symptoms, or a faded red color, were observed on the inner leaves of the infected lettuce plants. Then, the inner leaves bleached and appeared pale, while the top leaves became straight and elongated, and stopped growing. Gummosis was observed at the base of young leaves, and the whole plant became stunted and died. The disease was named lettuce chlorotic leaf rot disease. In 2008, there was a disease outbreak in Yong'an City with an incidence of approximately 30%. In 2012, total DNA was extracted from 0.1 g of leaf tissue collected from 20 symptomatic and five asymptomatic lettuce plants using the CTAB method. A PCR analysis was performed using the phytoplasma-specific primer set R16mF2/R16mR1 (1). An approximately 1.4-kb amplicon was obtained from all 20 symptomatic plants, but no corresponding DNA fragment was amplified from the five asymptomatic plants. PCR products were cloned in Escherichia coli DH5α, using the pMD18-T vector (TaKaRa, Japan), and two isolates were sequenced. The two 1,431-bp sequences were identical (GenBank Accession No. KJ668578). A BLAST analysis revealed a 99% identity between lettuce chlorotic leaf rot phytoplasma and mulberry dwarf phytoplasma, a group 16SrI phytoplasma described by Win et al. in 2012 (3). After analyzing with iPhyclassifier, the virtual RFLP pattern derived from the 16S rDNA F2n/R2 fragment was most similar to the reference pattern of the 16Sr group I, subgroup B (NC_005303), with a pattern similarity coefficient of 0.99 (2). Additionally, the leaf veins and roots with symptoms were processed for ultrastructural examinations using transmission electron microscopy. Many typical phytoplasma-like bodies were observed in the sieve elements in the leaf veins and roots, and they were spherical to oval or dumbbell shaped and 200 to 800 nm in diameter. In agreement with these findings, seven strains of phytoplasma from 16SrI-A and 16SrI-B subgroups were reported in association with lettuce plants exhibiting various types of symptoms which were not completely consistent with those observed in China (4). To our knowledge, this is the first report of a phytoplasma associated with lettuce in China. References: (1) R. E. Davis et al. Microbiol. Res. 158:229, 2003. (2) W. Wei et al. Int. J. Syst. Evol. Microbiol. 57:1855, 2006. (3) N. K. K. Win et al. J. Gen. Plant Pathol. 78:264, 2012. (4) J. Zhang et al. Phytopathology 94:842, 2004.

RXR agonists inhibit high glucose-induced upregulation of inflammation by suppressing activation of the NADPH oxidase-nuclear factor-κB pathway in human endothelial cells.

An inflammatory response induced by high glucose is a cause of endothelial dysfunction in diabetes and is an important contributing link to atherosclerosis. Diabetes is an independent risk factor of atherosclerosis and activation of retinoid X receptor (RXR) has been shown to exert anti-atherogenic effects. In the present study, we examined the effects of the RXR ligands 9-cis-retinoic acid (9-cis-RA) and SR11237 on high glucose-induced inflammation in human umbilical endothelial vein endothelial cells (HUVECs) and explored the potential mechanism. Our results showed that the inflammation induced by high-glucose in HUVECs was mainly mediated by the activation of nuclear factor-B (NF- κB). High glucose-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were in comparison, significantly decreased by treatment with RXR. The effect of RXR agonists was mainly due to the inhibition of NF-κB activation. Using pharmacological inhibitors and siRNA, we confirmed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was an upstream activator of NF-κB. Furthermore, RXR agonists significantly inhibited high glucose-induced activation of NADPH oxidase and significantly decreased the production of reactive oxygen species (ROS). To explore whether the rapid inhibitory effects of RXR agonists were in fact mediated by RXR, we examined the effect of RXR downregulation by RXR siRNA. Our results showed that RXR siRNA largely abrogated the effects of RXR agonists, suggesting the requirement of RXR expression. Therefore, we have shown that RXR is involved in the regulation of NADPH oxidase- NF-κB signal pathway, as the RXR ligands antagonized the inflammatory response in HUVECs induced by high glucose.

In-plane reorientation induced single laser pulse magnetization reversal.

Single Pulse All Optical Switching represents the ability to reverse the magnetization of a nanostructure using a femtosecond single laser pulse without any applied field. Since the first switching experiments carried out on GdFeCo ferrimagnets, this phenomena has been only recently extended to a few other materials, MnRuGa alloys and Tb/Co multilayers with a very specific range of thickness and composition. Here, we demonstrate that single pulse switching can be obtained for a large range of rare earth-transition metal multilayers, making this phenomenon much more general. Surprisingly, the threshold fluence for switching is observed to be independent of the laser pulse duration. Moreover, at high laser intensities, concentric ring domain structures are induced. These striking features contrast to those observed in Gd based materials pointing towards a different reversal mechanism. Concomitant with the demonstration of an in-plane magnetization reorientation, a precessional reversal mechanism explains all the observed features.

[Establishment of a nomogram prediction model using common preoperative indicators for early weight loss after laparoscopic sleeve gastrectomy].

Objectives: To construct a nomogram prediction model using common preoperative indicators for early weight loss (EWL) 1 year after laparoscopic sleeve gastrectomy (LSG). Methods: Relevant data of obese patients who had undergone LSG from January 2015 to May 2022 in Fujian Medical University Union Hospital and Quanzhou First Hospital Affiliated Fujian Medical University were analyzed. Patients with a history of major abdominal surgery, severe gastroesophageal reflux disease, pregnancy within 1 year after surgery, or who were lost to follow-up were excluded, resulting in a total of 200 patients in the study (190 from Fujian Medical University Union Hospital and 10 from Quanzhou First Hospital Affiliated Fujian Medical University). The participants were 51 men and 149 women of a mean age 29.9±8.2 years and a body mass index (BMI) 38.7±6.5 kg/m2. All patients in this group underwent standardized LSG procedure. Achieving ideal weight (BMI≤25 kg/m2) 1 year after LSG was defined as goal of EWL. Logistic regression analyses were performed to identify factors that independently influenced EWL. These factors were incorporated into the nomogram model. Receiver operating characteristic (ROC) curves (the larger the area under the curve [AUC], the better the predictive ability and accuracy of the model), likelihood ratio test (higher likelihood ratio indicates greater model homogeneity), decision curve analysis (higher net benefit indicates a better model), Akaike information criterion (AIC; smaller AIC indicates a better model), and Bayesian information criterion (BIC; smaller BIC indicates a better model) were used to validate the predictive ability of the column line diagram model. Results: In this study of 200 obese patients who underwent LSG surgery, 136 achieved EWL goal, whereas the remaining 64 did not. The rate of EWL goal achievement of the entire group was 68.0%. Compared with patients who did not achieve EWL goal, those who did had lower BMI, alanine transaminase, aspartate transaminase, triglycerides, and higher cholesterol. Additionally, the proportion of female was higher and the proportions of patients with fatty liver and hypertension lower in those who achieved EWL goal (all P<0.05). Univariate and multivariate logistic regression analysis revealed that preoperative BMI (OR=0.852, 95%CI: 0.796-0.912, P<0.001), alanine transaminase (OR=0.992, 95%CI: 0.985-0.999, P=0.024), presence of fatty liver (OR=0.185, 95%CI: 0.038-0.887, P=0.035) and hypertension (OR=0.374, 95%CI: 0.144-0.969, P=0.043) were independently associated with failure to achieve EWL goal. Cholesterol (OR=1.428, 95%CI: 1.052-1.939, P=0.022) was independently associated with achieving EWL goal. We used the above variables to establish an EWL nomogram model. ROC analysis, the likelihood ratio test, decision curve analysis, and AIC all revealed that the predictive value of the model was better than that of BMI alone (nomogram model vs. BMI: area under the curve 0.840 vs. 0.798, P=0.047; likelihood ratio: 58.785 vs. 36.565, AIC: 193.066 vs. 207.063, BIC: 212.856 vs. 213.660). Conclusion: Our predictive model is more accurate in predicting EWL after LSG compared with using BMI.

[Feasibility of a three-sided encapsulation procedure based on fascia anatomy in laparoscopic lateral lymph node dissection for middle and low rectal cancer].

Objective: To explore the feasibility and value of performing a three-sided encapsulation procedure based on fascia anatomy in laparoscopic lateral lymph node dissection (LLND) for middle and low rectal cancer. Methods: This was a retrospective review. The study cohort comprised patients who met the diagnostic criteria for rectal cancer according to the Chinese Guidelines for the Diagnosis and Treatment of Colorectal Cancer, had a short lymph node diameter of >5 mm on the lateral side within the 15 days before surgery, were evaluated as feasible candidates for laparoscopic total mesorectal excision+LLND surgery, had been diagnosed with low or intermediate level rectal cancer, and whose tumor was less than 8 cm away from the anal verge according to pathological examination of the operative specimen. Patients with a history of other malignant tumors of the abdomen or with incomplete follow-up data were excluded. Forty-two patients with middle and low rectal cancer who had undergone lateral lymph node dissection in diagnosis and treatment center of Gastrointestinal Cancer of Guangdong Hospital of Chinese Medicine from Jan.2018 to Dec.2022 were enrolled. There were 24 men (57.1%) and 18 women (42.9%) aged 58.4±11.8 years and the median BMI was 22.5 (19.3-24.1) kg/m2. The main point of the three-sided encapsulation procedure is to expand the external side medial to the external iliac artery and vein, narrowing the range of exterior side dissection. The anterior-medial side is designed to expand the vesical fascia to define the range of anterior-medial side extension. The internal side is fully extended to the ureterohypogastric nerve fascia; the distal point of the caudal extension reaches the level of the Alcock canal and the bottom reaches the piriformis, enabling dissection of the obturator nerve and No.283 lymph nodes. No.263D lymph nodes are dissected by exposing the internal iliac artery and its branches, dissecting the group No.263P lymph nodes, and severing the inferior vesical artery. Finally, the lateral lymphatic tissue is completely resected. Relevant variables were recorded, including the number of lateral lymph nodes detected, the rate of lymph node metastasis, operation duration, intraoperative blood loss, postoperative complications, postoperative hospital stay, and 3-year overall survival rate. Results: Laparoscopic surgery was successfully completed in all patients with no conversions to open surgery and no intraoperative complications. Twenty-seven (64.3%) of the study patients underwent left-sided LLND, 10 (23.8%) right-sided LLND, and five (11.9%) bilateral LLND, with lymph nodes cleared on both sides. All patients' lymph nodes were examined pathologically. A median of 17.0 (11.7, 26.0) lymph nodes was detected, the median of lateral lymph nodes being 5.0 (2.0, 10.2). The median operation time was 254.5 (199.0, 325.2) minutes. The median intra-operative blood loss was 50.0 (30.0, 100.0) mL. All patients were diagnosed with adenocarcinoma by pathological examination of the operative specimen. Two patients developed postoperative intestinal obstruction, one lymphatic leakage, and one a perineal incision infection. There were no cases of anastomotic leakage. The median postoperative hospital stay was 6.0 (5.0, 7.0) days and the median follow-up time 23.5 (9.0, 36.7) months. During follow-up, three patients (7.1%) died of tumor recurrence and metastasis. Two (4.8%) experienced mild urinary dysfunction, and one (2.4%) had moderate postoperative erectile dysfunction. One patient (2.4%) was found to have prostate and lung metastases 3 month after surgery. The 3-year overall survival rate was 74.4%. Conclusions: Three sided encapsulation is a safe and feasible procedure for LLND, achieving accurate and complete clearance of lateral lymphatic tissue.