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Chen Yang,1 Ying Liu,1 Wen-qi Xi,1 Chen-fei Zhou,2 Jin-ling Jiang,1 Tao Ma,1 Zheng-bao Ye,1 Jun Zhang,1 Zheng-gang Zhu1,2 1Department of Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China Purpose: The aim of this retrospective study was to investigate the relationship between UGT1A1 polymorphisms and toxicities in Chinese patients with pancreatic or biliary tract cancer receiving irinotecan-containing regimens as the second- or third-line chemotherapy.Patients and methods: A total of 36 patients with unresectable pancreatic cancer and 12 patients with unresectable biliary tract cancer were included. Approximately 33 patients were treated with FOLFIRI regimen, a chemotherapy regimen, where FOL stands for folinic acid, F for fluorouracil, and IRI for irinotecan (irinotecan 180 mg/m2 at day 1, CF 200 mg/m2 at day 1–2, 5-FU 400 mg/m2 at day 1–2, followed by continuous infusion of 5-FU 600 mg/m2 for 22 hours at day 1–2, every 2 weeks). The other 15 patients were treated with irinotecan monotherapy (180 mg/m2, every 2 weeks). UGT1A1*6/*28 polymorphisms were detected by direct sequencing.Results: The frequencies of GG, GA, AA genotypes for UGT1A1*6 were 70.8% (n=34), 25.0% (n=12), and 4.2% (n=2), respectively. And those of TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 79.2% (n=38), 18.8% (n=9), and 2.0% (n=1), respectively. A total of 22 patients (45.8%) had grade III–IV neutropenia, and six patients (12.5%) experienced grade III–IV diarrhea. The incidence of grade III–IV neutropenia in patients with UGT1A1*6 GA or AA genotype was 71.4%, which was significantly higher than that with GG genotype (35.3%, P=0.022). No relationship was found between grade III–IV neutropenia and UGT1A1*28 polymorphism. The statistical analysis between grade III–IV diarrhea and UGT1A1*6/*28 polymorphisms was not conducted in view of the limited number of patients.Conclusion: In Chinese patients with pancreatic or biliary tract cancer administered irinotecan-containing regimens, those with UGT1A1*6 variant may have a high risk of severe neutropenia. Keywords: UGT1A1 polymorphism, irinotecan, pancreatic cancer, biliary tract cancer, neutropenia, diarrhea

This review explores the critical role of exosomes in promoting angiogenesis, a key factor in skin flap survival. Skin flaps are widely used in reconstructive surgery, and their survival depends heavily on the formation of new blood vessels. Exosomes, small extracellular vesicles secreted by various cells, have emerged as important mediators of intercellular communication and play a crucial role in biological processes such as angiogenesis. Compared to traditional methods of promoting angiogenesis, exosomes show more selective and targeted therapeutic potential as they naturally carry angiogenic factors and can precisely regulate the angiogenesis process. The review will delve into the molecular mechanisms by which exosomes facilitate angiogenesis, discuss their potential therapeutic applications in enhancing skin flap survival, and explore future research directions, particularly the challenges and prospects of exosomes in clinical translation. By highlighting the unique advantages of exosomes in skin flap survival, this review provides a new perspective in this field and opens up new research directions for future therapeutic strategies.

Poor response to 5-fluorouracil (5-FU) remains an obstacle in the treatment of gastric cancer (GC). Super enhancers (SEs) are crucial for determining tumor cell survival under drug pressure. SE landscapes related to 5-FU-resistance are mapped to GC using chromatin immunoprecipitation-sequencing (ChIP-Seq). SiRNA transcription factors (TFs) screen determines master TF Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) activated by SE. High NR3C1 expression driven by SE correlated with 5-FU resistance in patient-derived organoids (PDOs). Phase separation formed by NR3C1 is observed using fluorescence recovery after photobleaching (FRAP). NR3C1 protein and Mediator promoted SE-related gene transcription via phase separation. SEs and NR3C1 co-binding patterns are explored using Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing. 5-FU-related genes driven by NR3C1 are identified using epigenetic reader inhibitor JQ1 and NR3C1 specific inhibitor Cort108297. NR3C1 knockdown increases 5-FU sensitivity and alters the SE landscape through enhancer reprogramming, reducing downstream 5-FU-related target genes. JQ1 and Cort108297 both improve 5-FU efficacy in PDOs and patient-derived xenografts (PDXs) by destroying SEs or inhibiting NR3C1. In conclusion, SE-driven NR3C1 promotes 5-FU resistance in GC. SE destruction and NR3C1 inhibition lead to enhancer reconstruction and reduce 5-FU-related gene transcription, providing alternative therapeutic strategies for improving 5-FU sensitivity., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Sepsis is a life-threatening condition marked by a severe systemic response to infection, leading to widespread inflammation, cellular signaling disruption, and metabolic dysregulation. The role of lipid and amino acid metabolism in sepsis is not fully understood, but aberrations in this pathway could contribute to the disease's pathophysiology., Methods: To explore the potential of lipid and amino acid compounds as biomarkers for the diagnosis and prognosis of sepsis, a two-sample Mendelian Randomization (MR) study was conducted, examining the relationship between sepsis and 249 serum lipid and amino acid-related markers. Key enzymes involved in synthesis of phosphatidylcholine, including choline/ethanolamine phosphotransferase 1 (CEPT1), choline phosphotransferase 1 (CPT1), and ethanolamine phosphotransferase 1 (EPT1), were also targeted for drug-target Mendelian randomization., Results: The study found that phosphatidylcholines (OR IVW : 0.88, 95%CI: 0.80-0.96, p = 0.005) and phospholipids in medium HDL (OR IVW : 0.86, 95%CI: 0.77-0.96, p = 0.007) potentially exhibit a protective effect against sepsis nominally. However, the potential drug target of CEPT1, CPT1, and EPT1 was found to be unrelated to septic outcomes., Conclusion: Our findings suggest that increasing levels of phosphatidylcholines and medium HDL phospholipids may reduce the incidence of sepsis. This highlights the potential of lipid-based biomarkers in the diagnosis and management of sepsis, opening avenues for new therapeutic strategies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Multiple prospective clinical studies have demonstrated that chemotherapy combined with immune checkpoint inhibitors (ICIs) can prolong the survival of patients with far-advanced gastric cancer. For patients with locally advanced gastric cancer (LAGC), preoperative neoadjuvant chemotherapy combined with immunotherapy has also achieved some encouraging results which benefit some patients, achieve clinical downstage, attenuate hidden metastases, increase R0 resection rate and reduce postoperative recurrence rate, etc. How to apply ICIs or combine immunotherapy with other therapies correctly in the course of neoadjuvant comprehensive treatment for patients with LAGC is still a very challenging and difficult problem. There are three basic principles in immunotherapy to be grasped: (1) Based on high-level clinical practice guidelines; (2) Based on the results of high-quality evidence-based medical research; and (3) Based on molecular pathology and tumor biomarkers. Perioperative immunotherapy for gastric cancer can be correctly applied if these three principles are organically integrated. Referring to the results of domestic and international clinical research in recent years, the three basic principles are demonstrated in this article for readers.

Large type 3 and type 4 gastric cancers (GC) have a significantly poor prognosis, primarily due to their high predisposition for peritoneal dissemination. The application of intraperitoneal chemotherapy has emerged as a viable therapeutic strategy for managing GC patients with peritoneal metastasis. This study is planned to enroll 37 resectable large type 3 or type 4 GC patients. These patients are scheduled to undergo a treatment comprising preoperative chemotherapy with paclitaxel, oxaliplatin and S-1, followed by D2 gastrectomy, and concluding with postoperative treatments that include prophylactic intraperitoneal chemotherapy. The study's primary objective is to evaluate the 3-year peritoneal recurrence rate. Secondary objectives are to assess the 3-year disease-free survival, 3-year overall survival and to monitor the adverse events. Clinical trial registration number: ChiCTR2400083253 (https://www.chictr.org.cn).

This case report describes a 47-year-old woman with systemic lupus erythematosus (SLE) complicated by Libman-Sacks endocarditis (LSE) who developed multiple organ dysfunction after mitral valve replacement surgery. The patient presented with a 5-day history of cough, sputum, and fever. Transthoracic echocardiography showed significant vegetations on the mitral valve. Biopsy was performed, and the pathological diagnosis was SLE complicated by LSE. After the mitral valve replacement surgery, the patient developed clinical manifestations of hepatic and renal dysfunction, cardiopulmonary failure, oliguria, and shock. The clinical symptoms significantly improved after administration of mechanical ventilation, continuous renal replacement therapy, plasma exchange, anti-inflammatory and anti-infection treatments, immunomodulatory and immunosuppressive therapies, and low-molecular-weight heparin anticoagulation. Multiple organ dysfunction after mitral valve replacement in patients with SLE complicated by LSE has rarely been reported. This report discusses the clinical manifestations, pathogenesis, and treatment of this severe complication. We hope the sharing of our experience in this case will provide a clinical basis for the treatment of severe multiple organ dysfunction after mitral valve replacement in patients with SLE complicated by LSE.

Proteasomes are overexpressed in multiple myeloma (MM) and proteasomal inhibitors (PIs) have been widely used for the treatment of MM. PIs are reported to induce MM cell apoptosis but impair necroptosis. In the present study, we found that PIs MG132 and bortezomib induce MM cell pyroptosis, a novel type of cell death, in a GSDME-dependent manner. Lack of GSDME totally blocks PI-induced pyroptosis. Interestingly, we found that Caspase-3/6/7/9 are all involved in pyroptosis triggered by PIs because the specific inhibitor of each caspase ablates GSDME activation. PIs markedly reduce mitochondrial membrane potential. Moreover, PIs disrupt the interaction of Bcl-2 and BAX, induce cytochrome c release from mitochondria to cytosol and activate GSDME. Furthermore, we found that overexpression of an N-terminal portion of GSDME suffices to release cytochrome c from mitochondria and to activate Caspase-3/9, suggesting N-GSDME might penetrate the mitochondrial membrane. Consistent with Bcl-2 inhibition, BAX can induce MM cell pyroptosis in a GSDME-dependent manner. In accordance with these findings, inhibition of Bcl-2 synergizes with PIs to induce MM cell pyroptosis. Therefore, the present study indicates that PIs trigger MM cell pyroptosis via the mitochondrial BAX/GSDME pathway and provides a rationale for combined treatment of MM with Bcl-2 and proteasome inhibitors to increase therapeutic efficiency via induction of pyroptosis., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: The best follow-up strategy for cancer survivors after treatment should balance the effectiveness and cost of disease detection while detecting recurrence as early as possible. Due to the low incidence of gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma [G-(MA)NEC], high-level evidence-based follow-up strategies is limited. Currently, there is a lack of consensus among clinical practice guidelines regarding the appropriate follow-up strategies for patients with resectable G-(MA)NEC., Materials and Methods: The study included patients diagnosed with G-(MA)NEC from 21 centers in China. The random forest survival model simulated the monthly probability of recurrence to establish an optimal surveillance schedule maximizing the power of detecting recurrence at each follow-up. The power and cost-effectiveness were compared with the National Comprehensive Cancer Network, European Neuroendocrine Tumor Society, and European Society for Medical Oncology Guidelines., Results: A total of 801 patients with G-(MA)NEC were included. The patients were stratified into four distinct risk groups utilizing the modified TNM staging system. The study cohort comprised 106 (13.2%), 120 (15.0%), 379 (47.3%), and 196 cases (24.5%) for modified groups IIA, IIB, IIIA, and IIIB, respectively. Based on the monthly probability of disease recurrence, the authors established four distinct follow-up strategies for each risk group. The total number of follow-ups 5 years after surgery in the four groups was 12, 12, 13, and 13 times, respectively. The risk-based follow-up strategies demonstrated improved detection efficiency compared to existing clinical guidelines. Further Markov decision-analytic models verified that the risk-based follow-up strategies were better and more cost-effective than the control strategy recommended by the guidelines., Conclusions: This study developed four different monitoring strategies based on individualized risks for patients with G-(MA)NEC, which may improve the detection power at each visit and were more economical, effective. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending follow-up strategies for G-(MA)NEC., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The prognosis of advanced gastric cancer (GC) invading the gastric serosa remains poor, mainly owing to high incidence of peritoneal recurrence. Patients with peritoneal metastases are often treated with neoadjuvant intraperitoneal and systemic chemotherapies (NIPS). Good responders to NIPS often undergo conversion gastrectomy. This study aims to explore biomarkers predicting the occurrence of peritoneal metastasis (PM) and evaluating the efficacy of NIPS in GC patients., Methods: We collected six peritoneal lavage (PL) samples from two patients with PM, two without PM, and two with diminished PM after NIPS via intraperitoneal access ports. We equally isolated microRNAs from exosomes derived from PL samples for deep sequencing. Two microRNAs (hsa-let-7g-3p and hsa-miR-10395-3p) were identified, and their expression levels were examined in PL samples of 99 GC patients using qRT-PCR. Moreover, we performed in vivo and in vitro functional assays to investigate effects of these microRNAs on metastasis and chemoresistance of GC cells., Results: Exosomal microRNA expression profiling of six PL samples indicated that the microRNA signature in exosomes of PLs from patients with diminished PM was similar to that from patients without PM. Expression levels of hsa-let-7g-3p and hsa-miR-10395-3p were associated with PM. In vivo and in vitro functional assays confirmed that hsa-let-7g-3p and hsa-miR-10395-3p are involved in GC metastasis and chemoresistance., Conclusion: PL-derived exosomes in GC contain large amounts of microRNAs related to PM. Moreover, hsa-let-7g-3p and hsa-miR-10395-3p could be used as biomarkers predicting PM and NIPS efficacy and are involved in GC metastasis and chemoresistance., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Recently, charge or spin nonlinear transport with nontrivial topological properties in crystal materials has attracted much attention. In this paper, we perform a comprehensive symmetry analysis for all 122 magnetic point groups (MPGs) and provide a useful dictionary for charge and spin nonlinear transport from the Berry curvature dipole, Berry connection polarizability and Drude term with nontrivial topological nature. The results are obtained by conducting a full symmetry investigation of the matrix representations of six nonlinear response tensors. We further identify every MPG that can accommodate two or three of the nonlinear tensors. The present work gives a solid theoretical basis for an overall understanding of the second-order nonlinear responses in realistic materials., (© The Author(s) 2023. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

Food-derived electrophilic compounds (FECs) are small molecules with electrophilic groups with potential cytoprotective effects. This study investigated the differential effects of six prevalent FECs on colitis in dextran sodium sulfate (DSS)-induced mice and the underlying relationship with molecular characteristics. Fumaric acid (FMA), isoliquiritigenin (ISO), cinnamaldehyde (CA), ferulic acid (FA), sulforaphane (SFN), and chlorogenic acid (CGA) exhibited varying improvements in colitis on clinical signs, colonic histopathology, inflammatory and oxidative indicators, and Nrf2 pathway in a sequence of SFN, ISO > FA, CA > FMA, CGA. Representative molecular characteristics of the “penetration-affinity−covalent binding” procedure, logP value, Keap1 affinity energy, and electrophilic index of FECs were theoretically calculated, among which logP value revealed a strong correlation with colitis improvements, which was related to the expression of Nrf2 and its downstream proteins. Above all, SFN and ISO possessed high logP values and effectively improving DSS-induced colitis by activating the Keap1−Nrf2 pathway to alleviate oxidative stress and inflammatory responses.

Although gastric cancer with para-aortic lymph node (PAN) metastasis is commonly regarded as unresectable, surgeons have explored the optimal treatment for patients with PAN metastases limited to No.16a2/b1 in the past few decades. Preoperative systemic therapy combined with D2 gastrectomy plus PAN dissection may improve the prognosis of these patients. In this multicenter phase II trial, 29 gastric cancer patients with PAN metastasis limited to No.16a2/b1 will receive preoperative treatment with nab-paclitaxel, oxaliplatin, S-1 (nab-POS: nab-paclitaxel, oxaliplatin, S-1) and sintilimab followed by D2 gastrectomy plus PAN dissection; and postoperative treatment with oral S-1, intravenous sintilimab and intraperitoneal paclitaxel. The end points for the study are 3-year overall survival, 3-year disease-free survival, pathological response rate, incidence of postoperative complications and adverse events.

Background: Cellular senescence plays a critical role in the occurrence and development, and immune modulation of cancer. This research primarily investigated the role of senescence-associated genes (SAGs) in the survival and tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC). Methods: From the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database, the gene expression profiles and clinical data of PDAC samples were downloaded. SAGs in the TCGA cohort were used to build a novel prognostic model and validated in the ICGC cohort. The relationship of signature with the immune landscape, tumor mutational burden (TMB), as well as the sensitivity of different therapies, was explored. Moreover, a nomogram was developed to predict the overall survival of PDAC patients. Results: A prognostic signature was constructed on basis of three SAGs, and patients in the low-risk score group had a longer survival time. The accuracy of the signature to distinguish different score groups was confirmed through principal component analysis (PCA) and the Receiver operator curves curve. The mRNA expression of the three signature genes was also verified in normal pancreatic and PDAC cell lines by RT-qPCR. The signature could independently predict the prognosis of PDAC patients and had broad applicability. Meanwhile, the nomogram predicted that 1- and 3-years survival rates were in good agreement with the observed overall survival rates. Low-risk patients had lower tumor mutational burden, and low-TMB patients had a better prognosis. Low- and high-risk patients exhibit distinct immune cell infiltration and immune checkpoint changes. By further analyzing the risk score, patients in the low-risk group were more responsive to immunotherapy and a variety of commonly used chemotherapeutic drugs. Conclusion: The prognostic signature can well predict the prognosis and assess the possibility of immunotherapy in personalized PDAC treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Chen, Miao, Jin and Wu.)

Increasing evidence has elucidated that the tumor microenvironment (TME) shows a strong association with tumor progression and therapeutic outcome. We comprehensively estimated the TME infiltration patterns of 111 gastric cancer (GC) and 21 normal stomach mucosa samples based on bulk transcriptomic profiles based on which GC could be clustered as three subtypes, TME-Stromal, TME-Mix, and TME-Immune. The expression data of TME-relevant genes were utilized to build a GC prognostic model-GC_Score. Among the three GC TME subtypes, TME-Stomal displayed the worst prognosis and the highest GC_Score, while TME-Immune had the best prognosis and the lowest GC_Score. Connective tissue growth factor (CTGF), the highest weighted gene in the GC_Score, was found to be overexpressed in GC. In addition, CTGF exhibited a significant correlation with the abundance of fibroblasts. CTGF has the potential to induce transdifferentiation of peritumoral fibroblasts (PTFs) to cancer-associated fibroblasts (CAFs). Beyond characterizing TME subtypes associated with clinical outcomes, we correlated TME infiltration to molecular features and explored their functional relevance, which helps to get a better understanding of carcinogenesis and therapeutic response and provide novel strategies for tumor treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sang, Dai, Yu, Chen, Fan, Liu, Li, Li, Wu, Hou, Yu, Feng, Zhu, Su, Li and Liu.)

Background: Neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) has shown promising results in gastric cancer (GC) with peritoneal metastasis. However, clinical practice experience of NIPS is still lacking in China. In this study, we investigate the efficacy and safety of NIPS in Chinese patients., Methods: Eligible patients received NIPS every 3 weeks. Gastrectomy was performed for patients who met the criteria of conversion surgery. The primary end point was 1-year overall survival (OS) rate. Secondary end points were the response rate, toxic effects, conversion surgery outcomes and median survival time (MST)., Results: Sixty-seven patients were enrolled. The primary endpoint was achieved with 1-year OS rate reached 67.2% (95% CI, 56.8%-79.4%). Conversion surgery was performed in 42 patients (62.9%), and R0 resection was achieved in 23 patients (54.8%) with the MST of 31.3 months (95% CI, 24.3-38.3). And the MST was 19.3 months (95% CI, 16.4-22.2) for all patients. Toxicity and surgical complications were well-tolerated. Moreover, sex, R0 resection, pathological nodal stage and tumor regression grade (TRG) were independent prognostic factors for patients who underwent conversion surgery., Conclusion: The NIPS is effective and safe in treating GC patients with peritoneal metastasis. Male patients, patients who underwent R0 resection, patients with ypN0-1 or TRG 1 after conversion surgery are more likely to benefit from the NIPS., Clinical Trial Registration: http://www.chictr.org.cn/, identifier https://clinicaltrials.gov/ ()., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Yuan, Lu, Xu, Wu, Xi, Shi, Wang, Ni, He, Yao, Zheng, Zhu, Liu, Zhang, Zhang, Li, Yan, Yan and Zhu.)

Background: The survival of patients with non-metastatic gastric adenocarcinoma (nmGaC), who are receiving more and more frequently chemotherapy, has improved throughout the last decades, while treatment-caused cardiotoxicity remains a major concern. This study aimed to investigate competing causes of mortality and prognostic factors within a large cohort of patients with resected nmGaC, and to describe the heart-specific mortalities of patients undergoing resection and chemotherapy and of all resected patients., Methods: In this population-based cohort study, data on patients diagnosed with nmGaC from 2004 through 2016, managed with resection with or without chemotherapy, followed up until the end of 2016, and surviving ≥ 1 month were retrieved from the US Surveillance, Epidemiology, and End Results-18 Program. Cumulative mortality functions were calculated. Prognostic factors for heart- and cancer-specific mortalities were evaluated using both multivariable-adjusted Fine-Gray subdistribution and cause-specific hazard functions., Results: Together 21,257 patients with resected nmGaC were eligible for analysis with an accumulated follow-up of 73,711 person-years, where 10,718 (50%) also underwent chemotherapy. Mortalities were overestimated when using the Kaplan-Meier method. Heart diseases were the most common non-cancer cause of mortality. Compared with all resected patients, heart-specific mortality of those also receiving chemotherapy was lower overall and especially at older ages. In the total group of patients, the 8-year cumulative mortalities from heart diseases were 4.4% and 2.0% in resected patients and those also receiving chemotherapy, respectively; in patients ≥ 80 years, the heart disease-specific mortalities were as high as 11.1% and 6.5%, respectively. In overall patients undergoing resection, older ages, black ethnicity, and location at gastric antrum/pylorus were associated with increased heart-specific mortality, while more recent period, female sex, Asian/Pacific Islanders, invasion of serosa, and more positive lymph nodes were associated with lower heart-specific mortality; among those further receiving chemotherapy, only the associations with period of diagnosis, age, and ethnicity were significant. Associations with older ages were stronger for heart-specific mortality than for cancer-associated mortality., Conclusions: Among survivors with resected nmGaC receiving chemotherapy, heart-specific mortality, the most common one among non-cancer causes of mortality, is not higher compared to overall resected patients in this observational study, suggesting that chemotherapy may be relatively safely administered to selected patients under strict indications. Age and ethnicity were major factors associated with heart-specific mortality in both overall resected patients and those further receiving chemotherapy. Overall and stratified cause-specific cumulative incidences of mortality are provided, which can be more clinically useful than the Kaplan-Meier estimates. Our study provides clinically useful evidence for tailored patient management., Competing Interests: None to declare., (Copyright 2022, Huang et al.)

Although recent advances in systemic chemotherapy have improved the clinical outcomes of gastric cancer patients with peritoneal metastasis, the peritoneum still represents a common site of treatment failure and disease recurrence. Neoadjuvant intraperitoneal-systemic chemotherapy has been acknowledged as a more aggressive treatment for gastric cancer patients with peritoneal metastasis. In this multicenter phase III randomized controlled trial, 238 patients will be randomly separated into two groups in a 2:1 ratio after laparoscopic exploration. The experimental arm will receive the proposed neoadjuvant intraperitoneal-systemic chemotherapy regimen, whereas the control group will receive a Paclitaxel + S-1 (PS) chemotherapy regimen. The endpoints for the study are overall survival, response rate, gastrectomy radicality rate, progression-free survival and adverse events.

Although complete omentectomy is traditionally performed in patients with gastric cancer as part of radical gastrectomy to ensure the elimination of micrometastases, the prognostic value of omentectomy during gastrectomy remains unclear. Retrospective studies have shown that the incidence of metastases in the greater omentum is very low in T1-T3 gastric cancer. Thus radical gastrectomy with D2 lymphadenectomy and preservation of the greater omentum may be a proper curative treatment for gastric cancer patients with T1-T3 tumors. The aim of this article is to describe the design and rationale for this prospective, randomized controlled DRAGON-05 trial, conducted to evaluate the prognostic value of omentum-preserving gastrectomy for patients with T1-T3 gastric cancer. Clinical trial registration: ChiCTR2000040045 (ClinicalTrials.gov).

Abstract: Cured leprosy patients have special physical conditions, which could pose challenges for safety and immunogenicity after immunization. We performed an observational clinical study aimed to identify the safety and immunogenicity of influenza vaccine in cured leprosy patients. A total of 65 participants from a leprosarium were recruited into leprosy cured group or control group, and received a 0.5 ml dose of the inactivated split-virion trivalent influenza vaccine and a follow-up 28 days proactive observation of any adverse events. Hemagglutination and hemagglutination inhibition test was performed to evaluate serum antibody titer, flow cytometry was conducted to screen of cytokines level. The total rate of reactogenicity was 0.0% [0/41] in leprosy cured group and 37.5% [9/24] in control group. The seroconversion rate for H1N1 was difference between leprosy cured group and control group (41.83% vs 79.17%, P = .0082), but not for H3N2 (34.25% vs 50.00%, P = .4468). At day 0, leprosy cured group have relatively high concentration of interleukin-6, interleukin-10, tumor necrosis factor, interferon-γ, and interleukin-17 compared to control group. The interleukin-2 concentration increased 2 weeks after vaccination compared to pre-vaccination in leprosy cured group, but declined in control group (0.92 pg/ml vs -0.02 pg/ml, P = .0147). Leprosy cured group showed a more rapid down-regulation of interleukin-6 when influenza virus was challenged compared to control group (-144.38 pg/ml vs -11.52 pg/ml, P < .0001). Subgroup analysis revealed that the immunization administration declined interleukin-17 concentration in Tuberculoid type subgroup, but not in Lepromatous type subgroup or control group. Clinically cured leprosy patients are relatively safe for influenza vaccine. Leprosy cured patient have immune deficit in producing antibody. Interleukin-6 and interleukin-17 were 2 sensitive indicators in immune response for leprosy affected patients. The identification of indicators might be help management of leprosy and used as predictive markers in leprosy early symptom monitoring., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Gastric cancer (GC) is a common malignant tumor with a high mortality rate., Aim: To determine the accuracy of preoperative imaging information obtained from the combined use of general gastroscopy (GS), endoscopic ultrasonography (EUS), and multi-detector computed tomography (MDCT) regarding absolute indication of endoscopic submucosal dissection (ESD) in early gastric cancer (EGC)., Material and Methods: The relationship between clinical features of 794 EGC patients and lymph node metastasis (LNM) was analyzed. Multivariate logistic regression analysis was used to investigate the risk factors for LNM. Additionally, the accuracy of diagnosis of imaging techniques for ESD indications was determined by receiver operating characteristic (ROC) analysis., Results: Data showed that tumor size > 2 cm (p = 0.0071), T1b stage (p < 0.0001), undifferentiated histology (p < 0.0001), and vascular invasion (p = 0.0007) were independent risk factors for LNM in patients with EGC. Indications for ESD have a specificity of 100% for the diagnosis of patients with LNM. Additionally, the diagnostic efficacy of the use of GS, EUS, and MDCT in identifying node positive status, T1a disease, tumor size ≤ 2 cm, and ulceration was found to be moderate with area under the curve (AUC) of receiver operating characteristic curve (ROC) of 0.71, 0.64, 0.72, and 0.68, respectively. Furthermore, the use of imaging techniques for overall indication criteria for ESD had a moderate utility value with an AUC of 0.71., Conclusions: Our data suggested that, based on the combined use of GS, EUS, and MDCT, a high specificity of patient selection for ESD treatment can be achieved., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2020 Fundacja Videochirurgii.)

Differences in the gene mutation spectra of younger and older Chinese adult AML patients and the prognostic significance of these differentially presented gene mutations are rarely reported. One hundred and thirteen newly diagnosed Chinese adults with AML, divided into groups of younger and older patients, were enrolled in this study. Bone marrow samples from the patients were analyzed using targeted next-generation sequencing with a panel of 141 genes. Ninety-eight mutated genes were detected and the top 10 mutated genes were KMT2D, FLT3, FAT1, ASXL1, NRAS, DNMT3A, RELN, TET2, JAK2, and KRAS. The top five functional groups were the tyrosine kinase pathway, transcription factors, DNA methylation, chromatin modifiers, and the JAK-STAT signaling pathway. Younger patients exhibited higher incidences of KMT2D (33.8% vs 10.4%, P = 0.004) and KRAS (15.4% vs 2.1%, P = 0.042) mutations than older patients; whereas, older patients harbored more SRSF2 (20.8% vs 0%, P = 0.002), transcription factor (85.4% vs 67.7%, P = 0.031), DNA methylation (58.3% vs 36.9%, P = 0.024), and RNA splicing (31.3% vs 12.3%, P = 0.013) mutations than younger patients. Moreover, patients with SRSF2 mutations exhibited a lower rate of overall survival (P < 0.001) and relapse-free survival (P < 0.001) than patients carrying wild-type SRSF2. In conclusion, rarely reported KMT2D, FAT1, and RELN mutations were detected at high frequencies in our cohort. The gene mutation spectrum of older patients was different to that of younger patients. Moreover, older patients harbored more SRSF2 mutations, which predicted lower rates of overall and relapse-free survival., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This study was to detect the expression level of transferrin receptor 2 (TfR2) in gastric cancer and to analyze its value in predicting the prognosis of gastric cancer patients. Real-time PCR (RT-qPCR) was applied to detect the mRNA expression of TfR2 in gastric cancer tissues and paired adjacent nontumorous tissues. Immunohistochemistry (IHC) and western blotting were used to determine the protein expression of TfR2 in gastric cancer, and the relationship with the prognosis of gastric cancer patients was analyzed. The results were: (1) The mRNA and protein levels of TfR2 in gastric cancer tissues were remarkably lower than those in adjacent nontumorous gastric tissue (P < .05). (2) Clinicopathological analysis showed that the expression level of TfR2 was significantly correlated with TNM stage of patients (P = .047). (3) The results of univariate survival analysis showed that histological grade, T stage, N stage, M stage, Lauren's classification, and TfR2 expression level influenced the overall survival of gastric cancer patients. Multivariate survival analysis showed that low TfR2 expression (HR = 1.671, 95%CI: 1.006-2.774, P = .047), poor differentiation (HR = 2.123, 95%CI: 1.188-3.795, P = .011), and M1 stage (HR = 8.541, 95%CI: 3.416-21.353, P < .001) were independent risk factors affecting the overall survival of gastric cancer patients. In conclusion, TfR2 exhibited low expression in gastric cancer tissue, and is an independent prognostic factor of gastric cancer patients., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.

5α-reductase inhibitors (5-ARI) are widely employed for the treatment of benign prostatic hyperplasia. It has been noted that 5-ARI exhibit the potential to attenuate the risk of prostate cancer, but consistent agreement has not been achieved. Moreover, the effect of 5-ARI on cancer-specific mortality and progression of prostate cancer remains unclear. Therefore, the goal of the current meta-analysis was to elucidate the impact of 5-ARI on the incidence and progression of prostate cancer. We searched for all studies assessing the effect of 5-ARI on risk of prostate cancer in PubMed, Embase, Medline, and Cochrane Library databases. Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) were accepted to evaluate the association between 5-ARI and the risk of prostate cancer. Synthetic results implied that subjects who accepted 5-ARI compared with the placebo group experienced a distinctly weakened overall incidence of prostate cancer (RR = 0.74; 95% CI: 0.66-0.82; P < 0.001). Subgroup analyses further revealed that 5-ARI reduction of the incidence of prostate cancer was limited to low-grade (Gleason score 2-6; RR = 0.68; 95% CI: 0.57-0.81; P < 0.001) and intermediate-grade tumors (Gleason score 7; RR = 0.81; 95% CI: 0.67-0.97; P = 0.023), but not high-grade tumors (Gleason score >7; RR = 1.19; 95% CI: 0.98-1.43; P = 0.069). The results also showed that 5-ARI treatment did not significantly alter prostate cancer-specific mortality (RR = 1.0; 95% CI: 0.95-1.05; P = 0.916). In addition, it was worth noting that 5-ARI treatment acted in a protective role that presented a dramatic benefit to delay the progression of low-risk tumors (RR = 0.58; 95% CI: 0.43-0.78; P < 0.001)., Competing Interests: None

The emerging of spin caloritronics leads to a series of new spin-thermal related effects, such as spin Seebeck effect (SSE), spin Nernst effect (SNE) and their corresponding inverse effects. Anomalous Righi-Leduc effect (ARLE) describes that a transverse temperature gradient can be induced by a longitudinal heat flow in ferromagnets. The driving force and the response of the ARLE are all involved with heat. It is curious if spin effects mediate the heat transport and provide extra influence. In this work, we investigate the ARLE and the interplay between the heat current, charge current, and spin current via linear response theory. We identified that spin effects do have clear roles in heat transport, which can be confirmed by phase shifts of voltage output varying with the direction of magnetization. Our formulas fit the experimental data very well. Moreover, we discuss more configuration of magnetization which is expected to be tested in the future. It should be emphasized that the present formalism including spin effects is out of the theory based on magnon transport, which may be conspicuous in the devices within the spin diffusion length.

Purpose: Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens., Experimental Design: A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms: least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival in the training cohort ( n = 160). The four-CpG classifier was validated in the internal testing cohort ( n = 68) and independent validation cohort ( n = 321)., Results: The four-CpG-based classifier discriminated patients with T-LBL at high risk of relapse in the training cohort from those at low risk ( P < 0.001). This classifier also showed good predictive value in the internal testing cohort ( P < 0.001) and the independent validation cohort ( P < 0.001). A nomogram incorporating five independent prognostic factors including the CpG-based classifier, lactate dehydrogenase levels, Eastern Cooperative Oncology Group performance status, central nervous system involvement, and NOTCH1 / FBXW7 status showed a significantly higher predictive accuracy than each single variable. Stratification into different subgroups by the nomogram helped identify the subset of patients who most benefited from more intensive chemotherapy and/or sequential hematopoietic stem cell transplantation., Conclusions: Our four-CpG-based classifier could predict disease relapse in patients with T-LBL, and could be used to guide treatment decision., (©2020 American Association for Cancer Research.)

Cesium lead halide perovskite nanocrystals have a narrow emission peak tunable in the visible wavelength range with a high quantum yield. They hold great potential for optoelectronic applications such as light-emitting diodes or electronic displays. However, cesium lead iodide (CsPbI 3 ) is not stable under ambient conditions, limiting its applications. Here, we use a solution surface treatment approach to improve the photostability of CsPbI 3 suspensions in toluene. When a CsPbBr 3 precursor is used via the method of heterogeneous surface treatment, the photoluminescence (PL) intensity is enhanced but the PL only lasts 2 days. In contrast, when a CsPbI 3 precursor is used via the method of homogeneous surface treatment, not only the PL intensity of CsPbI 3 suspensions is enhanced but also the stability with the PL lasts for 11 days. It is likely that a better protection on the core CsPbI 3 by itself can be achieved because of better matching of the material structure and surface chemistry., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Background: Endoscopic submucosal dissection (ESD) has increasingly gained broad application in the treatment of early gastric cancer (EGC). This study aimed at evaluating the clinical significance of lymph node metastasis (LNM) in patients with ulcer positive [UL (+)] EGC and assessing the feasibility of expanded indications of ESD for such cases., Methods: Patients with UL (+) EGC undergoing radical surgical resection between January 2012 and December 2018 were retrospectively reviewed. Associations between clinicopathological factors and the incidence of LNM were investigated by univariate and multivariate linear regression analysis., Results: Retrospective statistical analysis was performed on 653 EGC patients. The multivariate linear regression analysis showed that the presence of LNM was significantly associated with depth of invasion (P<0.0001) and lymphatic invasion (P<0.001). The proportion of EGC patients met absolute and expanded indication of ESD with positive LNM who were subject to the criteria of curative resection was 0.75% (4/532) and 6.67% (8/120), respectively. LNM between patients, which were subject to the absolute and expanded ESD indication, is significantly different (P=0.000274)., Conclusions: Our study revealed that 6.67% (8/120) of EGC patients who did not meet all criteria of curative resection were present with LNM. EGC patients with UL (+), differentiated adenocarcinoma, tumor invasion pathologically diagnosed as T1a, and tumor diameter ≤3 cm showed for ESD are suggested for a carefully weighed treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4303). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: Even though treatment modalities such as adjuvant systemic radio-chemotherapy and neoadjuvant chemotherapy (NAC) have individually have improved overall survival (OS) and progression-free survival (PFS) rates in advanced Gastric Cancer (AGC), the peritoneum still presides as a common site of treatment failure and disease recurrence. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been acknowledged as prophylaxis for peritoneal carcinomatosis (PC) in AGC patients and in this study, we aim at investigating the safety and efficacy of the combination of neoadjuvant laparoscopic HIPEC (NLHIPEC) with NAC in the neoadjuvant phase followed by surgery of curative intent with intraoperative HIPEC followed by adjuvant chemotherapy (AC)., Methods: In this multicenter Phase III randomized controlled trial, 326 patients will be randomly separated into 2 groups into a 1:1 ratio after laparoscopic exploration. The experiment arm will receive the proposed comprehensive Dragon II regimen while the control group will undergo standard R0 D2 followed by 8 cycles of AC with oxaliplatin with S-1 (SOX) regimen. The Dragon II regimen comprises of 1 cycle of NLHIPEC for 60mins at 43 ± 0.5 °C with 80 mg/m 2 of Paclitaxel followed by 3 cycles of NAC with SOX regimen and after assessment, standard R0 D2 gastrectomy with intraoperative HIPEC followed by 5 cycles of SOX regimen chemotherapy. The end-points for the study are 5 year PFS, 5 year OS, peritoneal metastasis rate (PMR) and morbidity rate., Discussion: This study is one of the first to combine NLHIPEC with NAC in the preoperative phase which is speculated to provide local management of occult peritoneal carcinomatosis or peritoneal free cancer cells while NAC will promote tumor downsizing and down-staging. The addition of the intraoperative HIPEC is speculated to manage dissemination due to surgical trauma. Where the roles of intraoperative HIPEC and NAC have individually been investigated, this study provides innovative insight on a more comprehensive approach to management of AGC at high risk of peritoneal recurrence. It is expected that the combination of NLHIPEC with NAC and HIPEC will increase PFS by 15% and decrease PMR after gastrectomy of curative intent., Trial Registration: World Health Organization Clinical Trials - International Registry Platform (WHO-ICTRP) with Registration ID ChiCTR1900024552, Registered Prospectively on the 16th July, 2019.

Background: An appropriate method of anastomosis is crucial for gastric cancer patients who require gastrojejunal anastomosis. Surgeons have proposed different types of modified gastrojejunostomies in the last two decades. We focused on two types of standard anastomosis, i.e., Uncut Roux-Y and Roux-Y gastrojejunostomies, and compared the differences in immediate postoperative complications between the two types., Methods: This is a retrospective study on 236 gastric cancer patients who underwent curative distal gastrectomy with gastrojejunal Roux-Y or Uncut Roux-Y anastomosis for six consecutive years. Immediate postoperative complications were compared between the two groups. The authors discussed the causes of the significant complications and their management., Results: There was no difference in demographics between the two groups (92 Roux-y Versus 144 Uncut Roux-y). The overall complication rate was 20.8% with 1.4% anastomotic leakage in the Uncut Roux-Y group versus 33.7% with 7.6% anastomotic failures in the Roux-Y group (p < 0.05). More abdominal infections occurred in the Roux-Y anastomosis group compared with the Uncut Roux-Y anastomosis group (p < 0.05). Duration of postoperative stay was significantly longer in patients with Roux-y anastomosis group (p < 0.05)., Conclusions: Considering the surgical simplicity and postoperative complications, the Uncut Roux-Y is a better choice for anastomosis in patients with gastric cancer undergoing gastrojejunostomy. A well-designed large cohort in a multi-centre randomized controlled trial is necessary to support these findings and compare other aspects.

Background: Lateral locking plate (LLP) fixation has gained popularity for the treatment of proximal humeral fractures (PHFs); however, complications can occur due to loss of the medial cortical buttress from fracture comminution., Materials and Methods: We designed a novel intramedullary anatomical medial strut with allograft bone (IAMSAB) using MIMICS software to specifically fill the intramedullary canal of the proximal humeral bone. We used finite element analysis to evaluate the biomechanical characteristics of a LLP, LLP-intramedullary fixation system (IFS), LLP-anatomical medial locking plate (AMLP), or the combined application of a LLP and IAMSAB (LLP-IAMSAB) fixation construct in patients with a PHF and an unstable medial column., Results: For axial or rotational loads, under (normal) Nor or osteoporotic (Ost) bone conditions, the LLP-IAMSAB fixation construct was significantly stiffer than the LLP-IFS fixation construct, and displacement at the fracture site after LLP-IAMSAB fixation was significantly less than after LLP or LLP-IFS fixation (P < 0.05). Stiffness of the LLP-IAMSAB and LLP-AMLP fixation constructs and displacement at the fracture site after LLP-IAMSAB and LLP-AMLP fixation were not significantly different. The IFS, AMLP, and IAMSAB shared the load in the LLP and decreased the risk of implant failure. There were no significant differences in von Mises stress and stress distribution after fixation with the LLP-IFS, LLP-AMLP, and LLP-IAMSAB constructs., Conclusion: These data suggest that the IAMSAB can provide direct medial support or resistance to rotation and augment the biomechanics of the LLP. The combined application of the IAMSAB and LLP may achieve functional outcomes that are similar to the LLP-AMLP fixation construct., (Copyright © 2019 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Following publication of the original article [1], the authors reported the following errors/updates.

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n = 75) and fetal thymus tissues (n = 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression: lower risk was associated with better prognosis (disease-free survival (DFS): hazard ratio (HR) 4.548, 95% CI 2.433-8.499, p < 0.001; overall survival (OS): HR 5.030, 95% CI 2.407-10.513, p < 0.001). This classifier displayed good performance in the internal testing set (n = 106) and the independent external set (n = 304). High risk was associated with more favorable response to HSCT (DFS: HR 1.675, 95% CI 1.127-2.488, p = 0.011; OS: HR 1.602, 95% CI 1.055-2.433, p = 0.027). When combined with ECOG-PS and/or NOTCH1/FBXW7 status, this classifier had even better prognostic performance in patients receiving HSCT (DFS: HR 2.088, 95% CI 1.290-3.379, p = 0.003; OS: HR 1.996, 95% CI 1.203-3.311, p = 0.007). The five-miRNA classifier may be a useful prognostic biomarker for T-LBL adults, and could identify subjects who could benefit from HSCT.

Background: To investigate the implications of prophylactic intraoperative Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with D2 radical gastrectomy for locally advanced Gastric Cancer (AGC) in a randomized case control study., Method: Eighty consecutive patients with locally AGC were randomly separated into 2 groups: HIPEC group (Curative Resection + intraoperative HIPEC with cisplatin 50 mg/m 2 at 42.0 ± 1.0 °C for 60 min) and Control group (Curative Resection only). Intraoperative and post-operative events, clinical recovery, morbidity and the disease-free survival (DFS) rates were closely monitored., Results: Among the 40 HIPEC group patients, the highest intracranial temperature recorded during the procedure was 38.2 °C but the patient made an eventless recovery. Mild renal dysfunction, hyperbilirubinemia and mild liver dysfunction were recorded in the HIPEC group but their incidences were found to be statistically insignificant when compared with the control group (P > 0.05). The initial post-operative analysis revealed shorter post-operative stay for in the HIPEC group but further analysis revealed that it was related to the incidence of postoperative complication. During a median follow-up time of 41 months, there were 9/39 and 15/38 cases of disease progression in HIPEC and Control groups respectively, with a more favorable 3-year DFS (76.9% vs 60.5%) and a lower peritoneal recurrence rate (5% vs 30%) in the HIPEC group., Conclusion: Prophylactic HIPEC with radical D2 Gastrectomy is safe and shows favorable survival and peritoneal recurrence rates for AGC with acceptable morbidity. Nevertheless, more structured multi-centered RCT should be carried out for more substantial evidence.

Colorectal cancer (CRC) is the third most common type of cancer. In recent decades, genomic analysis has played an increasingly important role in understanding the molecular mechanisms of CRC. However, its pathogenesis has not been fully uncovered. Identification of genes related to CRC as complete as possible is an important way to investigate its pathogenesis. Therefore, we proposed a new computational method for the identification of novel CRC-associated genes. The proposed method is based on existing proven CRC-associated genes, human protein-protein interaction networks, and random walk with restart algorithm. The utility of the method is indicated by comparing it to the methods based on Guilt-by-association or shortest path algorithm. Using the proposed method, we successfully identified 298 novel CRC-associated genes. Previous studies have validated the involvement of the majority of these 298 novel genes in CRC-associated biological processes, thus suggesting the efficacy and accuracy of our method.

The purpose of this study was to determine the diagnostic accuracy of serum inhibin B (INHB) as a predictor of the retrieval outcome of testicular haploid gametes (spermatids and testicular spermatozoa) in nonobstructive azoospermic men. Serum hormone levels, testicular volume, and histological evaluation were performed in 403 Chinese nonobstructive azoospermic men. Testicular haploid gamete was successfully retrieved in 213 of 403 patients (52.85%). The haploid gamete group always had higher INHB levels than the non-haploid gamete group. According to the receiver operating characteristic (ROC) curve analysis, INHB was a good predictor of testicular haploid gamete retrieval outcome in all patients (sensitivity: 77.93% and specificity: 91.58%) and patients with normal follicle-stimulating hormone (FSH; sensitivity: 88.52% and specificity: 70.83%). The area under the ROC curve (AUC) of INHB was similar to that of FSH in all patients or patients with normal FSH. In patients with elevated FSH, INHB was superior to FSH in predicting the presence of haploid gamete (AUC: 0.73 vs 0.55, P < 0.05), with a sensitivity of 60.00% and a specificity of 80.28%. It concluded that serum INHB as an effective marker for spermatogenesis was a significant predictor of testicular haploid gamete retrieval outcomes in nonobstructive azoospermic men. Especially, INHB is superior to FSH in predicting the presence of haploid gamete in the patients with elevated FSH., Competing Interests: None

Although extensively studied, the exact role of sleep in learning and memory is still not very clear. Sleep deprivation has been most frequently used to explore the effects of sleep on learning and memory, but the results from such studies are inevitably complicated by concurrent stress and distress. Furthermore, it is not clear whether there is a strict time-window between sleep and memory consolidation. In the present study we were able to induce time-locked slow-wave sleep (SWS) in mice by optogenetically stimulating GABAergic neurons in the parafacial zone (PZ), providing a direct approach to analyze the influences of SWS on learning and memory with precise time-windows. We found that SWS induced by light for 30 min immediately or 15 min after the training phase of the object-in-place task significantly prolonged the memory from 30 min to 6 h. However, induction of SWS 30 min after the training phase did not improve memory, suggesting a critical time-window between the induction of a brief episode of SWS and learning for memory consolidation. Application of a gentle touch to the mice during light stimulation to prevent SWS induction also failed to improve memory, indicating the specific role of SWS, but not the activation of PZ GABAergic neurons itself, in memory consolidation. Similar influences of light-induced SWS on memory consolidation also occurred for Y-maze spatial memory and contextual fear memory, but not for cued fear memory. SWS induction immediately before the test phase had no effect on memory performance, indicating that SWS does not affect memory retrieval. Thus, by induction of a brief-episode SWS we have revealed a critical time window for the consolidation of hippocampus-dependent memory.

Background: The objective of current study was to develop and validate a nomogram to predict overall survival in pancreatic neuroendocrine tumors (PNETs)., Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with PNETs between 2004 and 2015. Patients were randomly separated into the training set and the validation set. Cox regression model was used in training set to obtain independent prognostic factors to develop a nomogram for predicting overall survival (OS). The discrimination and calibration plots were used to evaluate the predictive accuracy of the nomogram., Results: A total of 3142 patients with PNETs were collected from the SEER database. Sex, age, marital status, primary site, TNM stage, tumor grade, and therapy were associated with OS in the multivariate models. A nomogram was constructed based on these variables. The nomogram for predicting OS displayed better discrimination power than the Tumor-Node-Metastasis (TNM) stage systems 7th edition in the training set and validation set. The calibration curve indicated that the nomogram was able to accurately predict 3- and 5-year OS., Conclusions: The nomogram which could predict 3- and 5-year OS were established in this study. Our nomogram showed a good performance, suggesting that it could be served as an effective tool for prognostic evaluation of patients with PNETs., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Gastric cancer (GC) remains one of the most common and malignant types of cancer due to its rapid progression, distant metastasis, and resistance to conventional chemotherapy, although efforts have been made to understand the underlying mechanism of this resistance and to improve clinical outcome. It is well recognized that tumor heterogeneity, a fundamental feature of malignancy, plays an essential role in the cancer development and chemoresistance. The model of tumor-initiating cell (TIC) has been proposed to explain the genetic, histological, and phenotypical heterogeneity of GC. TIC accounts for a minor subpopulation of tumor cells with key characteristics including high tumorigenicity, maintenance of self-renewal potential, giving rise to both tumorigenic and non-tumorigenic cancer cells, and resistance to chemotherapy. Regarding tumor-initiating cell of GC (GATIC), substantial studies have been performed to (1) identify the putative specific cell markers for purification and functional validation of GATICs; (2) trace the origin of GATICs; and (3) decode the regulatory mechanism of GATICs. Furthermore, recent studies demonstrate the plasticity of GATIC and the interaction between GATIC and its surrounding factors (TIC niche or tumor microenvironment). All these investigations pave the way for the development of GATIC-targeted therapy, which is in the phase of preclinical studies and clinical trials. Here, we interpret the heterogeneity of GC from the perspectives of TIC by reviewing the above-mentioned fundamental and clinical studies of GATICs. Problems encountered during the GATIC investigations and the potential solutions are also discussed., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest.

Background: The aim of the study was to develop and validate a nomogram to predict overall survival (OS) in biliary tract cancer (BTC)., Patients and Methods: Patients diagnosed with BTC between 2004 and 2014 were selected for the study from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were randomly allocated to 2 sets, the training set (n = 8,869) and the validation set (n = 8,766), for the purposes of validation. The prognostic effects of each variable were examined using univariate and multivariate analyses. Cox regression models and a nomogram were developed based on significant prognostic factors. The predictive and discriminatory capacity of the nomogram was evaluated by Harrell's concordance index (C-index) and calibration plots., Results: Data of 17,635 patients with BTC were collected from the SEER database. Age; race; tumor site; tumor grade; T, N, and M stage; marital status; and therapy were associated with survival in the multivariate models. All these factors were integrated to construct the nomogram. The nomogram for predicting OS displayed better discrimination power than the tumor-node-metastasis (TNM) stage system 6th edition in the training set and validation set. The calibration curve indicated that the nomogram was able to accurately predict 3- and 5-year OS., Conclusion: This predictive model has the potential to provide an individualized risk estimate of survival in patients with BTC., Competing Interests: Disclosure The authors declare no conflicts of interest in this work.

Photonic crystal (PC) materials have huge potentials as sensors for noninvasive and real-time monitoring glucose in tears. We developed a glucose-sensitive PC material based on monolayered colloidal crystals (MCCs). Polystyrene nanoparticles were first self-assembled into a highly ordered MCC, and this two-dimensional (2D) template was then coated by a 4-boronobenzaldehyde-functionalized poly(vinyl alcohol) hydrogel. Such a sensor efficiently diffracts visible light, whose structural color could change from red through yellow to green, as the glucose concentration altered from 0 to 20 mM, covering both tears' and bloods' physiological ranges. The sensor also represents a rapid response within 180 s at each titration of glucose, combining the characteristics of high accuracy and sensitivity in detecting the glucose concentration in tears, and this intelligent sensing material presents certain possibility for the frontier point-of-care glucose monitoring., Competing Interests: The authors declare no competing financial interest.

Background: Leprosy is an infectious disease caused by the bacterium Mycobacterium leprae. Influenza vaccine is an important influenza prevention strategy and the preparations used display good safety and tolerability profiles. But the safety of applying influenza vaccine on the clinical cured leprosy patients is unclear., Methods: We conducted an observational clinical study, in Wuhan between November 15, 2016 and March 1, 2017. Two groups of participants ≥50 years of age received a 0.5 ml dose of the inactivated split-virion trivalent influenza vaccine and a follow-up 28 days observation of any solicited and unsolicited adverse events., Results: A total of 134 subjects were included in the study. The total rate of reactogenicity was 5.4% [2/37] in leprosy group and 15.5% [15/ 97] in control group, the difference of reactogenicity between two groups was not significant (p = 0.1522). For solicited injection-sites adverse events (AEs), 12.4% [12/ 97] participants in the control group reported of itching, pain, erythema, swelling or induration, and no participants in leprosy group reported of any solicited injection-sites AEs. For solicited systemic AEs, 7.2% [7 / 97] participants in the control group reported of fever, malaise or headache, and 2.7% [1 / 37] participants in the leprosy group reported of fever, statistic result showed that the difference was not significant (p = 0.4438). Unsolicited AEs was reported by one male aged 76, 4 hours after vaccination administration, his plantar ulcer area began bleeding. All AEs were grade 1 or grade 2, and no recurrence of lepra reaction, AEs leading to early withdrawal from the study, or deaths were reported in this study., Conclusions: To our knowledge, the present study is the first clinical study to evaluate the safety of influenza vaccine in clinically cured leprosy patients. We concluded that clinically cured leprosy patients are relatively safe for influenza vaccine. More importantly, our study make a positive and scientific efforts to eradicate discrimination on leprosy. In our study, we described a patient with plantar ulcer undergoing bleeding for 4 hours after vaccine administration. Based on evidence we have, we interpret that this adverse event may probably associated with vaccine, and patients with ulcer and leprosy need intensive attention after vaccines administration.

Tumor metastasis is the leading cause of death in patients with advanced gastric cancer (GC). Limited therapeutic regimens are available for this condition, which is associated with a poor prognosis, and the mechanisms underlying tumor metastasis remain unclear. In the present study, increased histone methyltransferase G9A expression in GC tissues correlated with advanced stage and shorter overall survival, and in vitro and in vivo experiments revealed that G9A promoted tumor invasion and metastasis. Moreover, we observed that Reg IV induced G9A via the p-ERK/p-SP1 pathway. SP1 directly binds the G9A promoter and enhances G9A expression, and upregulated G9A then forms a transcriptional activator complex with P300 and GR, thereby promoting ITGB3 expression induced by dexamethasone (DEX) and contributing to GC metastasis. However, the G9A-mediated increase in ITGB3 expression was not dependent on the SET domain and methyltransferase activity of G9A. This study demonstrates that G9A is an independent prognostic marker and promotes metastasis in GC, thus suggesting that it may be a tumor biomarker and potential therapeutic target in GC.

Objective: To investigate the clinical significance of tumor associated macrophages (TAM) in multiple myeloma (MM) and the relationship with angiogenesis and immunosuppression. Methods: Seventy cases of MM patients diagnosed from August 2015 to June 2017 were enrolled in the study as experimental group, 20 cases of benign hematological diseases (13 with iron deficiency anemia and 7 with megaloblastic anemia) patients as control group. Immunohistochemical method was used to detect the expression of CD163, CD34 and VEGF in bone marrow samples, and flow cytometry was used to detect the proportion of regulatory T cell (Treg cells), ELISA was used to detect the level of IL-10, and the clinical features were analyzed. Results: ①Among the 70 patients, there were 31 males and 39 females with a median age of 65 (50~78) years old. TAM infiltration density, microvascular density (MVD), VEGF expression level, Treg ratio and IL-10 level in bone marrow samples of 70 MM patients were significantly higher than those of benign hematological diseases ( P <0.05). ②In the MM group, the above indexes of the patients with disease stabilized (15 cases) were lower than those of the newly diagnosed group (35 cases) and the relapse refractory group (20 cases) ( P <0.05), those of relapse refractory group were higher than those of newly diagnosed group ( P >0.05). ③Of the 35 newly diagnosed MM patients, 27 completed 4 courses of treatment. In the effective group (15 cases), the TAM infiltration density after treatment was significantly lower than that before treatment, the difference was statistically significant[(20.20±7.66) vs (28.87±11.97), t =2.362, P =0.025]; while in the ineffective group of 12 cases, the difference of the TAM infiltration density before and after treatment was not statistically significant[(42.00±13.76) vs (48.25±13.59), t =1.119, P =0.275]. ④TAM infiltration density in the effective group after bortezomib treatment (21 cases) were lower than those in the non-bortezomib treatment group (18 cases)[(16.52 ±4.26) vs (19.27 ±5.82), t =1.662, P =0.170]. ⑤The TAM infiltration density in MM patients was positively correlated with MVD, VEGF expression level, Treg cell ratio and IL-10 level ( P <0.001). Conclusion: The infiltration of TAM in the microenvironment of MM, which may promoting angiogenesis and inhibiting immune response, is related to the occurrence, development, therapeutic effect and drug resistance of MM.

Henoch Schönlein purpura (HSP) following vaccine administration has been described in case reports and in a small number of observational studies. We herein reported a case of HSP occurring in an otherwise healthy 37-year-old male after immunization with lyophilized purified vero cell rabies vaccine (PVRV). After the anti-allergy therapy with hormone, the purpuric lesions gradually disappeared. After evaluating, another PVRV with different dose (0.5 ml), strains, excipient and without residues was chosen for the new anti-rabies immunization program, and the patient has had no recurrence of allergic symptoms. Although significant lower than the levels of normal 20-50 year population at day 21, the neutralizing antibody (RVNA) titers of this boy showed adequate protective antibody (3.23 vs 7.15 IU/ml). This case report emphasizes the importance that clinicians should be aware of HSP as a potential adverse event associated with PVRV vaccination. And adverse events (AEs) after immunization should be carefully treated, changing immunization program in time is necessary. While enrolling a new anti-rabies immunization program, the properties of different rabies vaccines taking with special emphasis on strains, excipient and residues is imperative before vaccination so that an appropriate immune program can be managed to be initiated.