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OBJECTIVE Due to the proximity of craniopharyngioma to the optic apparatus, one of the most common complications after surgery is visual deterioration. Intraoperative visual evoked potential (VEP), as a means of real-time visual function monitoring, has been integrated into transsphenoidal surgery for pituitary adenoma to predict postoperative visual outcome. Compared with pituitary tumor, craniopharyngioma often adheres to optic nerves, with increased risk of postoperative visual impairment. Furthermore, extended endoscopic endonasal surgery (EEES) can provide direct visualization of the surgical plane between the craniopharyngioma and the optic nerves, which contributes to analysis of the mechanism of real-time VEP changes during surgery. Therefore, VEP monitoring applied during EEES for craniopharyngioma may have more clinical value. However, only 9 patients who underwent EEES with VEP monitoring for craniopharyngioma have been sporadically reported to date. In this paper, the authors present the largest series to date analyzing the clinical value of VEP to predict postoperative visual outcome in adult patients with craniopharyngioma. METHODS Sixty-five adult patients who underwent EEES with intraoperative VEP monitoring for primary craniopharyngioma were retrospectively reviewed. The association between changes in VEP amplitude and postoperative visual outcome was determined. In addition, other potential prognostic factors with regard to postoperative visual outcomes were included in the analysis. RESULTS Gross-total resection was achieved in 59 patients (90.8%). Reproducible and stable VEP was recorded in 128 of 130 eyes (98.5%). During surgery, VEP remained stable in 108 eyes, 10 (9.3%) of which had new visual acuity (VA) and/or visual field (VF) defects after surgery. Transient VEP decrease was recorded in 15 eyes, 4 (26.7%) of which had visual deterioration. Of the 5 eyes with permanent VEP decrease, 3 (60%) experienced postoperative visual impairment. Permanent VEP decrease (OR 19.868, p = 0.007) and tight adhesion (OR 6.104, p = 0.040) were independent adverse factors for postoperative VA deterioration. Tight adhesion (OR 7.150, p = 0.002) and larger tumor volume (OR 1.066, p = 0.001) were significant risk factors for postoperative VF defects. CONCLUSIONS Intraoperative VEP monitoring can serve as a real-time warning to guide surgeons to avoid postoperative visual impairment. It effectively predicted VA changes in adult patients with craniopharyngioma after EEES. Tight adhesion and larger tumor volume were also strong predictors of postoperative visual impairment.

Purpose. Red blood cell distribution width (RDW) is increased in a variety of inflammatory-related diseases. However, there is no report of its clinical significance in poststroke depression (PSD). This study explores the clinical significance of RDW in PSD patients. Methods. A total of 185 patients with first-ever acute ischaemic stroke (AIS) in the Second Hospital of Anhui Medical University were chosen as subjects. A retrospective observational study was conducted from February 2019 to February 2020. PSD patients were diagnosed at 6 months after stroke based on the Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Clinical and laboratory data were obtained from all patients. Coefficient of Variation (RDW-CV) and standard deviation (RDW-SD) were used to statistically report the performance of red blood cell distribution width. Results. At the 6-month follow-up, 46 patients were diagnosed with PSD. Compared with non-PSD patients, PSD patients exhibited an increase in RDW-CV and RDW-SD, which positively correlated with serum interleukin 6 (IL-6) concentrations. In PSD patients, only RDW-SD demonstrated a consistent positive association with the Hamilton Rating Scale for Depression (HAM-D) scores at 6 months after admission. RDW-CV, RDW-SD, and IL-6 were recognized as independent predictors of PSD. The area under the receiver operating characteristic (ROC) curve (AUC) of RDW-SD was 0.796 (95% CI: 0.731-0.852) for the prediction of PSD, which was superior to that of RDW-CV. The specificity for predicting PSD was 60.43%, and the sensitivity was 91.30% if RDW-SD was higher than 43.80 fL. Conclusions. RDW-SD is a simple, inexpensive, rapid, and easily accessible parameter that can be used to predict PSD in patients with stroke.

Physical and social environments influence immune homeostasis within adipose tissue, yet the mechanisms remain poorly defined. We report that an enriched environment (EE) housing modulates the immune cell population in white adipose tissue of mice including an increase in the abundance of natural killer (NK) cells. EE upregulates the expression of IL-15 and its receptor IL-15Rα specifically within mature adipocytes. Mechanistically, we show that hypothalamic brain-derived neurotrophic factor (BDNF) upregulates IL-15 production in adipocytes via sympathetic β-adrenergic signaling. Overexpressing BDNF mediated by recombinant adeno-associated virus (rAAV) vector in the hypothalamus expands adipose NK cells. Conversely, inhibition of hypothalamic BDNF signaling via gene transfer of a dominant negative TrkB receptor suppresses adipose NK cells. In white adipose tissue, overexpression of IL-15 using an adipocyte-specific rAAV vector stimulates adipose NK cells and inhibits the progression of subcutaneous melanoma, whereas local IL-15 knockdown blocks the EE effect. These results suggest that bio-behavioral factors regulate adipose NK cells via a hypothalamic BDNF-sympathoneural-adipocyte IL-15 axis. Targeting this pathway may have therapeutic significance for cancer.

The low abundance of circulating tumour DNA (ctDNA) in plasma samples makes the analysis of ctDNA biomarkers for the detection or monitoring of early-stage cancers challenging. Here we show that deep methylation sequencing aided by a machine-learning classifier of methylation patterns enables the detection of tumour-derived signals at dilution factors as low as 1 in 10,000. For a total of 308 patients with surgery-resectable lung cancer and 261 age- and sex-matched non-cancer control individuals recruited from two hospitals, the assay detected 52-81% of the patients at disease stages IA to III with a specificity of 96% (95% confidence interval (CI) 93-98%). In a subgroup of 115 individuals, the assay identified, at 100% specificity (95% CI 91-100%), nearly twice as many patients with cancer as those identified by ultradeep mutation sequencing analysis. The low amounts of ctDNA permitted by machine-learning-aided deep methylation sequencing could provide advantages in cancer screening and the assessment of treatment efficacy.

The treatment of stage IIIB non‐small cell lung cancer (NSCLC) is complicated, the best strategy is chosen individually and surgery is usually not recommended. A 50‐year‐old female was diagnosed with locally advanced lung adenocarcinoma (stage IIIB, T2bN3M0). Fluorescence in situ hybridization (FISH) analysis revealed an ALK rearrangement. Crizotinib was administered and progression was seen after five months. The patient then received ceritinib with a palliative intent, which led to downstaging (IIIA[N2]) with a radiological and metabolic response. Right lower lobe lobectomy was performed at 12 months post‐surgery, and the patient is still disease‐free according to the last computed tomography (CT) scan. The unintended downstaging from ceritinib provided a chance for resection in our patient who had ALK‐positive stage IIIB NSCLC after the failure of first‐line crizotinib, indicating potential usage of ceritinib in the neoadjuvant setting. Future perspective trials are warranted to investigate the role of ceritinib in earlier stages as a primary drug., Neoadjuvant chemotherapy can improve tumor resectability and survival. Despite some evidence that indicates potential efficacy of targeted therapies in patients with resectable NSCLC, the role of neoadjuvant ALK‐TKIs therapy is not clearly defined. The current report revealed that neoadjuvant treatment with the ALK tyrosine kinase inhibitor ceritinib in a crizotinib‐relapsed, stage IIIB lung adenocarcinoma led to downstaging and conversion to resectable status with pathological complete response. Prospective data are warranted to provide solid evidence to assess the potential efficacy of neoadjuvant ceritinib as a primary drug in earlier stages.

Background The purpose of this study was to compare the efficacy of osimertinib (OSI) versus afatinib (AFA) in patients with T790M-positive, non-small-cell lung cancer (NSCLC) and multiple central nervous system (CNS) metastases after failure of initial epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. Methods Consecutive patients with T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment were retrospectively identified from our medical institution during 2016–2018 and underwent either oral 80 daily OSI or oral 40 daily AFA every 3 weeks for up to 6 cycles, until disease progression, intolerable adverse events (AEs), or death. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS). Results The cohort consisted of 124 patients (OSI: n = 60, mean age = 64.24 years [SD: 12.33]; AFA: n = 64, mean age = 64.13 years [SD: 13.72]). After a median follow-up of 24 months (range, 3 to 28), a significant improvement in OS was detected (hazard ratio [HR] 0.59, 95% confidence interval [CI], 0.39–0.91; p = 0.0160; median, 13.7 months [95% CI, 11.1–14.8] for OSI vs 9.6 months [95% CI, 8.4–10.2] for AFA). The median duration of PFS was significantly longer with OSI than with AFA (HR 0.62; 95% CI, 0.41–0.91; p = 0.014; median, 4.5 months [95% CI, 3.5–5.7] vs 3.9 months [95% CI, 3.1–4.8]). The proportion of grade 3 or higher adverse events (AEs) was lower with OSI (22.4%) than with AFA (39.4%). Conclusions In patients with T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment, OSI may be associated with significantly improved survival benefit compared with AFA, with a controllable tolerability profile.

Type 1 diabetes (T1DM) is a strong risk factor for the development of cardiovascular disease. Flow-mediated dilatation (FMD) is an early noninvasive marker of endothelial function and it predicts future cardiovascular disease. However, the changes in FMD among T1DM children are still controversial. The present meta-analysis aimed to investigate whether FMD is impaired in children with T1DM. PubMed, EMBASE, Cochrane library, and Web of Science were searched for studies comparing FMD in children with T1DM and healthy controls. The Newcastle-Ottawa quality assessment scale for case–control studies was used to assess study quality. Data were pooled using a random effects models to obtain the weighted mean differences (WMD) in FMD and 95% CIs. Overall, 19 studies with 1245 patients and 872 healthy controls were included in this meta-analysis. Children with T1DM had significantly lower FMDs compared with healthy controls (WMD: −2.58; 95% CI: −3.36 to −1.81; P < .001). Meta-regression analysis revealed that low-density lipoprotein cholesterol levels impacted the observed difference in FMD between T1DM and healthy children. This meta-analysis showed that T1DM children have impaired endothelial function, which indicates they are at higher risk of developing cardiovascular disease in later life.

Chronic inflammation of autoimmune diseases, including type 1 diabetes (T1D), is mainly mediated by memory T(Tm) cells, predominantly effector memory T (Tem) cells. The roles of the programmed death-1 (PD-1) receptor on lymphocytes have been well studied in tumor and other infection models. However, little is known about the relationship between the expression of PD-1 on CD8+ Tem cells and the pathogenesis of T1D. A total of 52 patients diagnosed with T1D and 39 gender-, age-, and ethnically matched health control individuals were enrolled in this study. Peripheral blood mononuclear cells from these individuals were isolated and analyzed by flow cytometry. We evaluated the frequencies of PD-1+ CD8+ memory T cell subsets from patients' peripheral blood with T1D and the spleen cells of nonobese diabetic (NOD) mice in the present study. We also investigated the effects of blocking PD-1/PD-L1 pathway on islet’s inflammation in NOD mice. Frequencies of PD-1+ CD8+ Tem cells were decreased significantly in PBMC of patients with T1D (40.73 ± 12.72 vs 47.43 ± 15.56, *p

Aim Activin receptor-like kinase 7 (ALK7) acts as a key receptor for TGF-β family members, which play important roles in regulating cardiovascular activity. However, ALK7's potential role, and underlying mechanism, in the macrophage activation involved in atherogenesis remain unexplored. Methods ALK7 expression in macrophages was tested by RT-PCR, western blot, and immunofluorescence co-staining. The loss-of-function strategy using AdshALK7 was performed for functional study. Oil Red O staining was used to observe the foam cell formation, while inflammatory mediators and genes related to cholesterol efflux and influx were determined by RT-PCR and western blot. A PPARγ inhibitor (G3335) was used to reveal whether PPARγ was required for ALK7 to affect macrophage activation. Results The results exhibited upregulated ALK7 expression in oxidized low-density lipoprotein (Ox-LDL) induced bone marrow derived macrophages (BMDMs) and mouse peritoneal macrophages (MPMs), isolated from ApoE-deficient mice, while ALK7's strong immunoreactivity in BMDMs was observed. ALK7 knockdown significantly attenuated pro-inflammatory, but promoted anti-inflammatory, macrophage markers expression. Additionally, ALK7 silencing decreased foam cell formation, accompanied by the up-regulation of ABCA1 and ABCG1 involved in cholesterol efflux but the down-regulation of CD36 and SR-A implicated in cholesterol influx. Mechanistically, ALK7 knockdown upregulated PPARγ expression, which was required for the ameliorated effect of ALK7 silencing macrophage activation. Conclusions Our study demonstrated that ALK7 was a positive regulator for macrophage activation, partially through down-regulation of PPARγ expression, which suggested that neutralizing ALK7 might be promising therapeutic strategy for treating atherosclerosis.

Fibroblast growth factor 21 (FGF21) is a peptide hormone that serves as a potent effector of energy homeostasis. Increasingly, FGF21 is viewed as a promising therapeutic agent for type 2 diabetes, fatty liver disease, and other metabolic complications. Exogenous administration of native FGF21 peptide has proved difficult due to unfavorable pharmacokinetic properties. Here, we utilized an engineered serotype adeno-associated viral (AAV) vector coupled with a dual-cassette design to selectively overexpress FGF21 in visceral adipose tissue of insulin-resistant BTBR T+Itpr3tf/J (BTBR) mice. Under high-fat diet conditions, a single, low-dose intraperitoneal injection of AAV-FGF21 resulted in sustained benefits, including improved insulin sensitivity, glycemic processing, and systemic metabolic function and reduced whole-body adiposity, hepatic steatosis, inflammatory cytokines, and adipose tissue macrophage inflammation. Our study highlights the potential of adipose tissue as a FGF21 gene-therapy target and the promise of minimally invasive AAV vectors as therapeutic agents for metabolic diseases., Graphical Abstract, Queen et al. utilize an engineered viral vector to administer FGF21 gene therapy within adipose tissue in a non-invasive manner. As a result, metabolic health was improved and obesity-associated adipose immune signatures were reduced in a mouse model of dysregulated metabolism.

Macroenvironmental factors, including a patient’s physical and social environment, play a role in cancer risk and progression. Our previous preclinical studies have shown that the enriched environment (EE) confers anti-obesity and anti-cancer phenotypes that are associated with enhanced adaptive immunity and are mediated by brain-derived neurotrophic factor (BDNF). Natural killer (NK) cells have anti-cancer and anti-viral properties, and their absence or depletion is associated with inferior clinical outcomes. In this study, we investigated the effects of EE on NK cell maturation following their depletion. Mice living in EE displayed a higher proportion of NK cells in the spleen, bone marrow, and blood, compared to those living in the standard environment (SE). EE enhanced NK cell maturation in the spleen and was associated with upregulation of BDNF expression in the hypothalamus. Hypothalamic BDNF overexpression reproduced the EE effects on NK cell maturation in secondary lymphoid tissues. Conversely, hypothalamic BDNF knockdown blocked the EE modulation on NK cell maturation. Our results demonstrate that a bio-behavior intervention enhanced NK cell maturation and was mediated at least in part by hypothalamic BDNF.

Background To investigate the clinical, imaging and pathological features of dedifferentiated chondrosarcoma for better diagnosis. Methods Patients who had been confirmed to have dedifferentiated chondrosarcoma were enrolled in this study and analyzed in the clinical, imaging and pathological data. Results Twenty-five patients had pathologically confirmed dedifferentiated chondrosarcoma including 15 males and 10 females with an age range of 24–74 (median 58, interquartile range 49–65). Ten patients had the tumor at the femur, four at the ilium, two at the humerus, two at the tibia, two at cotyle, and one at each of the following locations: scapula, sacrum, rib, pubic branch, and calcaneus. Twenty-one patients had local pain and a soft tissue mass while the other four patients had only local pain without a soft tissue mass. Four patients had pathological fractures. Imaging showed extensive bone destruction with calcification inside the lesion and possible pathological fractures. On gross observation of the specimen, the chondrosarcoma components were usually located inside the bone, and the dedifferentiated sarcoma components were mainly located outside the bone. Microscopy showed the dedifferentiated tumor had two components: well-differentiated chondrosarcoma and poorly differentiated non-chondral sarcoma including malignant fibrous histiocytoma in eleven cases, osteosarcoma in ten cases, fibrosarcoma in two, liomyosarcoma in one, and lipoblastoma in the remaining one.. Followed up from 3 moths to 60 months (mean 15.6), eight patients died with a survival time of 10–23 months (mean 16), and the other 17 patients survived with the survival duration from three to 60 months (15). Conclusion Dedifferentiated chondrosarcoma is a fatal disease with multiple components, and most of the cases have dual morphological and imaging features of chondrosarcoma and non-chondrosarcoma. The imaging presentations are primarily of common central chondrosarcoma, combined with cortical destruction, soft tissue mass, and pathological fractures.

Gold nanoparticles (GNPs) are widely used in life sciences and medicine due to their simple preparation, stable physical and chemical properties, controllable optical properties and no significant toxicity. However, in recent years, studies have found that there are still many uncertain factors in the application of gold nanoparticles in the field of biomedicine, and there are few studies on the main excretion organs and kidneys of the body, especially the toxicological effects under the disease state have not been reported. Obviously, carrying out relevant research is of great significance for accelerating the clinical application of GNPs. Chronic kidney disease (CKD) is a group of chronic progressive diseases that have high prevalence and high mortality and are serious threats to human life and health. Renal tubular injury and interstitial fibrosis are key factors in renal dysfunction in chronic kidney disease. Drug and toxic kidney damage mostly involve renal tubular epithelial cells; hypoxia is the most common pathological condition of cells. In renal lesions, renal tubular epithelial cells often have hypoxia. Based on this, we propose the hypothesis of this study: glomerular filtration membrane damage in kidney disease, GNPs increase in urine, followed by reabsorption of renal tubular epithelial cells, thereby causing damage to the latter; if accompanied by hypoxia, GNPs it will aggravate renal tubular epithelial cell damage and promote tubulointerstitial fibrosis. In order to verify the above hypothesis, this study used a mouse model of adriamycin nephropathy and tubular epithelial cells and macrophages in vitro, and observed the damage of GNPs on renal tubular epithelial cells by various means, and explored related mechanisms. The results show that under normal oxygen conditions, GNPs can induce autophagy after cell entry, which can damage damaged proteins and organelles to maintain cell survival. In the absence of oxygen, nanoparticles entering cells increase and induce excessive autophagy. In the absence of oxygen, GNPs also aggregate in macrophages, which can cause decreased cell proliferation activity and induce activation of macrophage inflammasome, which induces inflammatory response: GNPs-induced secretion of hypoxic macrophages can be promoted.

Gefitinib, the first approved inhibitor for oral epidermal growth factor receptor (EGFR), has been proved to be effective in non-small cell lung cancer with EGFR mutation. However, there are many m...

Objective: The current state-of-the-art methods significantly improve the detection performance of the steady-state visual evoked potentials (SSVEPs) by using the individual calibration data. However, the time-consuming calibration sessions limit the number of training trials and may give rise to visual fatigue, which weakens the effectiveness of the individual training data. For addressing this issue, this study proposes a novel inter- and intra-subject maximal correlation (IISMC) method to enhance the robustness of SSVEP recognition via employing the inter- and intra-subject similarity and variability. Through efficient transfer learning, similar experience under the same task is shared across subjects. Methods: IISMC extracts subject-specific information and similar task-related information from oneself and other subjects performing the same task by maximizing the inter- and intra-subject correlation. Multiple weak classifiers are built from several existing subjects and then integrated to construct the strong classifiers by the average weighting. Finally, a powerful fusion predictor is obtained for target recognition. Results: The proposed framework is validated on a benchmark data set of 35 subjects, and the experimental results demonstrate that IISMC obtains better performance than the state of the art task-related component analysis (TRCA). Significance: The proposed method has great potential for developing high-speed BCIs.

Background To investigate the imaging features of hemangiomas in long tabular bones for better diagnosis. Methods Twenty-four patients with long bone hemangiomas confirmed by pathology were enrolled. Nineteen patients had plain radiography, fourteen patients had computed tomography (CT) and eleven had magnetic resonance imaging (MRI). The hemangioma was divided into medullary [13], periosteal [6] and intracortical type [5]. Results Among 19 patients with plain radiography, eleven patients were medullary, three periosteal, and five intracortical. In the medullary type, the lesion was primarily osteolytic, including five cases with irregular and unclear rims and one lesion having osteosclerotic and unclear rims. In three patients with the periosteal type, the lesion had clear rims with involvement of the cortical bone in the form of bone defect, including two cases with local thickened bone periosteum and one case having expansile periosteum. Five intracortical hemangiomas had intracortical osteolytic lesions with clear margins. Among 14 patients with CT imaging, 8 cases were medullary, three periosteal, and three intracortical. Among 8 medullary hemangiomas, one had ground glass opacity, and seven had osteolytic, expansile lesions like soft tissue density with no calcification. In three periosteal cases, the lesion was osteolytic with thickened periosteum and narrowed medullary cavity. In three intracortical hemangiomas, the lesion was of even soft tissue density with no calcification. Among 11 patients with MRI imaging, seven were medullary, two periosteal, and two intracortical. Among 7 medullary lesions, six were of hypointense signal on T1WI and hyperintensesignal on T2 WI. In two periosteal cases, the periosteum was thickened, with one case being of equal signal, and the other having no signal. Two intracortical hemangiomas were both of slightly low signal on T1WI but hyperintense signal on T2WI. Conclusions The long bone hemangiomas had characteristic cystic honeycomb-like presentations in plain radiograph. CT and MRI imagings are helpful for diagnosis of hemangiomas in long bone.

Adipose tissue is one of the largest organs, playing important roles in physiology and pathologies of multiple diseases. However, research related to adeno-associated virus (AAV) targeting adipose tissue has been left far behind studies carried out in the liver, brain, heart, and muscle. Despite initial reports indicating poor performance, AAV-mediated gene delivery to adipose tissue has continued to rise during the past two decades. AAV8 and a novel engineered hybrid serotype, Rec2, have been shown to transduce adipose tissue more efficiently than other serotypes so far tested and have been applied in most of the in vivo studies. The Rec2 serotype displays high efficacy of gene transfer to both brown and white fat via local and systemic administration. This review summarizes the advances in developing AAV vectors with enhanced adipose tropism and restricting off-target transgene expression. We discuss the challenges and strategies to search for and generate novel serotypes with tropism tailoring for adipose tissue and develop AAV vector systems to improve adipose transgene expression for basic research and translational studies., Graphical Abstract, AAV8 and a novel hybrid serotype, Rec2, show higher efficacy in transducing adipose tissue than do other serotypes. This review summarizes the advances in developing AAV vectors with enhanced adipose tropism and restricting off-target transgene expression. The challenges and strategies to develop AAV vector systems tailoring for adipose tissue are discussed.

Highlights • SHC014748M was proved to be more selective for PI3Kδ inhibition relative to other class i PI3K enzymes. • SHC014748M showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells and also inhibited phosphorylation of AKT, targets downstream of PI3Kδ. • In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. • SHC014748M seemed to be a novel promising compound in the treatment of B cell lymphomas and CLL., PI3Kδ (phosphatidylinositol 3-kinase-δ), one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ for patients with indolent non-Hodgkin lymphomas. Here in this paper, we comprehensively evaluated the in vitro and in vivo antitumor activity of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary chronic lymphocytic leukemia (CLL) cells. Scid mice were subcutaneously inoculated with the SU-DHL-6 cell line. SHC014748M was more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells. SHC014748M also inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in both lymphoma cells and primary CLL cells. In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 in patient serum decreased sharply after SHC014748M treatment. According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL.

Human cytomegalovirus (HCMV) infection in the respiratory tract leads to pneumonitis in immunocompromised hosts without available vaccine. Considering cytomegalovirus (CMV) mainly invades through the respiratory tract, CMV‐specific pulmonary mucosal vaccine development that provides a long‐lasting protection against CMV challenge gains our attention. In this study, N‐terminal domain of GP96 (GP96‐NT) was used as a mucosal adjuvant to enhance the induction of pulmonary‐resident CD8 T cells elicited by MCMV glycoprotein B (gB) vaccine. Mice were intranasally co‐immunized with 50 μg pgB and equal amount of pGP96‐NT vaccine 4 times at 2‐week intervals, and then i.n. challenged with MCMV at 16 weeks after the last immunization. Compared with pgB immunization alone, co‐immunization with pgB/pGP96‐NT enhanced a long‐lasting protection against MCMV pneumonitis by significantly improved pneumonitis pathology, enhanced bodyweight, reduced viral burdens and increased survival rate. Moreover, the increased CD8 T cells were observed in lung but not spleen from pgB/pGP96‐NT co‐immunized mice. The increments of pulmonary CD8 T cells might be mainly due to non‐circulating pulmonary‐resident CD8 T‐cell subset expansion but not circulating CD8 T‐cell populations that home to inflammation site upon MCMV challenge. Finally, the deterioration of MCMV pneumonitis by depletion of pulmonary site‐specific CD8 T cells in mice that were pgB/pGP96‐NT co‐immunization might be a clue to interpret the non‐circulating pulmonary‐resident CD8 T subset expansion. These data might uncover a promising long‐lasting prophylactic vaccine strategy against MCMV‐induced pneumonitis.

W922, a novel PI3K/Akt/mTOR pathway inhibitor, exhibits efficient anti‑tumor effects on HCT116, MCF‑7 and A549 human cancer cells compared with other synthesized compounds. The present study aimed to investigate its anti‑tumor effects on colorectal cancer cells. A total, of seven different colorectal cell lines were selected to test the anti‑proliferation profile of W922, and HCT116 was found to be the most sensitive cell line to the drug treatment. W922 inhibited HCT116 cell viability and cell proliferation in vitro in concentration‑ and time‑dependent manners. Furthermore, W922 suppressed the tumor growth in a xenograft mouse model and exhibited low toxicity. The proteomic alterations in W922‑treated HCT116 cells were found to be associated with cell cycle arrest, negative regulation of signal transduction and lysosome‑related processes. W922 caused cell cycle arrest of HCT116 cells in G0‑G1 phase, but only triggered slight apoptosis. In addition, the PI3K/Akt/mTOR signaling proteins were dephosphorylated upon W922 treatment. It has been reported that inhibition of mTOR is relevant to autophagy, and the present results also indicated that W922 was involved in autophagy induction. An autophagy inhibitor, chloroquine, was used to co‑treat HCT116 cells with W922, and it was identified that the cell cycle arrest was impaired. Moreover, co‑treatment of W922 and chloroquine led to a significant population of apoptotic cells, thus providing a promising therapeutic strategy for colorectal cancer.

Purpose Glioma is one of the most common malignant tumors affecting human health. Long non-coding RNA (lncRNA) TMPO-AS1 participates in the pathogenesis of various cancers. However, the role of lncRNA TMPO-AS1 in glioma remains largely unknown. This study aims to uncover the role of TMPO-AS1 and explore its potential mechanism in glioma. Methods Expression levels of TMPO-AS1 and miR-383-5p in glioma cell lines were measured by real-time quantitative PCR (RT-qPCR). CCK-8, colony formation, wound-healing, and Transwell assays were conducted to determine cell proliferation, migration and invasion abilities, respectively. Western blotting was applied to detect the expression of corresponding proteins. Immunofluorescence assay was performed to measure the expression of Ki67. The binding condition between TMPO-AS1 and miR-383-5p was verified by dual-luciferase reporter assay. Results We found that TMPO-AS1 was up-regulated while miR-383-5p was down-regulated in glioma cell lines, and knockdown of TMPO-AS1 significantly suppressed glioma cell proliferation, migration and invasion abilities. miR-383-5p was demonstrated to be a direct target of TMPO-AS1. Besides, inhibition of miR-383-5p abolished the effects of TMPO-AS1 knockdown on glioma cells. Conclusion In summary, our study revealed that inhibition of lncRNA TMPO-AS1 could suppress glioma progression through targeting miR-383-5p. TMPO-AS1 might be used as a therapeutic target for glioma treatment.

In utero exposure to environmental stress in both animals and humans could result in long-term epigenome alterations which further lead to consequences for adaptation and development in the offspring. Epigenetics, especially DNA methylation, is considered one of the most widely studied and well-characterized mechanisms involved in the long-lasting effects of in utero stress exposure. In this review, we outlined evidence from animal and human prenatal research supporting the view that prenatal stress could lead to lasting, broad and functionally organized signatures in DNA methylation which, in turn, could mediate exposure-phenotype associations. We also emphasized the advantage of using stressor from quasi-randomly assigned experiments. Furthermore, we discuss challenges that still need to be addressed in this field in the future.

Paraneoplastic pemphigus (PNP) is a severe autoimmune syndrome commonly triggered by neoplasms. The prognosis of CLL-associated PNP is dismal due to its refractory course and secondary infection and no standard treatment was recommended. We retrospectively reported six CLL with PNP cases from 842 cases of CLL including diagnosis, treatment and prognosis. The median time between the initial of CLL to PNP was 36 months while the median overall survival from the diagnosis of PNP was 26 months. And three cases died of lung infection while 5 developed pulmonary symptoms. And 5 cases received fludarabine-based chemotherapy before developing PNP, which suggesting fludarabine was one of potential causes of PNP. For the treatment, five patients were rescued by combined regimens including rituximab, methylprednisolone, immunoglobulin, fresh frozen plasma and the last received ibrutinib combined with short-term prednisone. Fludarabine-based regimen may be one of the potential causes of PNP. The combined regimen might shed a new light, while ibrutinib is a promising drug for CLL with PNP, but needs much more evidence. PNP should be carefully treated to guide early diagnosis and intervention for a better prognosis.

Social and environmental factors impact cancer and energy balance profoundly. Years ago, our lab established the existence of a novel brain-fat interaction we termed the "hypothalamic-sympathoneural-adipocyte (HSA) axis", through which complex environmental stimuli provided by an enriched environment regulate body composition, energy balance, and development of cancer. We have spent a significant portion of the past decade to further characterize the broad health benefits of an enriched environment (for example, leanness, enhanced immune function, and cancer resistance), and to identify mediators in the brain and periphery along the HSA axis. This review summarizes our recent work regarding the interface between endocrinology, immunology, cancer biology, aging, and neuroscience. We will discuss the interplay between these systemic phenomena and how the HSA axis can be targeted for regulation of cancer and aging.

As a receptor for transforming growth factor-β, nodal and activin, activin receptor-like kinase 7 (ALK7) previously acts as a suppressor of tumorigenesis and metastasis, which has emerged to play a key role in cardiovascular diseases. However, the potential effect and molecular mechanism of ALK7 on vascular smooth muscle cells' (VSMCs) phenotypic modulation have not been investigated. Using cultured mouse VSMCs with platelet-derived growth factor-BB administration, we observed that ALK7 showed a significantly increased expression in VSMCs accompanied by decreased VSMCs differentiation marker genes. Loss-of-function study demonstrated that ALK7 knockdown inhibited platelet-derived growth factor-BB-induced VSMCs phenotypic modulation characterized by increased VSMCs differentiation markers, reduced proliferation, and migration of VSMCs. Such above effects were reversed by ALK7 overexpression. Notably, we noticed that ALK7 silencing dramatically enhanced PPARγ expression, which was required for the attenuated effect of ALK7 knockdown on VSMCs phenotypic modulation. Collected, we identified that ALK7 acted as a novel and positive regulator for VSMCs phenotypic modulation partially through inactivation of PPARγ, which suggested that neutralization of ALK7 might act as a promising therapeutic strategy of intimal hyperplasia.

Background China media reported infant deaths following hepatitis B vaccination in late 2013, leading to temporary suspension of hepatitis B vaccine (HepB Event) until the deaths were shown to be coincidental and the vaccine was of standard, good quality. In 2016, a criminal ring in Shandong province that had been purchasing, improperly storing, and reselling Category 2 vaccines (private-sector) to 60 (of 200,000) clinics for 5 years, was exposed, publicized, and prosecuted, and the potential health and epidemiological impacts were investigated to determine whether revaccination was necessary (Shandong Vaccine Event). Methods We assessed parental confidence in vaccines through 9 telephone surveys in 6 and 11 provinces before, during, and after the two events. Provider confidence was assessed through in-person interviews following each event. Vaccine utilization was assessed using Immunization Information Management System data from township clinics. Results In the early stages of each event, approximately 30% of parents indicated vaccine hesitancy and 18% said they would refuse routine immunization. Five and nine months after each event, hesitancy and refusal decreased, but not to pre-event levels. During the Shandong Vaccine Event, 49·1% of parents indicated refusal to use Category 2 vaccines; six months later, the rate was 32·8%. Use of HepB decreased by 21% during the first 2 weeks of the HepB Event and by 12·6% during the first 4 weeks of Shandong Vaccine Event, but returned to baseline in less than 3 months. Use of Category 2 vaccine decreased by 49·5% in the first 3 weeks of the Shandong Vaccine Event and by 28·7% 6 months later. After the Shandong Vaccine Event, 64% of clinicians held high confidence in routine immunization, lower than at baseline. Conclusions The two events caused mistrust, loss of confidence, and decreases in use of vaccines by parents and providers. In addition to ensuring immunization program integrity, effective communications and ongoing monitoring of vaccine use and confidence should be included to restore confidence and trust in vaccines.

Pituitary adenoma (PA) is one of the most common intracranial tumors, and approximately 40% of all PAs are prolactinomas. Dopamine agonists (DAs), such as cabergoline (CAB), have been successfully used in the treatment of prolactinomas. The expression of dopamine type 2 receptor (DRD2) determines the therapeutic effect of DAs, but the molecular mechanisms of DRD2 regulation are not fully understood. In this study, we first demonstrated that DRD2 underwent proteasome-mediated degradation. We further employed the yeast two-hybrid system and identified kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), a substrate adaptor for the CUL3-RING ubiquitin (Ub) ligase complex, as a DRD2-interacting protein. KBTBD6/7 directly interacted with, and ubiquitinated DRD2 at five ubiquitination sites (K221, K226, K241, K251, and K258). CAB, a high-affinity DRD2 agonist, induced DRD2 internalization, and cytoplasmic DRD2 was degraded via ubiquitination under the control of KBTBD6/7, the activity of which attenuated CAB-mediated inhibition of the AKT/mTOR pathway. KBTBD7 knockout (KO) mice were generated using the CRISPR-Cas9 technique, in which the static level of DRD2 protein was elevated in the pituitary gland, thalamus, and heart, compared to that of WT mice. Consistently, the expression of KBTBD6/7 was negatively correlated with that of DRD2 in human pituitary tumors. Moreover, KBTBD7 was highly expressed in dopamine-resistant prolactinomas, but at low levels in dopamine-sensitive prolactinomas. Knockdown of KBTBD6/7 sensitized MMQ cells and primary pituitary tumor cells to CAB treatment. Conversely, KBTBD7 overexpression increased CAB resistance of estrogen-induced in situ rat prolactinoma model. Together, our findings have uncovered the novel mechanism of DRD2 protein degradation and shown that the KBTBD6/7-DRD2 axis regulates PA sensitivity to DA treatment. KBTBD6/7 may thus become a promising therapeutic target for pituitary tumors.

Background Mental task-based brain computer interface (BCI) systems are usually developed for neural prostheses technologies and medical rehabilitation. The mental workload was too heavy for the user to manipulate BCI effectively. Fortunately, electroencephalography (EEG) signal is not only used for BCI control but also relates to the changes of mental states. Objective We proposed a novel method for identifying non-effective trials of Steady State Visual Evoked Potential (SSVEP)-based BCI. Methods We used the subject-dependent and subject-independent alertness models identifying non-effective trials of SSVEP-BCI systems. Results The result implied that the subject-dependent alertness model was most useful for improving the classification accuracy in the task. However, the subject-independent alertness model could enhance the prediction ability of SSVEP-based BCI system. Conclusion In comparison to the conventional canonical correlation analysis (CCA) method without alertness-model filtering, the raise of precision was valuable for the technical development of BCI works. It demonstrated the effectiveness of our proposed subject-dependent and subject-independent methods.

Dispersal affects the spatial distribution and population structure of species. Dispersal is often male‐biased in mammals while female‐biased in birds, with the notable exception of the Anatidae. In this study, we tested genetic evidence for sex‐biased dispersal (SBD) in the Swan Goose Anser cygnoides, an Asian endemic and IUCN vulnerable species, which has been increasingly restricted to breeding on Mongolian steppe wetlands. We analyzed the genotypes of 278 Swan Geese samples from 14 locations at 14 microsatellite loci. Results from assignment indices, analysis of molecular variance, and five other population descriptors all failed to support significant SBD signals for the Swan Goose at the landscape level. Although overall results showed significantly high relatedness within colonies (suggesting high levels of philopatry in both sexes), local male genetic structure at the 1,050 km distance indicated greater dispersal distance for females from the eastern sector of the breeding range. Hence, local dispersal is likely scale‐dependent and female‐biased within the eastern breeding range. These findings are intriguing considering the prevailing expectation for there to be female fidelity in most goose species. We suggest that while behavior‐related traits may have facilitated the local genetic structure for the Swan Goose, several extrinsic factors, including the decreasing availability of the nesting sites and the severe fragmentation of breeding habitats, could have contributed to the absence of SBD at the landscape level. The long‐distance molt migration that is typical of goose species such as the Swan Goose may also have hampered our ability to detect SBD. Hence, we urge further genetic sampling from other areas in summer to extend our results, complemented by field observations to confirm our DNA analysis conclusions about sex‐specific dispersal patterns at different spatial scales in this species., We analyzed the genotypes of 278 Swan Geese samples from 14 locations at 14 microsatellite loci. We found no significant SBD signals at the landscape level, but local dispersal is likely scale‐dependent and female‐biased within the eastern breeding range. We urge further genetic sampling from other areas in summer to extend our results, complemented by field observations to confirm our DNA analyses conclusions about sex‐specific dispersal patterns at different spatial scales in this species.

Background Endonasal endoscopic skull base surgery has undergone rapid technological developments and is now widely performed, but its strengths and weaknesses deserve further investigation and deliberation. This study was performed to investigate the surgical indications, complications, and technical advantages and disadvantages of endonasal endoscopic skull base surgery. Methods The clinical data of 1886 endoscopic endonasal skull base surgeries performed in our ward at Beijing Tiantan Hospital from June 2006 to June 2016 were retrospectively analyzed. Results One thousand ninety-three (73.4%, 1490) pituitary adenomas, 54 (24.9%, 217) chordomas, 28 (80.0%, 35) craniopharyngiomas, and 15 (83.3%, 18) meningiomas underwent total resection. Two patients died postoperatively, both having pituitary adenomas. Other postoperative complications included olfactory disorders (n = 226, 11.9%), postoperative cerebrospinal fluid leakage (n = 78, 4.1%), hypopituitarism (n = 74, 3.9%), diabetes insipidus (n = 64, 3.4%), intracranial infection (n = 36, 1.9%), epistaxis (n = 24, 1.3%), vascular injury (n = 8, 0.4%), optic nerve injury (n = 8, 0.4%), and oculomotor movement impairment (n = 4, 0.2%). In total, 1517 (80.4%) patients were followed up for 6 to 126 months (average, 42.5 months) postoperatively. A total of 196 (13.2%) pituitary adenomas and 13 (37.1%) craniopharyngiomas recurred but no meningiomas recurred. Chordomas recurred in 97 (44.7%) patients, in whom 5-year survival rate was 65%. Conclusion Endoscopic surgery is an innovative surgical technique and the first choice for most midline extradural lesions such as chordomas, and an excellent choice for pituitary adenomas. It probably will be a good technique for many kinds of craniopharyngiomas and a common technique for most of skull base meningiomas, so the surgical indications of these cases should be chosen carefully to make good use of its respective advantages.

BACKGROUND Postoperative intra-abdominal septic complications of Crohn's disease substantially increase the healthcare expenditure and prolong hospitalization. OBJECTIVE We aimed to develop and validate a prediction model for intra-abdominal septic complications after bowel resection and primary anastomosis for Crohn's disease. DESIGN This was a retrospective cohort study. SETTINGS This study was conducted in a tertiary center. PATIENTS Data of 949 Crohn's disease-related primary bowel resections and anastomosis from January 2011 to December 2017 were collected. MAIN OUTCOME MEASURES Primary outcomes were prevalence of intra-abdominal septic complications. RESULTS Overall prevalence of intra-abdominal septic complications after Crohn's disease surgery was 11.6%. Predictors included preoperative C-reactive protein level ≥40 mg/L (OR = 3.545), preoperative glucocorticoids (OR = 1.829) and infliximab use (OR = 3.365), upper GI involvement (OR = 2.072), and hypoalbuminemia (albumin level

Background: The functions of microRNAs (miRNAs) in cancer progression have been recognized in recent years. However, the role of miR-4319 in esophageal squamous cell carcinoma (ESCC) remains unclear. Objective: We aimed to investigate the biological roles of miR-4319 in ESCC progression and the associated mechanisms. Methods: Real-time PCR was performed to examine the levels of miR-4319 in ESCC cell lines. The effects of miR-4319 and NOD-like receptor (NLR) family, caspase activation and recruitment domain (CARD) domain containing 5 (NLRC5) on cell proliferation and cell cycle progression were evaluated using MTT assay, colony formation and flow cytometry assays. Bioinformatics techniques and luciferase reporter assay were applied to validate NLRC5 as a miR-4319 target. Results: The miR-4319 expression was lower in ESCC cells than in the normal cell line. The expression of miR-4319 repressed cell growth and induced cell cycle arrest. NLRC5 was validated as a direct downstream target of miR-4319. Overexpression of NLRC5 potentiated the effects of miR-4319 on cell growth and cell cycle distribution. Conclusion: Our results demonstrated that miR-4319 might function as a tumor suppressor by targeting NLRC5 in ESCC.

Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular diseases. The current study explored the effect of mmLDL on the endothelin type A (ETA) receptor in mouse mesenteric arteries in vivo, as well as the role of autophagy in this process. mmLDL was injected via the caudal vein, and the Class III PI3K autophagic pathway inhibitor 3-methyladenine (3-MA) was injected intraperitoneally. The animals were divided into physiological saline (NS), mmLDL, and mmLDL + 3-MA groups. The dose-effect curve of endothelin-1- (ET-1-) induced mesenteric artery contraction was measured using myography, while ETA receptor mRNA expression was detected using real-time polymerase chain reactions, and the protein levels of the ETA receptor, class III PI3K, Beclin-1, LC3 II/I, p62, NF-κB, and p-NF-κB were observed using Western blot analysis. mmLDL significantly strengthened ET-1-induced contraction (the Emax value increased from 184.87 ± 7.46% in the NS group to 319.91 ± 20.31% in the mmLDL group (P<0.001), and the pEC50 value increased from 8.05 ± 0.05 to 9.11 ± 0.09 (P<0.01). In addition to upregulating the protein levels of Class III PI3K, Beclin-1, and LC3 II/I and downregulating that of p62, mmLDL significantly increased the mRNA expression and protein level of the ETA receptor and increased the protein level of p-NF-κB. However, these effects were significantly inhibited by 3-MA. mmLDL activates autophagy via the Class III PI3K/Beclin-1 pathway and upregulates the ETA receptor via the downstream NF-κB pathway. Understanding the effect of mmLDL on the ETA receptor and the underlying mechanisms may provide a new idea for the prevention and treatment of cardiovascular diseases.

Purpose: We aimed to investigate the association of single-nucleotide polymorphisms (SNPs) in HMGB1, REV3L, and NFE2L2 with prognosis in lung cancer patients with platinum-based chemotherapy. Methods: We have recruited 348 lung cancer patients treated with platinum. Log-rank test and Cox regression analysis were used to assess overall survival (OS) and progression-free survival (PFS) among SNP genotypes. Results: The results revealed that patients carrying TC or CC genotype in REV3L rs462779 (HR=0.67, 95% CI=0.51-0.90, P=0.007) and AG or GG genotype in HMGB1 rs1045411 (HR=0.61, 95% CI=0.38-0.99, P=0.046) had a better overall survival. Additionally, carrying TC or TT genotype in rs462779 had a lower risk (OR=0.38, 95% CI=0.17-0.89, P=0.025) of lymph node metastasis, carrying AG or AA genotype in rs1045411 was significantly related to early T stage (OR=0.47, 95% CI=0.29-0.76, P=0.002). In stratified analysis, patients with TC or CC genotype in rs462779 were significantly associated with overall survival in male patients, never-smokers, patients with younger age (≤56), no family history of cancer, adenocarcinoma, advanced stage (stage III or IV), or ECOG PS 0-1. While patients with AG or GG genotype in rs1045411 were significantly associated with overall survival in patients with advanced stage (stage III or IV) or ECOG PS 0-1. Conclusion: Our results indicate that the TC or CC genotype in rs462779 and AG or GG genotype in rs1045411 are contributed to better overall survival. The REV3L rs462779 and HMGB1 rs1045411 may serve as prognosis markers in lung cancer patients with platinum-based chemotherapy.

Laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy are the most common procedures performed in bariatric surgery and both have been demonstrated to have significant effectiveness in treating morbid obesity. However, comparative analysis of their effectiveness has not been well studied. This comparative analysis was conducted to determine whether Laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy have the same mid- and long-term outcomes in weight loss, resolution of obesity comorbidities and adverse events (AEs) of treatment.We searched the Cochrane Library, PubMed, Embase and Web of Science databases from the establishment of the database to January 1, 2020 for both randomized control trials and non-randomised interventional studies that studied Laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy with respect to weight loss outcomes, resolution of obesity comorbidities and AEs of treatment. Standardised mean differences, risk ratios and odds ratio with 95% confidence intervals were calculated to compare the outcomes of the groups. Two reviewers assessed the quality of the trials and extracted the data independently. All statistical analyses were performed using the standard statistical procedures in Review Manager 5.2.We included 20 studies (N = 2917 participants) in this meta-analysis. Our results showed no significant difference in excess weight loss between Laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy, with pooled Standardised mean differences of -0.16 (95% confidence interval: -0.52 to 0.19; P = 0.36) based on randomized control trials and 0.07 (95% confidence interval: -0.10 to 0.24; P = 0.41) based on non-randomised interventional studies. Further, the pooled results showed no significant differences in midterm and long-term weight loss outcomes between the comparative groups. Similarly, no significant difference was found in type 2 diabetes mellitus resolution. The pooled results indicated that patients receiving laparoscopic sleeve gastrectomy experienced fewer postoperative complication and reoperation rates, with pooled risk ratios of 1.66 (95% confidence interval: 1.33 to 2.07; P 0.00001) and 1.73 (95% confidence interval: 1.14 to 2.62; P = 0.01), respectively. Laparoscopic Roux-en-Y gastric bypass was superior to laparoscopic sleeve gastrectomy in managing dyslipidemia, hypertension and gastroesophageal reflux disease.The present meta-analysis indicated that both Laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy had the same effectiveness in resulting in excess weight loss and type 2 diabetes mellitus resolution. However, patients who received laparoscopic sleeve gastrectomy experienced fewer postoperative complication and reoperation rates than those who received Laparoscopic Roux-en-Y gastric bypass. Laparoscopic Roux-en-Y gastric bypass was superior in the management of dyslipidemia, hypertension and gastroesophageal reflux disease.

Advanced intrahepatic cholangiocarcinoma (ICC) is a highly challenging malignancy characterized by rapid progression and poor prognosis. Although programmed cell death-1/programmed cell death1 ligand-1 (PD-1/PD-L1) inhibitors licensed abroad have achieved certain effectiveness in treating various tumors, few studies have investigated the efficacies of these drugs on advanced ICC. Here, we describe a 63-year-old female patient with stage IV ICC involving the porta hepatis, retroperitoneal lymph nodes, and left adrenal gland, along with right femur metastasis. She suffered from lower back pain that had affected her sleep. A pathological fracture of her right femur was detected. Multiple lymph node metastases were found in the left adrenal glands, porta hepatis, and retroperitoneum. She failed the first- and secondline chemotherapies. After 6 cycles of combined therapy with sintilimab injection (PD-1) and tegafurgimeracil-oteracil potassium capsules (S-1), the patient's condition gradually improved and finally achieved partial remission (PR). The patient's pain score decreased, and her quality of life was significantly improved. The third-line treatment was efficacious and significantly improved survival. We can therefore speculate that PD-1 plays an important role in the treatment of advanced ICC and can benefit patients with similar conditions.

Although the function and regulation of SnRK1 have been studied in various plants, its molecular mechanisms in response to abiotic stresses are still elusive. In this work, we identified an AP2/ERF domain-containing protein (designated GsERF7) interacting with GsSnRK1 from a wild soybean cDNA library. GsERF7 gene expressed dominantly in wild soybean roots and was responsive to ethylene, salt, and alkaline. GsERF7 bound GCC cis-acting element and could be phosphorylated on S36 by GsSnRK1. GsERF7 phosphorylation facilitated its translocation from cytoplasm to nucleus and enhanced its transactivation activity. When coexpressed in the hairy roots of soybean seedlings, GsSnRK1(wt) and GsERF7(wt) promoted plants to generate higher tolerance to salt and alkaline stresses than their mutated species, suggesting that GsSnRK1 may function as a biochemical and genetic upstream kinase of GsERF7 to regulate plant adaptation to environmental stresses. Furthermore, the altered expression patterns of representative abiotic stress-responsive and hormone-synthetic genes were determined in transgenic soybean hairy roots after stress treatments. These results will aid our understanding of molecular mechanism of how SnRK1 kinase plays a cardinal role in regulating plant stress resistances through activating the biological functions of downstream factors.

Zinc is essential for almost all living organisms, since it serves as a crucial cofactor for transcription factors and enzymes. However, it is toxic to cell growth when present in excess. The present work aims to investigate the toxicity mechanisms induced by zinc stress in yeast cells. To this end, 108 yeast single-gene deletion mutants were identified sensitive to 6 mM ZnCl2 through a genome-wide screen. These genes were predominantly related to the biological processes of vacuolar acidification and transport, polyphosphate metabolic process, cytosolic transport, the process utilizing autophagic mechanism. A result from the measurement of intracellular zinc content showed that 64 mutants accumulated higher intracellular zinc under zinc stress than the wild-type cells. We further measured the intracellular ROS (reactive oxygen species) levels of 108 zinc-sensitive mutants treated with 3 mM ZnCl2. We showed that the intracellular ROS levels in 51 mutants were increased by high zinc stress, suggesting their possible involvement in regulating ROS homeostasis in response to high zinc. The results also revealed that excess zinc could generate oxidative damage and then activate the expression of several antioxidant defenses genes. Taken together, the data obtained indicated that excess zinc toxicity might be mainly due to the high intracellular zinc levels and ROS levels induced by zinc stress in yeast cells. Our current findings would provide a basis to understand the molecular mechanisms of zinc toxicity in yeast cells.

Objective Ascites, an accumulation of peritoneal fluid, is associated with poor prognosis of certain cancers. The potential mechanism that ascites worsens prognosis has not been well understood. Lipids have been reported to correlate with the prognosis of patients with epithelial ovarian cancer (EOC). Therefore, we aimed here to investigate whether lipids mediate the effect of ascites on the recurrence of EOC. Methods We collected the demographic and pathological data of 437 previously untreated patients with EOC to investigate the influence of ascites on recurrence. To identify the mechanism that mediates the potential influence of ascites on recurrence, we used ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) to determine the plasma lipid profiles of 53 patients with EOC. We used mediation analysis to evaluate if lipids mediated the effects of ascites on the recurrence of EOC. Results Patients with ascites had a poorer prognosis, which was associated with higher levels of carbohydrate antigen-CA125 (CA125) and FIGO stage. We identified six different lipid metabolites that were associated with ascites and recurrence. Mediation analysis revealed that the lipids LysoPC(P-15:0), PC(P-34:4), and PC(38:6) may mediate the effects of ascites on recurrence. Conclusion Our findings suggest that LysoPC(P-15:0), PC(P-34:4), and PC(38:6) mediate the effect of ascites on the prognosis of patients with EOC. We believe therefore that it is reasonable to consider metabolic interventions targeting the metabolism of LysoPC(P-15:0), PC(P-34:4), and PC(38:6) as a palliative treatment for patients with EOC with ascites. Further studies of more patients will be required to validate our findings.

Colorectal cancer (CRC) is one of the most common malignancies, and chemoresistance is one of the key obstacles in the clinical outcome. Here, we studied the function of B7-H3 in regulating cell cycle-mediated chemoresistance in CRC. The ability of B7-H3 in regulating chemoresistance was investigated via cell viability, clonogenicity, apoptosis and cycle analysis in vitro. Moreover, the role of B7-H3/CDC25A axis in regulating chemoresistance in vivo in the xenograft tumor models by intraperitoneal injection of oxaliplatin (L-OHP) and CDC25A inhibitors. The correlation between B7-H3 and CDC25A was examined in the CRC patients by immunohistochemistry (IHC) and pathological analyses. We found that B7-H3 could effectively enhance the resistance to a chemotherapeutic drug (oxaliplatin or 5-fluorouracil) via CDC25A. B7-H3 regulated the expression of CDC25A by the STAT3 signaling pathway in CRC cells. Furthermore, overexpression of B7-H3 enhanced chemoresistance by reducing the G2/M phase arrest in a CDC25A-dependent manner. Silencing CDC25A or treatment with CDC25A inhibitor could reverse the B7-H3-induced chemoresistance of cancer cells. Moreover, both B7-H3 and CDC25A were significantly upregulated in CRC samples compared with normal adjacent tissues and that the levels correlated with tumor stage. CDC25A was positively correlated with B7-H3 expression in this cohort. Taken together, our findings provide an alternative mechanism by which CRC cells can acquire chemoresistance via the B7-H3/CDC25A axis.

As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.

Incorporating poly(lactic-co-glycolic) acid (PLGA) microparticles into human mesenchymal stem cells (hMSC) aggregates has shown promising application prospects. However, the acidic degradation products and burst release of PLGA microparticles still need to be ameliorated. In this study, the PLGA/chitosan-heparin (P/C-h) composite microparticles were successfully fabricated by integrating the double emulsion and microfluidic technology through the precise manipulation of the emulsion composition and flow rate of the two-phase in a flow-focusing chip. The P/C-h microparticles were highly monodispersed with a diameter of 23.45 ± 0.25 μm and shell-core structure of the PLGA encapsulated C-h complex, which were suitable for the fabrication of hMSC aggregates. When the mass ratio of PLGA to the C-h complex was optimized to 2 : 1, the pH of the leach liquor of P/C-h microparticles remained neutral. Compared with those of PLGA microparticles, the cytotoxicity and the initial burst release (loaded FGF-2 and VEGF) were both significantly reduced in P/C-h microparticles. Furthermore, the survival, stemness, as well as secretion and migration abilities of cells in hMSC aggregates incorporating P/C-h microparticles were also enhanced. In summary, the P/C-h composite microparticles prepared by the droplet microfluidic technique support the optimal biological and functional profile of the hMSC aggregates, which may facilitate the clinical applications of MSC-based therapy.

Reduced hepatic Na+/K+-ATPase (NKA) activity and NKAα1 expression are engaged in the pathologies of metabolism diseases. The present study was designed to investigate the potential roles of NKAα1 in hepatic gluconeogenesis and glycogenesis in both hepatocytes and obese diabetic mice. Methods: Insulin resistance was mimicked by glucosamine (GlcN) in either human hepatocellular carcinoma (HepG2) cells or primary mouse primary hepatocytes. Obese diabetic mice were induced by high-fat diet (HFD) feeding for 12 weeks. Results: We found that both NKA activity and NKAα1 protein level were downregulated in GlcN-treated hepatocytes and in the livers of obese diabetic mice. Pharmacological inhibition of NKA with ouabain worsened, while activation of NKAα1 with an antibody against an extracellular DR region of NKAα1 subunit (DR-Ab) prevented GlcN-induced increase in gluconeogenesis and decrease in glycogenesis. Likewise, the above results were also corroborated by the opposite effects of genetic knockout/overexpression of NKAα1 on both gluconeogenesis and glycogenesis. In obese diabetic mice, hepatic activation or overexpression of NKAα1 stimulated the PI3K/Akt pathway to suppress hyperglycemia and improve insulin resistance. More importantly, loss of NKA activities in NKAα1+/- mice was associated with more susceptibility to insulin resistance following HFD feeding. Conclusions: Our findings suggest that NKAα1 is a physiological regulator of glucose homoeostasis and its DR-region is a novel target to treat hepatic insulin resistance.

BackgroundEpidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (e.g. gefitinib) currently remain the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) with activating EGFR mutation. However, acquired resistance to gefitinib, which occurs frequently through unidentified mechanisms, significantly attenuate therapeutic effectiveness. Previous miRNA microarray analysis reveals that expression levels of a conserved oncomiR miR-762 are significantly upregulated in gefitinib-resistant NSCLC cells. We therefore aim to elucidate the role and underlying mechanisms of miR-762 during the pathogenesis of gefitinib resistance.MethodsmiR-762 expression in gefitinib-resistant NSCLC tissues and cells was evaluated using RT-qPCR. The potential regulation of miR-762 expression by IL-6 was studied using pharmacological and biochemical approaches. Effects of miR-762 manipulation on sensitivity to gefitinib was assessed using MTT, apoptotic ELISA and xenograft model. Finally, the posttranscriptional regulation of active BCR related protein (ABR) by miR-762 was determined using luciferase assay and site-directed mutagenesis.ResultsmiR-762 expression was upregulated in gefitinib-resistant NSCLC tissues and cells, and this upregulation predicted a poor post-chemotherapy prognosis in NSCLC patients. miR-762 upregulation, induced by IL-6 signaling, significantly enhanced cell survival and rendered NSCLC cells unresponsiveness to gefitinib-elicited cell death. We finally provided the evidence that the oncogenic effect of miR-762 was mediated mainly through posttranscriptional repression of ABR in gefitinib-resistant NSCLC cells.ConclusionsOur findings provide a rationale for future efforts testing miR-762 inhibition and ABR restoration co-treatment in patients with recurrent EGFR mutant NSCLC to therapeutically combat the heterogeneity of EGFR-TKIs resistance mechanisms.

Gene-by-environment interactions influence brain development from conception to adulthood. In particular, the prenatal period is a window of vulnerability for the interplay between environmental and genetic factors to influence brain development. Rodent and human research demonstrates that prenatal maternal stress (PNMS) alters hippocampal volumes. Although PNMS affects hippocampal size on average, similar degrees of PNMS lead to different effects in different individuals. This differential susceptibility to the effects of PNMS may be due to genetic variants. Hence, we investigated the role of genetic variants of two SNPs that are candidates to moderate the effects of PNMS on hippocampal volume: COMT (rs4680) and BDNF (rs6265). To investigate this, we assessed 53 children who were in utero during the January 1998 Quebec ice storm. In June 1998 their mothers responded to questionnaires about their objective, cognitive, and subjective levels of stress from the ice storm. When children were 11 1/2 years old, T1-weighted structural magnetic resonance imaging (MRI) scans were obtained using a 3T scanner and analyzed to determine hippocampal volumes. We collected and genotyped the children’s saliva DNA. Moderation analyses were conducted to determine whether either or both of the SNPs moderate the effect of PNMS on hippocampal volumes. We found that objective hardship was associated with right hippocampal volume in girls, and that the BDNF and COMT genotypes were associated with left hippocampal volume in boys and girls. In addition, SNPs located on COMT moderated the effect of maternal objective distress in boys, and subjective distress in girls, on both right hippocampal volume. Thus, we conclude that an individual’s genotype alters their susceptibility to the effects of PNMS.

The environment of an organism can convey a powerful influence over its biology. Environmental enrichment (EE), as a eustress model, has been used extensively in neuroscience to study neurogenesis and brain plasticity. EE has also been used as an intervention for the treatment and prevention of neurological and psychiatric disorders with limited clinical application. By contrast, the effects of EE on the immune system are relatively less investigated. Recently, accumulating evidence has demonstrated that EE can robustly impact immune function. In this review, we summarize the major components of EE, the impact of EE on natural killer (NK) cells, EE’s immunoprotective roles in cancer, and the underlying mechanisms of EE-induced NK cell regulation. Moreover, we discuss opportunities for translational application based on insights from animal research of EE-induced NK cell regulation.

Mutations in DYNC1H1 have been shown to cause spinal muscular atrophy lower extremity predominant type 1 (SMALED1), an autosomal dominant genetic neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. Here, we describe monozygotic twins, one with a more severe upper motor neuron phenotype as a result of a suspected perinatal hypoxic-ischemic event and the other presenting a typical lower motor neuron phenotype. Using exome sequencing, we identified the novel de novo variant c.752G>T; p.Arg251Leu in DYNC1H1. We thereby add this variant to the growing list of mutations in DYNC1H1 that cause SMALED1.

As domain species in seep and vent ecosystem, Bathymodioline mussels has been regarded as a model organism in investigating deep sea chemosymbiosis. However, mechanisms underlying their symbiosis with chemosynthetic bacteria, especially how the host recognizes symbionts, have remained largely unsolved. In the present study, a modified pull-down assay was conducted using enriched symbiotic methane-oxidation bacteria as bait and gill proteins of Bathymodiolus platifrons as a target to isolate pattern recognition receptors involved in the immune recognition of symbionts. As a result, a total of 47 proteins including BpLRR-1 were identified from the pull-down assay. It was found that complete cDNA sequence of BpLRR-1 contained an open reading frame of 1479 bp and could encode a protein of 492 amino acid residues with no signal peptide or transmembrane region but eight LRR motif and two EFh motif. The binding patterns of BpLRR-1 against microbial associated molecular patterns were subsequently investigated by surface plasmon resonance analysis and LPS pull-down assay. Consequently, BpLRR-1 was found with high binding affinity with LPS and suggested as a key molecule in recognizing symbionts. Besides, transcripts of BpLRR-1 were found decreased significantly during symbiont depletion assay yet increased rigorously during symbionts or nonsymbiotic Vibrio alginolyticus challenge, further demonstrating its participation in the chemosynthetic symbiosis. Collectively, these results suggest that BpLRR-1 could serve as an intracellular recognition receptor for the endosymbionts, providing new hints for understanding the immune recognition in symbiosis of B. platifrons.

Small-molecule targeted antitumor drugs are considered to be a promising treatment that can improve the efficacy and reduce side effects. PI3K/Akt signaling pathway is constantly activated in various cancers. We recently synthesized a series of novel compounds of PI3K/Akt pathway inhibitors and found the most effective analog to be W934. In this study, we explored the in-vitro and in-vivo antitumor effects of W934 on A549 non-small-cell lung cancer cells and HCT116 colorectal cancer cells. In-vitro assays showed that W934 caused an inhibition of PI3Kα kinase. W934 can significantly suppress the viability of A549 and HCT116 cells with IC50 values of 0.25 and 0.23 μmol/l, respectively. Besides, the inhibitory effects on cell migration, invasion and apoptosis were also observed after treatment of W934 for the indicated hours. According to the cell cycle analysis, W934 caused an inhibition of G0-G1 phase progression and correspondingly decreased the percentage of cells in S and G2-M phases. Results of western blotting indicated that W934 concentration dependently suppressed the activation of the PI3K/Akt pathway. Meanwhile, the in-vivo effect was studied in an A549 xenograft mouse model. Oral administration of W934 inhibited the tumor growth in a dose-dependent manner. Hereby, W934 might be considered as a potential therapeutic drug candidate for non-small-cell lung cancer treatment.

Activation of the renin-angiotensin system (RAS) contributes to the pathogenesis of cardiovascular diseases. Sodium potassium ATPase (NKA) expression and activity are often regulated by angiotensin II (Ang II). This study is aimed at investigating whether DR-Ab, an antibody against 4thextracellular region of NKA, can protect Ang II-induced cardiomyocyte hypertrophy. Our results showed that Ang II treatment significantly reduced NKA activity and membrane expression. Pretreatment with DR-Ab preserved cell size in Ang II-induced cardiomyopathy by stabilizing the plasma membrane expression of NKA and restoring its activity. DR-Ab reduced intracellular ROS generation through inhibition of NADPH oxidase activity and protection of mitochondrial functions in Ang II-treated H9c2 cardiomyocytes. Pharmacological manipulation and Western blotting analysis demonstrated the cardioprotective effects were mediated by the activation of the AMPK/Sirt-3/PPARγsignaling pathway. Taken together, our results suggest that dysfunction of NKA is an important mechanism for Ang II-induced cardiomyopathy and DR-Ab may be a novel and promising therapeutic approach to treat cardiomyocyte hypertrophy.