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Background: Post-surgical recurrence of the metastatic colorectal cancer (mCRC) remains a challenge, even with adjuvant therapy. Moreover, patients show variable outcomes. Here, we set to identify gene models based on the perspectives of intrinsic cell activities and extrinsic immune microenvironment to predict the recurrence of mCRC and guide the adjuvant therapy.Methods: An RNA-based gene expression analysis of CRC samples (total = 998, including mCRCs = 344, non-mCRCs = 654) was performed. A metastasis-evaluation model (MEM) for mCRCs was developed using the Cox survival model based on the prognostic differentially expressed genes between mCRCs and non-mCRCs. This model separated the mCRC samples into high- and low-recurrence risk clusters that were tested using machine learning to predict recurrence. Further, an immune prognostic model (IPM) was built using the COX survival model with the prognostic differentially expressed immune-related genes between the two MEM risk clusters. The ability of MEM and IPM to predict prognosis was analyzed and validated. Moreover, the IPM was utilized to evaluate its relationship with the immune microenvironment and response to immuno-/chemotherapy. Finally, the dysregulation cause of IPM three genes was analyzed in bioinformatics.Results: A high post-operative recurrence risk was observed owing to the downregulation of the immune response, which was influenced by MEM genes (BAMBI, F13A1, LCN2) and their related IPM genes (SLIT2, CDKN2A, CLU). The MEM and IPM were developed and validated through mCRC samples to differentiate between low- and high-recurrence risk in a real-world cohort. The functional enrichment analysis suggested pathways related to immune response and immune system diseases as the major functional pathways related to the IPM genes. The IPM high-risk group (IPM-high) showed higher fractions of regulatory T cells (Tregs) and smaller fractions of resting memory CD4+ T cells than the IPM-low group. Moreover, the stroma and immune cells in the IPM-high samples were scant. Further, the IPM-high group showed downregulation of MHC class II molecules. Additionally, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and GDSC analysis suggested the IPM-low as a promising responder to anti-CTLA-4 therapy and the common FDA-targeted drugs, while the IPM-high was non-responsive to these treatments. However, treatment using anti-CDKN2A agents, along with the activation of major histocompatibility complex (MHC) class-II response might sensitize this refractory mCRC subgroup. The dysfunction of MEIS1 might be the reason for the dysregulation of IPM genes.Conclusions: The IPM could identify subgroups of mCRC with a distinct risk of recurrence and stratify the patients sensitive to immuno-/chemotherapy. Further, for the first time, our study highlights the importance of MHC class-II molecules in the treatment of mCRCs using immunotherapy.

Accumulating evidence has showed that anti-CASPR2 autoantibodies occur in a long list of neurological immune disorders including limbic encephalitis (LE). Belonging to the well-known neurexin superfamily, CASPR2 has been suggested to be a central node in the molecular networks controlling neurodevelopment. Distinct from other subfamilies in the neurexin superfamily, the CASPR subfamily features a unique discoidin (Disc) domain. As revealed by our and others' recent studies, CASPR2 Disc domain bears a major epitope for autoantibodies. However, structural information on CASPR2 recognition by autoantibodies has been lacking. Here, we report the crystal structure of human CASPR2 Disc domain at a high resolution of 1.31 A, which is the first atomic-resolution structure of the CASPR subfamily members. The Disc domain adopts a total β structure and folds into a distorted jellyroll-like barrel with a conserved disulfide-bond interlocking its N- and C-termini. Defined by four loops and located in one end of the barrel, the “loop-tip surface” is totally polar and easily available for protein docking. Based on structure-guided epitope prediction, we generated nine mutants and evaluated their binding to autoantibodies of cerebrospinal fluid from twelve patients with limbic encephalitis. The quadruple mutant G69N/A71S/S77N/D78R impaired CASPR2 binding to autoantibodies from eleven LE patients, which indicates that the loop L1 in the Disc domain bears hot spots for autoantibody interaction. Structural mapping of autoepitopes within human CASPR2 Disc domain sheds light on how autoantibodies could sequester CASPR2 ectodomain and antagonize its functionalities in the pathogenic processes.

Aberrant activation of Wnt/β-catenin signaling is closely associated with the development of various human cancers, especially colorectal cancers (CRC). The ubiquitin proteasome system (UPS) is essential in the regulation of Wnt signaling and inhibitors targeting the UPS could have great potential in CRC therapy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, plays a significant role in neoplastic diseases due to its well-known function of regulating the MDM2-p53 complex. Inspired by our recent study identifying the positive role of USP7 in the Wnt signaling, we report here that USP7 is overexpressed in colorectal carcinoma cell lines and tissues, which is closely related with the poor prognosis. USP7 knockdown inhibits the proliferation of CRC cells with different p53 status, and USP7 inhibition by its inhibitor P5091 attenuates the activity of Wnt signaling via enhanced ubiquitination and the subsequent degradation of β-catenin. In vitro, P5091 inhibited the proliferation and induced apoptosis of CRC cells. P5091 also suppressed in vivo tumor growth in the HCT116 xenograft mouse model, which is consistently associated with reduced expression of β-catenin and Wnt target genes. In conclusion, our preclinical study indicated that USP7 could be a potential drug target and its inhibitor P5091 deserves further development as anticancer agent for Wnt hyper-activated CRC therapy.

Background Colorectal cancer (CRC) is one of the most common malignancies, and it’s expected that the CRC burden will substantially increase in the next two decades. New biomarkers for targeted treatment and associated molecular mechanism of tumorigenesis remain to be explored. In this study, we investigated whether PDCD6 plays an oncogenic role in colorectal cancer and its underlying mechanism. Methods Programmed cell death protein 6 (PDCD6) expression in CRC samples were analyzed by immunohistochemistry and immunofluorescence. The prognosis between PDCD6 and clinical features were analyzed. The roles of PDCD6 in cellular proliferation and tumor growth were measured by using CCK8, colony formation, and tumor xenograft in nude mice. RNA-sequence (RNA-seq), Mass Spectrum (MS), Co-Immunoprecipitation (Co-IP) and Western blot were utilized to investigate the mechanism of tumor progression. Immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) were performed to determine the correlation of PDCD6 and MAPK pathway. Results Higher expression levels of PDCD6 in tumor tissues were associated with a poorer prognosis in patients with CRC. Furthermore, PDCD6 increased cell proliferation in vitro and tumor growth in vivo. Mechanistically, RNA-seq showed that PDCD6 could affect the activation of the MAPK signaling pathway. PDCD6 interacted with c-Raf, resulting in the activation of downstream c-Raf/MEK/ERK pathway and the upregulation of core cell proliferation genes such as MYC and JUN. Conclusions These findings reveal the oncogenic effect of PDCD6 in CRC by activating c-Raf/MEK/ERK pathway and indicate that PDCD6 might be a potential prognostic indicator and therapeutic target for patients with colorectal cancer.

Several studies have assessed the association of CD95L polymorphism with cervical cancer risk, but the data lack the power to provide compelling evidence. In this study, we aimed to clarify the association through a meta-analysis. A comprehensive search was conducted in PubMed, Embase, and Web of Science. The fixed-effects model was used to calculate odds ratio (OR) with 95 % confidence intervals (CIs). A total of five papers with six case–control studies were derived and finally included in this meta-analysis. The overall estimate did not reveal any significant association between CD95L −844C/T polymorphism and cervical cancer risk. Subgroup analysis in Asian population indicated nonsignificant nevertheless potentially increased risk in CC genotype carriers in comparison with the carriers of CT + TT genotypes (ORCC vs. CT + TT = 1.16, 95 % CI = 0.99–1.36, P for heterogeneity = 0.231). Based on current epidemiological studies, this meta-analysis suggests that CD95L polymorphism may not be a risk factor contributing to cervical cancer development.

// Jingfei Guo 1, 2, * , Qian Zhang 3, * , Xinyu Bi 1 , Jianguo Zhou 1 , Zhiyu Li 1 , Zhen Huang 1 , Yefan Zhang 1 , Muxing Li 1 , Xiao Chen 1 , Xuhui Hu 1 , Chi Yihebali 4 , Junbo Liang 5 , Jianmei Liu 6 , Jianjun Zhao 1 , Jianqiang Cai 1 , Hong Zhao 1 1 Department of Abdominal Surgical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China 2 Academy of Medical Sciences, Peking Union Medical College, Beijing, China 3 Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China 4 Department of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China 5 State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China 6 Laboratory of Cell and Molecular Biology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China * These authors have contributed equally to this work Correspondence to: Hong Zhao, email: zhaohong@cicams.ac.cn Jianqiang Cai, email: caijianqiang@cicams.ac.cn Jianjun Zhao, email: zjj8424@sina.com Keywords: midgut neuroendocrine tumor, liver metastasis, palliative surgery, primary tumor resection, survival benefit Received: August 15, 2016 Accepted: November 07, 2016 Published: December 24, 2016 ABSTRACT Background: Treatment for midgut neuroendocrine tumor patients with unresectable liver metastasis has long been a controversial issue. This system review aims to summarize existing evidence concerning the value of primary tumor resection in this group of patients. Results: 8 cohort studies were identified for qualitative analysis. None of them strictly met with the inclusion criteria and meta-analysis was impossible. There was a tendency towards better overall survival for the primary tumor resected group in all 8 studies, in which 6 demonstrated significant difference. Progression free survival to liver disease was prolonged and less patients died of liver failure in the resected group. Methods: MEDLINE, EMBASE and CENTRAL were searched until 2016/7/4 for relevant studies, with primary outcome being overall survival, and secondary outcome being progression free survival, cause of death and symptom relief. Conclusions: Current evidence supports resection of primary tumor for midgut neuroendocrine tumor patients with liver metastases, but randomized controlled trials are required to reach a final conclusion.

Background/Aim: Basal plasma leptin levels are higher in women than in men and also higher in obese than in lean subjects, but the dynamic leptin secretion has not been well studied. We tested whether the leptin secretory response to glucocorticoid or insulin differs by gender and adiposity status. Methods: Seventy-nine nondiabetic adults, comprising lean [body mass index (BMI; kg/m2) ≤25; n = 27], obese (BMI 30–40; n = 28), and massively obese (BMI >40; n = 24) subjects, participated in two separate studies. In study 1, the subjects received oral dexamethasone (4 mg), with blood sampling before and 8 and 16 h after ingestion. In study 2, the subjects underwent a two-step hyperinsulinemic (1.0 mU·kg–1/min for 3 h, then 2.0 mU·kg–1/min for 3 h), euglycemic (∼100 mg/dl) clamp. Blood samples were obtained at baseline and every 20 min during the clamp. Results: Basal and stimulated leptin levels were higher in women than in men, and higher in the obese groups than in lean subjects. The percentage increase above baseline leptin was similar among men and women within each group, but was ∼30% lower in massively obese compared to lean subjects. Conclusion: Leptin secretory responses to glucocorticoid or insulin stimulation are preserved across a broad adiposity range, with higher absolute responses in women than in men.

LIU, JIANMEI, HASAN ASKARI, AND SAMUEL DAGOGO-JACK. Basal and stimulated plasma leptin in diabetic subjects. Obes Res. Objective: To determine whether leptin secretion is impaired in diabetes, we compared basal and stimulated plasma leptin levels in diabetic subjects and healthy controls. Research Methods and Procedures: Blood samples for assay of leptin and other hormones were obtained at baseline in 54 diabetic patients and 65 controls, and 8 hours, 16 hours, and 40 hours following ingestion of dexamethasone (4 mg) in 6 healthy and 12 controls. C-peptide status was defined as “negative” if ≤0.1 ng/mL or “positive” if ≥0.3 ng/mL, in fasting plasma. Results: Basal plasma leptin levels were 19. 7±2. 2 ng/mL in nondiabetic subjects, 13. 4±1. 5 ng/ml in C-peptide negative (n = 28) and 26. 1±23. 7 ng/mL in C-peptide positive (n = 26, p = 0. 001) diabetic patients. Dexamethasone increased leptin levels of controls (n = 6) to 145±17% of baseline values at 8 hours (p = O. O3), 224±18% at 16 hours (p = 0. 01), and 134218% at 40 hours (p = 0. 05). The corresponding changes were 108±13%, 126±23%, and 98±16% in C-peptide negative (n = 6), and 121±10%, 144±16% (p = 0. 03), and 147±23% (p = 0. 11) in C-peptide positive (n = 6) diabetic patients, respectively. The peak stimulated leptin levels were lower in the diabetic patients, compared with controls. Plasma insulin increased (p = 0. 02) in controls, but not in the diabetic patients, following dexamethasone. Discussion: Although diabetic patients have normal plasma leptin levels under basal conditions, their leptin responses to glucocorticoid are impaired, probably because of the concomitant insulin secretory defect. A subnormal leptin secretory response could worsen obesity and insulin resistance in diabetes.

Objective To determine the relationship between plasma leptin and insulin-like growth factor-I (IGF-I) levels in healthy subjects and patients with chronic renal insufficiency at baseline, and during administration of recombinant human IGF-I in the renal impaired patients. Subjects 20 healthy subjects (six men, 14 women, age: 42.7 +/- 3.2 y) and nine subjects with chronic renal insufficiency (five men, four women, age: 53.6 +/- 3.7 y). Intervention Daily s.c. injection of recombinant human IGF-I (50 micrograms/kg) for 24 d. Measurements Fasting plasma levels of leptin, IGF-I, growth hormone, C-peptide, glucagon and IGF binding proteins by specific radioimmunoassays at baseline in all subjects and serially during IGF-I therapy in the renal impaired subjects. Results Baseline leptin levels were correlated with body mass index (BMI, R = 0.72, P = 0.0001) but not IGF-I levels (R = 0.02). During IGF-I therapy, plasma IGF-I levels increased from 128 +/- 17.4 ng/ml at baseline to 250 +/- 36.8 ng/ml on day 3 (P = 0.003) and 323 +/- 61.6 ng/ml on day 24 (P = 0.01), whereas leptin levels declined: 24.4 +/- 10.3 ng/ml (baseline), 19.5 +/- 6.2 ng/ml (day 3, P = 0.028), and 17.2 +/- 4.9 ng/ml (day 24, P = 0.05). Conclusion Basal plasma leptin and IGF-I levels are not correlated; however, chronic administration of recombinant IGF-I is associated with an early and sustained decrease in plasma leptin levels. IGF-I may have an inhibitory effect on leptin secretion in humans.

Context: Published studies indicate marked variability in plasma leptin levels among persons with similar body mass index (BMI). We tested the hypothesis that such variations in leptin levels reflect differences in insulin sensitivity. Subjects and Methods: Using euglycemic clamp, we assessed insulin sensitivity (ISI) in 57 nondiabetic adults (36 women, 21 men), whose BMI ranged from 20 to 78 kg/m2. We identified 38 age-matched subjects, stratified by fasting leptin (normal

Leptin has anorectic, anti-obesity, and insulin-sensitizing properties. We recently reported subnormal responses to the leptin secretagogue dexamethasone in diabetes (DM). To determine whether this defect precedes or follows the occurrence of diabetes, we have studied 37 adults: 11 with type 2 DM diagnosed within 6 months prior to study, 16 with chronic (or =20 years) DM, and 10 healthy controls. After baseline measurements, subjects ingested dexamethasone (4 mg), followed by blood sampling 16 and 40 h later. Nadir plasma cortisol levels (2.5 mg/dl) occurred 16 h after dexamethasone ingestion in all study groups; this period of maximal biological action of dexamethasone was associated with peak plasma leptin levels. The peak dexamethasone-stimulated plasma leptin responses (% baseline, +/-SEM) were 188+/-18.7% among healthy controls, 180+/-13.8% among new DM patients, and 127+/-10.5% (P0.01) in chronic DM patients. Following dexamethasone ingestion, plasma glucose remained stable in the control and new DM groups but increased by 240% in the chronic DM patients; in contrast, plasma insulin increased significantly in controls and new DM patients but not in patients with chronic DM. These results indicate that plasma leptin responses to secretagogue are preserved in newly diagnosed diabetes patients but markedly attenuated in patients with long-standing diabetes, who also were unable to augment insulin secretion during glucocorticoid treatment. Thus, defective glucocorticoid augmentation of plasma leptin, probably related to beta-cell failure, may be a novel chronic complication of diabetes. Theoretically, such a defect could contribute to the obesity and insulin resistance associated with diabetes.