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Stroke is the second leading cause of death globally and the most common cause of severe disability. Several barriers need to be addressed more effectively to treat stroke, including efficient delivery of therapeutic agents, rapid release at the infarct site, precise imaging of the infarct site, and drug distribution monitoring. The present study aimed to develop a bio-responsive theranostic nanoplatform with signal-amplifying capability to deliver rapamycin (RAPA) to ischemic brain tissues and visually monitor drug distribution. A pH-sensitive theranostic RAPA-loaded nanoparticle system was designed since ischemic tissues have a low-pH microenvironment compared with normal tissues. The nanoparticles demonstrated good stability and biocompatibility and could efficiently load rapamycin, followed by its rapid release in acidic environments, thereby improving therapeutic accuracy. The nano-drug-delivery system also exhibited acid-enhanced magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging signal properties, enabling accurate multimodal imaging with minimal background noise, thus improving drug tracing and diagnostic accuracy. Finally, in vivo experiments confirmed that the nanoparticles preferentially aggregated in the ischemic hemisphere and exerted a neuroprotective effect in rats with transient middle cerebral artery occlusion (tMCAO). These pH-sensitive multifunctional theranostic nanoparticles could serve as a potential nanoplatform for drug tracing as well as the treatment and even diagnosis of acute ischemic stroke. Moreover, they could be a universal solution to achieve accurate in vivo imaging and treatment of other diseases.

Background Deterioration of sleep quality has been reported to contribute to the incidence of diabetes and may be responsible for glycemic status in diabetes. The present study explored the relationship between sleep quality and glycemic variability in patients with type 2 diabetes (T2D). Methods We recruited 111 patients with T2D for this cross-sectional study. Each patient underwent flash glucose monitoring for 14 days to obtain glycemic variability parameters, such as standard deviation of glucose (SD), coefficient of variation of glucose (CV), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), and time in glucose range of 3.9–10 mmol/L (TIR3.9–10). After 14 days of flash glucose monitoring, each patient received a questionnaire on the Pittsburgh Sleep Quality Index (PSQI) to evaluate subjective sleep quality. HbA1c was also collected to assess average glucose. Results HbA1c was comparable among the subgroups of PSQI score tertiles. Across ascending tertiles of PSQI scores, SD, CV and MAGE were increased, while TIR3.9–10 was decreased (p for trend p for trend = 0.090). Moreover, PSQI scores were positively correlated with SD, CV, MODD and MAGE (r = 0.322, 0.361, 0.308 and 0.354, respectively, p < 0.001) and were inversely correlated with TIR3.9–10 (r = − 0.386, p < 0.001). After adjusting for other relevant data by multivariate linear regression analyses, PSQI scores were independently responsible for SD (β = 0.251, t = 2.112, p = 0.041), CV (β = 0.286, t = 2.207, p = 0.033), MAGE (β = 0.323, t = 2.489, p = 0.018), and TIR3.9–10 (β = − 0.401, t = − 3.930, p < 0.001) but not for MODD (β = 0.188, t = 1.374, p = 0.177). Conclusions Increased glycemic variability assessed by flash glucose monitoring was closely associated with poor subjective sleep quality evaluated by the PSQI in patients with T2D.

Accumulating studies indicate that circadian clock genes are pivotal regulators of tumorigenesis and development of various cancers. Nevertheless, their implications in pancreatic adenocarcinoma (PAAD) remain poorly characterized. We investigated the expression pattern of circadian clock genes and evaluated their prognostic values in PAAD. Firstly, we systematically analyzed data from The Cancer Genome Atlas (TCGA) database pertaining to patient clinical information and gene expression data. We found that 19 of 20 circadian clock genes showed significantly different expression levels in comparisons between PAAD and normal tissues. In addition, 10 circadian clock genes with regression coefficients were selected to construct a new risk signature, which was then identified as an independent prognostic factor for PAAD. Mechanistically, circadian clock genes in PAAD may impact the basic state of cells and the composition of tumor-infiltrating immune cells, thus affecting disease prognosis. Finally, we construct a novel prognostic nomogram on the basis of histological nodes and risk score to precisely predict prognosis of patients with PAAD. In conclusion, our study uncovered the important role of circadian clock genes in PAAD and developed a risk signature as a promising prognostic biomarker for patients with PAAD.

Peng Ju Liu,1 Hui Ping Lou,2 Yan Ning Zhu3 1Department of Clinical Nutrition, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Medical Examination Center, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Peng Ju LiuDepartment of Clinical Nutrition, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, #1 Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel +86 10-69155550Fax +86 10-69155551Email lpjjia@126.comBackground: The hypertriglyceridemic waist phenotype (HWP) has exhibited a strong association with metabolic syndrome, a condition closely linked with nonalcoholic fatty liver disease (NAFLD). However, no study has investigated whether the HWP can accurately predict NAFLD among premenopausal and postmenopausal women or whether alternative anthropometric indexes could replace waist circumference (WC) in the HWP. We examined the power of phenotypes combining triglyceride (TG) levels with anthropometric indexes such as body mass index (BMI), WC, waist-to-hip ratio, waist-to-height ratio, and percent body fat, to detect NAFLD among premenopausal and postmenopausal women.Methods: We conducted a cross-sectional study of 1125 premenopausal women and 654 postmenopausal women who had received an annual health checkup. For all the participating women, we measured both anthropometric and biochemical indexes, such as serum lipid levels. NAFLD diagnoses were made on the basis of abdominal ultrasonography findings. The receiver operating characteristic curve and area under the curve (AUC) were used to evaluate the indicators’ ability to detect NAFLD.Results: Among the indicators of hepatic steatosis, the combined phenotypes of TG level (≥ 1.50 mmol/L) and BMI (≥ 24.0 kg/m2) exhibited the largest AUC (0.841, 95%confidence interval [CI] 0.812– 0.871, P< 0.001) for premenopausal women, whereas WC alone exhibited the highest predictive potential (0.765, 95% CI 0.729– 0.801, P< 0.001) for postmenopausal women.Conclusion: Out of all the phenotypes combining a single anthropometric index with TG level or WC and TG level, the combination of TG level and BMI was the best indicator of NAFLD for premenopausal women. For screening NAFLD in postmenopausal women, WC alone was superior to all other indicators.Keywords: nonalcoholic fatty liver disease, hepatic steatosis, anthropometric index, hypertriglyceridemic waist phenotype, menopause

Spinal cord injury (SCI) is a severe neurological disease; however, there is no effective treatment for spinal cord injury. Neuroinflammation involves the activation of resident microglia and the infiltration of macrophages is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Parthenolide (PN) has been reported to exert anti-inflammatory effects in fever, migraines, arthritis, and superficial inflammation; however, the role of PN in SCI therapeutics has not been clarified. In this study, we showed that PN could improve the functional recovery of spinal cord in mice as revealed by increased BMS scores and decreased cavity of spinal cord injury in vivo. Immunofluorescence staining experiments confirmed that PN could promote axonal regeneration, increase myelin reconstitution, reduce chondroitin sulfate formation, inhibit scar hyperplasia, suppress the activation of A1 neurotoxic reactive astrocytes and facilitate shift from M1 to M2 polarization of microglia/macrophages. To verify how PN exerts its effects on microglia/macrophages polarization, we performed the mechanism study in vitro in microglia cell line BV-2. PN could significantly reduce M1 polarization in BV2 cells and partially rescue the decrease in the expression of M2 phenotype markers of microglia/macrophage induced by LPS, but no significant effect on M2 polarization stimulated with IL-4 was observed. Further study demonstrated PN inhibited NF-κB signal pathway directly or indirectly, and suppressed activation of signal transducer and activator of transcription 1 or 3 (STAT1/3) via reducing the expression of HDAC1 and subsequently increasing the levels of STAT1/3 acetylation. Overall, our study illustrated that PN may be a promising strategy for traumatic SCI.

To observe the clinical efficacy of tuina manipulations in treating different types of tic disorders (TD). Eligible TD patients were classified into three types, transient tic disorders (TTD), chronic multiple tic disorders (CMTD) and Tourette syndrome (TS), according to their disease duration and severity. The three types of children were treated with the same tuina manipulations. Changes in the Yale global tic severity scale (YGTSS) score, effective rate for tic, and cervical spine imaging examination results (including asymmetry of the lateral atlanto-dental interval, broadened anterior atlanto-dental interval, C2 spinous process deviation, occipito-atlanto-axial flexion/extension instability) were observed after 1-month and 3-month treatments respectively. The YGTSS score changed significantly after 1-month and 3-month treatments compared with that before treatment (both P

Regorafenib has improved the survival of patients with refractory metastatic colorectal cancer (mCRC), yet the mechanisms of inherited or acquired resistance are not well understood. A total of 50 patients with refractory mCRC were enrolled. Circulating tumor cell (CTC) enumeration was carried out at baseline, day 21 after initiation of regorafenib, and at the time of progression of disease (PD) using the CellSearch System (Veridex LLC, NJ, USA). Poly(A) mRNA was extracted from CTCs, and gene expression of epithelial and epithelial‐mesenchymal transition markers was analyzed by a multiplex‐PCR based DNA Chip. Patients with fewer than 3 CTCs at baseline and day 21 had a longer progression‐free survival than those with 3 or more CTCs (3.3 vs 2.0 months, P = .008 and 3.3 vs 2.0 months, P = .004, respectively). Patients with fewer than 3 CTCs at baseline and day 21 had a longer overall survival (OS) than those with 3 or more CTCs (10.0 vs 4.6 months, P, We identified circulating tumor cell count as a prognostic marker in metastatic colorectal cancer patients treated with regorafenib. Circulating tumor cell EGFR expression was significantly increased with regorafenib at the time of disease progression, suggesting this to be a mode of resistance and lending further mechanistic evidence for the synergistic effects seen with regorafenib and anti‐EGFR mAbs.

Background: Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are important for both the integrated diagnosis and the prognosis of diffuse gliomas. The p.R132H mutation of IDH1 is the most frequently observed IDH mutation, while IDH2 mutations were relatively rarely studied. The aim of the study was to determine the pathological and genetic characteristics of lowergrade gliomas that carry IDH2 mutations. Methods: Data from 238 adult patients with lower-grade gliomas were retrospectively analyzed. The status of IDH1/2 gene mutations, telomerase reverse transcriptase (TERT) promoter mutations, O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p/19q co-deletion and the expressions of IDH1 R132H, alpha-thalassemia X-linked mental retardation, and p53 were evaluated. Progression-free survival (PFS) and overall survival (OS) were calculated via Kaplan-Meier estimation using the log-rank test. Results: Totally, 71% (169/238) of patients were positive for IDH mutations, including 12 patients harboring mutations in IDH2. Among the 12 patients with IDH2 mutations, ten patients harbored the R172K mutation, one patient harbored the R172S mutation and one harbored the R172W mutation. Of these, 11 tumors occurred in the frontal lobe and showed morphology typical of oligodendroglioma. The proportion of grade II tumors was higher than that of grade III tumors in IDH2 mutant-gliomas. IDH2 mutations were frequently associated with TERT promoter mutations, 1p/19q co-deletion and MGMT promoter methylation. IDH2 mutations were associated with better outcomes compared with IDH wild-type gliomas (P < 0.05). However, the PFS and OS did not differ from that of IDH1 mutant patients (P = 0.95 and P = 0.60, respectively). Conclusions: IDH2 mutations are more frequent in oligodendrogliomas and associated with a better prognosis. IDH2 mutations may segregate in distinct clinico-pathological and genetic subtypes of gliomas, and therefore may merit routine investigation. Key words: Isocitrate dehydrogenase 1; Isocitrate dehydrogenase 2; Telomerase reverse transcriptase; Glioma; Oligodendroglioma

Eosinophil (Eo) degranulation plays a central role in the initiations of allergic attacks. Flagellin (FGN), the major component of bacterial flagella, has immune regulatory functions. This study aims to investigate the role of FGN in alleviating the allergic reaction by stabilizing Eos. A toll-like receptor 5-knockout mouse strain was employed to test the role of FGN in stabilizing Eos. An airway allergy mouse model was developed to test the administration of FGN in alleviating the airway allergy by stabilizing Eos. The results showed that FGN was required in stabilizing Eos in the airway tissues. FGN prevented specific antigen-induced Eo activation. Oxidative stress was associated with the antigen-induced Eo activation that could be counteracted by the presence of FGN. The FGN levels were lower and chymase levels were higher in the airway tissues of mice with allergic inflammation. Negative correlation was detected between the data of FGN and chymase in the lung tissues. Chymase physically contacted FGN to speed up its degradation. The administration of FGN alleviated experimental allergic inflammation in the mouse airways by stabilized Eos in the lung tissues. In conclusion, FGN contributes to Eo stabilization. The administration of FGN alleviates the experimental airway allergy. The data suggest that FGN can be a candidate to be employed in the treatment of allergic disorders.

Background Primary cutaneous CD30+ lymphoproliferative diseases are the second most common group of cutaneous T-cell lymphomas, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL), and borderline cases. These diseases form a spectrum and may show overlapping histopathological, phenotypic, and genetic features. In the 2016 WHO classification, LyP with 6p25.3 rearrangement was introduced as a rare new subtype of LyP and showed distinctive clinicopathological features. The striking biphasic histopathologic pattern presented with larger transformed lymphocytes diffusely infiltrating the dermis and smaller atypical cells infiltrating the epidermis like pagetoid reticulosis. Methods Herein we report two cases of pcALCL with organic processes involving the DUSP22-IRF4 locus on 6p25.3 that show the same particular biphasic histopathologic pattern. We review the literature regarding five similar reported cases and discuss the clinical, pathologic immunotype and follow-up features. Results Our findings suggest that the biphasic histopathologic pattern is not a unique characteristic of LyP with 6p25.3 rearrangement. Conclusions Cutaneous CD30+ lymphoproliferative diseases with 6p25.3 rearrangement may have the same biphasic histopathological pattern and favorable prognosis, although a variety of clinical manifestations ranging from LyP to pcALCL and even anaplastic lymphoma kinase negative systemic ALCL with secondary cutaneous involvement may be observed. This article is protected by copyright. All rights reserved.

Fibrosis, which is characterized by excessive extracellular matrix (ECM) deposition, is a wound-healing response to organ injury and may promote cancer and failure in various organs, such as the heart, liver, lung, and kidney. Aging associated with oxidative stress and inflammation exacerbates cellular dysfunction, tissue failure, and body function disorders, all of which are closely related to fibrosis. Sirtuin-1 (SIRT1) is a class III histone deacetylase that regulates growth, transcription, aging, and metabolism in various organs. This protein is downregulated in organ injury and fibrosis associated with aging. Its expression and distribution change with age in different organs and play critical roles in tissue oxidative stress and inflammation. This review first described the background on fibrosis and regulatory functions of SIRT1. Second, we summarized the relationships of SIRT1 with other proteins and its protective action during fibrosis in the heart, liver, lung and kidney. Third, the activation of SIRT1 in therapies of tissue fibrosis, especially in liver fibrosis and aging-related tissue injury, was analyzed. In conclusion, SIRT1 targeting may be a new therapeutic strategy in fibrosis.

Background The core nursing outcomes for laryngeal carcinoma in China needed further screening and revision. This study aimed to evaluate and revise a questionnaire according to the “Core Nursing Outcomes for Otorhinolaryngology Head-Neck” of the Nursing Outcomes Classification (NOC, 5th Edition), and determine suitable postoperative nursing outcomes for patients with laryngeal carcinoma in China. Methods The commonly used postoperative nursing outcomes for laryngeal carcinoma were screened using a questionnaire given to 93 nurses. An initial expert consultation questionnaire was constructed to discuss the indicators for each nursing outcome. A total of 20 experts were identified using the Delphi method, and their recommendations and revisions on the selected nursing outcomes were collected. Results A total of 14 postoperative core nursing outcomes and 69 indicators were identified for postoperative patients with laryngeal carcinoma, which are subordinate to 4 domains of the NOC: “Physiologic Health”, “Psychosocial Health”, “Health Knowledge & Behavior”, and “Perceived Health”. Conclusions The screening and revision of the NOC outcomes and indicators of the Delphi method could be applied to assess the effect of nursing intervention and the quality of the nursing service in China.

BackgroundAcute pharyngitis and tonsillitis are common respiratory diseases for which children seek medical care. Their main clinical manifestation is sore throat which interferes with patients’ quality of life. However, there is no proven effective or safe method to treat it. It is necessary to find an excellent strategy to reduce sore throat and reduce the burden of acute illness. We designed the randomized controlled trial with the characteristics of traditional Chinese medicine (TCM) to determine the clinical positioning of Kai-Hou-Jian spray (children’s type) (KHJS) through evidence-based research. This trial aims to evaluate the immediate analgesic efficacy of KHJS on sore throat caused by acute pharyngitis and tonsillitis (wind-heat syndrome/heat exuberance in lung and stomach syndrome) in children and to observe its safety.Methods/designThis is a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. It will include 240 children with acute pharyngitis/tonsillitis from 7 study sites across China. All participants are randomly assigned to two parallel treatment groups, one with KHJS and the other with placebo sprays, for 5 consecutive days. The primary outcome is the time of analgesic onset. Secondary outcomes include duration of analgesic effect, area under time curve of 0–3 h Wong-Baker FACES Pain Rating Scale (WBS) score (AUC0-3 h), rate of analgesic onset, rate of disappearance of sore throat, changes of WBS score (in days), effective rate of pharyngeal signs, and effective rate of TCM syndrome. The incidence of adverse events during the trial is the primary safety outcome. In addition, vital signs and laboratory tests before and after medication are monitored.DiscussionTo our knowledge, this will be the first clinical trial to explore the immediate analgesic efficacy of a Chinese patent medicine spray for acute pharyngitis/tonsillitis induced sore throat in children in a multicenter, randomized, double-blinded, parallel-group, placebo-controlled manner. Not only might it prove the efficacy and safety of KHJS in the treatment of sore throat caused by acute pharyngitis/tonsillitis in children, but it might also provide evidence for the treatment of acute sore throat with Chinese herbal medicine.Trial registrationA multicenter, randomized, double-blind, very low-dose, parallel controlled trial for the immediate analgesic effect and safety of Kai-Hou- Jian spray (children's type) in the treatment of sore throat caused by acute pharyngitis and tonsillitis in children. Chinese Clinical Trial RegistryChiCTR2000031599. Registered on 5 April 2020

Background: Vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first approved on the 8th of December 2020. Though safe and effective, very rare side effects continue to be identified as global vaccination advances. They do not necessarily leave “a signal” in public registries if the incidence remains below previously reported total incidence levels. Optic neuritis (ON) is a rare but recognised adverse event after immunisation. The risk of post-vaccination ON and visual outcome in the context of global vaccination efforts against SARS-CoV-2 are not known. Methods: A global report on 73 deep-phenotyped individuals with post-SARS-CoV-2 vaccination ON observed in 15 of 55 countries with designated experts between 14 February to 18 July 2021. Statistical analyses were performed on type of vaccine, number of jabs, time to onset of ON, demographics, clinical features and treatment. Paraclinical data included immunological testing for autoantibodies against myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4, magnetic resonance imaging (MRI) of the brain and orbits, retinal optical coherence tomography (OCT). The primary outcome was the visual acuity (VA). Findings: The characteristics of the 69 individuals included, differed from pre-COVID whole population-based incidence studies in frequency of bilateral presentation, age distribution and radiological features more commonly found in immune-mediated ON. Most events (67%) occurred after vaccination with AstraZeneca, followed by Pfizer-BioNTech (26%) and Sinovac (7%). In 56 this was after the first and in 13 after the second jab with the same vaccine. Autoantibodies against MOG were present in 15 and not detected for aquaporin-4. The condition was steroid responsive in most (58/62), requiring plasma exchange in a few (5) with spontaneous recovery in the remainder (7). The incidence was highest in the UK (0.036 per 100,000 persons) where vaccination commenced earliest. Importantly, the pattern of presentation in time lagged about 1-5 weeks behind the pattern of national age group vaccination. The median VA at presentation was logMAR 1.0 and recovered to 0.0. Interpretation: Post-SARS-CoV-2 vaccination ON is an extremely rare adverse event with generally good outcome of visual function. The global incidence of post-vaccination ON (0.0017 per 100,000 persons) is lower than for ON (3.74 per 100,000 persons in the UK). A causal relationship is plausible, but the overall risk benefit balance is in favour of SARS-CoV-2 vaccination. Funding Information: None. Declaration of Interests: None. Ethics Approval Statement: Reporting of patients was approved by the Institutional Research Board at Moorfields Eye Hospital (study number CaRS_24).

Cetuximab, an IgG1 EGFR-directed antibody, promotes antibody-dependent cell-mediated cytotoxicity. We hypothesized that single-nucleotide polymorphisms (SNPs) in immune regulatory pathways may predict outcomes in patients with metastatic colorectal cancer treated with cetuximab-based regimens. A total of 924 patients were included: 105 received cetuximab in IMCL-0144 and cetuximab/irinotecan in GONO-ASL608LIOM01 (training cohort), 225 FOLFIRI/cetuximab in FIRE-3 (validation cohort 1), 74 oxaliplatin/cetuximab regimens in JACCRO CC-05/06 (validation cohort 2), and 520 FOLFIRI/bevacizumab in FIRE-3 and TRIBE (control cohorts). Twelve SNPs in five genes (IDO1, PD-L1, PD-1, CTLA-4, CD24) were evaluated by PCR-based direct sequencing. We analyzed associations between genotype and clinical outcomes. In the training cohort, patients with the CD24 rs52812045 A/A genotype had a significantly shorter median PFS and OS than those with the G/G genotype (PFS 1.3 vs. 3.6 months, OS 2.3 vs. 7.8 months) in univariate (PFS HR 3.62, p = 0.001, OS HR 3.27, p = 0.0004) and multivariate (PFS HR 3.18, p = 0.009, OS HR 4.93, p = 0.001) analyses. Similarly, any A allele carriers in the JACCRO validation cohort had a significantly shorter PFS than G/G carriers (9.2 vs. 11.8 months, univariate HR 1.90, p = 0.011, multivariate HR 2.12, p = 0.018). These associations were not demonstrated in the control cohorts. CD24 genetic variants may help select patients with metastatic colorectal cancer most likely to benefit from cetuximab-based therapy.

Peng Ju Liu,1 Hui Ping Lou,2 Yan Ning Zhu3 1Department of Clinical Nutrition, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Medical Examination Center, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, China Academic Medical Science and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Peng Ju Liu Tel +86-10-69155550Fax +86-10-69155551Email lpjjia@126.comBackground: It has been suggested that hypertriglyceridemic waist (HW) phenotype is strongly associated with metabolic syndrome (MetS); however, there are very limited studies integrating triglyceride (TG) and waist circumference (WC) into a continuous variable to investigate the predictive power of this phenotype. Inspired from the triglyceride glucose index (TyG), we developed an integrated continuous index termed waist-triglyceride index (WTI) which was calculated as Ln [TG (mg/dl) WC (cm)/2].Objective: We aimed to examine the potential of WTI in screening for MetS by comparing this quantitative index with the qualitative HW phenotype and other frequently used indices.Methods: A cross-sectional study was conducted in a total of 3460 non-diabetic adults who participated in an annual health checkup. MetS was defined by the update National Cholesterol Education Program/Adult Treatment Panel ш criteria for Asian Americans. Receiving operating characteristic (ROC) curve and areas under the curve (AUC) were employed to evaluate the performance of the involved indices in screening for MetS. Statistical differences among the AUC values of the indices were compared.Results: In both genders, the AUC value of WTI, TyG or HW phenotype was markedly larger than that of each anthropometric index alone. In men, there were no statistical differences in the AUC values among WTI, TyG and HW phenotype, whereas in women, the AUC value of WTI was significantly larger than that of HW phenotype [difference between area (DBA): 0.042, 95% CI: 0.0224– 0.0617, P < 0.0001] and was nominally and significantly smaller than that of TyG (DBA: 0.00646, 95% CI: 0.000903– 0.012, P = 0.0227).Conclusion: Our results suggest that there are discriminatory performance between the WTI and HW phenotype in the detection of MetS in women rather than in men. Appropriate markers for screening MetS in population study should be considered according to the genders.Keywords: metabolic syndrome, hypertriglyceridemic, waist circumference, triglyceride glucose index, hypertriglyceridemic waist phenotype

Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2H1 SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients. Patients and methods: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) (n = 230, discovery cohort) and first-line FOLFIRI plus BEV (n = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing. Results: In the FOLFOXIRI + BEV-treated cohort expressing wild-type KRAS, progression-free survival (PFS) was shorter for the RPA2 rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07&ndash, 5.03, p = 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27&ndash, 6.94, p = 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant RAS and RPA2 rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09&ndash, 0.62, p = 0.002) but no superiority of FOLFOXIRI + BEV was observed for the RAS mutant, RPA2 rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56&ndash, 1.07, p = 0.12) or the RAS wild-type, RPA2 rs7356 C/C variant subgroup. Conclusion: RPA2 SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a RAS status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV.

On 12 November 2019, one couple from the Sonid Left Qi (County) in the Inner Mongolia Autonomous Region was diagnosed with pneumonic plague in Beijing. The wife acquired the infection from her husband. Thereafter, two bubonic plague cases were identified in Inner Mongolia on November 16th and 24th. In this study, genome-wide single nucleotide polymorphism (SNP) analysis was used to identify the phylogenetic relationship of Yersinia pestis strains isolated in Inner Mongolia. Strains isolated from reservoirs in 2018 and 2019 in Inner Mongolia, together with the strain isolated from Patient C, were further clustered into 2.MED3m, and two novel lineages (2.MED3q, 2.MED3r) in the 2.MED3 population. According to the analysis of PCR-based molecular subtyping methods, such as the MLVA 14 scheme and seven SNP allele sequencing, Patients A/B and D were classified as 2.MED3m. In addition, strains from rodents living near the patients’ residences were clustered into the same lineage as patients. Such observations indicated that human plague cases originated from local reservoirs. Corresponding phylogenetic analysis also indicated that rodent plague strains in different areas in Inner Mongolia belong to different epizootics rather than being caused by spreading from the same epizootic in Meriones unguiculatus in 2019., Author summary The plague still poses a significant threat to human health, such as in Madagascar, which experienced a large pneumonic plague outbreak in 2017. The pneumonic plague always arouses great concern for its pathogenicity and propagation, especially in densely populated cities. In November 2019, one couple in the Inner Mongolia Autonomous Region suffered pneumonic plague and was transferred to Beijing. Subsequently, another two bubonic plague cases were identified in Inner Mongolia. Genome-wide SNP analysis, together with two PCR-based molecular subtying methods, was used for source-tracking purposes. Corresponding results indicated that human plague cases originated from local rodent plague epizootics. Because there were no obvious geographic barriers between the plague foci area in Inner Mongolia and its counterpart area in Mongolia, early warning and risk communication is necessary.

Background Through enhancement of the Wnt signalling pathway, R-spondins are oncogenic drivers in colorectal cancer. Experimental data suggest that the R-spondin/Wnt axis stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis. We therefore hypothesise that variations within R-spondin genes predict outcome in patients with metastatic colorectal cancer (mCRC) treated with upfront FOLFIRI and bevacizumab. Patients and methods 773 patients with mCRC enrolled in the randomised phase III FIRE-3 and TRIBE trials and receiving either FOLFIRI/bevacizumab (training and validation cohorts) or FOLFIRI/cetuximab (control group) were involved in this study. The impact of six functional single-nucleotide polymorphisms (SNPs) within the R-spondin 1-3 genes on outcome was evaluated. Results RAS and KRAS wild-type patients harbouring any G allele of the RSPO2 rs555008 SNP had a longer overall survival compared with those having a TT genotype in both the training (FIRE-3) and validation (TRIBE) cohorts (29.0 vs 23.6 months, P = 0.009 and 37.8 vs 19.4 months, P = 0.021 for RAS wild-type patients and 28.4 vs 22.3 months, P = 0.011 and 36.0 vs 23.3 months, P = 0.046 for KRAS wild-type patients). Conversely, any G allele carriers with KRAS and RAS mutant tumours exhibited a shorter progression-free survival compared with TT genotype carriers, whereas the results were clinically more evident for KRAS mutant patients in both the training and validation cohorts (8.1 vs 11.2 months, P = 0.023 and 8.7 vs 10.3 months, P = 0.009). Conclusion Genotyping of the RSPO2 rs555008 polymorphism may help to select patients who will derive the most benefit from FOLFIRI/bevacizumab dependent on (K)RAS mutational status.

Activin/myostatin signaling has a critical role not only in cachexia but also in tumor angiogenesis. Cachexia is a frequent complication among patients with advanced cancer and heavily pretreated patients. We aimed to evaluate the prognostic significance of cachexia-associated genetic variants in refractory metastatic colorectal cancer (mCRC) patients treated with regorafenib. Associations between twelve single nucleotide polymorphisms in 8 genes (INHBA, MSTN, ALK4, TGFBR1, ALK7, ACVR2B, SMAD2, FOXO3) and clinical outcome were evaluated in mCRC patients of three cohorts: a discovery cohort of 150 patients receiving regorafenib, a validation cohort of 80 patients receiving regorafenib and a control cohort of 128 receiving TAS-102. In the discovery cohort, patients with any G variant in FOXO3 rs12212067 had a significantly lower response rate (P = 0.031) and overall survival (OS) than those with a T/T in univariate analysis (4.5 vs. 7.6 months, hazard ratio [HR] = 1.63, 95% confidence interval [CI] = 1.09-2.46, P = 0.012). Among female patients, those with any G variant in INHBA rs2237432 had a significantly longer OS than those with an A/A in both univariate (7.6 vs. 4.3 months, HR = 0.57, 95%CI = 0.34-0.95, P = 0.021) and multivariable (HR = 0.53, 95%CI = 0.29-0.94, adjusted P = 0.031) analysis. This association was confirmed in female patients of the validation cohort, though without statistical significance (P = 0.059). Conversely, female patients with any G allele in the control group receiving TAS-102 did not show a longer OS. This was the first study evaluating the associations between polymorphisms in cachexia-associated genes and outcomes in refractory mCRC patients treated with regorafenib. Further studies should be conducted to confirm these associations.

Cannabinoids are reported to regulate cardiovascular functions. Cannabinoid receptors 1 (CB1Rs) are widely expressed in both the neuronal system and vascular system, but the contribution of CB1Rs in vascular smooth muscle (CB1RSM) to cardiovascular functions is not clear yet. In this research, we analyzed the effects of CB1RSM on blood pressure, vasoconstriction, and vasodilation abilities by using conditionally CB1R knockout mice (CB1RSMKO). The results show no significant difference in basal blood pressure between the conscious CB1RSMKO and control mice, indicating that CB1RSM is not essential for basal blood pressure maintenance. The constriction of the CB1RSMKO mesenteric artery in vitro was not significantly altered compared with that of the control mice. In contrast, the relaxation to CB1R agonist 2-AG or WIN55212-2 was decreased in CB1RSMKO vessels, suggesting that activation of CB1RSM mediates the vasodilation effect of cannabinoids. Ischemia stroke mouse model was used to further identify the potential function of CB1RSM in pathological conditions, and the results showed that the infarct volume in CB1RSMKO mice is significantly increased compared with the control littermates. These results suggest that vascular CB1R may not play a central role in basal vascular health maintenance but is protective in ischemia states, such as stroke. The protection function may be mediated, at least partly, by the relaxation effect of CB1RSM-dependent activities of endocannabinoids.

Regorafenib confers the benefit of longer survival in metastatic colorectal cancer patients. The CCL5/CCR5 pathway modulates endothelial progenitor cell migration and vascular endothelial growth factor A production. Genetic variants of CCL4 and CCL3 may predict outcomes, and the different frequencies of CCL5 homozygote may explain ethnic differences in the development of severe hand–foot skin reactions. BACKGROUND: The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. PATIENTS AND METHODS: We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. RESULTS: CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand–foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). CONCLUSION: Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand–foot skin reaction in mCRC patients receiving regorafenib therapy.

SUMMARY: By analysing cephalometrics before and after the treatment of Angle’s class II division 1 malocclusion, soft tissue profile changes were observed, and to explore whether there was a correlation between the change of posterior occlusal plane (OP-P) and soft tissue profile. The study aimed to provide a theoretical reference in the clinical diagnosis and orthodontic treatment of early permanent dentition of Angle class II division 1 malocclusion patients. We randomly selected 20 cases of orthodontics in Shanxi Medical University orthodontics patients (aged 12-18 years) of the lateral cephalograms, Winceph 8.0 software was used to measure the posterior occlusal plane (OP-P), TUL-EP, TLL-EP, nasolabial angle, upper lip base thickness, upper lip tension, lower lip H line distance, chin soft tissue thickness and Z angle. And SPSS 22.0 software was used to analyze the correlation between OP-P and other measurement indexes. The change of posterior occlusal plane was positively related to the distance from upper lip to the esthetic plane, the distance from lower lip to the esthetic plane, the tension of the upper lip and distance from lower lip to H line, and the change of posterior occlusal plane was negatively related to nasolabial angle and Z angle. The change of posterior occlusal plane had no significant correlation with upper lip base thickness and soft tissue chin thickness. The change of posterior occlusal plane has an important guiding significance for orthodontic treatment,by focusing on the change of the posterior occlusal plane to achieve the purpose of changing the soft tissue profile.

Through bioinformatics analysis, a novel lncRNA, LINC00460, was implicated in the development of multiple cancers. However, the precise expression pattern, clinical significance and biological function of LINC00460 in colorectal cancer (CRC) remain unknown. Network databases were used to investigate the correlation between LINC00460 and CRC. In situ hybridization was performed to verify the precise expression pattern and clinical significance of LINC00460 in a CRC tissue microarray, which included 92 pairs of CRC and adjacent normal tissues. The effect of LINC00460 on proliferation was evaluated by MTT, colony formation assays and flow cytometry employing SW620 and HCT116 cell lines. Cell migration and matrigel invasion assays were performed to investigate whether LINC00460 is involved in the metastasis of CRC. The expression of LINC00460 was significantly upregulated in CRC tissues and cells, associated with early stage CRC and low disease-free survival. The downregulated of LINC00460 expression increased cell proliferation by regulating the cell cycles of SW620 and HCT116 cells. LINC00460 knockdown did not affect cell migration or invasion in vitro. These findings suggest that LINC00460 may be an interesting target for the development of CRC.

BACKGROUND The hypermethylated in cancer 1/sirtuin 1 (HIC1/SIRT1) axis plays an important role in regulating the nucleotide excision repair pathway, which is the main oxaliplatin-induced damage-repair system. On the basis of prior evidence that the variable number of tandem repeat (VNTR) sequence located near the promoter lesion of HIC1 is associated with HIC1 gene expression, the authors tested the hypothesis that this VNTR is associated with clinical outcome in patients with metastatic colorectal cancer who receive oxaliplatin-based chemotherapy. METHODS Four independent cohorts were tested. Patients who received oxaliplatin-based chemotherapy served as the training cohort (n = 218), and those who received treatment without oxaliplatin served as the control cohort (n = 215). Two cohorts of patients who received oxaliplatin-based chemotherapy were used for validation studies (n = 176 and n = 73). The VNTR sequence near HIC1 was analyzed by polymerase chain reaction analysis and gel electrophoresis and was tested for associations with the response rate, progression-free survival, and overall survival. RESULTS In the training cohort, patients who harbored at least 5 tandem repeats (TRs) in both alleles had a significantly shorter PFS compared with those who had fewer than 4 TRs in at least 1 allele (9.5 vs 11.6 months; hazard ratio, 1.93; P = .012), and these findings remained statistically significant after multivariate analysis (hazard ratio, 2.00; 95% confidence interval, 1.13-3.54; P = .018). This preliminary association was confirmed in the validation cohort, and patients who had at least 5 TRs in both alleles had a worse PFS compared with the other cohort (7.9 vs 9.8 months; hazard ratio, 1.85; P = .044). CONCLUSIONS The current findings suggest that the VNTR sequence near HIC1 could be a predictive marker for oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Cancer 2017;123:4506-14. © 2017 American Cancer Society.

The TLR7 and TLR9 signalings are implicated in the regulation of the immune system through type-I interferon induction. Preclinical studies have demonstrated the immunomodulatory and antitumor effects of TLR7 and TLR9 agonists in combination with cetuximab. We tested the hypothesis that genetic variations in TLR7 and TLR9 and their downstream molecules IRF5 and IRF7 were associated with outcomes in metastatic colorectal cancer (mCRC) patients receiving cetuximab-based chemotherapy. Six single nucleotide polymorphisms (SNPs) in TLR7, TLR9, IRF5 and IRF7 were tested for the association with RR, PFS, and OS in KRAS-wild type mCRC patients. Patients treated with FOLFIRI + cetuximab or FOLFIRI + bevacizumab in the FIRE-3 trial served as a discovery set (FIRE3-Cet, n = 244) or a control set (FIRE3-Bev, n = 246), respectively. Patients treated with FOLFOX or SOX + cetuximab in the JACCRO-CC05/06 trial served as a validation set (JACCRO, n = 76). Genomic DNA isolated from tumor tissue samples was analyzed by PCR-based direct sequencing. In the discovery cohort, patients with the TLR7 rs3853839 G/G variant showed a trend toward longer PFS than those with any C variants (median 10.0 vs. 11.8 months, HR 1.39, p = 0.092). This preliminary association was confirmed in the validation cohort, and those with the G/G genotype showed a PFS benefit compared with others (univariate: 9.1 vs. 11.6 months, HR 2.04, p = 0.005, multivariate: HR 2.02, 95% CI: 1.14-3.55, p = 0.015). This association was not observed in the control cohort. Our findings suggest that TLR7 rs3853839 predicts the outcome of cetuximab-based chemotherapy in mCRC patients.

The Insulin-like growth factor (IGF)/IGF-receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF-1R SNPs in mCRC patients enrolled in the FIRE-3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and four SNPs of IGF1-IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct-sequencing in the FIRE-3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/- carriers (N= 105) achieved significantly worse OS compared to T/T (N = 464) in univariate (HR = 1.32 [95%CI 1.03-1.70], p = 0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/- variant (N= 280) achieved improved PFS compared to C/C (N = 257) in univariate (HR = 0.77 [95%CI 0.64-0.92], p = 0.004) and in multivariable. In the RAS wild-type subgroup IGF1 rs2946834 T/- carriers showed better PFS and OS compared to C/C (univariate HR for PFS = 0.65 [95%CI 0.51-0.81], p

Background Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102's main anti-tumor action. We tested whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102. Patients and methods We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of 52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients receiving regorafenib. Single nucleotide polymorphisms of genes involved in HR (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX, RAD51) and cell cycle checkpoint (ATR, CHEK1, CHEK2, CDKN1A, TP53, CHE1, PIN1, PCNA) were analyzed by PCR-based direct sequencing. Results In univariate analysis for the evaluation cohort, patients with any G allele in ATM rs609429 had longer overall survival (OS) than those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95% CI: 0.14-0.99, P = 0.022). Patients carrying any A allele in XRCC3 rs861539 had significantly longer progression-free survival (PFS) (3.8 vs. 2.3 months, HR 0.44, 95% CI: 0.21-0.92, P = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08-0.79, P = 0.012) than those with the G/G variant. In multivariable analysis, ATM rs609429 remained significant for OS (P = 0.020). In the validation cohort, patients having ATM rs609429 with any G allele showed longer OS and PFS; the G/A variant in XRCC3 rs861539 showed longer OS, though without statistical significance. Conclusion Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.

Background and Purpose: Acute/subacute cerebral venous thrombosis (CVT) with venous infarction often has poorer outcomes than CVT alone. Exploring biomarkers relevant to venous infarction and CVT severity would contribute to improved therapy and prognosis of CVT patients with venous infarction. It remains unclear whether blood-brain barrier(BBB) related proteins and hs-CRP play a crucial role in the pathogenesis of CVT with venous thrombosis. Methods: 59 Patients were divided into four groups: acute/subacute CVT patients with venous infarct(ASVI group, n=30), acute/subacute CVT patients without venous infarct(ASOVI group, n=13), chronic CVT group(n=9) and control subjects(n=7). Hs-CRP, claudin-5, occludin, MMP-9, GFAP and S100B were measured on admission in serum and/or cerebrospinal fluid(CSF). Initial CVT severity was assessed by the NIHSS. Results: In ASVI group, only serum claudin-5 and hs-CRP were significantly higher than ASOVI group (3.15±1.20 vs. 2.41±0.57, p=0.025; 19.13±15.22 vs. 5.65±6.19, P=0.001, respectively). AUCs for serum claudin-5 and Hs-CRP did not have significant difference (0.70,[95%CI:0.54-0.86]vs.0.795[95%CI:0.66-0.93], P=0.409). AUC for the combination of serum claudin-5 and hs-CRP was greater than that for claudin-5 alone (0.86 [95%CI: 0.75-0.97]vs.0.70[95%CI:0.54-0.86],P=0.0352). After adjustment, serum claudin-5 (adjusted OR, 17.85 [95% CI: 1.23-258.62], P=0.035) and hs-CRP (adjusted OR, 29.22, [95% CI:2.15-397.46], P=0.011) were significantly associated with venous infarction. When serum claudin-5 and hs-CRP were greater than or equal to their cut-off values (2.74 mg/l and 10.97mg/l), 100% of patients had venous infarcts. In ASVI group, hs-CRP was positively associated with NIHSS ( r =0.640; 95%CI, 0.340- 0.821; P&lt 0.001). Conclusions: For acute/subacute CVT patients, s erum claudin-5 and hs-CRP may be clinically valuable biomarkers associated with venous infarction. Hs-CRP was correlated with CVT severity. Anti-inflammation therapy may be useful in the management of severe CVT patients.

BACKGROUND: Epidermal growth factor receptor signaling blockade increases CCL5 expression that regulate either the anti-tumor immune response or tumor progression. We investigated the potential role of CCL5/CCR5 axis in cetuximab-based treatment in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC from the FIRE-3 trial: an evaluation cohort of 244 patients receiving cetuximab plus FOLFIRI; and a control cohort of 247 patients receiving bevacizumab plus FOLFIRI. Single nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analyzed by PCR-based direct sequencing. RESULTS: Patients in the evaluation cohort with any CCL5 rs2280789 G allele had shorter overall survival (OS) compared with those with the A/A variant (HR 1.56, P=0.024). Patients carrying any CCR5 rs1799988 T allele had a trend toward lower response rate than those with the C/C variant (68 vs. 81%, P=0.078). In the analysis based on primary tumor location (left-sided [L]: right-sided [R]), remarkable differences in outcomes were observed between patients with L-CCR5 SNPs C/C variant (L-C/C), L-any T, R-T/T and R-any C as follows: median OS, 38.5, 30.6, 27.1, 15.8 months, P

Early VEGF-A reduction (EVR) by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BEV). The CCL5/ CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first-line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n = 48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF-A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24–0.83, p = 0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26–0.95, p = 0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF-A levels at baseline and a greater decrease in VEGF-A levels at day 14 compared to the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first-line treatment for mCRC.

Chronic stress has been observed to increase the risk of developing depression and induce neuronal alterations of synaptic plasticity, yet the underlying molecular mechanisms remain unclear. Here, we found that the ubiquitously expressed RNA-binding protein HuR was up-regulated in the medial prefrontal cortex (mPFC) of mice following chronic stress. In adult mice, AAV-Cre-mediated knockout of HuR in the mPFC prevented anxiety-like and depression-like behaviors induced by chronic stress. HuR was also required for the stress-induced dendritic spine loss and synaptic transmission deficits. Moreover, HuRflox/flox;Nex-Cre mice, which induce HuR loss of function from embryonic development, exhibited enhanced synaptic functions. Notably, we ascertained RhoA signaling to be regulated by HuR and involved in the modulation of structural synaptic plasticity in response to chronic stress. Our results demonstrate HuR is a critical modulator for the regulation of stress-induced synaptic plasticity alterations and depression, providing a potential therapeutic target for the treatment of depressive disorders.

We report a case of bilateral symmetrical superior visual field defects in a 72-year-old man first reported during the recovery from systemic capillary leak syndrome (SCLS). During the acute illness, he required extensive and prolonged fluid replacement and mechanical ventilation for severe hypotension, shock and multiorgan dysfunction. His visual field defect and optic nerve changes were consistent with a diagnosis of ischaemic optic neuropathy. These remained unchanged over 3 years and he retained excellent 6/7.5 visual acuity bilaterally. We hypothesised the mechanism of bilateral segmental infarction of the optic nerve head to be caused by the hypercoagulable and hypovolaemic state, in addition to pre-existing vascular disease and hypertension. This case highlights the importance of including optic nerve examination in the management plan of SCLS, particularly in individuals with underlying vascular risk factors.

Using approved methods, circulating tumor cells (CTCs) are only isolated from blood in 30%–50% of metastatic colorectal cancer (mCRC) patients. We previously validated a technique to isolate circulating tumor cells (CTCs) in a cohort of mCRC patients by combining immunomagnetic enrichment of EpCAM(+)/CD45(−) cells with qRT-PCR amplification of CK20 and survivin expression. Here, we examined the prognostic utility of CTC epithelial-mesenchymal transition (EMT) and stem cell gene expression. An 8 ml blood sample was collected from 78 consecutive mCRC patients before treatment with investigational and standard chemotherapeutics. The mRNA expression of EMT (PI3Ka, Akt-2, Twist1) and stem cell (ALDH1) markers was measured. Associations between CTC gene expression and progression-free survival (PFS) and overall survival (OS) were determined using Cox regression models. Among patients without CK20 or survivin-expressing CTCs (n = 17), 55% had expression of ALDH1, PI3Ka and/or Akt-2. Patients with positive CTC Akt-2 expression had a significantly shorter median PFS (3.0 versus 4.0 months) compared with those without CTC Akt-2 expression in univariable (hazard ratio (HR) = 1.61; log-rank P =0.034) and multivariable analyses (HR= 1.70; adjusted P =0.041). In univariable analysis, CTC ALDH1 expression was associated with shorter OS (10.0 versus 38.6 months; HR = 2.04, P =0.021). Patients with CTCs expressing ALDH1, PI3Ka and/or Akt-2 had a significantly inferior PFS (3.0 versus 7.7 months; HR= 1.88, P = 0.015) and OS (10.0 versus 26.8+ months; HR = 2.25, P = 0.050) in univariable, but not multivariable, analysis. Conclusions: CTC Akt-2 expression may serve as a clinically useful prognostic marker in mCRC patients and warrants further evaluation in prospective trials.

// Martin D. Berger 1 , Dongyun Yang 2 , Yu Sunakawa 1 , Wu Zhang 1 , Yan Ning 1 , Satoshi Matsusaka 1 , Satoshi Okazaki 1 , Yuji Miyamoto 1 , Mitsukuni Suenaga 1 , Marta Schirripa 1 , Annika Medea Lenz 1 , Pierre Bohanes 1 , Afsaneh Barzi 1 , Jane C. Figueiredo 1, 2 , Diana L. Hanna 1 , Heinz-Josef Lenz 1, 2 1 Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 2 Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Correspondence to: Heinz-Josef Lenz, email: lenz@usc.edu Keywords: age, ethnicity/race, sex, rectal cancer, survival Received: May 14, 2016 Accepted: July 01, 2016 Published: July 19, 2016 ABSTRACT Most studies report on colon and rectal cancers collectively, even though biologic and prognostic differences exist between these disease entities. Here, we investigated the effects of sex, age, and ethnicity/race on rectal cancer (RC) mortality by stage focusing on differences before and after 2004. Using the SEER database, we identified 105,511 patients diagnosed with RC from 1988-2012. Main outcomes were disease-specific survival (DSS) and overall survival (OS). In patients with stage I-III RC, women achieved a longer DSS (HR 0.87, P < 0.001) than men, independent of age, from 1988-2012. In stage IV disease, the sex disparity favoring women was limited to the age 18-44 yr cohort (DSS HR 0.79, P < 0.001). The sex difference in DSS ( P interaction = 0.009) was significantly reduced from 2004 to 2012 across all ages. Hispanics and Native Americans with locoregional RC had inferior DSS relative to Whites from 1988-2003, but these differences were not evident from 2004-2012 ( P interaction = 0.001). Additionally, Asians with stage I-III RC had superior DSS from 2004 on compared to Whites. Mortality in African American patients improved modestly overall and remained significantly higher than other ethnicities/races across all stages. Sex disparities have narrowed in patients with metastatic RC, but persist in patients with stage I-III disease. These differences are most evident among young patients (18-44 years), where sex disparities have even widened in stage I-III disease. While outcomes have improved for Asians, Hispanics, and Native Americans with stage I-III rectal cancer, black-white disparities remain in all disease stages.

The epithelial–mesenchymal transition (EMT) is an important mechanism of resistance to angiogenesis inhibition. The ability of EMT pathway genetic variants to predict the efficacy of antiangiogenic therapy is unknown. We analyzed associations between functional SNPs in EMT-related genes and outcomes in metastatic colorectal cancer (mCRC) patients undergoing first-line bevacizumab-based chemotherapy. A total of 220 mCRC patients were included in this study: 143 patients treated with first-line bevacizumab-based chemotherapy (bevacizumab cohort) and 77 patients treated with cetuximab-based chemotherapy (cetuximab cohort). SNPs in TWIST1 (rs2285682, rs2285681), ZEB1 (rs10826943, rs2839658), SNAIL (rs1543442, rs4647958), and E-cadherin (rs16260) genes were analyzed by PCR-based direct sequencing. Patients carrying a TWIST1 rs2285682 G allele had a significantly longer median progression-free survival (PFS) of 18.1 months and overall survival (OS) of 44.1 months compared with those with the T/T genotype, who had a median PFS of 13.3 months (HR, 0.57; P = 0.003) and OS of 29.2 months (HR, 0.53; P = 0.001) in the bevacizumab cohort. In multivariate analysis, associations between TWIST1 rs2285682 and PFS and OS remained significant. Among women, the G allele of TWIST1 rs2285682 (PFS HR, 0.39; P = 0.007; OS HR, 0.30; P = 0.001) and TWIST1 rs2285681 (PFS HR, 0.27; P < 0.001; OS HR, 0.25; P < 0.001) was associated with improved survival. No significant associations were found in the cetuximab cohort. Our findings suggest that TWIST1 polymorphisms are associated with survival in mCRC patients treated with first-line bevacizumab-based chemotherapy and may serve as clinically useful biomarkers for antiangiogenic therapy. Mol Cancer Ther; 15(6); 1405–11. ©2016 AACR.

Objective— Increased plasma concentrations of angiotensin II (Ang II) have been implicated in many cardiovascular diseases, such as atherosclerosis, aortic aneurysms, and myocardial infarction, in humans. However, it is not known whether high levels of plasma Ang II affect coronary plaque stability and subsequent myocardial infarction. This study was designed to examine whether elevated plasma Ang II can directly induce coronary events, such as acute coronary syndrome. Approach and Results— To examine the above hypothesis, we infused Ang II (100 ng/min per kg [low group] and 200 ng/min per kg [high group]) or saline vehicle via osmotic minipumps into Watanabe heritable hyperlipidemic rabbits, a model of human familial hypercholesterolemia and atherosclerosis. Infusion of Ang II resulted in mortality rates of 50% and 92% in the low- and high-Ang II groups, respectively, whereas there were no deaths in the vehicle group. Pathological analysis revealed that Ang II–infused Watanabe heritable hyperlipidemic rabbits that died showed myocardial infarction. Furthermore, Ang II–infused Watanabe heritable hyperlipidemic rabbits exhibited coronary plaque erosion and rupture that were associated with thrombosis. Conclusions— These findings suggest that increased blood levels of Ang II can destabilize coronary plaques and trigger the thrombosis, which possibly induces myocardial infarction. The model described in this study provides a novel means for the study of human acute coronary syndrome.

Optical coherence tomography angiography (OCTA) is a non-invasive retinal imaging innovation that has been gaining popularity for the evaluation of the retinal vasculature. Of clinical importance is its current use either as an alternative or in conjunction with conventional dye-based angiography in neovascular age-related macular degeneration. OCTA is not without limitations and these include image artefact, a relatively small field of view and failure of the segmentation algorithms, which can confound the interpretation of findings. While there are numerous publications on OCTA in neovascular AMD, few have examined the diagnostic accuracy of this new technology compared with the accepted gold standard of fundus fluorescein angiography (FFA). In this review, we summarise the literature on the clinical application of OCTA in nAMD. In particular, we have reviewed the published articles that have reported the sensitivity and specificity of OCTA in the diagnosis of nAMD, and those that have described and or correlated the morphological findings and compared them to dye-based angiography.摘要: 光学相干断层扫描血管造影 (OCTA) 是一种无创、新型的视网膜成像技术, 在视网膜血管性疾病的评估方面应用得越来越广泛。其临床重要性在于, 目前可替代作为新生血管性年龄相关性黄斑变性 (nAMD) 常规检查的血管造影或与常规血管造影相补充。 OCTA 也有其局限性, 如图像伪影、观察范围有限以及分割算法的失误, 由此可能会影响对结果解释的准确性。目前有大量关于OCTA在nAMD诊断中应用的文献报道, 但很少有人将这种新技术与公认的金标准眼底荧光血管造影 (FFA) 在诊断的准确性方面进行对比。在这篇综述中, 我们总结了 OCTA 在 nAMD 诊疗中的临床应用, 特别是总结了OCTA 在 nAMD 诊断中的敏感性和特异性以及形态学改变与常规 FFA 发现的相关性。.

Ovarian cancer is the leading malignancy of the female reproductive system and is associated with inconspicuous early invasion and metastasis. We have previously reported that the oncogene OTUB1 plays a crucial role in ovarian cancer progression, but the role of its isoform, the non‐coding RNA OTUB1‐isoform2, in ovarian cancer is still elusive. Here, we reported that OTUB1‐isoform2 expression in ovarian cancer tissues was significantly higher than that in the paired paratumorous tissues (P

A recent genome-wide association study identified seven single-nucleotide polymorphisms (SNPs) in region 16q24, near the Forkhead box-F1 (FOXF1) gene, which confer susceptibility to esophageal adenocarcinoma. We examined whether these SNPs are associated with clinical outcomes in gastric cancer (GC) patients in Japan and the United States. A total of 362 patients were included in this study: 151 Japanese GC patients treated with first-line S1 plus CDDP (training cohort) and 211 GC patients from Los Angeles County (LAC; validation cohort). Genomic DNA was isolated from whole blood or tumor tissue and analyzed by PCR-based direct DNA sequencing. Cox proportional hazard regression analyses were used to assess relationships between FOXF1 SNPs and progression-free survival (PFS) and overall survival (OS). FOXF1 rs3950627 was significantly associated with survival in both the training and validation cohorts. Japanese patients with the C/C genotype had a longer PFS (median 8.2 vs 5.3 months, hazard ratio (HR) 1.44, P=0.037) and OS (median 16.4 vs 12.2 months, HR 1.44, P=0.043) compared to patients with any A allele. Similarly, LAC patients with the C/C genotype had improved OS (3.9 vs 2.3 years, HR 1.5, P=0.022). Subgroup analyses showed these associations were specific to male patients and primary tumor subsite. Our findings suggest that FOXF1 rs3950627 might be a promising prognostic marker in GC patients.The Pharmacogenomics Journal advance online publication, 11 April 2017; doi:10.1038/tpj.2017.9.

BACKGROUND No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-β receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study. MATERIALS AND METHODS Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal χ approach was used to determine the messenger RNA levels associated with progression-free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database. RESULTS High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages. CONCLUSION ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.

Estrogen has been shown not only to reduce the incidence of colorectal cancer but also gastric cancer (GC). Polymorphisms in estrogen receptor β gene, ESR2, correlate with colorectal cancer survival. To better understand the role of ESR2 in GC, genomic DNA extracted from 169 Japanese patients and 172 patients from Los Angeles County (LAC) was analyzed for association of overall survival (OS) with three ESR2 polymorphisms, which are of biological significance using multivariable Cox proportional hazard regression. ESR2 rs1271572 (C > A) and rs3020443 (T > G) had univariate and multivariable associations with OS in the Japanese cohort, whereas the C allele of ESR2 rs2978381 (T > C) predicted favorable OS in the Japanese cohort but worse OS in the LAC cohort. The interaction term of the ESR2 rs2978381 and cohort group reached statistical significance. Our study provides evidence that genetic variations in ESR2 gene are significantly associated with survival in patients with locally advanced GC.

Background Tumor dormancy has been described as a state of hibernation. Dormancy can be switched to proliferation by different pathways, which may play a critical role in tumor recurrence. In this study, we investigated genetic variations within genes involved in tumor dormancy and their association with recurrence and outcome in patients with colorectal liver metastases (CLM) who underwent neoadjuvant bevacizumab-based chemotherapy. Patients and methods Genomic DNA was extracted from resected CLM (FFPE) from 149 patients. Single-nucleotide polymorphisms (SNPs) in 14 genes associated with dormancy were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS), overall survival (OS) and recurrence patterns. Results NME1 rs34214448 C>A was significantly associated with RFS in univariable analysis (P = 0.039) and with intrahepatic recurrence (P = 0.014). NOTCH3 rs1044009 T>C and CD44 rs8193 C>T showed a significant difference in 3-year OS rates (P = 0.004 and P = 0.042, respectively). With respect to radiological response, CD44 rs8193 C>T variant genotypes were associated with a significantly higher response rate (P = 0.033). Recursive partitioning analyses revealed that Dll4 rs12441495 C>G, NME1 rs34214448 C>A and NOTCH3 rs1044009 T>C were the dominant SNPs predicting histological response, RFS and OS, respectively. Conclusion Our data suggest that gene variations within genes involved in tumor dormancy pathways are associated with response and outcome in patients with resected CLM. These data may lead to new and more effective treatment strategies targeting tumor dormancy.

Study objective To evaluate the effects of epinephrine (1:200,000) in the epidural space on the incidence of blood vessel injury by epidural catheter insertion for cesarean section. Design Prospective observational study. Setting University-affiliated teaching hospital. Patients Four hundred laboring women with singleton cephalic presentations at term who underwent cesarean section and requested continuous epidural analgesia. Interventions Predistension of 5 mL of isotonic sodium chloride solution containing epinephrine (1:200,000) or 5 mL of isotonic sodium chloride solution through an epidural needle before catheter insertion. Measurements Cases with bloody fluid in the epidural needle or catheter during catheter insertion, aspiration of frank blood from the epidural catheter, and blood noted in the caudal end of the epidural catheter upon removal were recorded. Main results Eight parturients were excluded from the analysis for technical reasons. There were no significant differences between patients in the 2 groups with respect to cases with bloody fluid in the epidural needle during catheter insertion (7.6% vs 9.8%, P = .44), the epidural catheter during catheter placement (6.0% vs 6.7%, P = .80), aspiration of frank blood in the epidural catheter (1.0% vs 1.0 %, P = .98), and blood noted in the caudal end of the epidural catheter upon removal (27.3% vs 30.4 %; P > .49). Conclusion Twenty-five micrograms of epinephrine (1:200,000) in the epidural space does not reduce the incidence of blood vessel injury induced by insertion of an epidural catheter.

Background: The difference between renal oncocytomas (RO) and renal clear cell carcinomas (RCCs) presents the greatest diagnostic challenge. The aim of this study was to retrospectively determine if RO and RCCs could be differentiated on computed tomography (CT) images on the basis of their enhancement patterns with a new enhancement correcting method. Methods: Forty-six patients with a solitary renal mass who underwent total or partial nephrectomy were included in this study. Fourteen of those were RO and 32 were RCCs. All patients were examined with contrast-enhanced CT. The pattern and degree of enhancement were evaluated. We selected the area that demonstrated the greatest degree of enhancement of the renal lesion in the corticomedullary nephrographic and excretory phase images. Regions of interest (ROI) were also placed in adjacent normal renal cortex for normalization. We used the values of the normal renal cortex that were measured at the same time as divisors. The ratios of lesion-to-renal cortex enhancement were calculated for all three phases. The Student′s t-test and Pearson′s Chi-square test were used for statistical analyses. Results: All RCCs masses showed contrast that appeared to be better enhanced than RO on all contrast-enhanced phases of CT imaging, but there was no significant difference in absolute attenuation values between these two diseases (P > 0.05). The ratio of lesion-to-cortex attenuation in the corticomedullary phase showed significantly different values between RO and RCCs. The degree of contrast enhancement in RCCs was equal to or greater than that of the normal renal cortex, but it was less than that of the normal cortex in RO in the corticomedullary phase. The ratio of lesion-to-cortex attenuation in the corticomedullary phase was higher than the cut off value of 1.0 in most RCCs (84%, 27/32) and lower than 1.0 in most RO (93%, 13/14) (P < 0.05). In the nephrographic phase, the ratio of lesion-to-cortex attenuation was higher than that in the corticomedullary phase in most RO (71%, 10/14), showing a prolonged enhancement pattern; and was lower than that in most RCCs (97%, 31/32), showing an early washout pattern (P < 0.05). In the differentiation of RO from RCCs, the sensitivity was 93%, specificity 84%, positive predictive value 72%, negative predictive value 84%, and accuracy for RO was 87, if the ratio of lesion-to-cortex attenuation in a cortex phase was lower than the cutoff value of 1.0. The sensitivity was 71%, specificity was 97%, positive predictive value was 91%, negative predictive value was 91%, and accuracy for RO was 89%, if the ratio of lesion-to-cortex attenuation in nephrographic phase was higher than that in the corticomedullary phase. Conclusions: The ratios of renal lesion-to-cortex attenuation ratios may be helpful in differentiating RO from RCCs.

Obesity is an established risk factor for colorectal cancer (CRC) incidence and it is also linked to CRC recurrence and survival. Polymorphisms located in obesity-related genes are associated with an increased risk of developing several cancer types including CRC. We evaluated whether single-nucleotide polymorphisms in obesity-related genes may predict tumor recurrence in colon cancer patients.Genotypes were obtained from germline DNA from 207 patients with stage II or III colon cancer at the Norris Comprehensive Cancer Center. Nine polymorphisms in eight obesity-related genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA, and DSCR1) were evaluated. The primary endpoint of the study was the 3-year recurrence rate. Positive associations were also tested in an independent Japanese cohort of 350 stage III CRC patients.In univariate analysis, for PPARrs1801282, patients with a CC genotype had significantly lower recurrence probability (29 ± 4% SE) compared with patients with a CG genotype (48 ± 8% SE) [hazard ratio (HR): 1.77; 95% confidence interval (CI), 1.01-3.10; P = 0.040]. For DSCR1rs6517239, patients with an AA genotype had higher recurrence probability than patients carrying at least one allele G (37 ± 4% SE vs. 15 ± 6% SE) (HR: 0.51; 95% CI, 0.27-0.94; P = 0.027). This association was stronger in the patients bearing a left-sided tumor (HR: 0.34; 95% CI, 0.13-0.88; P = 0.018). In the Japanese cohort, no associations were found.This hypothesis-generating study suggests a potential influence of polymorphisms within obesity-related genes in the recurrence probability of colon cancer. These interesting results should be evaluated further.

Integrins (ITGs) are key elements in cancer biology, regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Moving from the hypothesis that ITGs could have different effects in stage II and III colon cancer, we tested whether a comprehensive panel of germline single-nucleotide polymorphisms (SNPs) in ITG genes could predict stage-specific time to tumor recurrence (TTR). A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole-blood samples were analyzed for germline SNPs in ITG genes using PCR-restriction fragment length polymorphism or direct DNA sequencing. In the multivariable analysis, stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (hazard ratio (HR)=4.027, 95% confidence interval (95% CI) 1.556-10.421, P=0.004). This association was also significant in the combined stage II-III cohort (HR=1.975, 95% CI 1.194-3.269, P=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases the combined analysis of ITGB1 rs2298141 and ITGA4 rs7562325 allowed to identify three distinct prognostic subgroups (P=0.009). The interaction between stage and the combined ITGB1 rs2298141 and ITGA4 rs7562325 on TTR was significant (P=0.025). This study identifies germline polymorphisms in ITG genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data may help to select subgroups of patients who may benefit from ITG-targeted treatments.