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BACKGROUND Acute lung injury (ALI) is a common and life-threatening complication of severe acute pancreatitis (SAP). There are currently limited effective treatment options for SAP and associated ALI. Calycosin (Cal), a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties, but its effect on SAP and associated ALI has yet to be determined. AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism. METHODS SAP was induced via two intraperitoneal injections of L-arg (4 g/kg) and Cal (25 or 50 mg/kg) were injected 1 h prior to the first L-arg challenge. Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically. An in vitro model of lipopolysaccharide (LPS)-induced ALI was established using A549 cells. Immunofluorescence analysis and western blot were evaluated in cells. Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1. RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI. Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP. Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, IL-1β, HMGB1 and chemokine (CXC motif) ligand 1 in lung tissue. Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B (NF-κB) p65 in lung tissues and an in vitro model of LPS-induced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI. Furthermore, molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1. CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.

Background Acute pancreatitis (AP) is an inflammatory disease in which the regulatory pathway is complex and not well understood. Soluble suppression of tumorigenicity 2 (sST2) protein receptor functions as a decoy receptor for interleukin (IL)-33 to prevent IL-33/suppression of tumorigenicity 2L (ST2L)-pathway-mediated T helper (Th)2 immune responses. Aim To investigate the role of sST2 in AP. Methods We assessed the association between sST2 and severity of AP in 123 patients enrolled in this study. The serum levels of sST2, C-reactive protein (CRP) and Th1- and Th2-related cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-2, IL-4, IL-5 and IL-13, were measured by highly sensitive ELISA, and the severity of AP in patients was evaluated by the 2012 Atlanta Classification Criteria. Results Serum sST2 levels were significantly increased in AP patients, and further, these levels were significantly elevated in severe AP (SAP) patients compared to moderately severe AP (MSAP) and mild AP (MAP) patients. Logistic regression showed sST2 was a predictor of SAP [odds ratio (OR): 1.003 (1.001-1.006), P = 0.000]. sST2 cutoff point was 1190 pg/mL, and sST2 above this cutoff was associated with SAP. sST2 was also a predictor of any organ failure and mortality during AP [OR: 1.006 (1.003-1.009), P = 0.000, OR: 1.002 (1.001-1.004), P = 0.012, respectively]. Additionally, the Th1-related cytokines IFN-γ and TNF-α in the SAP group were higher and the Th2-related cytokine IL-4 in the SAP group was significantly lower than those in MSAP and MAP groups. Conclusion sST2 may be used as a novel inflammatory marker in predicting AP severity and may regulate the function and differentiation of IL-33/ST2-mediated Th1 and Th2 Lymphocytes in AP homeostasis.

Injury or disease in the somatosensory nervous system may cause broad molecular changes and lead to neuropathic pain. Excitatory synaptic transmission in somatosensory pathways conveys the somatosensory information from the peripheral to the central nervous system. Long-term effects of excitatory synaptic transmission on the pain pathway contribute to neuropathic pain hypersensitivity. Synaptic strength is dynamically regulated and undergoes bidirectional changes, manifested by two primary forms of synaptic plasticity, long-term potentiation and long-term depression (LTD), which are mediated by insertion and endocytosis of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), respectively. Molecular mechanisms of LTP have been extensively studied; on the other hand, the role of AMPAR endocytosis in the pain-related synaptic enhancement is less well known. Recent research in the anterior cingulate cortex reveals that loss of LTD contributes to the maintenance of neuropathic pain, which provides the novel perspective of the mechanism of LTD also being critical for maintaining neuropathic pain. More importantly, exploring the molecular mechanism of LTD may help with the development of novel analgesic strategies to manage neuropathic pain.

Steroid receptor coactivator 1 (SRC-1) is one of the coactivators recruited by the nuclear receptors (NRs) when NRs are activated by steroid hormones, such as glucocorticoid. SRC-1 is abundant in hippocampus and hypothalamus and is also related to some major risk factors for depression, implicated by its reduced expression after stress and its effect on hypothalamus-pituitary-adrenal gland axis function. However, whether SRC-1 is involved in the formation of depression remains unclear. In this study, we firstly established chronic unpredictable stress (CUS) to induce depressive-like behaviors in mice and found that SRC-1 expression was reduced by CUS. A large number of studies have shown that neuroinflammation is associated with stress-induced depression and lipopolysaccharide (LPS) injection can lead to neuroinflammation and depressive-like behaviors in mice. Our result indicated that LPS treatment also decreased SRC-1 expression in mouse brain, implying the involvement of SRC-1 in the process of inflammation and depression. Next, we showed that the chronic unpredictable mild stress (CUMS) failed to elicit the depressive-like behaviors and dramatically promoted the expression of SRC-1 in brain of wild type mice. What's more, the SRC-1 knockout mice were more susceptible to CUMS to develop depressive-like behaviors and presented the changed expression of glucocorticoid receptor. However, SRC-1 deficiency did not affect the microglia activation induced by CUMS. Altogether, these results indicate a correlation between SRC-1 level and depressive-like behaviors, suggesting that SRC-1 might be involved in the development of depression induced by stress.

Background Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established. Methods To identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis. Results We discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; β=0.26, P=1.20×10-9); the locus we identified at GALNT12 (rs7856182; β=0.73, P=2.38×10-9) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels (P=1.40×10-2) and disease risk (P=6.55×10-3). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls. Conclusions Our data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.

Background and objectives IgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy. Design, setting, participants, & measurements We performed a two-stage exome chip–based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored. Results We identified three non-HLA gene regions (FBXL21, CCR6, and STAT3) and one HLA gene region (GABBR1) with suggestive significance (Pmeta Conclusions Five novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation.

This study sought to investigate the biological effects of specific MIF inhibitor, ISO-1, on the proliferation, migration and invasion of PANC-1 human pancreatic cells in vitro, and on tumour growth in a xenograft tumour model in vivo. The effect of ISO-1 on PANC-1 cell proliferation was examined using CCK-8 cell proliferation assay. The effect of ISO-1 on collective cell migration and recolonization of PANC-1 cells was evaluated using the cell-wound closure migration assay. The effect of ISO-1 on the migration and invasion of individual PANC-1 cells in a 3-dimensional environment in response to a chemo-attractant was investigated through the use of Transwell migration/invasion assays. Quantitative real time PCR and western blot analyses were employed to investigate the effects of ISO-1 on MIF, NF-κB p65 and TNF-α mRNA and protein expression respectively. Finally, a xenograft tumor model in BALB/c nude mice were used to assess the in vivo effects of ISO-1 on PANC-1-induced tumor growth. We found high expression of MIF in pancreatic cancer tissues. We demonstrated that ISO-1 exerts anti-cancer effects on PANC-1 cell proliferation, migration and invasion in vitro, and inhibited PANC-1 cell-induced tumour growth in xenograft mice in vivo. Our data suggests that ISO-1 and its derivative may have potential therapeutic applications in pancreatic cancer.

Background The discovery and use of antibiotics have produced tremendous benefits for human society, however, with the large-scale use of antibiotics in medicine, animal husbandry and other fields, more and more antibiotic-resistant bacteria have emerged. Since diseases caused by such antibiotic-resistant bacteria could require more drastic measures to treat, the emergence of such resistant bacteria in food has attracted much concern. Scope and approach In this review, we summarized the interplay between antibiotic resistance and food-associated stress tolerance, and the hypothesized molecular mechanisms for the cross protection in bacteria. Key findings and conclusions In this review, we found that some common food-associated stresses, such as cold, acid, osmosis and sanitizers could provide cross protection for bacteria against antibiotics. In turn, antibiotic resistance could also render bacteria more tolerant to food-associated stresses. Meanwhile, novel nonthermal technologies may more likely result in little or no difference in bacterial antibiotic resistance, and this can be an advantage over traditional sterilization methods. Several molecular mechanisms for the cross protection between antibiotics and food-associated stresses have been discussed in this review. General stress response (e.g., sigma factors and two-component system), SOS response, mutations, and other mechanisms have been proposed as strategies for bacteria acquisition of cross protection.

The purpose of this study was to investigate the diagnostic performance of the automated breast ultrasound system (ABUS) compared with hand-held ultrasonography (HHUS) and mammography (MG) for breast cancer in women aged 40 y or older. A total of 594 breasts in 385 patients were enrolled in the study. HHUS, ABUS and MG exams were performed for these patients. Follow-up and pathologic findings were used as the reference standard. Based on the reference standard, 519 units were benign or normal and 75 were malignant. The sensitivity, specificity, accuracy and Youden index were 97.33%, 89.79%, 90.74% and 0.87 for HHUS; 90.67%, 92.49%, 92.26% and 0.83 for ABUS; 84.00%, 92.87%, 91.75% and 0.77 for MG, respectively. The specificity of ABUS was significantly superior to that of HHUS (p = 0.024). The area under the receiver operating characteristic curve was 0.936 for HHUS, which was the highest, followed by 0.916 for ABUS and 0.884 for MG. However, the difference was not statistically significant (p > 0.05). In conclusion, the diagnostic performance of ABUS for breast cancer was equivalent to HHUS and MG and potentially can be used as an alternative method for breast cancer diagnosis.

Acute pancreatitis (AP) is a common serious acute condition of the digestive system that remains a clinical challenge. Severe acute pancreatitis (SAP) in particular is characterized by high morbidity and mortality. The present study was designed to investigate the protective effect of Galangin (Gal), a natural flavonol obtained from lesser galangal, on L-arginine-induced SAP in mice and in AR42J cells. Amylase and lipase activities were measured and the histopathology of the pancreas, lung, and kidney was evaluated. Inflammation and oxidative stress were assessed using ELISA, western blotting, RT-PCR, and immunohistochemistry. Gal was shown to reduce proinflammatory cytokine production and reactive oxygen species (ROS) generation in vivo and in vitro. L-arginine treatment reduced the expression of components of the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and the downstream protein heme oxygenase-1 (HO-1) in mice, whereas Gal increased their expression. Furthermore, the Nrf2/HO-1 pathway inhibitor brusatol prevented the anti-inflammatory and antioxidant effects of Gal in mice with SAP. Taken together, our results imply that Gal has protective effects in L-arginine-induced SAP that are induced by the upregulation of the Nrf2/HO-1 pathway, which has anti-inflammatory and antioxidant effects. Thus, Gal may represent a promising treatment for SAP.

Background Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region to SLE susceptibility. Our aim is to find a functional variant in this region. Methods The genetic association results in the CTLA4-ICOS region from previous GWAS were adopted to select the potential variant which was further replicated in two independent cohorts (Henan cohort 2053 SLE patients and 1845 healthy controls, Beijing cohort 2303 SLE patients and 19,262 healthy). In order to explore the functional significance in SLE, bioinformatics with validation experiments (including electrophoretic mobility shift assay and luciferase reporter assay) and mRNA expression analysis were also performed. Results A variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, pmeta = 7.02×10−11, OR 1.19, 95%CI 1.13–1.26). The bioinformatics suggested that rs17268364 might affect the expression of CTLA4, not ICOS. The rs17268364 risk G allele containing sequence reduced the expression of the reporter gene by binding transcriptional repressor Ewing sarcoma breakpoint region 1 (EWSR1). Following genotype-mRNA expression, the analysis also showed the risk allele of rs17268364 was associated with low CTLA4 expression in lupus nephritis (LN) patients. Healthy individuals carrying rs17268364 risk G allele was significantly correlated with higher levels of IFN-α signature including increased lymphocyte antigen 6E (LY6E) (p=0.031), interferon-stimulated gene 15 (ISG15) (p=0.038), interferon regulatory factor 9 (IRF9) (p=0.028), and interferon regulatory factor 5 (IRF5) (p=0.040) mRNA expression. Conclusions The present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population.

Background The N-terminal fragment of proB-type natriuretic peptide (NT-proBNP) is an established predictive marker for sepsis-related mortality in adult. This retrospective study aimed to determine age-stratified cut-off values for serum levels of NT-proBNP and mortality from sepsis in children under 18 years. Material/Methods Patients were stratified by age as follows

Glaucoma is a disease involving impaired visual function accompanied by degeneration and necrosis of the optic nerve. Epigallocatechin-3-gallate (EGCG) exerts a neuroprotective effect against the degeneration of retinal ganglion cells. However, whether EGCG can relieve glaucoma and the possible mechanisms remain unclear. In order to determine the function of EGCG in glaucoma, an acute glaucoma rat model was established. Optic neuropathology was examined by haematoxylin-eosin staining and immunofluorescence staining for class III-β tubulin. The levels of inflammation-associated cytokines, such as interleukin (IL)-4, IL-6, TNF-α, IL-1β, IL-13 and IFN-γ were measured by flow cytometry. T cell proliferation was assessed by the carboxyfluorescein diacetate succinimidyl ester method. Finally, the functional role of EGCG in glaucoma was explored. The levels of the inflammation-associated proteins p-IκBα and p-p65 were measured by western blot analysis. The results showed that optic nerve injury occurred, and elevated levels of the inflammatory cytokines IL-4, IL-6, TNF-α, IL-1β, IL-13 and IFN-γ were observed in the rat model of acute glaucoma. In addition, an increased T lymphocyte proliferation rate and imbalance of Th1/Th2 cytokines were present in the models. Importantly, treatment with EGCG significantly alleviated optic nerve injury. At the molecular level, EGCG decreased the levels of inflammation-associated cytokines, decreased the proliferation rate of T lymphocyte cells, and repaired the imbalance of Th1/Th2 cytokines. Moreover, EGCG inhibited the increase in the phosphorylation of IκBα and p65 caused by modelling and thus suppressed the activation of the nuclear factor (NF)-κB signalling pathway. The findings of the present study indicate that EGCG could attenuate the symptoms of glaucoma and inhibit inflammatory responses by suppressing the NF-κB signalling pathway in a rat glaucoma model.

Significance A tomato fruit ripening–specific transcription factor, SlLOB1 predominantly influences fruit cell wall–related gene regulation and textural changes during fruit maturation and thus is distinct from broadly acting ripening transcription factors described to date that influence many ripening processes. As such, SlLOB1 is an intermediate regulator primarily influencing a physiological subdomain of the overall ripening transition., Fruit softening is a key component of the irreversible ripening program, contributing to the palatability necessary for frugivore-mediated seed dispersal. The underlying textural changes are complex and result from cell wall remodeling and changes in both cell adhesion and turgor. While a number of transcription factors (TFs) that regulate ripening have been identified, these affect most canonical ripening-related physiological processes. Here, we show that a tomato fruit ripening–specific LATERAL ORGAN BOUNDRIES (LOB) TF, SlLOB1, up-regulates a suite of cell wall–associated genes during late maturation and ripening of locule and pericarp tissues. SlLOB1 repression in transgenic fruit impedes softening, while overexpression throughout the plant under the direction of the 35s promoter confers precocious induction of cell wall gene expression and premature softening. Transcript and protein levels of the wall-loosening protein EXPANSIN1 (EXP1) are strongly suppressed in SlLOB1 RNA interference lines, while EXP1 is induced in SlLOB1-overexpressing transgenic leaves and fruit. In contrast to the role of ethylene and previously characterized ripening TFs, which are comprehensive facilitators of ripening phenomena including softening, SlLOB1 participates in a regulatory subcircuit predominant to cell wall dynamics and softening.

Object: The fluid management strategy in ARDS is not very clear. A secondary analysis of RCT data was conducted to identify patients with ARDS benefitting from a conservative strategy of fluid management.Methods: The data of this study were downloaded from the ARDS network series of randomized controlled trials (Conservative Strategy vs. Liberal Strategy in 2006). Based on the clinical feature of patients, within the first 24 h after admission, clustering was performed using the k-means clustering algorithm to identify the phenotypes of ARDS. Survival was analyzed using the Kaplan-Meier survival analysis to assess the effect of the two fluid management strategies on the 90-day cumulative mortality. Categorical/dichotomic variables were analyzed by the chi-square test. Continuous variables were expressed as the mean and standard deviation and evaluated through a one-way ANOVA. A P-value < 0.05 was defined as the statistically significant cut-off value.Results: A total of 1,000 ARDS patients were enrolled in this unsupervised clustering research study, of which 503 patients were treated with a conservative fluid-management strategy, and 497 patients were treated with a liberal fluid-management strategy. The first 7-day cumulative fluid balance in patients with the conservative strategy and liberal strategy were −136 ± 491 ml and 6,992 ± 502 ml, respectively (P < 0.001). Four phenotypes were found, and the conservative fluid-management strategy significantly improved the 90-day cumulative mortality compared with the liberal fluid-management strategy (HR = 0.532, P = 0.024) in patients classified as “hyperinflammatory anasarca” phenotype (phenotype II). The characteristics of this phenotype exhibited a higher WBC count (20487.51 ± 7223.86/mm3) with a higher incidence of anasarca (8.3%) and incidence of shock (26.6%) at baseline. The furthermore analysis found that the conservative fluid management strategy was superior to the liberal fluid management strategy in avoiding superinfection (10.10 vs. 14.40%, P = 0.037) and returned to assisted breathing (4.60 vs. 16.20%, P = 0.030) in patients classified as “hyperinflammatory anasarca” phenotype. In addition, patients with other phenotypes given the different fluid management strategies did not show significant differences in clinical outcomes.Conclusion: Patients exhibiting a “hyperinflammatory anasarca” phenotype could benefit from a conservative fluid management strategy.

Nerve injury in the somatosensory pathway may induce maladaptive changes at the transcriptional or protein level, contributing to the development and maintenance of neuropathic pain. In contrast to the retrosplenial cortex (RSC), which processes nociceptive information and exhibits structural and molecular changes after nerve injury, detailed transcriptional changes in the RSC are not yet known. Here we confirm the involvement of the RSC in regulating pain sensation and observe that the same peripheral stimulation activates more retrosplenial neurons after nerve injury; reducing the activities of CaMKIIα+ splenial cells relieves peripheral pain hypersensitivity after nerve injury. Using a single-cell RNA sequencing (scRNA-seq) approach, we identified cell-type-specific gene expression changes after nerve injury, and the gene set enrichment analysis results revealed suppressed ion homeostasis in CaMKIIα+ neurons. Furthermore, examination of the expression of genes encoding ligand-gated ion channels showed a decrease in Gabar1a but an increase in Gria1 in CaMKIIα+ neurons; consistently, we confirmed the unbalanced excitatory/inhibitory synaptic transmission by using the electrophysiological recording approach. Moreover, micro-infusion of 1-Naphthyl acetyl spermine in the RSC to reduce excitatory synaptic transmission alleviated peripheral pain hypersensitivity. Our data confirm the involvement of the RSC in pain regulation and provide information on cell type-dependent transcriptomic changes after nerve injury, which will contribute to the understanding of the mechanisms mediating neuropathic pain.

Severe acute pancreatitis (SAP) is often associated with pulmonary inflammation leading to acute lung injury. Daphnetin, a natural coumarin derivative, has been reported to exert anti-inflammatory effects. Here, we explored the effect and possible mechanism of daphnetin in a mouse model of SAP-associated lung injury induced by an intraperitoneal injection of l-arginine. The severity of pancreatic and lung injury is determined by histology and its score. Immunostaining of inflammatory and apoptotic cells was used to demonstrate lung tissue inflammation and apoptosis; ELISA analysis of serum and tissue cytokine levels; and western blotting and immunohistochemical staining for the activated Janus kinase 2 (JAK2)–signal transducer and activator of transcription protein 3 (STAT3) signalling pathway in lung tissues. Daphnetin pretreatment significantly reduced SAP-induced pancreatic and lung tissue damage, reduced interleukin-6 and tumour necrosis factor-α concentrations in both serum and lung tissues, reduced serum amylase and myeloperoxidase activities, and reduced macrophage (CD11b) and neutrophil (Ly6G) infiltration and cell apoptosis in the lung tissue. Moreover, SAP-induced phosphorylation of JAK2 and STAT3 in the lung tissue was also significantly diminished by the daphnetin pretreatment. These results indicated that daphnetin reduces SAP-associated lung tissue damage, likely by inhibiting the activation of JAK2–STAT3 signalling.

Exposure to chronic stress can influence nociception and further induce hyperalgesia. Whether stress modulation of pain in female animals occurs in an estrous cycle-specific manner is still unclear. We profiled the changes in nociception (thermal, mechanical, formalin-evoked acute and inflammatory pain) of female Sprague-Dawley rats after treatment with chronic unpredictable mild stress (CUMS) and investigated whether these changes occur in an estrous cycle-dependent manner. The results showed that CUMS female rats exhibited a lower mechanical withdrawal threshold in proestrus and estrus, a longer formalin-evoked licking time in metestrus and diestrus, but no changes in the latency time on the tail-flick test. The present study findings suggest that chronic stress induces mechanical and formalin-evoked acute hyperalgesia of female rats in an estrous cycle-dependent manner.SUMMARYOur studies showed that chronic stress increased nociceptive sensitivity of female rats. Furthermore females had different stress-induced pain responses in different estrous phases: mechanical hyperalgesia in proestrus and estrus, formalin-evoked acute hyperalgesia in metestrus and diestrus.

Background: Cytidine deaminase (CDA) polymorphisms may affect the response to gemcitabine/cisplatin chemotherapy in patients with non-small cell lung cancer (NSCLC). This study is designed to investigate the associations of CDA-79A>C and 208G>A polymorphisms and gemcitabine/cisplatin chemotherapy effectiveness in Xinjiang Uyghur and Han patients. Methods: This prospective cohort study enrolled consecutive patients with stage IIIb/IV NSCLC administered gemcitabine/cisplatin chemotherapy at the First Affiliated Hospital, Medical College of Shihezi University and the First People’s Hospital, Kashgar Region. CDA-A79C and CDA-G208A polymorphisms were detected by direct sequencing. Progression-free survival was analyzed by the Kaplan-Meier method. Associations of A79C and G208A polymorphisms with treatment effectiveness and progression-free survival were analyzed using logistic regression and multivariate Cox regression analyses. Subgroup analyses based on ethnicity were performed. Results: The study enrolled 120 patients. A79C and G208A polymorphisms followed the Hardy-Weinberg equilibrium. The frequencies of the AA, AC, and CC genotypes and the A and C alleles of A79C were 52.2%, 29.9%, 17.9%, 67.2%, and 32.8%, respectively, in Han patients and 75.4%, 18.9%, 5.7%, 84.9%, and 5.1%, respectively, in Uyghur patients. Uyghur patients had lower frequencies of A79C-AC/CC genotypes, A79C-C allele, G208A-GA genotype, and G208A-A allele ( PConclusion: For Uyghur and Han ethnic groups, A79C and G208A polymorphisms can be used as a promising biomarker for the chemotherapy efficacy and prognosis of NSCLC.

Objective We reported an outbreak of human parainfluenza virus type 1 (HPIV1) in a kindergarten and explored the genetic characteristics of HPIV1 hemagglutinin-neuraminidase (HN) and fusion (F) genes to provide more evidence about HPIV1 outbreaks. Methods Suspected cases were the children with an influenza-like illness during June 20 to 26, 2018. Nasopharyngeal swabs were collected and screened to determine the presence of respiratory pathogens by real-time fluorescent quantitative polymerase chain reaction. The HN and F gene sequences of HPIV-positive samples were further amplified and sequenced to confirm the HPIV genotype and identify genetic characteristics. A phylogenetic tree, based on the HN and F genes, was reconstructed by maximum likelihood method. Results Fourteen children in the outbreak were diagnosed as upper respiratory tract infection. The most common symptom was cough (10/14), followed by rhinorrhea (5/14), sore throat (4/14), headache (1/14), and abdominal pain (1/14). Eight patients were positive for HPIV1 and negative for other pathogens. Phylogenetic tree demonstrated that the eight strains from the year 2018 in our study located in the clade 2.3. Two specific substitutions (N333S and I509M) in the amino acids of the F protein and two substitutions (V19A and L436I) in the HN protein were different from other strains in the clade 2. Conclusion HPIV1 was attributed to the outbreak, which may be related to the genetic variations of HPIV1.

A new three-dimensional (3D) zinc(II) metal–organic framework (MOF) {[Zn2(abtc)(H2O)3](DMA)}n bearing the rigid organic ligand 3,3′,5,5′-azobenzene-tetracarboxylic acid (H4abtc) were prepared by reaction of zinc(II) nitrate and H4abtc in a mixed solvent of DMA and water at 80 °C for 3 days. Compared with pristine hydrated 1, the dehydrated 1a exhibits highly efficient catalytic activity for cyanosilylation of carbonyl compounds with a low catalyst loading of 0.1 mol% at room temperature under solvent-free conditions, which due to the open Zn2+ sites as catalytically activated sites played a significant role in the heterogeneous catalytic process. Based on the experimental results, a possible reaction mechanism has also been proposed. Next, the inhibitory effect of compound 1a on Hela cervical cancer cell viability was evaluated by CCK-8 assay, and the percentage of cell cycles was determined in flow cytometry. Besides, the transwell assay also performed to detect the effect of compound 1a on cell migration and invasion.

Our aim was to investigate the diagnostic potential of an automated breast ultrasound (ABUS) system in differentiating benign and malignant breast masses compared with handheld ultrasound (HHUS).Women were randomly and proportionally selected from outpatients and underwent both HHUS and ABUS examinations. Masses with final American College of Radiology Breast Imaging Reporting and Data System categories 2 and 3 were considered benign. Masses with final Breast Imaging Reporting and Data System categories 4 and 5 were considered malignant. The diagnosis was confirmed by pathologic results or at least a 1-year follow-up. Automated breast US and HHUS were compared on the basis of their sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Diagnostic consistency and areas under the receiver operating characteristic curves were analyzed. The maximum diameters of masses were compared among HHUS, ABUS, and pathologic results.A total of 599 masses in 398 women were confirmed by pathologic results or at least a 1-year follow-up; 103 of 599 masses were malignant, and 496 were benign. There were no significant differences between ABUS and HHUS in terms of diagnostic accuracy (80.1% versus 80.6%), specificity (77.62% versus 80.24%), positive predictive value (46.12% versus 46.46%), and negative predictive value (97.96% versus 95.67%). There were significant differences in sensitivity (92.23% versus 82.52%; P .01) and areas under the curve (0.85 versus 0.81; P .05) between ABUS and HHUS. The correlation of the maximum diameter was slightly higher between ABUS and pathologic results (r = 0.885) than between HHUS and pathologic results (r = 0.855), but the difference was not significant (P .05).Automated breast US is better than HHUS in differentiating benign and malignant breast masses, especially with respect to specificity.

BACKGROUND Cardiac remote ischemic conditioning (RIC) is a noninvasive cardioprotective method in ischemia-reperfusion injury and acute myocardial infarction (AMI). The aims of this study were to investigate the effects of RIC in a rat model of AMI. MATERIAL AND METHODS Adult male Sprague-Dawley rats included the AMI group that underwent ligation of the left anterior descending (LAD) coronary artery (n=24), the RIC group that consisted the AMI rat model treated with RIC once daily in the left hind limb until days 1, 7 and 14 (n=24), and the sham group (n=24). Myocardial infarct size was measured by routine histology with triphenyltetrazolium chloride (TTC) and Masson's trichrome histochemical staining for myocardial necrosis and fibrosis, respectively. Serum levels of Bcl-2, Bax, caspase-3, and inducible nitric oxide synthase (iNOS) were measured by enzyme-linked immunosorbent assay (ELISA). The apoptosis index was detected using the TUNEL assay. Spectrophotometry of the myocardium was used to identify mitochondrial complexes and myocardial ATP. RESULTS The RIC group showed improved cardiac hemodynamics, reduced the size of the myocardial infarction, upregulated expression of Bcl-2, and down-regulation of the levels of Bax, caspase-3, and iNOS, and reduced cardiac myocyte apoptosis and inhibited the opening of the mitochondrial permeability transition pore (MPTP). CONCLUSIONS In a rat model of AMI, RIC improved the hemodynamic index, reduce the levels of apoptosis and myocardial injury, and improved mitochondrial function.

BACKGROUND A floating shoulder may be associated with catastrophic neurovascular injury and requires a multidisciplinary approach for its management. To maximize the likelihood of good patient outcomes, this unique injury pattern should be recognized in patients as early as possible. This can be difficult to achieve, however, as there are currently few reports of floating shoulder in the literature, meaning that associated neurovascular injuries may be overlooked. CASE SUMMARY We present here a rare case of floating shoulder with axillary artery injury in a 34-year-old woman. The patient complained of pain and numbness of her left upper limb after losing control of her motorcycle on a highway and falling from the vehicle 2 h ago. No blood pressure reading could be obtained from her left upper limb and no blood oxygen readings could be obtained from any of her left fingers. Computed tomography angiography and duplex ultrasonography revealed interruption of blood flow through the axillary artery, with distal flow being maintained through collateral arteries. The clinical diagnosis including fracture of the left proximal humerus, the left clavicle, and the left scapula, left axillary artery rupture, and left brachial plexus injury. We successfully performed open reduction and internal fixation of the fracture and vascular repair. The patient showed satisfactory recovery that was observed during 4-mo follow-up. CONCLUSION Emergency surgery can be an effective therapeutic option for the closed floating shoulder with catastrophic axillary artery injury.

The aim of this study was to explore the relationships among gut microbiota disturbances and serum and spinal cord metabolic disorders in neuropathic pain. 16S rDNA amplicon sequencing and serum and spinal cord metabolomics were used to identify alterations in the microbiota and metabolite profiles in the sham rats and the chronic constriction injury (CCI) model rats. Correlations between the abundances of gut microbiota components at the genus level, the levels of serum metabolites, and pain-related behavioural parameters were analysed. Ingenuity pathway analysis (IPA) was applied to analyse the interaction networks of the differentially expressed serum metabolites. First, we found that the composition of the gut microbiota was different between rats with CCI-induced neuropathic pain and sham controls. At the genus level, the abundances of Helicobacter, Phascolarctobacterium, Christensenella, Blautia, Streptococcus, Rothia and Lactobacillus were significantly increased, whereas the abundances of Ignatzschineria, Butyricimonas, Escherichia, AF12, and Corynebacterium were significantly decreased. Additionally, 72 significantly differentially expressed serum metabolites and 17 significantly differentially expressed spinal cord metabolites were identified between the CCI rats and the sham rats. Finally, correlation analysis showed that changes in the gut microbiota was significantly correlated with changes in serum metabolite levels, suggesting that dysbiosis of the gut microbiota is an important factor in modulating metabolic disturbances in the context of neuropathic pain. In conclusion, our research provides a novel perspective on the potential roles of the gut microbiota and related metabolites in neuropathic pain.

An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r2 ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.

Deficits in fragile X mental retardation 1 protein lead to fragile X syndrome (FXS) with mental retardation and social activity disorder. Until now, the neuronal circuits that mediate the social impairments of FXS were mostly unclear. Accidently, we found fewer c-fos expression in RSG of KO than WT mice after social behavior test. Inactivation of RSG neurons decreased social novelty but not the sociability of naive mice. Interestingly, although the RSG neurons of KO mice had higher background activity, fewer social contact-related Ca2+ neurons were observed during social interaction test via one-photon Ca2+ imaging in freely-behaving mice. Strikingly, enhancing the activity of RSG neurons rescued the abnormal social novelty in KO mice. Further studies proved that the innervations from the subiculum and ACC to RSG contributes to the social behavior. Take together, we found that abnormal activity in the retrosplenial granular cortex (RSG) led to social novelty deficits in Fmr1-knockout (KO) mice. Moreover, selective manipulation of RSG neurons may be an effective strategy to treat the social deficits in FXS.One Sentence SummaryDeletion of FMRP leads to lower social-related neuronal activity in the RSG; this causes social novelty deficits in Fmr1-KO mice.

Background Ramsay Hunt syndrome (RHS) is caused by a reactivation of varicella-zoster virus (VZV) infection, and it is characterized by the symptoms of facial paralysis, otalgia, auricular rash, and/or an oral lesion. Elderly patients or immunocompromised patients, deep pain at the initial visit and no prompt treatment are significant predictors of postherpetic neuralgia (PHN). When PHN occurs, especially involved cranial polyneuropathy, multiple modalities should be administered for patients with the intractable PHN. The use of thermography in the follow-up of PHN secondary to RHS with multicranial nerve involvement has not yet been described yet in the literature. Case presentation The patient was a 78-year-old man with the chief complaint of a 3-month history of PHN secondary to RHS with polycranial nerve (V, VII, VIII, and IX) involvement. Multimodality therapy with oral gabapentin, pulsed radiofrequency (PRF) application to the Gasserian ganglion for pain in the trigeminal nerve region, linear-polarized near-infrared light irradiation for pain in the facial nerve region, and 2% lidocaine spray for pain in the glossopharyngeal nerve region was used to the treat patient, and follow-up evaluations included thermography. This comprehensive treatment obviously improved the quality of life, resulting in considerable pain relief, as indicated by a decrease in the numerical rating scale (NRS) score from 9 to 3 and a decrease in thermal imaging temperature from higher to average temperature on the ipsilateral side compared with the contralateral side. Lidocaine spray on the tonsillar branches of the glossopharyngeal nerve resulted in an improvement in odynophagia, and the NRS score decreased from 9 to 0 for glossopharyngeal neuralgia after three applications. Conclusion Although the use of thermography in the follow-up of RHS with multiple cranial nerve (V, VII, VIII, and IX) involvement is very rare, in this patient, thermal imaging showed the efficacy of combination therapy (oral gabapentin, 2% lidocaine sprayed, PRF application and linear-polarized near-infrared light irradiation) and that is a good option for treatment.

Background Acute kidney injury (AKI) is an important complication of severe acute pancreatitis (SAP) with a poor prognosis. The methyl ester of (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), an inhibitor of macrophage migration inhibitory factor (MIF), has protective effects against many diseases. Our previous study confirmed MIF inhibition alleviated SAP. Here, we explored the effects of ISO-1 in an experimental mouse model of SAP-associated AKI induced by l -arginine. Methods Mice were randomly divided into four treatment groups (n = 6 each): control (CON), SAP, SAP + ISO-1, and ISO-1. Histopathologic examination was used to observe damage in pancreatic and renal tissues. Biochemical and enzyme-linked immunosorbent assays (ELISA) kits were used to measure the serologic indicators amylase, lipase, creatinine, uric acid, interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Immunohistochemistry was used to detect protein expression of NLRP3, ASC and caspase-1, and the infiltration of myeloperoxidase (MPO)-positive neutrophils in kidney tissue. Western blotting was used to detect NLRP3, ASC and caspase-1 and IL-1β protein expression, and real-time PCR was used to measure MIF, IL-6, TNF-α, IL-1β and IL-18 mRNA levels in kidney tissue. Results ISO-1 treatment alleviated pathological damage in pancreatic and renal tissues, and reduced the serum levels of amylase, lipase, creatinine, uric acid, IL-6 and TNF-α. ISO-1 also reduced protein expression of NLRP3, ASC, caspase-1 and IL-1β, mRNA expression of MIF, IL-6, TNF-α, IL-1β and IL-18, and the infiltration of MPO-positive neutrophils in kidney tissue. Conclusion ISO-1 has a protective effect against experimental SAP-associated AKI. And the mechanism may be associated with ISO-1 inhibiting NLRP3 inflammasome signaling pathway.

Background Liver injury is one of the most common complications during sepsis. Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine. This study explored the role of MIF in the lipopolysaccharide (LPS)-induced liver injury through genetically manipulated mouse strains. Methods The model of LPS-induced liver injury was established in wild-type and Mif-knockout C57/BL6 mice. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) were detected, and the expressions of MIF, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured. Liver histopathology was conducted to assess liver injury. Moreover, the inhibitions of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and 4-iodo-6-phenylpyrimidine (4-IPP) were used to evaluate their therapeutic potential of liver injury. Results Compared with wild-type mice, the liver function indices and inflammation factors presented no significant difference in the Mif−/− mice. After 72 h of the LPS-induced liver injury, serum levels of ALT, AST, and TBil as well as TNF-α and IL-1β were significantly increased, but the knockout of Mif attenuated liver injury and inflammatory response. In liver tissue, mRNA levels of TNF-α, IL-1β and NF-κB p65 were remarkably elevated in LPS-induced liver injury, while the knockout of Mif reduced these levels. Moreover, in LPS-induced liver injury, the inhibitions of MIF with ISO-1 and 4-IPP alleviated liver injury and slightly attenuated inflammatory response. Importantly, compared to mice with LPS-induced liver injury, Mif knockout or MIF inhibitions significantly prolonged the survival of the mice. Conclusions In LPS-induced liver injury, the knockout of Mif or MIF inhibitions alleviated liver injury and slightly attenuated inflammatory response, thereby prolonged the survival of the mice. Targeting MIF may be an important strategy to protect the liver from injury during sepsis.

Insulin resistance promotes the occurrence of liver cancer and decreases its chemosensitivity. Rosiglitazone (ROSI), a thiazolidinedione insulin sensitiser, could be used for diabetes with insulin resistance and has been reported to show anticancer effects on human malignant cells. In this paper, we investigated the combination of ROSI and chemotherapeutics on the growth and metastasis of insulin-resistant hepatoma. In vitro assay, ROSI significantly enhanced the inhibitory effects of adriamycin (ADR) on the proliferation, autophagy and migration of insulin-resistant hepatoma HepG2/IR cells via downregulation of EGFR/ERK and AKT/mTOR signalling pathway. In addition, ROSI promoted the apoptosis of HepG2/IR cells induced by ADR. In vivo assay, high fat and glucose diet and streptozotocin (STZ) induced insulin resistance in mice by increasing the body weight, fasting blood glucose (FBG) level, oral glucose tolerance, fasting insulin level and insulin resistance index. Both the growth of mouse liver cancer hepatoma H22 cells and serum FBG level in insulin resistant mice were significantly inhibited by combination of ROSI and ADR. Thus, ROSI and ADR in combination showed a stronger anti-tumour effect in insulin resistant hepatoma cells accompanying with glucose reduction and might represent an effective therapeutic strategy for liver cancer accompanied with insulin resistant diabetes.

BackgroundHerpangina is a highly infectious disease, which is usually prevalent in preschool children.MethodsThis study analyzed the clinical and pathogenic characteristics of herpangina children to demonstrate the epidemiology of herpangina. Clinical manifestations, laboratory indicators and pharyngeal swabs were collected from children with herpangina who were monitored by Tongzhou Center for Disease Control and Prevention in Beijing, 2008. Utilizing pharyngeal swabs, virus extraction and amplification were performed for nucleotide identification and sequencing. The phylogenetic analysis was conducted based on all sequences amplified in this study and strains retrieved from GenBank.ResultsAmong 190 children with herpangina, 69.0% (131/190) were positive for enterovirus. Eight genotypes were identified, mainly including CV-A6 (39/131), CV-A4 (25/131), CV-A10 (24/131). The phylogenetic analysis showed one CV-A6 strain of Tongzhou was imported from Japan. CV-A10 strains were clustered into five groups (A-E). The dominant cluster of CV-A10 was Group E6 between 2009 and 2013, and converted to Group E5 after 2013. CV-A6 was the predominant pathogen causing herpangina in Tongzhou in 2018, followed by CV-A4 and CV-A10.ConclusionsThe circulation of coxsackievirus had spatiotemporal cluster. In controlling the transmission of herpangina, the surveillance and reporting system should be enhanced.

Lu Lu,1 Hongyuan Chen,2 Longkun Wang,1 Lin Zhao,3 Yanna Cheng,3 Aijun Wang,4 Fengshan Wang,1 Xinke Zhang3 1Key Laboratory of Chemical Biology (Ministry of Education), Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of General Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 4Surgical Bioengineering Laboratory, Department of Surgery, UC Davis Health Medical Center, Sacramento, CA, USACorrespondence: Fengshan Wang; Xinke ZhangSchool of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, No. 44 Wenhuaxi Road, Jinan 250012, People’s Republic of ChinaTel/Fax +86 531 88382490Email fswang@sdu.edu.cn; zhangxinke@sdu.edu.cnPurpose: Vascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin-1 (NRP-1) are two prominent synergistic receptors overexpressed on new blood vessels in glioma and may be promising targets for antiglioma therapy. The aim of this study was to design a dual receptor targeting and blood-brain barrier (BBB) penetrating peptide-modified polyethyleneimine (PEI) nanocomplex that can efficiently deliver the angiogenesis-inhibiting secretory endostatin gene (pVAXI-En) to treat glioma.Materials and Methods: We first constructed the tandem peptide TAT-AT7 by conjugating AT7 to TAT and evaluated its binding affinity to VEGFR-2 and NRP-1, vasculature-targeting ability and BBB crossing capacity. Then, TAT-AT7-modified PEI polymer (PPTA) was synthesized, and a pVAXI-En-loaded PPTA nanocomplex (PPTA/pVAXI-En) was prepared. The physicochemical properties, cytotoxicity, transfection efficiency, capacities to cross the BBB and BTB (blood-tumor barrier) and glioma-targeting properties of PPTA/pVAXI-En were investigated. Moreover, the in vivo anti-angiogenic behaviors and anti-glioma effects of PPTA/pVAXI-En were evaluated in nude mice.Results: The binding affinity of TAT-AT7 to VEGFR-2 and NRP-1 was approximately 3 to 10 times greater than that of AT7 or TAT. The cellular uptake of TAT-AT7 in endothelial cells was 5-fold and 119-fold greater than that of TAT and AT7 alone, respectively. TAT-AT7 also displayed remarkable efficiency in penetrating the BBB and glioma tissue in vivo. PPTA/pVAXI-En exhibited lower cytotoxicity, stronger BBB and BTB traversing abilities, higher selective glioma targeting and better gene transfection efficiency than PEI/pVAXI-En. More importantly, PPTA/pVAXI-En significantly suppressed the tube formation and migration of endothelial cells, inhibited glioma growth, and reduced the microvasculature in orthotopic U87 glioma-bearing nude mice.Conclusion: Our study demonstrates that PPTA/pVAXI-En can be exploited as an efficient dual-targeting nanocomplex to cross the BBB and BTB, and hence it represents a feasible and promising nonviral gene delivery system for effective glioma therapy.Keywords: VEGFR-2 and NRP-1 targeting, glioma penetration, multifunctional peptide, anti-angiogenesis, gene delivery system

PurposeBiomechanical comparison of wedge and biconcave deformity of different height restoration after augmentation of osteoporotic vertebral compression fractures was analyzed by three-dimensional finite element analysis (FEA).MethodsThree-dimensional finite element model (FEM) of T11-L2 segment was constructed from CT scan of elderly osteoporosis patient. The von Mises stresses of vertebrae, intervertebral disc, facet joints, displacement, and range of motion (ROM) of wedge and biconcave deformity were compared at four different heights (Genant 0–3 grade) after T12 vertebral augmentation.ResultsIn wedge deformity, the stress of T12 decreased as the vertebral height in neutral position, flexion, extension, and left axial rotation, whereas increased sharply in bending at Genant 0; L1 and L2 decreased in all positions excluding flexion of L2, and T11 increased in neutral position, flexion, extension, and right axial rotation at Genant 0. No significant changes in biconcave deformity. The stress of T11-T12, T12-L1, and L1-L2 intervertebral disc gradually increased or decreased under other positions in wedge fracture, whereas L1-L2 no significant change in biconcave fracture. The utmost overall facet joint stress is at Genant 3, whereas there is no significant change under the same position in biconcave fracture. The displacement and ROM of the wedge fracture had ups and downs, while a decline in all positions excluding extension in biconcave fracture.ConclusionsThe vertebral restoration height after augmentation to Genant 0 affects the von Mises stress, displacement, and ROM in wedge deformity, which may increase the risk of fracture, whereas restored or not in biconcave deformity.

Qian-Kun Yang,1,* Yan-Na Su,2,* Wei Wang,1,* Nan Wang,3 Zhong-Xiang Yao,4,* Xiao-Jing Zhang1 1Department of Bone and Soft Tissue Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of China; 2Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110042, People’s Republic of China; 3Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of China; 4Department of Physiology, Army Medical University, Chongqing 400038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Jing ZhangDepartment of Bone and Soft Tissue Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of ChinaEmail zhangxiaojing@cancerhosp-ln-cmu.comBackground: Nutritional and immune status is paramount for the overall survival (OS) of patients with advanced osteosarcoma. Comprehensive prognostic predictors based on the two indices are scarce. This study aimed to construct and validate individualized web dynamic nomograms based on CONUT score or/and peripheral blood CD4+/CD8+ ratio for OS in patients with advanced osteosarcoma.Materials and Methods: The clinical data of 376 advanced osteosarcoma patients from January 2000 to December 2019 were retrospectively collected. Data from the 301 patients (diagnosed in the first 15 years) were used as the development set and data from the remaining 75 patients were assigned as the validation set. Multivariate Cox regression analyses were conducted and three prediction models were constructed, namely, CD4+/CD8+ ratio univariate model (model 1), CONUT score univariate model (model 2), and CD4+/CD8+ ratio plus CONUT score (model 3). These models were visualized by conventional nomograms and individualized web dynamic nomograms, and their performances were further evaluated by C-index, calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA), respectively.Results: In multivariate Cox analysis, age, metastasis, ALP, CD4+/CD8+ ratio, chemotherapy, and CONUT score were identified as independent prognostic factors for OS. The calibration curves of the three models all showed good agreement between the actual observation and nomogram prediction for 1-year overall survival. In the development set, the C-index and area under the curve (AUC) of model 3 (0.837, 0.848) were higher than that of model 1 (0.765, 0.773) and model 2 (0.712, 0.749). Similar trends were observed in the validation set. The net benefits of model 3 were better than the other two models within the threshold probability of 36– 80% in DCA.Conclusion: CONUT score and peripheral CD4+/CD8+ ratio are easily available, reliable, and economical prognostic predictors for survival prediction and stratification in patients with advanced osteosarcoma, but the two predictors combined can establish a better prognosis prediction model.Keywords: CONUT score, osteosarcoma, survival, nomogram

Management of chronic pain is still hard, and new analgesic drugs are needed. Evodiamine (Evo) and rutaecarpine (Rut) are two major active components of Evodia rutaecarpa, a Chinese traditional medicine that has been used as an analgesic for a long time. However, their effects on peripheral hypersensitivity remain unknown. Similar to capsaicin, the Evo and Rut were docked to the transient receptor potential cation channel subfamily V member 1 (TRPV1) in molecular simulation experiments. Moreover, Evo (10 µM) and Rut (50 µM) activated TRPV1 on human embryonic kidney 293 (HEK293) cells in electrophysiological recording experiments. Behaviorally, the application of Evo and Rut reduced peripheral hypersensitivity in a dose-dependent manner, which was blocked by capsazepine (a selective inhibitor of TRPV1). Furthermore, both Evo and Rut increased time in the open arms of the elevated plus maze on mice with nerve injury. These observations suggested that Evo and Rut reduced peripheral hypersensitivity and anxiety in mice with nerve injury or inflammation via TRPV1.

To evaluate the association between congenital missing of maxillary lateral incisor (MLI) with cervical vertebral body fusions, posterior arch deficiency, and both anomalies. A total of 64 subjects (24 males and 40 females; mean age 16 ± 4.5 years) were detected to have congenital missing of MLI and selected as a study group. Two hundred and fifty-six subjects (87 males and 169 females, mean age 18.1 ± 3.2 years) were assigned to the control group. In the congenital absence of MLI, 53.7% revealed cervical column body fusion, 11.1% indicated a posterior arch deficiency, and 9.3% showed cervical column body fusion with posterior arch deficiency. Morphological deviations of the cervical column showed significant associations with congenital absence of MLI compared to control group (p 0.05). Subjects with congenial MLI tend to have an increased frequency of cervical anomaly.

Two novel Ru(ii) polypyridyl complexes bearing imidazo-phenanthroline conjugated hydroxybenzoic acid groups were designed to enhance the tumor targeting ability as photosensitizers for photodynamic therapy. [Ru(bpy)2(phcpip)] (ClO4)2 (Ru-1) and [Ru(bpy)2(ohcpip)] (ClO4)2 (Ru-2) (bpy = 2,2'-bipyridine; phcpip = 2-(3-carboxyl-4-hydroxyphenyl) imidazo [4,5-f]phenanthroline; ohcpip = 2-(2-hydroxyl-3-carboxyphenyl) imidazo [4,5-f] [1,10] phenanthroline) were synthesized and their photodynamic antitumor activities were investigated. Both complexes displayed high photocytotoxicity toward cancerous cell lines HepG2, A549, MCF-7, and MDA-MB-231, but low photocytotoxicity toward normal cell lines GES-1 and Huvec. They were mainly localized at the nucleus of HepG2 cells after 24 h incubation, arrested the cell cycle at the G2/M phase and induced cancer cell apoptosis through reactive oxygen species (ROS) mediated pathways. Tumor targeting of the complexes is attributed to stronger molecular binding to DNA.

Microvesicles (MVs) have been shown to be involved in pathophysiology of ischemic heart diseases. However, the underlying mechanisms are still unclear. Here we investigated the effects of MVs derived from ischemic preconditioning (IPC-MVs) on myocardial ischemic/reperfusion (I/R) injury in rats. Myocardial IPC model was elicited by three cycles of ischemia and reperfusion of the left anterior descending (LAD) coronary artery. IPC-MVs from the peripheral blood of the above animal model were isolated by ultracentrifugation and characterized by flow cytometry and transmission electron microscopy. IPC-MVs were administered intravenously (7 mg/kg) at 5 min before reperfusion procedure in I/R injury model which was induced by 30-min ischemia and 120-min reperfusion of LAD in rats. We found that total IPC-MVs and different phenotypes, including platelet-derived MVs (PMVs), endothelial cell-derived MVs (EMVs), leucocyte-derived MVs and erythrocyte-derived MVs (RMVs) were all isolated which were identified membrane vesicles (

Previous studies demonstrated that SIP-SII, a sulfated derivative of SIP that is isolated from the ink of Sepiella maindroni, showed significant inhibition of tumor growth and metastasis. In this study, the effects of SIP-SII on the migration, invasion and molecular mechanism in ovarian cancer cell line, SKOV-3 cells, were investigated. The flow cytometry, confocal microscope observation, western blot and RT-PCR results indicated that SIP-SII located on cell membrane and inhibited the expression and activation of epidermal growth factor receptor (EGFR). Moreover, the binding capacity of SIP-SII with EGFR was confirmed by surface plasmon resonance (SPR) analysis and co-localization of EGFR and SIP-SII. Accordingly, SIP-SII was proved to attenuate the EGF-induced EGFR phosphorylation and migration by western blot and wound healing assay, respectively. Additionally, SIP-SII inhibited p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells significantly. What is more, SIP-SII showed amplified inhibitory activity on migration, invasion, and MMP-2 expression in combination with p38-specific inhibitor, PI3K-specific inhibitor or mTOR-specific inhibitor in SKOV-3 cells. Therefore, the mechanism that SIP-SII suppressed EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways to inhibit migration and invasion of SKOV-3 cells was demonstrated. These findings suggested that SIP-SII might be used as a potential inhibitor against tumor metastasis.

Multidrug resistance (MDR) is one of major obstacles to effective chemotherapeutic treatment of cancer. This study showed that DHPAC, 2-(6-ethoxy-3-(3-ethoxyphenylamino) -1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy) acetamide, a novel compound that binds to the same site on microtubules as colchicine, has high anti-tumour activity in vincristine-resistant oral epidermoid carcinoma (KB/V) cells. It found that the presence of DHPAC strongly inhibited KB/V cell growth in vivo and in mice xenograft. The inhibitory effect of DHPAC is much stronger than that by colchicine in these KB/V cells (IC50: 64.4nM and 458.0nM respectively). Treatment of the cells with DHPAC induced cell apoptosis by reducing mitochondrial membrane potential and altered the expression of several apoptosis-related proteins such as Bcl-2, Bax, Caspase-9, Cytochrome c and PARP. DHPAC treatment also caused cell rest in G2/M phase by regulating of the expression of a number of cell cycle-related proteins (e.g. Cyclin B1, Cdc2, Cdc25b, Cdc25c, RSK2). Furthermore, DHPAC presence inhibits PTEN phosphorylation and PTEN/Akt/NF-κB signalling. Thus, DHPAC has potent anti-cancer activity in MDR tumuors and may be a potential therapeutic agent for the treatment of vincristine-resistant human oral epidermoid carcinoma.

ATP-sensitive K+ (K-ATP) channels play significant roles in regulating the excitability of dopamine neurons in the substantia nigra zona compacta (SNC). We showed previously that K-ATP channel function is up-regulated by AMP-activated protein kinase (AMPK). This study extended these studies to the neurons adjacent to the SNC in the ventral tegmental area (VTA). Using patch pipettes to record whole-cell currents in slices of rat midbrain, we found that the AMPK activator A769662 increased the amplitude of currents evoked by the K-ATP channel opener diazoxide in presumed dopamine-containing VTA neurons. However, current evoked by diazoxide with A769662 was significantly smaller in VTA neurons compared to SNC neurons. Moreover, a significantly lower proportion of VTA neurons responded to diazoxide with outward current. However, A769662 was able to increase the incidence of diazoxide-responsive neurons in the VTA. In contrast, A769662 did not potentiate diazoxide-evoked currents in presumed non-dopamine VTA neurons. These results show that AMPK activation augments K-ATP currents in presumed dopamine neurons in the VTA and SNC, although diazoxide-evoked currents remain less robust in the VTA. We conclude that K-ATP channels may play important physiological roles in VTA and SNC dopamine neurons.

To explore the potential mechanisms of glutamate and its receptors in stress-induced hyperalgesia.The stress-induced hyperalgesia, glutamate and its receptors are listed as key items in the pubmed database and the related articles are searched.Glutamate level is increased under stress and associated with stress-induced hyperalgesia. Moreover, the role of glutamate in stress-induced hyperalgesia depends on its subtypes of its receptors.Increased glutamate during stress connect with ionotropic glutamate receptors can prompt hyperalgesia, but connect with metabotropic glutamate receptors can inhibit hyperalgesia.

Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC ); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the ‘two-hit’ event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC., The pathogenesis of oesophageal squamous cell carcinoma is a multi-step process but the genetic determinants behind this progression are unknown. Here the authors use multi-region exome sequencing to comprehensively investigate the genetic evolution of precursor dysplastic lesions and untransformed oesophagus.