Search

To investigate the effect of mouse nerve growth factor (mNGF) on axonal injury after traumatic brain injury (TBI) combined with seawater drowning (SWD) in rats and the possible mechanism, we assigned 78 SD rats by random into sham group (Group A, n = 14), TBI+SWD group (Group B, n = 32), and mNGF group (Group C, n = 32). The compound injury model of rats was established by Marmarou method (450 g×1.5 m) and intratracheal pumping seawater (3 ml/kg). Rats in Group C were subject to intraperitoneal injection of mNGF (3 ug/kg) immediately after injury, and Group A as well as Group B were intraperitoneally injected the same amount of normal saline. Modified neurological severity scores(mNSS) was performed on rats at 12 h, 24 h, 72 h as well as 168 h, respectively after injury. HE staining showed that 24 h after injury, the swelling of nerve cells in Group C was relatively milder and the tissue edema was similar to that in Group B. At 72 h and 168 h after injury, the matrix looseness, cell swelling, and nuclear condensation in Group C were improved in comparison with Group B. (2) Compared with group B, mNSS of group C decreased signally at 72 h and 68 h after injury (P β-APP, NF-L, and AQP4 were decreased in Group C in comparison with Group B at 12 h, 24 h, 72 h and 168 h after injury. (4) Brain water content in Group C was similar to that in Group B (P >0.05). (5) At 12 h after injury, the expression of TNF-α in Group C was signally lower than that in Group B (P < 0.05). Our reseache showed that mNGF might play a neuroprotective role by reducing cerebral edema and inflammatory response after TBI+SWD injury in rats, thereby restoring part of the injured axons in TBI+SWD rats.

Background There is a lack of targeted therapeutic options for squamous cell lung cancer (SCC). Accelerated hypertension is an issue with many targeted therapies for lung cancer. This study aimed to analyze the efficacy of anlotinib, based on progression‐free survival (PFS) and overall survival (OS) in patients with SCC, stratified by hypertension and Eastern Cooperative Oncology Group (ECOG) score. Methods This was a post hoc analysis of a multicenter, double‐blind, phase III ALTER0303 randomized controlled trial. Only patients with SCC were included. The occurrence of hypertension during the study period was defined according to CTCAE 4.03. OS and PFS were the primary and secondary endpoints, respectively. The patients were stratified according to hypertension and ECOG score, respectively. Results The median PFS in the patients who developed hypertension was longer than in those who did not (7.2 (95% CI: 3.5–11.0) versus 3.2 (95% CI: 1.2–5.3) months, p = 0.001; HR (95% CI), 0.4 (0.2–0.8)). In the ECOG 0 patients, the median PFS in the patients who developed hypertension versus those who did not was 5.6 vs. 1.8 months, respectively (Figure 2(d)). In the ECOG 1 patients, the median PFS in the patients who developed hypertension versus those who did not was 7.0 (95% CI: 3.0–11.0) vs. 4.8 (95% CI: 1.2–8.5) months (p = 0.043). No statistically significant differences were found in OS in the stratified analyses. Conclusions The occurrence of hypertension might be a clinical indicator predicting the efficacy of third‐line anlotinib treatment in patients with SCC., In SCC patients who received third‐line anlotinib treatment, the median PFS was longer in patients who developed hypertension than in those who did not. Our results suggest that the occurrence of hypertension during treatment might be a clinical indicator predicting the efficacy of third‐line anlotinib in patients with SCC.

The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) poses a growing challenge in terms of its prevention and treatment. The ‘multiple hits’ hypothesis of multiple insults, such as dietary fat intake, de novo lipogenesis, insulin resistance, oxidative stress, mitochondrial dysfunction, gut dysbiosis and hepatic inflammation, can provide a more accurate explanation of the pathogenesis of NAFLD. Betaine plays important roles in regulating the genes associated with NAFLD through anti-inflammatory effects, increased free fatty oxidation, anti-lipogenic effects and improved insulin resistance and mitochondrial function; however, the mechanism of betaine remains elusive.

A severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected more than 25.6 million and killed 852,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry. Currently, extensive efforts are being made to produce vaccines against a surface fragment of a SARS-CoV-2, such as the spike protein, in order to boost protective antibody responses. It was previously unknown how spike protein-targeting antibodies would affect innate inflammatory responses to SARS-CoV-2 infections. Here we generated a highly purified recombinant protein corresponding to the RBM of SARS-CoV-2, and used it to screen for cross-reactive monoclonal antibodies (mAbs). We found two RBM-binding mAbs that competitively inhibited its interaction with human ACE2, and specifically blocked the RBM-induced GM-CSF secretion in both human monocyte and murine macrophage cultures. Our findings have suggested a possible strategy to prevent SARS-CoV-2-elicited “cytokine storm”, and provided a potentially useful criteria for future assessment of innate immune-modulating properties of various SARS-CoV-2 vaccines., One Sentence Summary: RBM-binding Antibodies Inhibit GM-CSF Induction.

Acute traumatic intraparenchymal hematoma (tICH) expansion is a devastating neurological complication that is associated with poor outcome after cerebral contusion. This study aimed to develop and validate a novel noncontrast computed tomography (CT) (NCCT) multihematoma fuzzy sign to predict acute tICH expansion. In this multicenter, prospective cohort study, multihematoma fuzzy signs on baseline CT were found in 212 (43.89%) of total 482 patients. Patients with the multihematoma fuzzy sign had a higher frequency of tICH expansion than those without (90.79% (138) vs. 46.71% (71)). The presence of multihematoma fuzzy sign was associated with increased risk for acute tICH expansion in entire cohort (odds ratio [OR]: 16.15; 95% confidence interval (CI) 8.85–29.47; P

Nonalcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in developing countries. The pathogenesis is complex, and there is currently no effective treatment. Betaine is an essential intermediate in choline catabolism and an important component of the methionine cycle. Betaine deficiency is associated with NAFLD severity, and its mechanism needs to be further elaborated. In this study, an NAFLD mouse model was established by feeding ApoE−/− mice a high-fat diet. The effects of betaine on NAFLD were investigated, including its mechanism. In this study, after treatment with betaine, blood lipid levels and liver damage were significantly decreased in the NAFLD mouse model. The fat infiltration of the liver tissues of high-fat diet (HFD)-fed mice after betaine administration was significantly improved. Betaine treatment significantly upregulated AMP-activated protein kinase (AMPK), fibroblast growth factor 10 (FGF10), and adipose triglyceride lipase (ATGL) protein levels both in vivo and in vitro and suppressed lipid metabolism-related genes. Furthermore, the overexpression of FGF10 increased the protein level of AMPK and decreased lipid accumulation in HepG2 cells. Taken together, the data strongly suggest that betaine significantly prevents high-fat diet-induced NAFLD through the FGF10/AMPK signaling pathway in ApoE−/− mice.

Background Anlotinib showed significant survival benefits in advanced non‐small cell lung cancer (NSCLC) patients as a third‐ or further‐line treatment in the ALTER0303 trial. We aimed to evaluate the efficacy of anlotinib in patients with different histologies. Methods The ALTER0303 trial was a randomized, open‐label, phase 3 study of anlotinib in NSCLC patients previously treated with at least two lines of chemotherapy or a tyrosine kinase inhibitor (TKI) in 31 centers in China. Patients were randomly assigned at a 2:1 ratio to receive anlotinib (12 mg QD from days 1 to 14 of a 21‐day cycle) or placebo until progression or intolerable toxicity. The primary endpoint was overall survival (OS). We assessed the efficacy of anlotinib in histological subgroups in the full analysis set. Results In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. In the ACC subgroup, the median OS time was significantly improved with anlotinib compared with placebo (9.6 months vs 6.9 months, P = .0051), as was the median progression‐free survival (PFS) time (5.5 months vs 1.4 months, P, In this study, we evaluated the efficacy of anlotinib as third‐ or further‐line treatment for patient with different histological types of NSCLC. In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. Our findings suggest that anlotinib significantly improves PFS and OS in ACC patients and has a tendency to prolong survival in SCC patients.

While pregnancy increases the risk for severe COVID19, the clinical and immunological implications of COVID19 on maternal-fetal health remain unknown. Here, we present the clinical and immunological landscapes of 93 COVID19 mothers and 45 of their SARS-CoV-2-exposed infants through comprehensive serum proteomics profiling for >1400 cytokines of their peripheral and cord blood specimens. Prenatal SARS-CoV-2 infection triggers NF-κB-dependent proinflammatory immune activation. Pregnant women with severe COVID19 show increased inflammation and unique IFNλ antiviral signaling, with elevated levels of IFNL1 and IFNLR1. Furthermore, SARS-CoV-2 infection re-shapes maternal immunity at delivery altering the expression of pregnancy complication-associated cytokines, inducing MMP7, MDK, ESM1, and reducing BGN and CD209. Finally, COVID19-exposed infants exhibit induction of T cell-associated cytokines (IL33, NFATC3 and CCL21), while some undergo IL-1β/IL-18/CASP1 axis-driven neonatal respiratory distress despite birth at term. Our findings demonstrate COVID19-induced immune rewiring in both mothers and neonates, warranting long-term clinical follow-up to mitigate potential health risks., Graphical Abstract, The study performed by Foo et al. unveils distinct immune alterations of mothers and infants induced by SARS-CoV-2 infection during pregnancy. These findings highlight the importance of long-term post-pregnancy clinical follow-up of mother-infant dyads to prevent potential unforeseen health conditions following prenatal SARS-CoV-2 infection.

Tumor-derived exosomes play a vital role in the process of cancer development. Quantitative analysis of exosomes and exosome-shuttled proteins would be of immense value in understanding cancer progression and generating reliable predictive biomarkers for cancer diagnosis and treatment. Recent studies have indicated the critical role of exosomal programmed death ligand 1 (PD-L1) in immune checkpoint therapy and its application as a patient stratification biomarker in cancer immunotherapy. Here, we present a nanoplasmonic exosome immunoassay utilizing gold-silver (Au@Ag) core-shell nanobipyramids and gold nanorods, which form sandwich immune complexes with target exosomes. The immunoassay generates a distinct plasmonic signal pattern unique to exosomes with specific exosomal PD-L1 expression, allowing rapid, highly sensitive exosome detection and accurate identification of PD-L1 exosome subtypes in a single assay. The developed nanoplasmonic sandwich immunoassay provides a novel and viable approach for tumor cell-derived exosome detection and analysis with quantitative molecular details of key exosomal proteins, manifesting its great potential as a transformative diagnostic tool for early cancer detection, prognosis, and post-treatment monitoring.

Sepsis remains a common cause of death in intensive care units, accounting for approximately 20% of total deaths worldwide. Its pathogenesis is partly attributable to dysregulated inflammatory responses to bacterial endotoxins (such as lipopolysaccharide, LPS), which stimulate innate immune cells to sequentially release early cytokines (such as tumor necrosis factor (TNF) and interferons (IFNs)) and late mediators (such as high-mobility group box 1, HMGB1). Despite difficulties in translating mechanistic insights into effective therapies, an improved understanding of the complex mechanisms underlying the pathogenesis of sepsis is still urgently needed. Here, we review recent progress in elucidating the intricate mechanisms underlying the regulation of HMGB1 release and action, and propose a few potential therapeutic candidates for future clinical investigations. Published version

INTRODUCTION Acute traumatic intraparenchymal hematoma (tICH) expansion is a major cause of clinical deterioration after brain contusion. Here, an accurate prediction tool for acute tICH expansion is proposed. METHODS A multicenter hospital-based study for multivariable prediction model was conducted among patients (889 patients in a development dataset and 264 individuals in an external validation dataset) with initial and follow-up computed tomography (CT) imaging for tICH volume evaluation. Semi-automated software was employed to assess tICH expansion. Two multivariate predictive models for acute tICH expansion were developed and externally validated. RESULTS A total of 198 (22.27%) individuals had remarkable acute tICH expansion. The novel Traumatic Parenchymatous Hematoma Expansion Aid (TPHEA) model retained several variables, including age, coagulopathy, baseline tICH volume, time to baseline CT time, subdural hemorrhage, a novel imaging marker of multihematoma fuzzy sign, and an inflammatory index of monocyte-to-lymphocyte ratio. Compared with multihematoma fuzzy sign, monocyte-to-lymphocyte ratio, and the basic model, the TPHEA model exhibited optimal discrimination, calibration, and clinical net benefits for patients with acute tICH expansion. A TPHEA nomogram was subsequently introduced from this model to facilitate clinical application. In an external dataset, this device showed good predicting performance for acute tICH expansion. CONCLUSIONS The main predictive factors in the TPHEA nomogram are the monocyte-to-lymphocyte ratio, baseline tICH volume, and multihematoma fuzzy sign. This user-friendly tool can estimate acute tICH expansion and optimize personalized treatments for individuals with brain contusion.

Sepsis can be simulated in animals by perforating the cecum via a surgical procedure termed "cecal ligation and puncture" (CLP), which induces similar inflammatory responses as observed during the clinical course of human sepsis. In addition to anesthetic agents, many Institutional Animal Care and Use Committees often recommend the use of additional analgesic agents (such as opioid) to further augment the initial anesthetic effects. However, emerging evidence suggest that a commonly recommended opioid, buprenorphine, dramatically elevated circulating interleukin (IL)-6 levels, and reduced animal survival in male C57BL/6 mice, but not in female mice possibly due to the complex interference of estrous cycles, fueling an ongoing debate regarding the possible impact of analgesic administration on the sepsis-induced systemic inflammation. As per the recommendation of a local government agency, we performed a pilot study and confirmed that repetitive administration of buprenorphine indeed markedly elevated circulating levels of four sepsis surrogate markers (e.g., IL-6, KC, monocyte chemoattractant protein-1, and granulocyte-colony stimulating factor) in 20% to 60% of septic animals. This complication may adversely jeopardize our ability to use the CLP model to reliably simulate human sepsis, and to understand the complex mechanism underlying the pathogenesis of lethal sepsis. Thus, for experimental sepsis studies set to survey systemic inflammation and animal lethality at relatively later stages (e.g., at 24 h post CLP and beyond), we strongly recommend not to repetitively administer buprenorphine to eliminate its potential complication to animal sepsis models.

Endovascular treatment (EVT) is safe and effective for acute ischemic stroke (AIS) caused by large artery occlusion in the anterior circulation. However, some patients require decompressive craniectomy (DC), despite having undergone a timely EVT. This study aimed to evaluate the risk factors for subsequent DC after EVT. This retrospective cohort study comprised 138 patients who received EVT between April 2015 and June 2019 at our center. The need for subsequent DC was defined as cerebral edema or/and hemorrhagic transformation caused by large ischemic infarction, with a ≥ 5-mm midline shift and clinical deterioration after EVT. The relationship between risk factors and DC after EVT was assessed via univariate and multivariable logistic regression. Thirty (21.7%) patients required DC. These patients tended to have atrial fibrillation (P = 0.037), sedation (P = 0.049), mechanical ventilation (P = 0.008), poorer collateral circulation (P = 0.003), a higher baseline National Institutes of Health Stroke Scale (NIHSS) score (P

Aim Autophagy is a self-protective process, and it confers cancer cells resistance against radio-chemotherapeutics. To induce cancer cell death, a series of compounds of 3-((4-((7-chloroquinolin-4-yl)amino)butyl)amino)-7-substituted benzo[e][1,2,4]triazine 1-oxide or CQBTO containing two critical chemical groups were designed and synthesized. One compound, benzo[e][1,2,4]triazine 1-oxide, yielded free radicals to trigger autophagy, and the other one, chloroquine (CQ), was an inhibitor of autophagy. We hypothesized that the compounds could kill cancer cells effectively by inducing incomplete autophagy. Methods In vitro cultured non-small cell lung carcinoma cells and primary lung tumors in mice in vivo were used to test the lethal effects of CQBTO on cancer cells and toxicity to normal tissues. Cell viability was examined using the CCK8 assay. Genomic instability was determined with the cytochalasin B-blocked micronucleus assay. Cell cycle distribution was analyzed by propidium iodide staining and flow cytometry. Western blotting and immunofluorescence were used to detect the induction and localization of LC3, a biomarker for autophagy. Results Compared with CQ, three CQBTO compounds were lethal to lung cancer cells, and CQBTO-3 was the most effective. The LD50 for CQBTO-3 was 21 μΜ in A549 cells and 21.5 μΜ in Calu-1 cells, which was lower than that of CQBTO-2 or CQBTO-1. Induction of LC3 foci and an increase in the LC3II/LC3I ratio demonstrated the induction of autophagy by CQBTO-3 in A549 cells, whereas no obvious micronuclei or cell cycle arrest was observed. No detectable toxicity to normal mice was observed. CQBTO-3 improved the quality of mouse life, reduced the number and size of existing tumors, and suppressed tumor formation. Conclusion CQBTO-3 is a potential chemical compound for lung cancer treatment.

Objective The neutrophil to lymphocyte ratio (NLR) has been proposed to capture the inflammatory status of patients with various conditions involving the brain. This retrospective study aimed to explore the association between the NLR and the early growth of traumatic intracerebral haemorrhage (tICH) in patients with traumatic brain injury (TBI). Methods A multicentre, observational cohort study was conducted. Patients with cerebral contusion undergoing baseline computed tomography for haematoma volume analysis within 6 h after primary injury and follow‐up visits within 48 h were included. Routine blood tests were performed upon admission, and early growth of tICH was assessed. Prediction accuracies of the NLR for the early growth of tICH and subsequent surgical intervention in patients were analysed. Results There were a total of 1077 patients who met the criteria included in the study cohort. Univariate analysis results showed that multiple risk factors were associated with the early growth of tICH and included in the following multivariate analysis models. The multivariate logistic regression analysis results revealed that the NLR was highly associated with the early growth of tICH (p

BACKGROUND: Myocardial blood flow (MBF) quantitation with cadmium-zinc-telluride (CZT) dynamic single-photon emission computed tomography (SPECT) is being increasingly investigated toward clinical utilization. METHODS: In this prospective study, forty-nine patients with suspected or known coronary artery disease (CAD) underwent a rest/adenosine triphosphate (ATP) stress dynamic and routine gated myocardial perfusion imaging (MPI) by CZT SPECT and then received coronary angiography (CAG). Quantitative diagnosis from the dynamic SPECT and a flow diagram was automatically obtained by the dedicated software and compared with the result of semi-quantitative analysis with gated MPI using the angiographic stenosis as the reference standard. RESULTS: When stenosis ≥50% was considered at the participant level, the sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV) and accuracy (AC) of the quantitative diagnosis were higher than semi-quantitative method as (84.4% vs. 65.6%, 88.2% vs. 70.6%, 93.1% vs. 80.8%, 75.0% vs. 52.2%, 85.7% vs. 67.3%) (all P

Background There is an urgent need to develop a non-invasive imaging technique for detecting colorectal dysplasia and cancer. Technology for early and real-time microscopic assessments to select the most representative biopsy sites would also be of clinical value. In this study, we explored the sensitivity of optical coherence tomography (OCT) in detecting local lesions to demonstrate its potential for the early detection of colorectal dysplasia and cancer. Methods An azoxymethane/dextran sodium sulfate mouse model of colorectal carcinogenesis was utilized. Mice were imaged by OCT, and colorectal tissue sections were observed with hematoxylin and eosin staining. The results of the parallel analyses were compared to evaluate the performance of OCT in imaging and early screening of colorectal lesions. Results Dysplasia and cancer could be distinguished from normal colon tissues based on the OCT images. However, simple morphological changes observed in the OCT images were not sufficient to distinguish different degrees of dysplasia or distinguish dysplasia from cancerous tissues. The Youden index and diagnostic efficiency of OCT for colorectal dysplasia and cancer were 62.50% and 82.14%, respectively, while the sensitivity and specificity were 87.50% and 75.00%, respectively. Further, the positive and negative predictive values were 82.35% and 81.82%, respectively. Conclusions Based on our findings, we predict that OCT is a promising non-invasive imaging technique that can offer excellent positive detection rates and diagnostic accuracy for early colorectal dysplasia and cancer. This technique is expected to be valuable in realizing real-time qualitative analysis and guided targeted biopsy.

The development of abdominal aortic aneurysm (AAA) is attributed to psychological and physical factors. Topiramate, which is an agonist of the GABAA receptor, makes contributions to neuronal disease and is partially involved in immune regulation, may be effective upon abdominal aortic aneurysm progression. We used experimental abdominal aortic aneurysm models: Angiotensin II (Ang II)-induced ApoE-/- male mice (Ang II/APOE model) in our study. In the Ang II/APOE model, all mice (n=64) were divided into four groups: sham group (PBS treatment), control group (Ang II treatment), low-dose group (Ang II + low-dose topiramate, 3 mg/day per mouse), and high-dose group (Ang II + high-dose topiramate, 6 mg/day per mouse). All treatments began on the day after surgery. Moreover, collected tissues and cultured cell were used for histology and biochemical examination. In vitro, the effects of topiramate on bone marrow-derived macrophage stimulated by LPS were investigated. Our data implied that topiramate treatment significantly promoted macrophages preservation and conversion of M1 to M2 macrophage phenotypes in vivo and in vitro. Accordingly, proinflammatory activities mediated by the M1 macrophages were decreased and the repair process mediated by M2 macrophages was enhanced. The low-dose and high-dose groups had abdominal aortic aneurysm incidences of 50% and 37.5%, respectively, compared with 75% in the control group. Topiramate, a promising drug for the psychological disease, that target neuro-immune-induced macrophage polarization may attenuate experimental abdominal aortic aneurysm progression.

Purpose. To explore the potential of monocyte-to-lymphocyte ratio (MLR) at hospital admission for predicting acute traumatic intraparenchymal hematoma (tICH) expansion in patients with cerebral contusion. Patients and Methods. This multicenter, observational study included patients with available at-hospital admission (baseline) and follow-up computed tomography for volumetric analysis (retrospective development cohort: 1146 patients; prospective validation cohort: 207 patients). Semiautomated software assessed tICH expansion (defined as ≥33% or 5 mL absolute growth). MLR was acquired from routine blood tests upon admission. We constructed two predictive models: basic combined model of clinical and imaging variables and MLR combined model of both MLR and other variables in the basic model. Receiver operating characteristic (ROC) analysis and decision curve analysis (DCA) were used to estimate the performance of MLR for predicting acute tICH expansion. Results. MLR was significantly larger in patients with acute tICH expansion compared to those without acute tICH expansion (mean [SD], 1.08 [1.05] vs. 0.59 [0.37], P < 0.001 ). A nonlinear positive relationship between MLR and the incidence of acute tICH expansion was observed. Multivariate logistic regression indicated MLR as an independent risk factor for acute tICH expansion (odds ratio (OR), 5.88; 95% confidence interval (CI), 4.02-8.61). The power of the multivariate model for predicting acute tICH expansion was substantially improved with the inclusion of MLR (AUC 0.86 vs. AUC 0.74, P < 0.001 ), as was also observed in an external validation cohort (AUC 0.83 vs. AUC 0.71, P < 0.001 ). The net benefit of MLR model was higher between threshold probabilities of 20-100% in DCA. For clinical application, a nomogram derived from the multivariate model with MLR was introduced. In addition, MLR was positively associated with 6-month unfavorable outcome. Conclusion. MLR is a novel predictor for traumatic parenchymatous hematoma expansion. A nomogram derived from the MLR model may provide an easy-to-use tool for predicting acute tICH expansion and promoting the individualized treatment of patients with hemorrhagic cerebral contusion. MLR is associated with long-term outcome after cerebral contusion.

Mechanical overload of the vascular wall is a pathological hallmark of life-threatening abdominal aortic aneurysms (AAA). However, how this mechanical stress resonates at the unicellular level of vascular smooth muscle cells (VSMC) in AAA is undefined. Here, we combined novel ultrasound tweezers-based micromechancal system and single-cell RNA sequencing to map defective mechano-phenotype signature of VSMC niched in AAA. VSMC gradually adopted a mechanically solid-like state by upregulating cytoskeleton (CSK) crosslinker, α-actinin2, which stiffened VSMC cell membrane thereby directly powering the activity of mechano-sensory ion channel Piezo1 during AAA development. Theoretical modelling predicted that in AAA, such CSK alterations fueled cell membrane tension thereby blocking physiological mechanoallostatic responses of VSMC. Single-cell mechanical measurements and frequency spectrum analysis validated the mechanosensation deficiency in VSMC during AAA development. Our findings demonstrate that deviations of mechanosensation behaviors of VSMC is detrimental for AAA and identifies Piezo1 as a novel target to curb AAA onset.

BACKGROUND: There is an urgent need to develop a noninvasive imaging technique for the diagnosis of early inflammatory lesions or early and real-time microscopic assessment before selecting the most representative biopsy sites. METHODS: In this study, a dextran sulfate sodium colitis model was developed, and intestinal histological damage scores measured the degree of inflammation in colitis. According to these scores, 6 parameters were designed for hematoxylin and eosin (HE) sections based on morphological changes, and 2 parameters were designed for optical coherence tomography (OCT) images to measure submucosal edema by morphological changes to evaluate inflammation degrees in the colon. Spearman’s rank correlation method was used to compare the correlation between the submucosal morphological changes and the different degrees of inflammation. One-way analysis of variance (ANOVA) was used for comparisons among groups, while receiver operating characteristic (ROC) curves of the indicators in HE sections and OCT images were plotted. RESULTS: In HE sections, angle of mucosal folds (r=0.853, P

Arthritogenic alphaviruses cause debilitating inflammatory disease, and current therapies are restricted to palliative approaches. Here, we show that following monocyte-driven muscle inflammation, tissue recovery is associated with the accumulation of CX3CR1+ macrophages in the muscle. Modulating inflammatory monocyte infiltration using immune-modifying microparticles (IMP) reduced tissue damage and inflammation and enhanced the formation of tissue repair-associated CX3CR1+ macrophages in the muscle. This shows that modulating key effectors of viral inflammation using microparticles can alter the outcome of disease by facilitating the accumulation of macrophage subsets associated with tissue repair., Arthritogenic alphaviruses such as Ross River and Chikungunya viruses cause debilitating muscle and joint pain and pose significant challenges in the light of recent outbreaks. How host immune responses are orchestrated after alphaviral infections and lead to musculoskeletal inflammation remains poorly understood. Here, we show that myositis induced by Ross River virus (RRV) infection is driven by CD11bhi Ly6Chi inflammatory monocytes and followed by the establishment of a CD11bhi Ly6Clo CX3CR1+ macrophage population in the muscle upon recovery. Selective modulation of CD11bhi Ly6Chi monocyte migration to infected muscle using immune-modifying microparticles (IMP) reduced disease score, tissue damage, and inflammation and promoted the accumulation of CX3CR1+ macrophages, enhancing recovery and resolution. Here, we detail the role of immune pathology, describing a poorly characterized muscle macrophage subset as part of the dynamics of alphavirus-induced myositis and tissue recovery and identify IMP as an effective immunomodulatory approach. Given the lack of specific treatments available for alphavirus-induced pathologies, this study highlights a therapeutic potential for simple immune modulation by IMP in infected individuals in the event of large alphavirus outbreaks.

Circulating tumor cells (CTCs) carried by the patient’s bloodstream are known to lead to the metastatic spread of cancer. It is becoming increasingly clear that an understanding of the nanomechanical characteristics of CTCs, such as elasticity and adhesiveness, represents advancements in tracking and monitoring cancer progression and metastasis. In the present work, we describe a combined microfluidic–atomic force microscopy (AFM) platform that uses antibody–antigen capture to routinely isolate and nanomechanically characterize CTCs present in blood samples from prostate cancer patients. We introduce the reversible assembly of a microfluidic device and apply refined and robust chemistry to covalently bond antibodies onto its glass substrate with high density and the desired orientation. As a result, we show that the device can efficiently capture CTCs from patients with localized and metastatic prostate cancer through anti-EpCAM, anti-PSA, and anti-PSMA antibodies, and it is suitable for AFM measurements of captured intact CTCs. When nanomechanically characterized, CTCs originating from metastatic cancer demonstrate decreased elasticity and increased deformability compared to those originating from localized cancer. While the average adhesion of CTCs to the AFM tip surface remained the same in both the groups, there were fewer multiple adhesion events in metastatic CTCs than there were in their counterparts. The developed platform is simple, robust, and reliable and can be useful in the diagnosis and prognosis of prostate cancer as well as other forms of cancer.

We report Zika virus (ZIKV) vertical transmission in 130 infants born to PCR+ mothers at the time of the Rio de Janeiro epidemic of 2015–2016. Serum and urine collected from birth through the first year of life were tested by quantitative reverse transcriptase polymerase chain reaction (PCR) and/or IgM Zika MAC-ELISA. Four hundred and seven specimens are evaluated; 161 sera tested by PCR and IgM assays, 85 urines by PCR. Sixty-five percent of children (N = 84) are positive in at least one assay. Of 94 children tested within 3 months of age, 70% are positive. Positivity declines to 33% after 3 months. Five children are PCR+ beyond 200 days of life. Concordance between IgM and PCR results is 52%, sensitivity 65%, specificity 40% (positive PCR results as gold standard). IgM and serum PCR are 61% concordant; serum and urine PCR 55%. Most children (65%) are clinically normal. Equal numbers of children with abnormal findings (29 of 45, 64%) and normal findings (55 of 85, 65%) have positive results, p = 0.98. Earlier maternal trimester of infection is associated with positive results (p = 0.04) but not clinical disease (p = 0.98). ZIKV vertical transmission is frequent but laboratory confirmed infection is not necessarily associated with infant abnormalities., Here, Brasil et al. investigate mother to child Zika virus (ZIKV) transmission rates in a large longitudinal cohort of pregnant ZIKV-positive women with their infants followed from the time of maternal infection through birth and onwards, finding high in utero transmission rates that do not predict clinical outcomes, suggesting follow-up of children with antenatal ZIKV exposure is necessary.

Objectives Anlotinib is a novel multi-target tyrosine Kinase inhibitor that inhibits VEGFR2/3, FGFR1-4, PDGFD α/β, c-Kit and Ret. In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small-cell lung cancer (NSCLC) patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study assessed quality of life (QoL) in these patients. Methods Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. The QoL were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the associated EORTC Quality of Life Lung Cancer Specific Module (QLQ-LC13) at baseline, end of cycle 1, end of every two cycles, and at the final visit. The analyses were conducted in the first 6 cycles. Differences in scores of 10 points or more between two arms or from baseline were considered clinically meaningful. Results A total of 437 patients were assigned to anlotinib (n = 294) and placebo (n = 143). The completion rates of the QoL questionnaires were from 69.9% to 97.0%. Mean scores of QLQ-C30 and QLQ-LC13 subscales were similar in the anlotinib and placebo arms at baseline. Compared to placebo, anlotinib improved role functioning, social functioning, dyspnea, insomnia, constipation and financial problems. Only sore mouth or tongue symptom was worse in the anlotinib arm than in the placebo arm. Conclusions Anlotinib improved quality of life versus placebo in advanced NSCLC patients who had received at least two previous chemotherapies. The QoL analyses provided evidence that anlotinib should be a choice for the third-line treatment or beyond in advanced NSCLC.

Objective: Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-Kit, and c-MET; therefore, it exhibits both antitumor and anti-angiogenetic activities. A phase III trial has shown that anlotinib improved progression-free survival (PFS) and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC), who presented with progressive disease or intolerance after standard chemotherapy. This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods: Data were collected from March 2015 to January 2017 from a randomized, double-blind, placebo-controlled, multicenter, phase III trial of anlotinib (ALTER0303). A total of 437 patients were enrolled and randomly allocated (2:1) to the anlotinib and placebo groups. Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS. Cox proportional hazards model was adopted for multivariate prognostic analysis. Results: Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS. Meanwhile, elevated thyroid-stimulating hormone, blood glucose, and triglyceride levels; hypertension; and hand–foot syndrome were independent protective factors of PFS. High post-therapeutic peripheral blood granulocyte/lymphocyte ratio, an Eastern Cooperative Oncology Group (ECOG) score ≥ 2, and the sum of the maximal target lesion length at baseline were independent risk factors of OS, and hypertriglyceridemia was an independent protective factor of OS. Conclusions: This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC, and the baseline characteristics of the therapeutically dominant populations were then identified.

Ma et al. dissected the heterogeneous leukemia chemoresistance mechanisms using a leukemia-on-a-chip bone marrow niche model., B cell acute lymphoblastic leukemia (B-ALL) blasts hijack the bone marrow (BM) microenvironment to form chemoprotective leukemic BM “niches,” facilitating chemoresistance and, ultimately, disease relapse. However, the ability to dissect these evolving, heterogeneous interactions among distinct B-ALL subtypes and their varying BM niches is limited with current in vivo methods. Here, we demonstrated an in vitro organotypic “leukemia-on-a-chip” model to emulate the in vivo B-ALL BM pathology and comparatively studied the spatial and genetic heterogeneity of the BM niche in regulating B-ALL chemotherapy resistance. We revealed the heterogeneous chemoresistance mechanisms across various B-ALL cell lines and patient-derived samples. We showed that the leukemic perivascular, endosteal, and hematopoietic niche-derived factors maintain B-ALL survival and quiescence (e.g., CXCL12 cytokine signal, VCAM-1/OPN adhesive signals, and enhanced downstream leukemia-intrinsic NF-κB pathway). Furthermore, we demonstrated the preclinical use of our model to test niche-cotargeting regimens, which may translate to patient-specific therapy screening and response prediction.

BACKGROUND: Lung cancer remains one of the deadliest cancers worldwide. The ALTER0303 trial revealed that anlotinib might be used as a third-line or further treatment in non-small cell lung cancer (NSCLC) patients. Meanwhile, the impact of previous therapy strategies on the efficiency of anlotinib still remains unknown. METHODS: The subgroup of patients in ALTER0303 were analyzed by using Kaplan-Meier estimates, Pearson χ(2), or Fisher’s exact test. RESULTS: There was no statistical significance on progression-free survival (PFS) and overall survival (OS) among patients in different previous antiangiogenic treatments groups. Patients in the chest radiotherapy (CRT) group had longer median PFS than the non-CRT group (5.93 vs. 4.63 m, P=0.027). Regardless of what kind of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) and chemotherapy regimens were used previously, all patients gained longer PFS in the anlotinib group, while only patients treated with vinorelbine/platinum in the EGFR wild type group, pemetrexed/platinum, vinorelbine/platinum, and gefitinib in the EGFR mutation group, and EGFR TKI used as the first line group could benefit from anlotinib on OS. When the OS was calculated from the time of diagnosis to the death, anlotinib could have increased median OS about 6 months (33.8 vs. 27.8 m, P

Importance Congenital Zika virus (ZIKV) infection may present with a spectrum of clinical and neuroradiographic findings. Objective To determine whether neuroimaging findings for infants with a history of ZIKV exposure are associated with infant clinical outcomes and gestational age at antenatal ZIKV infection. Design, Setting, and Participants This cohort study retrospectively reviewed neuroimaging results (computed tomography and/or magnetic resonance imaging scans) of 110 ZIKV-exposed infants from a maternity and children’s hospital in Rio de Janeiro, Brazil, following the 2015 to 2016 ZIKV epidemic. Neuroimaging from March 1, 2016, to June 30, 2017, was evaluated to determine whether findings were associated with clinical outcomes and the timing of maternal ZIKV infection. Data were analyzed from July 1, 2017, to August 30, 2018. Exposures Neuroimaging (computed tomography and/or magnetic resonance imaging) was performed on ZIKV-exposed infants after birth. Blood and/or urine specimens from mothers and infants were tested for ZIKV by polymerase chain reaction assay. Main Outcomes and Measures Neuroimaging studies were evaluated for structural abnormalities and other forms of brain injury. Results A total of 110 infants with a mean (SD) gestational age of 38.4 (2.1) weeks had neuroimaging and clinical outcome data reviewed. Of these, 71 (65%) had abnormal neuroimaging findings, with the majority (96%) classified as having severe ZIKV infection at birth. The most common neuroimaging abnormalities were structural abnormalities including brain calcifications, especially at the cortico-subcortical white matter junction, cortex malformations, ventriculomegaly, and reduced brain volumes, followed by brainstem hypoplasia, cerebellar hypoplasia, and corpus callosum abnormalities. Frequency of abnormal imaging was higher in infants with specific clinical findings as opposed to those without them; these findings included fetal brain disruption sequence (100% vs 35%), microcephaly (100% vs 30%), congenital contractures (100% vs 58%), ophthalmologic abnormalities (95% vs 44%), hearing abnormalities (100% vs 58%), and neurologic symptoms (94% vs 10%). Four of 39 infants (10%) without initial evidence of severe ZIKV infection and normal findings on neurologic evaluation at birth had abnormal neuroimaging findings. Neuroimaging abnormalities differed by trimester of maternal ZIKV infection, with 63% of infants born to mothers infected in the first trimester, 13% of infants born to mothers infected in the second trimester, and 1% of infants born to mothers infected in the third trimester exhibiting neuroimaging abnormalities. The odds of abnormal neuroimaging were 7.9 times greater for infants with first trimester ZIKV exposure compared with other trimesters combined (odds ratio, 7.9; 95% CI, 3.0-20.4;P Conclusions and Relevance Neuroimaging abnormalities of computed tomography and/or magnetic resonance imaging scans were common in ZIKV-exposed infants. While neuroimaging abnormalities were seen in 10% of infants without clinically severe ZIKV, most occurred almost exclusively among those with clinically severe ZIKV, especially among those with a history of ZIKV exposure in the first trimester.

In previous study, we designed novel α-pinene derivatives based on theories of bioalkylating agents using α-pinene as lead compound and patented these compounds, in which compound α-pinene derivative GY-1 (6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl-4-methylbenzenesulfonat) showed strongest inhibition on hepatoma carcinoma cell BEL-7402. In this study, we investigated effect of GY-1 on hepatocellular carcinoma in vitro and in vivo, and explored its mechanism of anti-hepatoma. The results showed that GY-1 showed good anti-liver cancer activity with the IC50 of 84.7 μmol/L in vitro, inhibited tumor growth in vivo with dose-dependent, and GY-1 could arrest the growth of hepatoma cells in the S phase and induced apoptosis in hepatoma cells, down-regulated the expression of C-myc, CDK2 and CyclinE, and up-regulate p53.

We have recently reported an important role of Connexin 43 (Cx43) hemichannels in the pathogenesis of lethal sepsis through facilitating ATP efflux to potentiate the double-stranded RNA-activated protein kinase R (PKR)-dependent macrophage activation. Here we further elucidated the possible role of Pannexin 1 (Panx1) hemichannel in lethal sepsis by assessing its expression along with the impact of a Panx1-specific mimetic inhibitory peptide, 10Panx, on macrophage hemichannel activity in vitro and animal sepsis lethality in vivo. Both crude bacterial lipopolysaccharide (LPS) and purified serum amyloid A (SAA) effectively induced the expression and extracellular release of Panx1 by macrophages or monocytes as judged by Western blotting and immunocytochemistry assays. In animal model of lethal sepsis, Panx1 expression levels were significantly elevated in the heart, but reduced in the kidney, lung, spleen, and blood. At relatively lower doses (10, 50, and 100 mg/kg), the Panx1 mimetic peptide, 10Panx, reproducibly exacerbated the sepsis-induced animal lethality, reducing survival rates from 60–70% to 0–10%. Consistently, 10Panx did not inhibit, but rather promoted, the LPS-induced elevation of Lucifer Yellow dye uptake, ATP release, and Nitric Oxide (NO) production. Collectively, these findings suggested that elevated macrophage Panx1 expression and hemichannel activation contribute to the pathogenesis of lethal sepsis.

Sepsis refers to a life-threatening organ dysfunction caused by a dysregulated host response to infection. Its pathogenesis is partly attributable to dysregulated inflammatory responses orchestrated by innate immune cells (e.g., macrophages and monocytes) that sequentially release early (e.g., TNF, IL-1, and IFN-γ) and late (e.g., HMGB1) pro-inflammatory mediators. As a ubiquitous nuclear protein, HMGB1 is constitutively expressed and can be actively secreted in response to exogenous pathogen-associated molecular pattern molecules (PAMPs, e.g., ds-RNA, CpG-DNA, and endotoxin) or endogenous cytokines [e.g., interferon (IFN)-γ or IFN-β]. In addition to active secretion, HMGB1 can also be passively released from damaged cells following ischemia/reperfusion, trauma, or toxemia, thereby serving as damage-associated molecular pattern (DAMP). Even during microbial infections, the PAMP-elicited inflammatory response may be accompanied by cell injury and DAMP release that further amplifies the cytokine storm to precipitate organ dysfunction. Here we discuss the evidence that support extracellular HMGB1 as a key mediator of inflammatory diseases and discuss the potential of several HMGB1-targeting therapies in animal models of lethal sepsis. Although microbial infection-induced sepsis is indistinguishable from sterile injury-elicited systemic inflammatory response syndrome, it may be more advantageous to develop strategies that specifically attenuate DAMP-mediated inflammatory responses without compromising the PAMP-mediated innate immunity.

Background To construct a new and improved model of acute subdural hematoma in rats. New method 30 male adult Sprague-Dawley rats(SD rats) were selected and randomly divided into two groups. The traditional model group was based on Miller's model construction method, and the improved model group was based on improved needle, injection site and operation method. The improved model was evaluated by comparing the physiological indicators, behavioral scores, magnetic resonance performance and HE staining results of the two groups of rats. Results The physical signs of the rats in the two groups were similar. The survival rate of the improved group was higher than that of the traditional group. The hematoma in the improved model was thicker and concentrated in the ipsilateral side, as revealed by HE staining and MRI. The improved method has less intrusions on the cortex around the injection site and is more stable than the traditional model. Comparison with existing method(s) The operation difficulty of the improved model is reduced and easier. The survival rate of the improved group was higher than that of the traditional group. And the improved model will have more research possibilities. Conclusion The improved model is based on the traditional model. Although it has some shortcomings, it can also be used in different research fields of the traditional model. The operation for the improved model is easier to perform. And the improved model has more applications in research.

The current widespread outbreak of Zika virus (ZIKV) infection has been linked to severe clinical birth defects, particularly microcephaly, warranting urgent study of the molecular mechanisms underlying ZIKV pathogenesis. Akt-mTOR signaling is one of the key cellular pathways essential for brain development and autophagy regulation. Here, we show that ZIKV infection of human fetal neural stem cells (fNSCs) causes inhibition of the Akt-mTOR pathway, leading to defective neurogenesis and aberrant activation of autophagy. By screening the three structural proteins and seven nonstructural proteins present in ZIKV, we found that two, NS4A and NS4B, cooperatively suppress the Akt-mTOR pathway and lead to cellular dysregulation. Corresponding proteins from the closely related dengue virus do not have the same effect on neurogenesis. Thus, our study highlights ZIKV NS4A and NS4B as candidate determinants of viral pathogenesis and identifies a mechanism of action for their effects, suggesting potential targets for anti-ZIKV therapeutic intervention.

For the clinical management of sepsis, antibody-based strategies have only been attempted to antagonize pro-inflammatory cytokines, but not yet been tried to target harmless proteins that may interact with these pathogenic mediators. Here we report an antibody strategy to intervene in the harmful interaction between tetranectin (TN) and a late-acting sepsis mediator, high mobility group box 1 (HMGB1), in pre-clinical settings. We discovered that TN could bind HMGB1 to reciprocally enhance their endocytosis, thereby inducing macrophage pyroptosis and consequent release of lactate dehydrogenase (LDH) and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). The genetic depletion of TN expression or supplementation of exogenous TN protein at sub-physiological doses distinctly affected the outcomes of potentially lethal sepsis, revealing a previously under-appreciated beneficial role of TN in sepsis. Furthermore, the administration of domain-specific polyclonal and monoclonal antibodies effectively inhibited TN/HMGB1 interaction and endocytosis and attenuated the sepsis-induced TN depletion and tissue injury, thereby rescuing animals from lethal sepsis. Our findings point to a possibility of developing antibody strategies to prevent harmful interactions between harmless proteins and pathogenic mediators of human diseases.

Background Anlotinib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and stem cell factor receptor (c-Kit). In the phase III ALTER-0303 trial (Clinical Trial Registry ID: NCT 02388919), anlotinib significantly improved overall survival versus placebo in advanced non-small cell lung cancer patients who had received at least two previous chemotherapy and epidermal growth factor receptor/anaplastic lymphoma kinase targeted therapy regimens. This study summarized adverse event management in this trial. Methods Patients were randomized (2:1) to anlotinib or placebo up to progression or intolerable toxicity. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and managed by investigators. Key strategies for preventing and managing the most common adverse events included patient education, supportive care, and dose modification. Results Between February 2015 and August 2016, 294 patients received anlotinib. A total of 170 (57.8%) patients received antihypertensive medications for hypertension, 53 (18.0%) patients received levothyroxine for hypothyroidism, 24 (8.2%) patients received fibrates for hypertriglyceridemia, 11 (3.7%) patients took cortisone cream for hand-foot syndrome, and 38 (12.9%) patients received anti-diarrheal medications for diarrhea. Dose reduction and drug discontinuation were required in 24 (8.16%) and 31 (10.54%) patients in the anlotinib group, respectively. Conclusion Anlotinb-related adverse events could be controlled by patient education, prophylactic measures, early and active intervention, and dose modification.

Background An intricate fetal-maternal immune crosstalk during pregnancy is essential for a healthy birth. Hence, the infection-induced alterations of maternal immunity often lead to adverse outcomes for mother and/or child. The emergence of Zika virus (ZIKV) infection in pregnant women has been associated with more than 3,000 cases of microcephaly and nervous system malformations. Methods To explore the potential correlation of ZIKV-induced alteration of maternal immunity with fetal abnormalities, we performed extensive sera immunoprofiling of 74 pregnant women: 30 symptomatic ZIKV+ pregnant patients and 30 healthy pregnant controls in ZIKV-endemic Rio de Janeiro, along with 14 healthy pregnant controls in non-endemic Los Angeles. Results Extensive multiplexing analysis of 69 cytokines revealed that CXCL10, CCL2, and CCL8 chemokines were specifically associated with symptomatic ZIKV+ infection during pregnancy, and distinct immunoprofiles were detected at different trimesters in ZIKV-infected pregnant women. Intriguingly, the high CCL2 level and its inverse correlation with CD163, TNFRSF1A, and CCL22 levels was apparently associated with ZIKV-induced abnormal birth. Conclusion Our findings provide insights into the alteration of ZIKV-elicited maternal immunity, serving as a potential clinical biomarker platform. Funding NIH (CA200422, CA180779, DE023926, AI073099, AI116585, AI129496, AI140705, AI069120, AI056154, AI078389, AI28697, AI40718 and AI129534-01), Hastings Foundation, Fletcher Jones Foundation, Departamento de Ciencia e Tecnologia (DECIT/25000.072811/2016-17) do Ministerio da Saude do Brasil, and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior CAPES/88887.116627/2016-01.

Current Chinese national guidelines recommend routine screening for liver cancer in patients positive for HBsAg, irrespective of fibrosis status, age, or family history of liver cancer. We aim to evaluate whether the recommended screening strategy could reduce liver-cancer-specific mortality. We conducted a liver cancer mass screening trial in Xiaolan Town, Zhongshan City, China, among residents aged 35–64 years in 2012. All volunteers were offered serological testing for hepatitis B virus surface antigen (HBsAg). We proposed biannual screening using serum alpha-fetoprotein (AFP) and ultrasonography examination for subjects positive for HBsAg. Among 17,966 participants (26.2% of 68,510 eligible residents) who were free of liver cancer at baseline in 2012, we identified 57 incident cases of liver cancer within the first 4 years of follow-up (i.e., 43 among 2,848 HBsAg-positive participants and 14 among 15,118 HBsAg-negative participants), compared with 104 cases identified in non-participants (N = 50,544). A total of 207 participants had the recommended number of ultrasonography examinations (every 6 months) during the screening period. Compared with cases identified from non-participants, the cases arising among participants were more likely to be at early stage and had better survival than those among non-participants. However, we did not observe a reduction in liver cancer-specific mortality rate among participants (relative risk = 1.04, 95% confidence interval = 0.68, 1.58, P = 0.856). Our demonstration screening study does not show a reduction in liver cancer mortality within the first 4 years of follow-up according to current guidance in China, although long-term efficacy remains to be evaluated. Targeted surveillance among high-risk individuals as recommended by international guidelines, along with measures to improve compliance, should be evaluated in the Chinese population.

Cancer stem-like cells (CSCs) have been shown to initiate tumorigenesis and cancer metastasis in many cancer types. Although identification of CSCs through specific marker expression helps define the CSC compartment, it does not directly provide information on how or why this cancer cell subpopulation is more metastatic or tumorigenic. In this study, the functional and biophysical characteristics of aggressive and lethal inflammatory breast cancer (IBC) CSCs at the single-cell level are comprehensively profiled using multiple microengineered tools. Distinct functional (cell migration, growth, adhesion, invasion and self-renewal) and biophysical (cell deformability, adhesion strength and contractility) properties of ALDH+ SUM149 IBC CSCs are found as compared to their ALDH- non-CSC counterpart, providing biophysical insights into why CSCs has an enhanced propensity to metastasize. It is further shown that the cellular biophysical phenotype can predict and determine IBC cells' tumorigenic ability. SUM149 and SUM159 IBC cells selected and modulated through biophysical attributes-adhesion and stiffness-show characteristics of CSCs in vitro and enhance tumorigenicity in in vivo murine models of primary tumor growth. Overall, the multiparametric cellular biophysical phenotyping and modulation of IBC CSCs yields a new understanding of IBC's metastatic properties and how they might develop and be targeted for therapeutic interventions.

Circulating tumor cells (CTCs) escape from primary or metastatic lesions and enter into circulation, carrying significant information of cancer progression and metastasis. Capture of CTCs from the bloodstream and the characterization of these cells hold great significance for the detection, characterization, and monitoring of cancer. Despite the urgent need from clinics, it remains a major challenge to capture and retain these rare cells from human blood with high specificity and yield. Recent exciting advances in micro/nanotechnology, microfluidics, and materials science have enable versatile, robust, and efficient cell isolation and processing through the development of new micro/nanoengineered devices and biomaterials. This review provides a summary of recent progress along this direction, with a focus on emerging methods for CTC capture and processing, and their application in cancer research. Furthermore, classical as well as emerging cellular characterization methods are reviewed to reveal the role of CTCs in cancer progression and metastasis, and hypotheses are proposed in regard to the potential emerging research directions most desired in CTC-related cancer research.

The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (μCT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. IMPORTANCE Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.

Clinically, coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) is generally used to treat patients with ischemic heart failure. However, the optimal treatment strategy remains unknown. This study examined the efficacy of the two coronary revascularization strategies for severe ischemic heart failure by using a meta-analysis. Studies comparing the efficacy of CABG and PCI were obtained from PubMed, EMBASE, Google Scholar and Cochrane Central Register of Controlled Trials (CENTRAL). The quality of each eligible article was evaluated by Newcastle-Ottawa Quality Assessment Scale (NOS), and the meta-analysis was performed using Stata version 12.0 software. Eventually, 12 studies involving 9248 patients (n=4872 in CABG group; n=4376 in PCI group) were subject to the meta-analysis for subsequent pooling calculation. The pooled hazard ratio (HR) [HR=0.83, 95% CI (0.76, 0.90), P

Extensive studies suggested epigallocatechin-3-gallate (EGCG) has significant neuroprotection against multiple central neural injuries, but the underlying mechanisms still remain poorly elucidated. Here we provide evidence to support the possible involvement of extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase/ protein kinase B (PI3K/AKT) pathways in EGCG-mediated protection against corticosterone-induced neuron injuries. As an essential stress hormone, corticosterone could induce obvious neurotoxicity in primary hippocampal neurons. Pre-treatment with EGCG ameliorated the corticosterone-induced neuronal injuries; however, it was blocked by pharmacological inhibitors for ERK1/2 (U0126) and PI3K/AKT (LY294002). Furthermore, the results confirmed that EGCG restored the corticosterone-induced decrease of ERK1/2 and PI3K/AKT phosphorylation, and attenuated the corticosterone-induced reduction of peroxisome proliferators-activated receptor-γ coactivator-1α (PGC-1α) expression and ATP production. Taken together, these findings indicated that EGCG has significant neuroprotection against corticosterone-induced neuron injuries partly via restoring the ERK1/2 and PI3K/AKT signaling pathways as well as the PGC-1α-mediated ATP production.

OBJECTIVE The neutrophil to lymphocyte ratio (NLR) has been reported to be a predictor of outcome in critical illness. Objective of this study was to investigate the changes of the NLR in patients with severe traumatic brain injury (TBI) and analyze the relationship between the NLR and TBI outcome. SETTING China. PARTICIPANTS A total of 855 patients with severe TBI from January 2007 to April 2012. DESIGN Retrospective. MAIN MEASUREMENT Data on the NLR and other indicators were collected. After follow-up until death or 1 year, the relationship between the NLR and TBI outcome was analyzed retrospectively. RESULTS The final analysis included 688 patients. There were 508 (73.8%) who had an unfavorable outcome by 1 year after head trauma. The value of the NLR on admission was significantly higher in the unfavorable outcome group than in the favorable outcome group (P < .001). Multivariate logistic analysis showed that higher NLR was associated with an unfavorable outcome (odds ratio, 1.100; P < .001). Receiver operating characteristic curve analysis showed that the NLR had a sensitivity of 60.2% and a specificity of 71.1% for predicting unfavorable outcome at 1 year on the basis of the best threshold. CONCLUSION The NLR might be useful as a novel predictor for 1-year outcome and mortality in severe TBI.

Coronary artery disease (CAD) is a complex disease resulting from a combination of environmental and genetic factors. We hypothesized that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) rs1801133 C/T, matrix metalloproteinases (MMPs)-2, tumour necrosis factor (TNF)-α, macrophage migration inhibitory factor (MIF) rs755622 G/C and cyclin D1 (CCND1) rs678653 G/C contribute to CAD susceptibility. We examined the association between the five polymorphisms and the risk of CAD in a Chinese population of 435 CAD patients and 480 controls. Genotyping was performed using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI/TOF MS). When the MTHFR rs1801133 CC homozygote genotype was used as the reference group, the TT or CT/TT genotypes were associated with a significantly increased risk for CAD. The CT heterozygote genotype was not associated with the risk for CAD. Logistic regression analyses revealed that MMP-2 rs243865 C/T, TNF-α rs1800629 A/G, MIF rs755622 G/C and CCND1 rs678653 G/C polymorphisms were not associated with the risk of CAD. These findings suggest that the MTHFR rs1801133 C/T polymorphism is associated with CAD development. Future larger studies with other ethnic populations are required to confirm current findings.

e20503 Background: As a promising multi-target tyrosine kinase inhibitor (TKI), anlotinib hydrochloride significantly improved overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients in the phase 3 trial (ALTER0303). Here, we demonstrated the efficacy of anlotinib in SCC patients with or without hypertension. Methods: Patients (n = 439) were randomized in a 2:1 ratio to receive anlotinib (12mg daily for 14 days in a 21 day cycle) or placebo. The primary endpoint was OS and second endpoints were PFS, ORR, DCR and QoL. The correlation between hypertension and efficacy (PFS and OS) was analyzed in SCC patients treated with anlotinib. Results: For different ECOG score (0 and 1) SCC patients (n = 46) in the anlotinib arm, the PFS was significantly improved in patients with hypertension in ECOG 1 group (7.00 vs 4.83 months, p = 0.043). There is no statistical difference in other subgroups. Moreover, for the SCC patients in anlotinib arm, PFS was significantly prolonged in patients with hypertension compared to the patients without hypertension (7.23 vs 3.23 months; HR = 0.36; 95% CI, 0.16–0.84; P = 0.001). However, the median OS of the patients with hypertension was numerically but not statistically longer than the patients without hypertension (13.93 vs 6.30 months; HR = 0.56; 95%CI, 0.26-1.22; P = 0.100). Conclusions: In the ALTER0303 trial, anlotinib significantly improved PFS with a potential benefit of OS for SCC patients with hypertension. And ECOG score does not affect the efficacy of anlotinib in SCC patients with or without hypertension. Clinical trial information: NCT02388919. [Table: see text]

The association between the platelet-derived growth factor D (PDGFD) gene and atherosclerosis has been widely proven, whereas the relationship between the PDGFD gene and ischaemic stroke remains unconfirmed.A case-control study was performed to further evaluate the association of the C → G mutation of rs7950273 in the PDGFD gene with ischaemic stroke (IS) in a Chinese Han population.This study recruited 3033 cases and 2807 controls from general hospitals in the southern, central and northern areas of China. The MGB probe and Taqman 7900HT Sequence Detection System were applied for genotyping.Genotype was not significantly associated with ischaemic stroke in total. After adjustment for gender, age, BMI, hypertension, diabetes mellitus and smoking, the CG and GG genotypes were still not associated with ischaemic stroke (p = 0.892 and p = 0.582 for CG and GG, respectively).This study suggests that the polymorphism of rs7950273 in the PDGFD gene is not associated with ischaemic stroke in the Chinese Han population. Further studies on the gene-gene and gene-environment interactions for the PDGFD gene and ischaemic stroke are needed.

Background Circulating tumor cells (CTCs) have shown prognostic relevance in many cancer types. However, the majority of current CTC capture methods rely on positive selection techniques that require a priori knowledge about the surface protein expression of disseminated CTCs, which are known to be a dynamic population. Methods We developed a microfluidic CTC capture chip that incorporated a nanoroughened glass substrate for capturing CTCs from blood samples. Our CTC capture chip utilized the differential adhesion preference of cancer cells to nanoroughened etched glass surfaces as compared to normal blood cells and thus did not depend on the physical size or surface protein expression of CTCs. Results The microfluidic CTC capture chip was able to achieve a superior capture yield for both epithelial cell adhesion molecule positive (EpCAM+) and EpCAM- cancer cells in blood samples. Additionally, the microfluidic CTC chip captured CTCs undergoing transforming growth factor beta-induced epithelial-to-mesenchymal transition (TGF-β-induced EMT) with dynamically down-regulated EpCAM expression. In a mouse model of human breast cancer using EpCAM positive and negative cell lines, the number of CTCs captured correlated positively with the size of the primary tumor and was independent of their EpCAM expression. Furthermore, in a syngeneic mouse model of lung cancer using cell lines with differential metastasis capability, CTCs were captured from all mice with detectable primary tumors independent of the cell lines’ metastatic ability. Conclusions The microfluidic CTC capture chip using a novel nanoroughened glass substrate is broadly applicable to capturing heterogeneous CTC populations of clinical interest independent of their surface marker expression and metastatic propensity. We were able to capture CTCs from a non-metastatic lung cancer model, demonstrating the potential of the chip to collect the entirety of CTC populations including subgroups of distinct biological and phenotypical properties. Further exploration of the biological potential of metastatic and presumably non-metastatic CTCs captured using the microfluidic chip will yield insights into their relevant differences and their effects on tumor progression and cancer outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2638-x) contains supplementary material, which is available to authorized users.

Human respiratory syncytial virus (hRSV) is a common respiratory virus that is usually no cause for alarm. Symptoms of hRSV usually resemble those of the common cold and can go undiagnosed. However, infants as well as the elderly are at risk for developing severe cases, which can lead to high morbidity and mortality rates especially if there are underlying health issues. Despite many years of effort, no vaccine or specific treatments exist and RSV is still the leading cause of infant hospitalizations worldwide. Here, we describe methods to infect two widely used small animal models: laboratory mice and cotton rats.