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Traumatic peri-contusional penumbra represents crucial targets for therapeutic interventions after traumatic brain injury (TBI). Current resuscitative approaches may not adequately alleviate impaired cerebral microcirculation and, hence, compromise oxygen delivery to peri-contusional areas. Low-frequency oscillations in cerebral blood flow (CBF) may improve cerebral oxygenation in the setting of oxygen deprivation. However, no method has been reported to induce controllable oscillations in CBF and it hasn’t been applied as a therapeutic strategy. Electrical stimulation of the trigeminal nerve (TNS) plays a pivotal role in modulating cerebrovascular tone and cerebral perfusion. We hypothesized that TNS can modulate CBF at the targeted frequency band via the trigemino-cerebrovascular network, and TNS-induced CBF oscillations would improve cerebral oxygenation in peri-contusional areas. In a rat model of TBI complicated by hemorrhagic shock, TNS-induced CBF oscillations conferred significant preservation of peri-contusional tissues leading to reduced lesion volume, attenuated hypoxic injury and neuroinflammation, increased eNOS expression, improved neurological recovery and better 10-day survival rate, despite not significantly increasing CBF as compared with those in immediate and delayed resuscitation animals. Our findings indicate that low-frequency CBF oscillations enhance cerebral oxygenation in peri-contusional areas, and play a more significant protective role than improvements in non-oscillatory cerebral perfusion or volume expansion alone.

BACKGROUND Burn injury still has a high attributable mortality. The elevated mortality rate of severe burns is still concerning. Hepatic inflammation and injury are common after burns and are associated with poor outcomes. Necroptosis is a programmed cell death linked with inflammation. Thus, assessing necroptotic pathways in the liver can lead to new therapeutic modalities to improve mortality after severe burns. METHODS Mice underwent 15% total body surface area burn or sham injury. Three hours after burn, the mice were euthanized to collect blood and livers. Histology, injury markers, genes expression, and tissue protein levels were compared between groups. RESULTS Compared with sham, burned mice had heightened liver inflammatory cell infiltration and edema. Serum aspartate aminotransferase and alanine aminotransferase were increased by 4.9- and 3.4-fold, respectively, in burned mice relative to sham (p < 0.05). Expression of tumor necrosis factor α, interleukin-6, interleukin-1β, and CXCL1 (KC) genes were elevated in livers of burned mice by 10-, 86-, 10-, and 828-fold, respectively, compared with sham (p < 0.05). Expression of necroptotic genes, namely, receptor-interacting protein kinases 1 and 3, and mixed lineage kinase domain-like in livers of burned mice were increased by 10-, 13-, and 4.5-fold, respectively, relative to sham (p < 0.05). Receptor-interacting protein kinase 1 and phosphorylated mixed lineage kinase domain-like protein levels measured by Western-blot in livers after burn injury were elevated by 22- and 17-fold, respectively, compared with sham (p < 0.05). CONCLUSION Liver damage occurs early after burns in mice and is associated with elevation of proinflammatory cytokines, chemokine, and proteins involved in the necroptotic pathway. This study suggests that necroptosis plays a role in the pathogenesis of liver failure secondary to burn injury.

Background The relationship between clinical responses in pediatric infradiaphragmatic craniopharyngioma (Q-CP) and inflammatory response is still unclear. The objective of this study was to investigate the clinical significance of tumor inflammatory response in pediatric Q-CPs. Methods The inflammatory response was evaluated by measuring the number of inflammatory cells in the tumor near adenohypophysis junction. The specimens were classified as mild, moderate, or severe based on the number of inflammatory cells. In addition, the levels of pro-inflammatory cytokines and chemokines in the specimens were measured using a cytokine antibody array. Clinical outcomes were analyzed and compared to the markers of inflammatory response. Results IL-6 and IL-8 were highly expressed in pediatric Q-CPs, and the transcription level of IL-6 was the highest in the severe group. Most patients (87.3%) had hypopituitarism; the severe inflammation group had an increased incidence of hypopituitarism, which correlated with significantly lower probability of recurrence-free survival and worsened functional status. Conclusions Inflammatory response is common in craniopharyngiomas and is closely related to their biological behavior and the patients' clinical prognosis. Further studies of the relationship between craniopharyngiomas and the inflammatory response will enable the discovery of potential therapeutic targets, which will reduce morbidity and result in better outcomes for pediatric Q-CP patients. Impact Pediatric infradiaphragmatic craniopharyngiomas are histologically benign brain tumors that often follow an aggressive clinical course.The inflammatory response in craniopharyngioma is common, which is closely related to the biological behavior and clinical prognosis.Several inflammatory and immune markers have been identified in CP; inflammation is an important role in the pathogenesis of hypopituitarism.The aim was to study the relationship between craniopharyngioma and inflammatory response and find potential therapeutic targets can reduce morbidity and result in better outcomes.

Background Hemorrhagic shock (HS) caused by rapid loss of a large amount of blood is the leading cause of early death after severe injury. When cells are damaged during HS, many intracellular components including DNA are released into the circulation and function as endogenous damage-associated molecular patterns (DAMPs) that can trigger excessive inflammatory response and subsequently multiple organ dysfunction. We hypothesized that the administration of deoxyribonuclease I (DNase I) could reduce cell-free DNA and attenuate tissue damage in HS. Methods Eight-week-old male C57BL/6 mice underwent HS by controlled bleeding from the femoral artery for 90 min, followed by resuscitation with Ringer's lactate solution (vehicle) or DNase I (10 mg/kg BW). Results At 20 h after HS, serum levels of cell-free DNA were increased by 7.6-fold in the vehicle-treated HS mice compared with sham, while DNase I reduced its levels by 47% compared with the vehicle group. Serum levels of tissue injury markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase) and proinflammatory cytokine interleukin 6 were significantly reduced in the DNase I–treated mice. In the lungs, messenger RNA levels of proinflammatory cytokines (interleukin 6 and interleukin 1 β), chemoattractant macrophage inflammatory protein - 2, and myeloperoxidase activity were significantly decreased in HS mice after DNase I. Finally, DNase I significantly improved the 10-day survival rate in HS mice. Conclusions Administration of DNase I attenuates tissue damage and systemic and lung inflammation, leading to improvement of survival in HS mice. Thus, DNase I may potentially serve as an adjunct therapy for managing patients with HS.

Background The New Delhi metallo-β-lactamase-1 (NDM-1)-positive plasmid and its variants pose daunting threats to public health. Hospital sewage was considered as an important reservoir of antibiotic genes. Numerous and diverse taxa of multidrug-resistant (MDR) bacteria carrying NDM-1-positive plasmids have been identified during routine surveillance of hospital sewage. We herein report a carbapenem-resistant Acinetobacter towneri strain AeBJ009 with an NDM-1-positive plasmid isolated from hospital sewage. Materials and Methods Bacteria were isolated from cultures of hospital sewage and identified by using the Vitek 2 compact system and 16S rRNA sequencing. The blaNDM-1 gene was amplified and confirmed by sequencing. Antimicrobial susceptibility testing was performed using AST-GN14 on the Vitek2 compact system. In addition, the blaNDM-1 gene was located by Southern blotting. Conjugation experiment and whole-genome sequencing were performed for further analysis. Results Strain AeBJ009 was isolated from hospital sewage and identified as A. towneri. Antimicrobial susceptibility testing revealed an MDR phenotype. Pulsed-field gel electrophoresis and Southern blotting showed that strain AeBJ009 carries three plasmids and that blaNDM-1 is located on the 47kb plasmid pNDM-AeBJ009. However, the conjugation experiment to transfer pNDM-AeBJ009 to Escherichia coli strain J53 was unsuccessful. Whole-genome sequencing found that pNDM-AeBJ009 contains a Tn125 element carrying blaNDM-1 . The ble gene downstream of blaNDM-1 displayed a single-nucleotide polymorphism compared to its homologue on plasmid pM131_NDM1. BLAST analysis using the Comprehensive Antibiotic Resistance Database identified no gene polymorphisms with 100% identity to our ble variant. Conclusion The A. towneri strain AeBJ009 exhibiting an extended spectrum of antibiotic resistance was isolated from hospital sewage and may potentially exacerbate the risk of MDR bacterial infections. The prevention of nosocomial infections due to drug-resistant bacteria will require enhanced monitoring and control of MDR pathogens in environmental reservoirs.

INTRODUCTION: Neonatal sepsis remains a leading cause of infant mortality. Cold-inducible RNA binding protein (CIRP) is an inflammatory mediator that induces TNF-α production in macrophages. C23 is a CIRP-derived peptide that blocks CIRP from binding its receptor. We therefore hypothesized that treatment with C23 reduces systemic inflammation and protects the lungs in neonatal sepsis. METHODS: Sepsis was induced in C56BL/6 mouse pups (5–7 days) by intraperitoneal injection of adult cecal slurry (0.525 mg/g body weight, LD(100)). One hour later pups received retro-orbital injection of C23 (8 mg/kg) or vehicle (normal saline). Ten hours after sepsis induction, blood and tissues were collected for analysis. RESULTS: C23 treatment resulted in a 58% and 69% reduction in serum levels of proinflammatory cytokines IL-6 and IL-1β, respectively, and a 40% and 45% reduction of AST and LDH, as compared to vehicle-treated septic pups. In the lungs, C23 treatment reduced expression of cytokines IL-6 and IL-1β by 78% and 74%. In addition, the mRNA level of neutrophil chemoattractants KC and MIP-2 were reduced by 84% and 74%, respectively. These results corresponded to a reduction in histologic lung injury score. Vehicle-treated pups scored 0.49 ± 19, while C23 treatment reduced scores to 0.29 ± 0.12 (p

Normal tissue injury from accidental or therapeutic exposure to high-dose radiation can cause severe acute and delayed toxicities, which result in mortality and chronic morbidity. Exposure to single high-dose radiation leads to a multi-organ failure, known as acute radiation syndrome, which is caused by radiation-induced oxidative stress and DNA damage to tissue stem cells. The radiation exposure results in acute cell loss, cell cycle arrest, senescence, and early damage to bone marrow and intestine with high mortality from sepsis. There is an urgent need for developing medical countermeasures against radiation injury for normal tissue toxicity. In this review, we discuss the potential of applying secretory extracellular vesicles derived from mesenchymal stromal/stem cells, endothelial cells, and macrophages for promoting repair and regeneration of organs after radiation injury.

There are limited data regarding the safety and efficacy of cold snare polypectomy (CSP) for large colorectal polyps. We evaluated factors affecting the clinical outcomes of CSP for polyps between 5 and 15 mm in size.This was a prospective single-center observational study involving 1000 patients undergoing colonoscopy. Polyps (5-15 mm) were removed using CSP, and biopsies were taken from the resection margin. The primary outcome was the incomplete resection rate (IRR), and was determined by the presence of residual neoplasia on biopsy. Correlations between IRR and polyp size, morphology, histology, and resection time were assessed by generalized estimating equation model.A total of 440 neoplastic polyps were removed from 261 patients. The overall IRR was 2.27%, 1.98% for small (5-9 mm) vs 3.45% for large (10-15 mm) polyps (P = .411). In univariate analysis, the IRR was more likely to be related to sessile serrated lesions (odds ratio [OR], 6.93; 95% confidence interval [CI], 1.88-25.45; P = .004), piecemeal resection (OR, 11.83; 95% CI, 1.20-116.49; P = .034), and prolonged resection time60 seconds (OR, 7.56; 95% CI, 1.75-32.69; P = .007). In multivariable regression analysis, sessile serrated lesions (OR, 6.45; 95% CI, 1.48-28.03; P = .013) and resection time (OR, 7.39; 95% CI, 1.48-36.96; P = .015, respectively) were independent risk factors for IRR. Immediate bleeding was more frequent with resection of large polyps (6.90% vs 1.42%; P = .003). No recurrence was seen on follow-up colonoscopy in 37 cases with large polyps.CSP is safe and effective for removal of colorectal polyps up to 15 mm in size, with a low IRR. (ClinicalTrials.gov; Number: NCT03647176).

Background Cold-inducible RNA-binding protein is a novel damage-associated molecular pattern that causes inflammation. C23, a short peptide derived from cold-inducible RNA-binding protein, has been found to have efficacy in blocking cold-inducible RNA-binding protein's activity. We hypothesized that C23 reduces inflammation and tissue injury induced by intestinal ischemia-reperfusion. Methods Male C57BL/6 mice were subjected to 60 minutes of intestinal ischemia by clamping the superior mesenteric artery. Immediately after reperfusion, either normal saline (vehicle) or C23 peptide (8 mg/kg body weight) was injected intraperitoneally. Four hours after reperfusion, blood, intestinal, and lung tissues were collected for analysis of inflammatory and tissue injury parameters. Results Cold-inducible RNA-binding protein levels in the intestinal tissues were significantly increased following intestinal ischemia-reperfusion. Histologic examination of the intestine revealed a significant reduction in injury score in the C23 group by 48% as compared with the vehicles after intestinal ischemia-reperfusion. The serum levels of lactate dehydrogenase and aspartate aminotransferase were increased in animals that underwent vehicle-treated intestinal ischemia-reperfusion, whereas C23-treated animals exhibited significant reductions by 48% and 53%, respectively. The serum and intestinal tissue levels of tumor necrosis factor α were elevated in vehicle-treated intestinal ischemia-reperfusion mice but decreased by 72% and 69%, respectively, in C23-treated mice. Interleukin-6 mRNA levels in the lungs were reduced by 86% in the C23-treated group in comparison to the vehicle-treated group after intestinal ischemia-reperfusion. Expression of macrophage inflammatory protein 2 and level of myeloperoxidase activity in the lungs were dramatically increased after intestinal ischemia-reperfusion and significantly reduced by 91% and 25%, respectively, in the C23-treated group. Conclusion C23 has potential to be developed into a possible therapy for reperfusion injury after mesenteric ischemia and reperfusion.

Objectives Histological discrepancies between biopsy and resection specimens are common. In this study, we aimed to analyze the risk factors predicting histological upgrade or downgrade of biopsy-diagnosed gastric low-grade dysplasia (LGD). Methods The medical records of patients with 104 biopsy-diagnosed gastric LGD from January 2011 to December 2017 were collected. The association of endoscopic characteristics with histological discrepancies between the biopsy and resection specimens was analyzed. The risk factors for histological upgrade were studied using the multivariate analysis. Results Among the 104 lesions, 88 were removed by endoscopic resection and 16 were monitored. The upgrade and downgrade rates of the pathological diagnosis were 48.9% and 12.5%, respectively. Lesion size >20 mm, surface redness and positive results in magnifying endoscopy with narrow band imaging (ME-NBI) were risk factors for histological upgrade. Compared with the negative ME-NBI group, the positive ME-NBI group had a higher upgrade rate (56.8% vs 7.1%) but a lower downgrade rate (2.7% vs 64.3%). In addition, 11 of the 16 the gastric LGD with negative ME-NBI findings were monitored, and all 11 lesions regressed to gastritis during follow-up. Conclusions Endoscopic resection should be recommended in cases of LGD showing surface redness, with a lesion size of >20 mm or positive ME-NBI result, whereas regular follow-up may be an option for LGD with negative ME-NBI result.

Background Endoscopic resection has been used for high-grade intraepithelial neoplasia (HGIN) and superficial esophageal squamous cell carcinoma (ESCC) with limited risk of lymph node metastasis. However, some of these lesions cannot be accurately diagnosed based on forceps biopsy prior to treatment. In this study we aimed to investigate how to solve this histological discrepancy and avoid over- and under-treatment. Methods The medical records of patients with superficial esophageal squamous cell neoplasia who underwent endoscopic resection at our hospital from January 2012 to December 2019 were reviewed retrospectively. The histological discrepancy between the biopsy and resected specimens was calculated and its association with clinicopathological parameters was analyzed. Results A total of 137 lesions from 129 patients were included. The discrepancy rate between forceps biopsy and resected specimens was 45.3% (62/137). Histological discrepancy was associated with the histological category of the biopsy (p p = 0.002) and type B intrapapillary capillary loops (p p = 0.001), location (p = 0.018), and pink color sign (p = 0.002). Conclusions Histological discrepancy between forceps biopsy and resected specimens is common in clinical practice. Recognizing the risk factors for each histological category of biopsy may reduce these discrepancies and improve clinical management.

Osteoporosis (OP) is a highly prevalent orthopedic condition in postmenopausal women and the elderly. Currently, OP treatments mainly include bisphosphonates, receptor activator of nuclear factor kappa-B ligand (RANKL) antibody therapy, selective estrogen receptor modulators, teriparatide (PTH1-34), and menopausal hormone therapy. However, increasing evidence has indicated these treatments may exert serious side effects. In recent years, Traditional Chinese Medicine (TCM) has become popular for treating orthopedic disorders. Erxian Decoction (EXD) is widely used for the clinical treatment of OP, but its underlying molecular mechanisms are unclear thanks to its multiple components and multiple target features. In this research, we designed a network pharmacology method, which used a novel node importance calculation model to identify critical response networks (CRNs) and effective proteins. Based on these proteins, a target coverage contribution (TCC) model was designed to infer a core active component group (CACG). This approach decoded the mechanisms underpinning EXD’s role in OP therapy. Our data indicated that the drug response network mediated by the CACG effectively retained information of the component-target (C-T) network of pathogenic genes. Functional pathway enrichment analysis showed that EXD exerted therapeutic effects toward OP by targeting PI3K-Akt signaling (hsa04151), calcium signaling (hsa04020), apoptosis (hsa04210), estrogen signaling (hsa04915), and osteoclast differentiation (hsa04380) via JNK, AKT, and ERK. Our method furnishes a feasible methodological strategy for formula optimization and mechanism analysis and also supplies a reference scheme for the secondary development of the TCM formula.

Background: Most gastric cancer (GC) patients are diagnosed at an advanced stage, which indicates their poor prognosis. We aimed to investigate novel fecal microbial markers for clinical application in the screening and early diagnosis of gastric cancer (GC). Methods: This is an observational study from three cohorts. In discovery cohort, 16S rRNA gene analysis was performed in paired samples (gastric tissues, feces) from GC and CG patients to determine differential microbes. The relative abundances of the differential microbes were detected using qPCR in training cohort. The diagnostic efficacy of fecal marker Sa/Sc was validated in validation cohort. Findings: 575 gastric cancer (GC) patients, 468 chronic gastritis (CG) patients were enrolled from ten hospitals in China. Significant enrichments of Streptococcus anginosus (Sa) and Streptococcus constellatus (Sc) in both cancerous tissues (P < 0·05) and feces ( P < 0·0001) were observed in patients with intraepithelial neoplasia, early and advanced GC. Either the marker parallel test Sa ∪ Sc or single marker Sa/Sc demonstrated superior sensitivity (Sa: 75·6% vs. 72·1%, P

Background: Platinum-based regimens have been routinely used in the clinical treatment of patients with esophageal squamous cell carcinoma (ESCC). However, administration of these drugs is frequently accompanied by drug resistance. Revealing the underlying mechanisms of the drug resistance and developing agents that enhance the sensitivity to platinum may provide new therapeutic strategies for the patients. Methods: Immunohistochemistry, western blotting, RT-PCR, flow cytometry and immunofluorescence microscopy were used to detect the expression of Shh pathway members and cancer stem cell(CSC) biomarkers in ESCC specimens and cell lines. Functional assays, including MTT, tumorsphere formation assay, RTCA and an in vivo tumour growth assay, were conducted to assess the effect of Dihydroartemisinin (DHA) on the proliferation and renewal ability of ESCC cells. HPLC was used to examine the concention of cisplatin in ESCC cells.Results: We found that the poor outcome of ESCC patients receiving platinum-based regimens was associated with co-expression of Shh and Sox2. The sensitivity of ESCC cell lines to cisplatin was related to their activity of Shh signaling. Manipulating of Shh expression markedly changed the sensitivity of ESCC cells to platinum. Continuous treatment with cisplatin resulted in the activation of Shh signaling and enhanced cancer stem cell-like phenotypes in ESCC cells. DHA, a classic antimalarial drug, was identified as a novel inhibitor of Shh pathway. Treatment with DHA attenuated the cisplatin-induced activation of the Shh pathway in ESCC cells and synergized the inhibitory effect of cisplatin on proliferation, sphere and colony formation of ALDH-positive ESCC cells in vitro and growth of ESCC cell-derived xenograft tumors in vivo. Conclusion: These results demonstrate that the Shh pathway is an important player in cisplatin-resistant ESCC and DHA acts as a promising therapeutic agent to sensitize ESCC to cisplatin treatment.

Thrombocytopenia remains a challenge in myeloid malignancies, needing safer and more effective therapies. JNJ-26366821, a pegylated synthetic peptide thrombopoietin (TPO) mimetic not homologous to endogenous TPO, has an in-vitro EC50 of 0.2 ng/mL for the TPO receptor and dose dependently elevates platelets in volunteers. We demonstrate that JNJ-26366821 increases megakaryocytic differentiation and megakaryocytic colony formation in healthy controls and samples from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). JNJ-26366821 had no effect on proliferation of malignant myeloid cell lines at doses up to 1000 ng/mL and malignant patient-derived mononuclear cells showed no increased cell growth or leukemic colony formation capacity at concentrations between 0.2 ng/mL and 10 ng/mL. Furthermore, JNJ-26366821 did not enhance in-vivo engraftment of leukemic cells in an AML xenotransplantation murine model. Our results show that JNJ-26366821 stimulates megakaryopoiesis without causing proliferation of the malignant myeloid clones in MDS/AML and provides the rationale for clinical testing of JNJ-26366821 in myeloid malignancies.

The discrete Tchebichef transform (DTT) is a transform method based on discrete orthogonal Tchebichef polynomials, which have applications found in image processing and pattern recognition. This paper first introduces the positive and inverse transform of DTT, so that readers can have a certain understanding of the mathematical background of DTT. Then it introduces and summarizes the application and research advance of DTT. Finally, some ideas about the prospect of DTT application are put forward. This paper is a comprehensive summary of the existing development of DTT and can be used as a reference for DTT research.

Rapid and accurate etiologic diagnosis accelerates targeted antimicrobial therapy. Metagenomic analysis has played a critical role in pathogen identification. In this study, we leveraged the advantages of both the MinION and BGISEQ-500 platforms to make a bacteriologic diagnosis from a culture-negative lung tissue sample from an immunocompromised patient with severe pneumonia. Real-time nanopore sequencing rapidly identified Klebsiella pneumoniae by an 823 bp specific sequence within 1 min. Genomic analysis further identified bla SHV-12, bla KPC-2, bla TEM-1, bla CTX-M-65, and other resistance genes. The same sample was further sequenced on the BGISEQ-500 platform, which presented consistent results regarding the most top dominant pathogens and provided additional information of resistance genes. Revised antibiotic treatment was followed by the patient's clinical recovery. Though sample preparation and the interpretation of final results still need to be improved further, metagenomic sequencing contributes to the accurate diagnosis of culture-negative infections and facilitates the rational antibiotic therapy.

Introduction Sepsis is the third leading cause of morbidity and mortality in neonates. Sepsis in neonates is characterized as the systemic inflammation owing to infection within the first 28days after birth. The molecular mechanism causing the exaggerated inflammation phenotype in neonates has not been completely elucidated. Receptor interacting protein kinase 3 (RIPK3) is a protein identified as a mediator in programmed necrosis or necroptosis. We hypothesize that RIPK3 could be responsible for the inflammatory response in neonates and that deficiency in the RIPK3 protein attenuates inflammation and organ injury in neonatal sepsis. Methods Male and female C57BL6 wild-type (WT) and RIPK3 knock-out (KO) newborn mice aged 5–7days (3–4g body weight) were injected intraperitoneally with 0.9mg/g cecal slurry (CS). At 10h after injection, the newborns were euthanized and blood, the lungs and gut tissues were collected. Results At 10h after CS injection, serum cytokines IL-6 and IL-1β in the WT mice were increased by 511- and 43-fold whereas in KO mice, these levels were increased by 166-fold and 22-fold, respectively. Lung IL-1β in the WT mice increased by 7-fold after CS injection whereas only a 4-fold increase was seen in the KO mice. In the lungs of CS injected KO mice, the injury score, MIP-2 mRNA, myeloperoxidase (MPO) activity and TUNEL staining were significantly reduced by 76%, 70%, 26% and 74%, respectively compared to the CS WT mice. Gut TUNEL staining was also reduced by 80%. Conclusion The deficiency in RIPK3 attenuated serum and lung cytokines, lung injury and neutrophil infiltration and lung and gut apoptosis. These data suggest that RIPK3, in part, is responsible for the systemic inflammatory response in neonatal sepsis.

Background/Aims: Colonoscopy screening has been accepted broadly to evaluate the risk and incidence of colorectal cancer (CRC) during health examination in outpatients. However, the intrusiveness, complexity and discomfort of colonoscopy may limit its application and the compliance of patients. Thus, more reliable and convenient diagnostic methods are necessary for CRC screening. Genome instability, especially copy-number variation (CNV), is a hallmark of cancer and has been proved to have potential in clinical application. Methods: We determined the diagnostic potential of chromosomal CNV at the arm level by whole-genome sequencing of CRC plasma samples (n = 32) and healthy controls (n = 38). Arm level CNV was determined and the consistence of arm-level CNV between plasma and tissue was further analyzed. Two methods including regular z score and trained Support Vector Machine (SVM) classifier were applied for detection of colorectal cancer. Results: In plasma samples of CRC patients, the most frequent deletions were detected on chromosomes 6, 8p, 14q and 1p, and the most frequent amplifications occurred on chromosome 19, 5, 2, 9p and 20p. These arm-level alterations detected in plasma were also observed in tumor tissues. We showed that the specificity of regular z score analysis for the detection of colorectal cancer was 86.8% (33/38), whereas its sensitivity was only 56.3% (18/32). Applying a trained SVM classifier (n = 40 in trained group) as the standard to detect colorectal cancer relevance ratio in the test samples (n = 30), a sensitivity of 91.7% (11/12) and a specificity 88.9% (16/18) were finally reached. Furthermore, all five early CRC patients in stages I and II were successfully detected. Conclusion: Trained SVM classifier based on arm-level CNVs can be used as a promising method to screen early-stage CRC.

Finite element model can estimate bone strength better than BMD. This study used such a model to determine its association with hip fracture risk and found that the strength estimate provided limited improvement over the hip BMDs in predicting femoral neck (FN) fracture risk only. Bone fractures occur only when it is loaded beyond its ultimate strength. The goal of this study was to determine the association of femoral strength, as estimated by finite element (FE) analysis of DXA scans, with incident hip fracture as a single condition or with femoral neck (FN) and trochanter (TR) fractures separately in older men. This prospective case-cohort study included 91 FN and 64 TR fracture cases and a random sample of 500 men (14 had a hip fracture) from the Osteoporotic Fractures in Men study during a mean ± SD follow-up of 7.7 ± 2.2 years. We analysed the baseline DXA scans of the hip using a validated plane-stress, linear-elastic FE model of the proximal femur and estimated the femoral strength during a sideways fall. The estimated strength was significantly (P

Wire twisting is the commonest method of median sternotomy closure. However, wire twisting weakens the wire and fracture may occur at the base of the twisted portion. We investigated how wire twisting affects the physical characteristics of sternotomy closure since rigid fixation promotes quicker primary bone healing. The maximum strength and rigidity of wire closure were tested in a steel sternal model, with varying number of twists, ranging from none to ten twists. Pearson correlation coefficient was used to investigate the relationship between the number of twists versus the maximum closure strength and rigidity. Regression analysis was used to relate closure rigidity with test load and number of wire twists. Maximum rigidity occurred at two-twists, and decreased from three to ten-twists. Pearson correlation coefficient showed a strong relationship between the number of twists versus maximum closure strength (r = 0.833, p = 0.003) and rigidity (r = 0.819, p = 0.004). The regression model identified load (p

Background Intestinal ischemia-reperfusion can occur in shock and mesenteric occlusive diseases, causing significant morbidity and mortality. Aside from local injury, intestinal ischemia-reperfusion can result in remote organ damage, particularly in the lungs. Cold-inducible RNA-binding protein (CIRP) was identified as a novel inflammatory mediator. We hypothesized that a deficiency in CIRP would protect the lungs during intestinal ischemia-reperfusion injury. Methods Intestinal ischemia was induced in adult male C57BL/6 wild-type and CIRP knock-out (CIRP−/−) mice via clamping of the superior mesenteric artery for 60 minutes. Reperfusion was allowed for 4 hours or 20 hours, and blood, gut, and lung tissues were harvested for various analyses. Results After intestinal ischemia-reperfusion, the elevated levels of serum lactate dehydrogenase and inflammatory cytokine interleukin-6 were reduced by 68% and 98%, respectively, at 20 hours after ischemia-reperfusion in CIRP−/− mice compared with the wild-type mice. In the gut, mRNA levels of inflammatory cytokine interleukin-6 were reduced by 67% at 4 hours after ischemia-reperfusion in CIRP−/− mice. In the lungs, inflammatory cytokine interleukin-6 protein and myeloperoxidase activity were reduced by 78% and 26% at 20 hours and 4 hours after ischemia-reperfusion, respectively, in CIRP−/− mice. Finally, the elevated lung caspase-3 was significantly decreased by 55%, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells decreased by 91%, and lung injury score decreased by 37% in CIRP−/− mice at 20 hours after ischemia-reperfusion. Conclusion Increased levels of proinflammatory cytokines, myeloperoxidase, and apoptosis are the hallmarks of acute respiratory distress syndrome. We noticed after intestinal ischemia-reperfusion the proinflammatory milieu in lungs was elevated significantly, while the CIRP−/− mice had significantly decreased levels of proinflammatory cytokine, myeloperoxidase, and apoptotic cells leading to decreased lung injury. These findings strongly established a causal link between CIRP and acute respiratory distress syndrome during intestinal ischemia-reperfusion injuries. Targeting CIRP may therefore be beneficial for treatment of intestinal ischemia-reperfusion-associated acute respiratory distress syndrome acute respiratory distress syndrome.

Full light photo-Fenton and photo-thermal effect are of great importance but deserve attentions far insufficient in advanced oxidation progresses for extensive environmental remediation. Herein, ultraviolet-visible-near infrared (UV–vis-NIR) light absorbance and photo-thermal conversion were induced into H2O2 activation towards refractory antibiotics elimination from wastewater through green recyclable rGO-ZnFe2O4 developed via ultrasonic method. Interestingly, photo-thermal synergy presents much superior performance than that of solely photo-Fenton or thermal-Fenton process. Multiple light reflection inner ZnFe2O4 microsphere strengthens UV–vis capture and thermal conversion in degradation reaction. Orbital hybridization and electron rearrangement endow rGO-ZnFe2O4 wide NIR absorbency, fast thermal transfer and photo-generated electrons-holes separation for photo-thermal Fenton progress. Degradation rate of ciprofloxacin on rGO-ZnFe2O4 is found 3 times of ZnFe2O4 under full light exposure which can heat solution from room temperature to 70 °C, while 4 times under NIR irradiation where solution is heated to 46 °C. The great differences are mainly originated from photo-induced thermal energy, which in-situ heating active sites to lower H2O2 activation barrier, accelerate Fe2+/Fe3+ cycle and facilitate spread of radicals. Radicals contribute in OH > h+ > O2 − under full light irradiation, while perform in h+ > O2 − > OH when taking away photo-generated heat. Results based on systematic experiments and theory calculation imply the strong potential of photo-thermal Fenton in pollutants control, which proposes novel strategy in Fenton reaction for environmental remediation with effective utilization of solar energy.

Background and Aim Multiple colorectal polyps are relevant in hereditary colorectal cancer (CRC) syndromes, which are thought to be caused by multiple events including germline mutations. This study was aimed to characterize germline mutations in Chinese patients with multiple colorectal polyps. Methods Patients with > 10 colorectal polyps at the Department of Gastroenterology of the PLA Army General Hospital were enrolled from January 2014 to December 2015. These patients were divided into the high-risk, moderate-risk, and mild-risk groups. White blood cell samples were collected, and DNA was extracted to sequence a panel of 19 genes previously associated with CRC by next-generation sequencing. Results A total of 96 patients were enrolled in the study. Pathogenic germline mutations were found in 24 (24/33, 72.73%), nine (9/24, 37.5%), and three patients (3/39, 7.7%) in the high-risk, moderate-risk, and mild-risk groups, respectively. Based on the results given, we suggested a strategy about gene sequencing test for the patients with multiple polyps, and the sensitivity and specificity of the screening strategy were 97% and 57%, respectively. Four of eight patients with MUTYH pathogenic germline mutations had the c.A934-2G monoallelic germline mutation, whereas three of eight patients had the C55T MUTYH germline mutation. Concurrent pathogenic germline mutations in APC and MUTYH were also observed. Conclusions A genetic screening strategy comprising 19 genes was effective to screen for hereditary CRC syndromes in patients with multiple colorectal polyps. The MUTYH germline mutation hotspots in Chinese patients may be different from those in Caucasian patients.

Background Sepsis remains one of the leading causes of infant death worldwide. It is characterized by uncontrolled inflammatory responses due to proven bacterial infection. Despite improvement in supportive care and the availability of effective antibiotics, no specific therapy targeting the dysregulated inflammatory response is available for neonatal sepsis. Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a secretory glycoprotein abundantly present in human milk. MFG-E8 suppresses the systemic inflammatory responses in adult murine injury models by improving the clearance of dying cells. We hypothesized that exogenous administration of recombinant mouse MFG-E8 could inhibit the exaggerated inflammatory response and lung injury in a murine model of neonatal sepsis. Methods Neonatal sepsis was induced in 5- to 7-day-old male and female C57BL6 mice using an intraperitoneal injection of cecal slurry. At 1 hour after sepsis induction, a single dose of 40 μg/kg recombinant mouse MFG-E8 or vehicle was administered via retro-orbital injection. All neonates were returned to their mothers as a group. At 10 hours after cecal slurry injection, pups were killed and blood and lung tissues were collected. Control mice underwent a similar procedure with the exception of cecal slurry intraperitoneal injection. Results Serum lactate dehydrogenase, IL-1β, and IL-6 were significantly increased 10 hours after cecal slurry injection. Treatment with recombinant mouse MFG-E8 decreased these levels by 30%, 56%, and 37%, respectively. Lung morphology was significantly compromised in the vehicle group after cecal slurry injection, whereas the recombinant mouse MFG-E8–treated groups demonstrated a 48% improvement in the lung injury score. Lung IL-6 and MIP-2 protein levels were significantly reduced with recombinant mouse MFG-E8 treatment. Lung neutrophil infiltration as observed by Gr-1 staining and, TUNEL-positive cells were also significantly reduced with recombinant mouse MFG-E8 treatment. Conclusion Treatment with recombinant mouse MFG-E8 attenuated inflammation and lung injury in murine neonatal sepsis. Thus, MFG-E8 could be developed as a possible therapy for neonatal sepsis.

The Wnt/β-catenin pathway has been involved in regulating inflammation in various infectious and inflammatory diseases. Sepsis is a life-threatening condition caused by dysregulated inflammatory response to infection with no effective therapy available. Recently elevated Wnt/β-catenin signaling has been detected in sepsis. However, its contribution to sepsis-associated inflammatory response remains to be explored. In this study, we show that inhibition of Wnt/β-catenin signaling reduces inflammation and mitigates sepsis-induced organ injury. Using in vitro LPS-stimulated RAW264.7 macrophages, we demonstrate that a small-molecule inhibitor of β-catenin responsive transcription, iCRT3, significantly reduces the LPS-induced Wnt/β-catenin activity and also inhibits TNF-α production and IκB degradation in a dose-dependent manner. Intraperitoneal administration of iCRT3 to C57BL/6 mice, subjected to cecal ligation and puncture-induced sepsis, decreases the plasma levels of proinflammatory cytokines and organ injury markers in a dose-dependent manner. The histological integrity of the lungs is improved with iCRT3 treatment, along with reduced lung collagen deposition and apoptosis. In addition, iCRT3 treatment also decreases the expression of the cytokines, neutrophil chemoattractants, as well as the MPO activity in the lungs of septic mice. Based on these findings we conclude that targeting the Wnt/β-Catenin pathway may provide a potential therapeutic approach for treatment of sepsis.

Acute kidney injury (AKI) is most commonly caused by sepsis in critically ill patients, and it is associated with high morbidity and mortality. The pathophysiology of sepsis-induced AKI is generally accepted to include direct inflammatory injury, endothelial cell dysfunction, and apoptosis. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein with a known role in the enhancement of apoptotic cell clearance and regulation of inflammation. We hypothesize that administration of recombinant mouse MFG-E8 (rmMFG-E8) can protect mice from kidney injuries caused by sepsis.Sepsis was induced in 8-wk-old male C57BL/6 mice by cecal ligation and puncture (CLP). rmMFG-E8 or phosphate-buffered saline (vehicle) was injected intravenously at a dosage of 20 μg/kg body weight at time of CLP (n = 5-8 mice per group). After 20 h, serum and renal tissue were harvested for various analyses. The renal injury markers blood urea nitrogen (BUN) and creatinine were determined by enzymatic and chemical reactions, respectively. The gene expression analysis was carried out by real-time quantitative polymerase chain reaction.At 20 h after CLP, serum levels of BUN and creatinine were both significantly increased in the vehicle group compared with the sham group, whereas the mice treated with rmMFG-E8 had a significant reduction in BUN and creatinine levels by 28% and 24.1%, respectively (BUN: 197.7 ± 23.6 versus 142.3 ± 20.7 mg/dL; creatinine: 0.83 ± 0.12 versus 0.63 ± 0.06 mg/dL; P 0.05). Expressions of novel biomarkers of renal tissue injury neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 were also significantly downregulated by 58.2% and 95%, respectively, after treatment with rmMFG-E8. Proinflammatory cytokine interleukin-6 and tumor necrosis factor-α messenger RNA (mRNA) were significantly reduced by 50.8% and 50.3%, respectively, in rmMFG-E8-treated mice compared with vehicle-treated mice. The mRNA levels of the chemokines keratinocyte chemoattractant and macrophage inhibitory protein-2 were reduced by 85.1% and 78%, respectively, in mice treated with rmMFG-E8 compared with the vehicle mice. In addition, the expression of intercellular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) mRNA was downregulated by 35.6% and 77.8%, respectively, in rmMFG-E8-treated mice compared with the vehicle animals (P 0.05).Treatment with rmMFG-E8 reduces renal tissue injury induced by sepsis through inhibiting the production of proinflammatory cytokines and chemokine, as well as through the activation of endothelial cells. Thus, MFG-E8 may have a therapeutic potential for treating AKI induced by sepsis.

Finite element models of an isolated vertebral body cannot accurately predict compressive strength of the spinal column because, in life, compressive load is variably distributed across the vertebral body and neural arch. The purpose of this study was to develop and validate a patient-specific finite element model of a functional spinal unit, and then use the model to predict vertebral strength from medical images. A total of 16 cadaveric functional spinal units were scanned and then tested mechanically in bending and compression to generate a vertebral wedge fracture. Before testing, an image processing and finite element analysis framework (SpineVox-Pro), developed previously in MATLAB using ANSYS APDL, was used to generate a subject-specific finite element model with eight-node hexahedral elements. Transversely isotropic linear-elastic material properties were assigned to vertebrae, and simple homogeneous linear-elastic properties were assigned to the intervertebral disc. Forward bending loading conditions were applied to simulate manual handling. Results showed that vertebral strengths measured by experiment were positively correlated with strengths predicted by the functional spinal unit finite element model with von Mises or Drucker-Prager failure criteria ( R

The brown planthopper (BPH), Nilaparvata lugens (Stål), is a migratory and destructive sucking insect pest of rice. Silicon (Si) amendment to plants can confer enhanced resistance to herbivores and is emerging as a novel approach for pest management. In the present study, we tested the effects of Si addition at 0.16 (low) and 0.32 (high) g Si/kg soil on sucking behaviors and population growth in BPH. Si amendment increased Si content in rice stems and extended non-probing event and phloem puncture followed by sustained phloem ingestion over that in the no-Si-addition control. High Si addition rate prolonged the stylet pathway and the time needed to reach the first phloem puncture, shortened durations of phloem puncture and phloem ingestion, and decreased the proportion of individuals that produced sustained phloem ingestion. BPH female feeding on and preference for plants with the high Si addition rate were also reduced. As a result, Si application significantly decreased BPH population growth rates while increased population doubling time. These results indicate that Si amendment, especially at the high rate, confers enhanced rice plant resistance to BPH through impairment of BPH feeding. Our results highlight the potential of Si amendment as an alternative for BPH management.

Renal ischemia-reperfusion (RIR) injury is a common occurrence after major surgery and shock, leading to acute kidney injury (AKI). Osteopontin (OPN) is a secreted glycoprotein that acts as a proinflammatory cytokine and activator of T lymphocytes. We hypothesized that blockade of OPN reduces the severity of inflammation and injury in RIR. Renal ischemia was induced in adult C57BL/6 mice via bilateral clamping of renal pedicles for 35 min, followed by reperfusion for 24 h. Anti-OPN antibody (Ab), nonimmunized isotype immunoglobulin G, or normal saline was injected intravenously at the time of reperfusion. Blood and kidneys were collected for analysis. At 24 h after RIR, OPN mRNA and protein levels were significantly increased in renal tissue compared with sham mice. In serum, elevated levels of blood urea nitrogen and creatinine were reduced in anti-OPN Ab-treated mice compared with vehicle. Anti-OPN Ab-treated mice also had decreased mRNA levels of injury markers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 compared with the vehicle. The histologic architecture and apoptosis of renal tissue were improved in the anti-OPN Ab-treated mice. In renal tissue, inflammatory cytokines interleukin 6 and tumor necrosis factor-α protein levels were reduced in the Ab-treated mice. Natural killer (NK) cell infiltration was decreased after anti-OPN Ab treatment, as was neutrophil infiltration, shown by reduced chemokine expression and Gr1 renal immunohistochemical staining. These findings demonstrate a beneficial role of OPN blockade in RIR associated with NK cell-mediated downregulation of inflammatory cytokines and chemokines. Administration of anti-OPN Ab may therefore serve as an immunomodulatory adjunct in the treatment of RIR-induced AKI.

Hemorrhagic shock (HS) is a life-threatening condition resulting from rapid and significant loss of intravascular volume, leading to hemodynamic instability and death. Inflammation contributes to the multiple organ injury in HS. Type I interferons (IFNs), such as IFN-α and IFN-β, are a family of cytokines that regulate the inflammatory response through binding to IFN-α receptor (IFNAR) which consists of IFNAR1 and IFNAR2 chains. We hypothesized that type I IFNs provoke inflammation and worsen organ injury in HS.Male C57BL/6 mice (20-25 g) underwent hemorrhage by controlled bleeding via the femoral artery to maintain a mean arterial pressure of 27 ± 2.5 mm Hg for 90 minutes, followed by resuscitation for 30 minutes with two times shed blood volume of Ringer's lactate solution containing 1 mg/kg body weight of anti-IFNAR1 antibody (Ab) or control isotype-matched IgG (IgG). Blood and tissue samples were collected at 20 hours after the resuscitation for various analyses.The expression of IFN-α and IFN-β mRNAs was significantly elevated in lungs and liver of the mice after HS. The IFNAR1-Ab treatment significantly decreased serum levels of organ injury markers lactate dehydrogenase and aspartate aminotransferase, as well as improved the integrity of lung and liver morphology, compared to the IgG control. The protein levels of proinflammatory cytokines TNF-α and IL-6, and mRNA expression of proinflammatory chemokines monocyte chemoattractant protein (MCP)-1, MCP-2, macrophage inflammatory protein 2 (MIP-2), and keratinocyte cytokine (KC) in the lungs of the HS mice were significantly decreased after treated with IFNAR1-Ab. Moreover, the myeloperoxidase activity and number of apoptotic cells in the lungs of HS mice treated with IFNAR1-Ab were decreased in comparison to the IgG control.Administration of IFNAR1-Ab reduces inflammation and tissue injury. Thus, type I IFN signaling may be a potential therapeutic target for mitigating organ dysfunction in patients suffering from HS.Translational animal model.

OBJECTIVES To determine if trigeminal nerve stimulation can ameliorate the consequences of acute blood loss and improve survival after severe hemorrhagic shock. DESIGN Animal study. SETTING University research laboratory. SUBJECTS Male Sprague-Dawley rats. INTERVENTIONS Severe hemorrhagic shock was induced in rats by withdrawing blood until the mean arterial blood pressure reached 27 ± 1 mm Hg for the first 5 minutes and then maintained at 27 ± 2 mm Hg for 30 minutes. The rats were randomly assigned to either control, vehicle, or trigeminal nerve stimulation treatment groups. The effects of trigeminal nerve stimulation on survival rate, autonomic nervous system activity, hemodynamics, brain perfusion, catecholamine release, and systemic inflammation after severe hemorrhagic shock in the absence of fluid resuscitation were analyzed. MEASUREMENTS AND MAIN RESULTS Trigeminal nerve stimulation significantly increased the short-term survival of rats following severe hemorrhagic shock in the absence of fluid resuscitation. The survival rate at 60 minutes was 90% in trigeminal nerve stimulation treatment group whereas 0% in control group (p < 0.001). Trigeminal nerve stimulation elicited strong synergistic coactivation of the sympathetic and parasympathetic nervous system as measured by heart rate variability. Without volume expansion with fluid resuscitation, trigeminal nerve stimulation significantly attenuated sympathetic hyperactivity paralleled by increase in parasympathetic tone, delayed hemodynamic decompensation, and improved brain perfusion following severe hemorrhagic shock. Furthermore, trigeminal nerve stimulation generated sympathetically mediated low-frequency oscillatory patterns of systemic blood pressure associated with an increased tolerance to central hypovolemia and increased levels of circulating norepinephrine levels. Trigeminal nerve stimulation also decreased systemic inflammation compared with the vehicle. CONCLUSIONS Trigeminal nerve stimulation was explored as a novel resuscitation strategy in an animal model of hemorrhagic shock. The results of this study showed that the stimulation of trigeminal nerve modulates both sympathetic and parasympathetic nervous system activity to activate an endogenous pressor response, improve cerebral perfusion, and decrease inflammation, thereby improving survival.

BACKGROUND AND AIM Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. Patients with FAP are screened for germline mutations of two genes, APC and MUTYH. However, limited data exist on the clinical characterization and genotypic spectrum of FAP in China. This study was aimed to determine APC and MUTYH mutational status in a small cohort of FAP probands in China and to characterize the genotype-phenotype correlation in mutated patients. METHODS Mutation screening of 46 unrelated probands was performed using multigene panels by next-generation sequencing. Clinical data of the index were used to assess genotype-phenotype correlations. RESULTS Overall, 42 out of 46 (91.30%) unrelated probands found mutations, including 35 (76.09%) with APC mutations, 3 (6.52%) with MUTYH mutations, and 4 (8.70%) with both APC and MUTYH mutations. Ten APC genetic alterations variants were novel. The hereditary pattern of the family with both APC and MUTYH mutations was autosomal dominant inheritance. Upper gastrointestinal polyp was the most common extracolonic manifestations. The onset time for patients with both APC and MUTYH mutations was earlier than MUTYH mutation carriers and similar to APC mutation carriers. But the age of carcinogenesis for patients with both APC and MUTYH mutations was later than APC mutation carriers and similar to MUTYH mutation carriers. CONCLUSION In this study, we show the importance of using multigene panels that allow for a parallel comprehensive screening. We suggest that genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analyses simultaneously.

Background Renal ischemia-reperfusion injury, commonly caused by major operation and shock, leads to acute kidney injury and is associated with high morbidity and mortality. Cold-inducible ribonucleic acid-binding protein, a cold shock protein, has recently been identified as a damage-associated molecular pattern. We hypothesized that cold-inducible ribonucleic acid-binding protein exacerbates severity of injury in renal ischemia-reperfusion. Methods Renal ischemia was induced in an 8-week-old male C57BL/6 wild-type mice and Cirp−/− mice via bilateral clamping of renal pedicles for 30 minutes, followed by reperfusion for 5 or 24 hours and harvest of blood and renal tissue for analysis. Anti–cold-inducible ribonucleic acid-binding protein antibody or non-immunized immunoglobulin G (IgG) was injected intravenously (10 mg/kg body weight) at time of reperfusion. Results After renal ischemia-reperfusion, Cirp−/− mice demonstrated a reduction of blood urea nitrogen and creatinine of 53% and 60%, respectively, compared with wild-type mice. Serum IL-6 levels were reduced significantly: 70% in Cirp−/− mice compared with wild-type mice after renal ischemia-reperfusion. Levels of nitrotyrosine, an oxidatively modified protein marker, and cyclooxygenase-2, an inflammatory mediator, also were significantly decreased in the kidneys of the Cirp−/− mice compared with wild-type mice after renal ischemia-reperfusion. Renal caspase-3 activity was decreased in Cirp−/− mice compared with wild-type mice after renal ischemia-reperfusion, which corresponded to the reduction of apoptotic cells determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Injection of neutralizing anti-cold-inducible ribonucleic acid-binding protein antibody into wild-type mice led to an 82% reduction in blood urea nitrogen compared with the vehicle after renal ischemia-reperfusion. Conclusion Deficiency of cold-inducible ribonucleic acid-binding protein results in less renal injury after renal ischemia-reperfusion by attenuating inflammation and oxidative stress. Furthermore, blockade of cold-inducible ribonucleic acid-binding protein shows a protective effect, indicating cold-inducible ribonucleic acid-binding protein as a target in the treatment of renal ischemia-reperfusion.

Runt-related transcription factor 2 (RUNX2) is a regulator of embryogenesis and development, but has also been implicated in the progression of certain human cancer. This study aimed to elucidate the role of RUNX2 in the invasive and metastatic potentials of human gastric cancer (GC) and the underlying mechanisms. We found that the levels of RUNX2 expression in gastric cancer tissues were correlated with the differentiation degrees, invasion depth and lymph node metastasis. COX regression analysis indicated that RUNX2 was an independent prognostic indicator for GC patients. RUNX2 significantly increased the migration and invasion ability of GC cells in vitro and enhanced the invasion and metastatic potential of GC cells in an orthotopic GC model of nude mice. Mechanistically, RUNX2 directly bound to the promoter region of the gene coding for the chemokine receptor CXCR4 to enhance its transcription. CXCR4 knockdown or treatment with AMD3100, a CXCR4 inhibitor, attenuated RUNX2-promoted invasion and metastasis. These results demonstrate that RUNX2 promotes the invasion and metastasis of human GC by transcriptionally up-regulating the chemokine receptor CXCR4. Therefore, the RUNX2-CXCR4 axis is a potential therapeutic target for GC.

Background Hemorrhagic shock is the primary cause of morbidity and mortality in the intensive care units in patients under the age of 35. Several organs, including the lungs, are seriously affected by hemorrhagic shock and inadequate resuscitation. Excess free fatty acids have shown to trigger inflammation in various disease conditions. C75 is a small compound that inhibits fatty acid synthase, a key enzyme in the control of fatty acid metabolism that also stimulates fatty acid oxidation. We hypothesized that C75 treatment would be protective against hemorrhagic shock. Methods Adult male Sprague-Dawley rats were cannulated with a femoral artery catheter and subjected to controlled bleeding. Blood was shed to maintain a mean arterial pressure of 30 mm Hg for 90 minutes, then resuscitated over 30 minutes with a crystalloid volume equal to twice the volume of shed blood. Fifteen minutes into the 30-minute resuscitation, the rats received either intravenous infusion of C75 (1 mg/kg body weight) or vehicle (20% dimethyl sulfoxide). Blood and tissue samples were collected 6 hours after resuscitation (ie, 7.5 hours after hemorrhage) for analysis. Results After hemorrhage and resuscitation, C75 treatment decreased the increase in serum free fatty acids by 48%, restored adenosine triphosphate levels, and stimulated carnitine palmitoyl transferase-1 activity. Administration of C75 decreased serum levels of markers of injury (aspartate aminotransferase, lactate, and lactate dehydrogenase) by 38%, 32%, and 78%, respectively. Serum creatinine and blood urea nitrogen were also decreased significantly by 38% and 40%, respectively. These changes correlated with decreases in neutrophil infiltration in the lung, evidenced by decreases in Gr-1–stained cells and myeloperoxidase activity and improved lung histology. Finally, administration of C75 decreased pulmonary mRNA levels of cyclooxygenase-2 and interleukin-6 by 87% and 65%, respectively. Conclusion Administration of C75 after hemorrhage and resuscitation decreased the increase in serum free fatty acids, decreased markers of tissue injury, downregulated the expression of inflammatory mediators, and decreased neutrophil infiltration and lung injury. Thus, the dual action of inhibiting fatty acid synthesis and stimulating fatty acid oxidation by C75 could be developed as a promising adjuvant therapy strategy to protect against hemorrhagic shock.

In view of the problem of generational product consistent form feature is difficult to be predicted quantitatively, this paper presents a novel approach based on grey theory, Back propagation neural network (BP NN) and Markov chain, which is hereafter called the improved Grey-BP model with Markov chain (IGMBPM model). In the process of forecasting, due that the raw sequence consisted of product form feature points’ positions has the characteristics of poor sample, irregular and high volatility, firstly the traditional grey model is improved to be more suitable for the oscillating raw data, and the improved grey model is combined with BP NN for the purpose of enhancing the mutual influence between anterior and posterior data in sequence, in addition Markov chain is used to amend the final prediction results. The radiator grill profile of a certain type of automobile are taken as an example, the results of the IGMBPM model are compared with other models, the former shows better performance, which ve...

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females, with an estimated 1.4 million cases and 693,900 deaths in 2012. Colonoscopy is the cornerstone for the detection and prevention of CRC. In addition, endoscopic treatment for CRC at an early stage can effectively improve patients' quality of life and cure rate. Summary: This review focuses on endoscopic approaches, including white light endoscopy, chromoendoscopy, magnifying endoscopy and therapeutic endoscopy, for the evaluation and treatment of superficial colorectal neoplasms. Key Message: Understanding the preoperative evaluation, indications and techniques of endoscopic mucosal resection/endoscopic submucosal dissection as well as postoperative surveillance for superficial colorectal neoplasms is critical for providing appropriate management to the patients. Practical Implications: Endoscopic therapy, a method preserving organ function and improving quality of life, is a widely applied microinvasive treatment for superficial colorectal neoplasms. This review describes the basics and developments of endoscopic approaches and may facilitate daily practice for superficial colorectal neoplasms.

Sepsis is a major healthcare concern, especially in the elderly population. The use of an animal model closely resembling clinical conditions in this population may provide a better prediction in translating bench studies to the bedside. Ghrelin inhibits sympathetic nerve activity and inflammation in young septic animals; however, aged animals become hyporesponsive to ghrelin. In this study, we evaluated the efficacy of combined human ghrelin and growth hormone (GH) for sepsis treatment in the elderly utilizing a clinically relevant animal model of sepsis. Male Fischer 344 rats 22 to 24 months old were subjected to cecal ligation and puncture (CLP). Human ghrelin plus GH or vehicle (normal saline) was administered subcutaneously at 5 h after CLP. At 20 h after CLP, blood and tissue samples were collected for various analyses. Combined treatment attenuated serum levels of lactate, lactate dehydrogenase, creatinine, blood urea nitrogen, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in aged septic rats. The integrity of the microscopic structure in the lungs, liver and kidneys was well preserved after treatment. Expression of IL-6, TNF-α, macrophage inflammatory protein-2 and keratinocyte-derived chemokine as well as myeloperoxidase activity and caspase-3 activation were significantly reduced in the lungs and liver of treated rats. Moreover, treated rats showed an improvement in cardiovascular function and increased expression of ghrelin receptor and c-fos in the brainstem. Finally, the 10-d survival of aged septic rats was increased from 29% to 64% after combined treatment and was associated with less body weight loss. Our findings warrant the development of combined human ghrelin and GH for sepsis treatment in the geriatric population.

The chronic production of hepatitis B viral (HBV) antigens could cause inflammation and necrosis, leading to elevation of liver enzymes from necrotic hepatocytes, hepatitis, cirrhosis, hepatocellular carcinoma, and liver failure. However, no current treatment is capable of significantly reducing HBsAg expression in patients. Our previous studies had confirmed the ability of CRISPR-Cas9 in disrupting HBV cccDNA. Here, to inhibit HBV expression efficiently in the mouse model of chronic HBV infection, the miniaturized CRISPR-SaCas9 system compatible with a HBV core region derived guide-RNA had been packaged in recombinant adeno-associated virus (AAV) type 8, which lowered the levels of serum HBsAg, HBeAg, and HBV DNA efficiently in HBV transgenic mice during 58 days continuous observation after vein injection. It further confirms the potential of the CRISPR-Cas9 technique for use in hepatitis B gene therapy.

In this research, we investigate the acceptability of three new and emerging smart mobility options and quantify the associated willingness-to-pay values in the context of Lisbon using a comprehensive stated preferences (SP) survey. The smart mobility options include shared taxi, one-way car rental, and a novel combination of park-and-ride and school bus facilities. While previous surveys on smart mobility options had investigated limited number of alternatives in isolation, the SP survey used in this research presents the smart mobility options alongside the existing options and their traditional variants like congestion pricing and improved public transport systems. Further, the choice of mode, departure time and occupancy are investigated in a multidimensional framework. This resulted a large choice set (with 9 modes, 5 departure times, and 2 occupancy levels leading to 135 alternatives in total) and required a novel survey design. The main survey administered over the internet and computer aided personal interviews included 2372 valid SP observations from 1248 respondents. Multi-dimensional mixed logit models were used to capture the complex correlations introduced due to the non-traditional survey design. Results indicate a significant preference of one-way car rental and shared taxi for non-commute trips. For commute trips, improved versions of traditional public transport modes are favoured over smart mobility options. These findings, as well as the novel data collection and modelling approach, are expected to provide important information to transportation planners and policy makers working to implement smart mobility options in Lisbon as well as in other cities.

Background With the increase of diameters of colorectal tumours, procedure time of colorectal endoscopic submucosal dissection (CR – ESD) gradually prolonged. The aim of this study was to discuss the differences of ESD for colorectal tumours with different diameters, which was expected to provide some help for clinical work. Methods This was a retrospective study of clinical data. From October 2012 to December 2015, we examined a total of 210 patients who were treated by an endoscopic procedure for colorectal tumours in the Endoscopy Centre, the PLA Army General Hospital. The lesions were divided into two groups according to different diameters (≥4.0 cm VS Results The average procedure time of ESD of 210 colorectal tumour cases was 50.3±42.7 min and the average size was 7.98±10.84 cm2. En bloc resection rate was 91.4%, R0 resection rate was 90.5%, and the curative resection rate was 90.5%. Perforation rate was 5.2% (11/210), and the late-onset haemorrhage rate was 0.5% (1/210). Compared with lesions with the diameters of Conclusions ESDs of colorectal tumours with diameters greater than 4 cm require longer time, and the operation risk is higher. The operators should be more careful with non-rectal lesions.

Intestinal ischemia-reperfusion (I/R) occurs in various clinical settings, such as transplantation, acute mesenteric arterial occlusion, trauma, and shock. I/R injury causes severe systemic inflammation, leading to multiple organ dysfunction associated with high mortality. The ubiquitin proteasome pathway has been indicated in the regulation of inflammation, particularly through the NF-κB signaling pathway. PYR-41 is a small molecular compound that selectively inhibits ubiquitin-activating enzyme E1. A mouse model of intestinal I/R injury by clamping the superior mesenteric artery for 45 min was performed to evaluate the effect of PYR-41 treatment on organ injury and inflammation. PYR-41 was administered intravenously at the beginning of reperfusion. Blood and organ tissues were harvested at 4 h after reperfusion. PYR-41 treatment improved the morphological structure of gut and lung after I/R, as judged by hematoxylin and eosin staining. It also reduced the number of apoptotic terminal deoxynucleotidyl transferase dUTP nick end-labeling-positive cells and caspase-3 activity in the organs. PYR-41 treatment decreased the expression of proinflammatory cytokines IL-6 and IL-1β as well as chemokines keratinocyte chemoattractant and macrophage inflammatory protein-2 in the gut and lung, which leads to inhibition of neutrophils infiltrating into these organs. The serum levels of IL-6, aspartate aminotransferase, and lactate dehydrogenase were reduced by the treatment. The IκB degradation in the gut increased after I/R was inhibited by PYR-41 treatment. Thus, ubiquitination may be a potential therapeutic target for treating patients suffering from intestinal I/R. NEW & NOTEWORTHY Excessive inflammation contributes to organ injury from intestinal ischemia-reperfusion (I/R) in many clinical conditions. NF-κB signaling is very important in regulating inflammatory response. In an experimental model of gut I/R injury, we demonstrate that administration of a pharmacological inhibitor of ubiquitination process attenuates NF-κB activation, leading to reduction of inflammation, tissue damage, and apoptosis in the gut and lungs. Therefore, ubiquitination process may serve as a therapeutic target for treating patients with intestinal I/R injury.

Purpose: Metallothionein 2A (MT2A) suppresses the progression of human gastric cancer potentially through an “MT2A–NF-κB pathway” with unclear mechanisms. This study explored the role of a transcription factor, myeloid zinc-finger 1 (MZF1), in MT2A-NF-κB pathway and its clinical significance in gastric cancer. Experimental Design: MZF1 expression and function in gastric cancer were investigated in vitro and in vivo. The relationship between MZF1 and MT2A was determined by gain-of-function and loss-of-function assays in gastric cancer cells and an immortalized gastric cell line GES-1. The prognostic value of MZF1 expression in association with MT2A was evaluated using IHC in two cohorts. Results: MZF1 was epigenetically silenced in human gastric cancer cell lines and primary tumors. Overexpression of MZF1 in gastric cancer cells suppressed cell proliferation and migration, as well as the growth of xenograft tumors in nude mice. Knocking-down of MZF1 transformed GES-1 cells into a malignant phenotype characterized by increased cell growth and migration. Mechanistically, MZF1 was upregulated in both GC and GES-1 cells by MT2A ectopically expressed or induced upon treatment with a garlic-derived compound, diallyl trisulfide (DATS). MZF1 associated with MT2A was colocalized in the nuclei of GES-1 cells to target the promoter of NF-κB inhibitor alpha (NFKBIA). Clinically, MT2A and MZF1 were progressively downregulated in clinical specimens undergoing gastric malignant transformation. Downregulation of MT2A and MZF1 was significantly correlated with poorer patient prognosis. Conclusions: MT2A exerts its anti-gastric cancer effects by complexing with MZF1 to target NFKBIA. MT2A/MZF1 may serve as a valuable prognostic marker and a novel therapeutic target for human gastric cancer.

Sepsis is the third leading cause of death in the neonatal population, due to susceptibility to infection conferred by immaturity of both the innate and adaptive components of the immune system. Invariant natural killer T (iNKT) cells are specialized adaptive immune cells that possess important innate-like characteristics and have not yet been well-studied in septic neonates. We hypothesized that iNKT cells would play an important role in mediating the neonatal immune response to sepsis. To study this, we subjected 5- to 7-day-old neonatal C57BL/6 mice to sepsis by intraperitoneal (i.p.) cecal slurry (CS) injection. Thirty hours prior to or immediately following sepsis induction, pups received i.p. injection of the iNKT stimulator KRN7000 (KRN, 0.2 µg/g) or vehicle. Ten hours after CS injection, blood and tissues were collected for various analyses. Thirty-hour pretreatment with KRN resulted in better outcomes in inflammation, lung injury, and survival, while immediate treatment with KRN resulted in worse outcomes compared to vehicle treatment. We further analyzed the activation status of neonatal iNKT cells for 30 h after KRN administration, and showed a peak in frequency of CD69 expression on iNKT cells and serum IFN-γ levels at 5 and 10 h, respectively. We then used CD1d knockout neonatal mice to demonstrate that KRN acts through the major histocompatibility complex-like molecule CD1d to improve outcomes in neonatal sepsis. Finally, we identified that KRN pretreatment exerts its protective effect by increasing systemic levels of TGF-β1. These findings support the importance of iNKT cells for prophylactic immunomodulation in neonates susceptible to sepsis.

Extracellular cold-inducible RNA-binding protein (CIRP) functions as damage-associated molecular pattern and has been demonstrated to be responsible in part for the damage occurring after renal ischemia-reperfusion (I/R). A short peptide derived from CIRP, named C23, binds to myeloid differentiation factor 2, a Toll-like receptor 4 coreceptor. We hypothesize that C23 reduces renal ischemia-reperfusion (RIR) injury by blocking CIRP. We observed that pretreatment with C23 significantly decreased the levels of recombinant mouse CIRP-induced tumor necrosis factor-α (TNF-α) in a dose-dependent fashion in cultured macrophages. C57BL/6 mice were subjected to bilateral renal pedicle clamps for 35 min to induce ischemia, followed by reperfusion for 24 h and harvest of blood and renal tissue. C23 peptide (8 mg/kg) or vehicle was injected intraperitoneally at the beginning of reperfusion. Plasma TNF-α, interleukin 1 beta (IL-1β), and IL-6 levels were decreased in C23-treated RIR mice as compared with vehicle-treated mice by 74%, 85%, and 68%, respectively. Expressions of TNF-α and keratinocyte chemoattractant in the kidneys from C23-treated mice were decreased by 55% and 60%, respectively. Expression of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in the kidney of C23-treated mice were significantly reduced by 46% and 55%, respectively. Renal tissue histological assessments revealed significant reduction in damage score by 44% in C23-treated mice. Finally, a survival study revealed a significant survival advantage with a 70% survival rate in C23 group vs. 37% in vehicle group. Thus, C23 has potential as a novel therapy for the patients suffering from I/R-induced renal injury.

Cold-inducible RNA-binding protein (CIRP) is a novel sepsis inflammatory mediator and C23 is a putative CIRP competitive inhibitor. Therefore, we hypothesized that C23 can ameliorate sepsis-associated injury to the lungs and kidneys. First, we confirmed that C23 dose-dependently inhibited TNF-α release, IκBα degradation, and NF-κB nuclear translocation in macrophages stimulated with CIRP. Next, we observed that male C57BL/6 mice treated with C23 (8 mg/kg BW) at 2 h after cecal ligation and puncture (CLP) had lower serum levels of LDH, ALT, IL-6, TNF-α, and IL-1β (reduced by ≥39%) at 20 h after CLP compared with mice treated with vehicle. C23-treated mice also had improved lung histology, less TUNEL-positive cells, lower serum levels of creatinine (34%) and BUN (26%), and lower kidney expression of NGAL (50%) and KIM-1 (86%). C23-treated mice also had reduced lung and kidney levels of IL-6, TNF-α, and IL-1β. E-selectin and ICAM-1 mRNA was significantly lower in C23-treated mice. The 10-day survival after CLP of vehicle-treated mice was 55%, while that of C23-treated mice was 85%. In summary, C23 decreased systemic, lung, and kidney injury and inflammation, and improved the survival rate after CLP, suggesting that it may be developed as a new treatment for sepsis.

Decrease of CD4 T cell numbers causes immunosuppression in sepsis. We previously showed the beneficial role of ghrelin in sepsis. We hypothesize that the protective outcome of ghrelin in sepsis is mediated partially through the restoration of CD4 T cells' proliferation. Sepsis was induced in mice by cecal ligation and puncture (CLP). The percentage of CD4 T cells in spleen was assessed by flow cytometry and their proliferation was determined by carboxyfluorescein succinimidyl ester (CSFE). Compared to sham mice, the percentages of splenic CD4 T cells were reduced by 20%, 21%, and 29% at day 1, 2 and 3 after CLP, respectively. Human ghrelin was given to 3 day septic mice by s.c. injection at 5 and 24 h after CLP. Treatment with ghrelin restored the loss of CD4 T cells by increasing their proliferation in septic mice. The expression of cyclin D1 and B1 was significantly increased, while the expression of p57 was decreased in ghrelin-treated mice compared to vehicle-treated mice in sepsis. Treatment with human ghrelin significantly increased the p-AKT levels in the spleen compared to vehicle-treated septic mice. Human ghrelin plays an important role in reestablishing the proliferation of CD4 T cells and serves as a promising therapeutic agent in sepsis.

Dual-energy X-ray absorptiometry (DXA)-based finite element analysis (FEA) has been studied for assessment of hip fracture risk. Femoral strength (FS) is the maximum force that the femur can sustain before its weakest region reaches the yielding limit. Fracture risk index (FRI), which also considers subject-specific impact force, is defined as the ratio of von Mises stress induced by a sideways fall to the bone yield stress over the proximal femur. We compared risk stratification for prior hip fracture using FS and FRI derived from DXA-based FEA.The study cohort included women aged ≥65years undergoing baseline hip DXA, with femoral neck T-scores-1 and no osteoporosis treatment; 324 cases had prior hip fracture and 655 controls had no prior fracture. Using anonymized DXA hip scans, we measured FS and FRI. Separate multivariable logistic regression models were used to estimate odds ratios (ORs), c-statistics and their 95% confidence intervals (95% CIs) for the association of hip fracture with FS and FRI.Increased hip fracture risk was associated with lower FS (OR per SD 1.36, 95% CI: 1.15, 1.62) and higher FRI (OR per SD 1.99, 95% CI: 1.63, 2.43) after adjusting for Fracture Risk Assessment Tool (FRAX) hip fracture probability computed with bone mineral density (BMD). The c-statistic for the model containing FS (0.69; 95% CI: 0.65, 0.72) was lower than the c-statistic for the model with FRI (0.77; 95% CI: 0.74, 0.80) or femoral neck BMD (0.74; 95% CI: 0.71, 0.77; all P0.05).FS and FRI were independently associated with hip fracture, but there were differences in performance characteristics.

Potassium ion channels are emerging as promalignant factors involved in cancer progression. In this study, we found that invading human gastric cancer cells express high levels of inwardly rectifying potassium channel 2.1 (Kir2.1). Silencing Kir2.1 markedly reduced the invasive and metastatic capabilities as well as the epithelial–mesenchymal transition (EMT) of gastric cancer cells. The promalignant nature of Kir2.1 in gastric cancer cells was independent of potassium permeation but relied on its interaction with serine/threonine-protein kinase 38 (Stk38) to inhibit ubiquitination and degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2). Degradation of MEKK2 was mediated by small mothers against decapentaplegic-specific E3 ubiquitin protein ligase 1 (Smurf1), which resulted in activation of the MEK1/2–ERK1/2–Snail pathway in gastric cancer cells. In human gastric cancer tissues, expression was high and positively correlated with invasion depth and metastatic status of the tumors as well as poor overall patient survival. Cox regression analysis identified Kir2.1 as an independent prognostic indicator for patients with gastric cancer. Our results suggest that Kir2.1 is an important regulator of gastric cancer malignancy and acts as a novel prognostic marker and a therapeutic target for gastric cancer. Significance: Kir2.1 contributes to invasion and metastasis by a noncanonical ion permeation–independent signaling pathway and may act as a novel prognostic marker and therapeutic target for gastric cancer. Cancer Res; 78(11); 3041–53. ©2018 AACR.