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Oxidative damage and intestinal dysbiosis are regarded as crucial culprits in alcoholic liver disease (ALD). This study aimed to examine the protective effects of Echinacea purpurea polysaccharides (EPPs) against ALD and explore the underlying mechanisms based on hepatic oxidative stress, inflammation, and intestinal barrier function. Three polysaccharide fractions, namely, EPP40, EPP60, and EPP80, were obtained by stepwise ethanol precipitation, and their antioxidant activity in vitro was investigated. The results showed that EPP80 with Mw 11.82 kDa had the strongest radical-scavenging capacity against DPPH, ABTS, and •OH radicals. Besides, EPP80 comprised arabinose, galactose, glucose, mannose, galacturonic acid, and glucuronic acid in molar ratios of 13.42:25.12:10.92:8.59:2.07:0.82. The in vivo results showed that EPP80 increased the activities of antioxidant enzymes and reduced the levels of inflammatory cytokines both in mouse serum and liver. Moreover, EPP80 upregulated the expression of Occludin and ZO-1, revealing its protective effect against intestinal barrier dysfunction. Furthermore, EPP80 inhibited alcohol-induced oxidative damage by promoting the expression of Nrf2, HO-1, and NQO1 in the liver. In summary, EPP80 markedly scavenged free radicals in vitro and ameliorated alcohol-induced liver injury via Nrf2/HO-1 pathways in vivo. These findings suggested that EPP80 could provide effective supplementary support in preventing and treating ALD.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies and cause of death from cancer in China. Previous studies showed that autophagy and apoptosis inhibition are critical for the survival of ESCC cells. However, the underlying mechanisms remain to be clarified. Recently, we found that PIWIL2, a novel cancer testis protein, is highly expressed in ESCC and associated with high T-stage and poor 5-year survival rate in patients. Our further study showed that PIWIL2 can directly bind to IKK and promote its phosphorylation, leading to phosphorylation of IκB and subsequently nuclear translocation of NF-κB for apoptosis inhibition. Meanwhile, PIWIL2 competitively inhibits binding of IKK to TSC1, and thus deactivate mTORC1 pathway which suppresses ULK1 phosphorylation and initiation of autophagy. The mouse xenograft model suggested that PIWIL2 can promote ESCC growth in an IKK-dependent manner. This present work firstly revealed that PIWIL2 can play a role in regulating autophagy and apoptosis, and is associated with poor prognosis in ESCC patients, providing novel insights into the roles of PIWIL2 in tumorigenesis.

Chronic and excessive alcohol consumption can lead to the development of alcoholic liver disease (ALD), which is characterized by oxidative damage, inflammation, and impaired intestinal barrier function. To evaluate the effect of exopolysaccharides (EPS) from Sporidiobolus pararoseus on ALD, alcohol was used in this study to cause liver damage in mice. Then, the antioxidant and anti-inflammation activities and protective effect of EPS on the intestinal barrier function were further explored in an ALD model. The results show that the histopathological change and liver injury were significantly improved in the EPS group. EPS treatment significantly increased the levels of superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-Px) (P

Background Cone dystrophy with supernormal rod response (CDSRR) is an autosomal recessive retinal disorder characterized by myopia, dyschromatopsia, nyctalopia, photophobia, and nystagmus. CDSRR is caused by mutations in KCNV2, the gene encoding for an electrically silent Kv subunit (Kvs) named Kv8.2. Methods A Chinese CDSRR family was recruited. Complete ophthalmology clinical examinations were performed to clarify the phenotype. Genetic examination was underwent using whole exome sequencing (WES). In addition, a candidate gene was validated by Sanger sequencing. Expression analysis in vitro including immunoblotting, quantitative real‐time PCR (qRT‐PCR), and co‐immunoprecipitation experiments was performed to investigate the pathogenic mechanism of the identified gene variants. Results WES identified two KCNV2 heterozygous mutations from the proband. Sanger sequencing validated that the patient's parents had, respectively, carried those two mutations. Further in vitro functional experiments indicated that the mutated alleles had led the Kv8.2 proteins to fail in expressing and interacting with the Kv2.1 protein, respectively. Conclusions This study expanded the KCNV2 mutation spectrum. It can also be deduced that CDSRR has a broad heterogeneity. It is further confirmed that the inability expression of Kv8.2 proteins and the failure of Kv8.2 proteins to interact with Kv2.1 may have accounted for the etiology of CDSRR based on previous studies and this study., Compound heterozygous variations (c.731G>C and c.280dup) were revealed in the KCNV2 gene of a male with CDSRR. Functional analysis had confirmed that c.280dup may led to non‐sensed mRNA decay (NMD), which in turn makes the protein unable to express. In addition, it is also approved that the c.731G>C mutation, in which the Kv2.1 protein failed to interact with Kv8.2 proteins. For the etiology of CDSRR, our study suggested that the inability expression of Kv8.2 proteins along with the failure of interactions between the Kv2.1 protein and the Kv8.2 proteins may account for the occurrence of the CDSRR.

The direct effect of genetic variations on clinical phenotypes within schizophrenia (SZ) remains elusive. We examined the previously identified association of reduced gray matter concentration in the insula - medial prefrontal cortex and a quantitative trait locus located in 12q24 in a SZ dataset. The main analysis was performed on 1461 SNPs and 830 participants. The highest contributing SNPs were localized in five genes including TMEM119, which encodes a microglial marker, that is associated with neuroinflammation and Alzheimer's disease. The gene set in 12q4 may partially explain brain alterations in SZ, but they may also relate to other psychiatric and developmental disorders.

Immune checkpoint blockade (ICB) has a limited effect on colorectal cancer, underlining the requirement of co‐targeting the complementary mechanisms. Here, we identified prostaglandin E2 (PGE2) receptor 4 (EP4) as the master regulator of immunosuppressive myeloid cells (IMCs), which are the major driver of resistance to ICB therapy. PGE2‐bound EP4 promotes the differentiation of immunosuppressive M2 macrophages and myeloid‐derived suppressor cells (MDSCs) and reduces the expansion of immunostimulated M1 macrophages. To explore the immunotherapeutic role of EP4 signaling, we developed a novel and selective EP4 antagonist TP‐16. TP‐16 effectively blocked the function of IMCs and enhanced cytotoxic T‐cell‐mediated tumor elimination in vivo. Cell co‐culture experiments revealed that TP‐16 promoted T‐cell proliferation, which was impaired by tumor‐derived CD11b+ myeloid cells. Notably, TP‐16 and anti‐PD‐1 combination therapy significantly impeded tumor progression and prolonged mice survival. We further demonstrated that TP‐16 increased responsiveness to anti‐PD‐1 therapy in an IMC‐related spontaneous colorectal cancer mouse model. In summary, this study demonstrates that inhibition of EP4‐expressing IMCs may offer a potential strategy for enhancing the efficacy of immunotherapy for colorectal cancer., Immunosuppressive myeloid cells (IMCs) are a prominent driver of immunotherapy resistance in colorectal cancer. This study identifies EP4 as a master regulator of IMCs and highlights blockade of EP4 as a novel therapeutic strategy for enhancing immunotherapy in colorectal cancer.

Currently, various treatment options are available for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), mainly including medical therapy, open prostatectomy (OP), transurethral resection of prostate (TURP), and minimally invasive treatment, such as holmium laser enucleation (HoLEP), greenlight laser prostatectomy, photovaporization of the prostate, etc. [1–4]. Medical therapy, including the use of alpha-1-Blocker and 5-alpha reductase inhibitors, has been considered first-line treatment [5]. Surgical treatments are used for treatment in patients who are failed in medical treatment [6]. European Association of Urology suggests that TURP is considered as the standard therapy for patients with prostate volume (PV) ranges from 30 to 80 cm3, OP or HoLEP are considered as the gold standard when PV larger than 80 cm3 [2, 3, 7]. However, each treatment method has its advantages and disadvantages. The medication may affect blood pressure and sexual function. Surgical treatment is associated with prolonged hospitalization, postoperative pain, retrograde ejaculation, sexual dysfunction, and hemorrhage [3, 8–10].

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. DKK1 directly facilitated OP recruitment through suppression of its receptor LDL receptor–related protein 5 (LRP5) but not LRP6, upregulating Rnasek expression via inhibition of canonical WNT signaling. In clinical samples, RSPO2, LGR4, and DKK1 expression showed a positive correlation with BCa bone metastasis. Furthermore, soluble LGR4 extracellular domain (ECD) protein, acting as a decoy receptor for RSPO2 and RANKL, significantly alleviated bone metastasis and osteolytic lesions in a mouse bone metastasis model. These findings provide unique insights into the functional role of OPs as key components of the premetastatic niche for BCa bone metastasis and identify RSPO2/RANKL-LGR4 signaling as a promising target for inhibiting BCa bone metastasis.

Altres ajuts: SRB: The Australian Schizophrenia Research Bank (ASRB) was supported by the National Health and Medical Research Council of Australia (NHMRC) (Enabling Grant, ID 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief Investigators for ASRB were Carr, V., Schall, U., Scott, R., Jablensky, A., Mowry, B., Michie, P., Catts, S., Henskens, F., Pantelis, C. We thank Loughland, C., the ASRB Manager, and acknowledge the help of Jason Bridge for ASRB database queries. CP was supported by NHMRC Senior Principal Research Fellowships (IDs: 628386 & 1105825); GC was supported by the Schizophrenia Research Institute utilizing infrastructure funding from the New South Wales Ministry of Health and New South Wales Ministry of Trade and Investment (Australia); JMF was supported by NHMRC project grant (1063960) and the Janette Mary O'Neil Research Fellowship; MJG was supported by NHMRC as an R.D. Wright Biomedical Career Development Fellow (1061875). MJC was supported by NHMRC Senior Research Fellowship (1121474). CASSI: CSW is funded by the NSW Ministry of Health, Office of Health and Medical Research. CSW is a recipient of a National Health and Medical Research Council (Australia) Principal Research Fellowship (PRF) (#1117079). CIAM: The CIAM study (FMH - PI) was supported by the University Research Committee, University of Cape Town and South African funding bodies National Research Foundation and Medical Research Council. COBRE: The COBRE dataset and investigators were supported by NIH grants R01EB006841 & P20GM103472, as well as NSF grant 1539067. JT (senior author) and VDC are supported by 5R01MH094524. JMS is supported by R01 AA021771 and P50 AA022534. EONCKS: This work was supported by a New Partnership for Africa's Development (NEPAD) grant through the Department of Science and Technology of South Africa, the Medical Research Council of South Africa (grant number 65174). ESO: The ESO study was funded by NPU I - LO1611 and Ministry of Health, Czech Republic - Conceptual Development of Research Organization 00023001 (IKEM). FIDMAG/Project: This work was supported by the Catalan Government and several grants from the Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, 'Investing in your future'): Miguel Servet Research Contracts and Research Project Grants. FOR2107 Marburg: The FOR2107 Marburg study was funded by the German Research Foundation (DFG), Tilo Kircher (speaker FOR2107; DFG grant numbers KI588/14-1, KI588/14-2), Axel Krug (KR 3822/5-1, KR 3822/7-2), Igor Nenadic (NE 2254/1-2), Carsten Konrad (KO 4291/3-1). FOR2107 Muenster: The FOR2107 Muenster study was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). TH was supported by grants from the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4). Frankfurt: MRI was performed at the Frankfurt Brain Imaging Center, supported by the German Research Council (DFG) and the German Ministry for Education and Research (BMBF; Brain Imaging Center Frankfurt/Main, DLR 01GO0203). GIPSI: This study was supported by Colciencias PRISMA-U.T. Huilong1 & Huilong2: This study was funded by the National Natural Science Foundation of China (81761128021; 31671145; 81401115; 81401133), Beijing Municipal Science and Technology Commission grant (Z141107002514016) and Beijing Natural Science Foundation(7162087, Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding (XMLX201609; zylx201409). IGP: This study was funded by Project Grants from the Australian National Health and Medical Research Council of Australia (NHMRC; APP630471 and APP1081603), the Macquarie University's Australian Research Council Centre of Excellence in Cognition and its Disorders (CE110001021). Johns Hopkins: Supported by National Institutes of Health Grant Nos. MH-092443, MH-094268 (Silvio O. Conte Center), MH-105660, and MH-107730; foundation grants from Stanley, RUSK/S-R, and NARSAD/Brain and Behavior Research Foundation. Madrid: Supported by the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III, co-financed by ERDF Funds from the European Commission, "A way of making Europe", CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds and European Union Seventh Framework Program and H2020 Program; Fundación Familia Alonso, Fundación Alicia Koplowitz and Fundación Mutua Madrileña. MPRC1 & MPRC2: Support was received from NIH grants U01MH108148, 2R01EB015611, R01MH112180, R01DA027680, R01MH085646, P50MH103222 and T32MH067533, a State of Maryland contract (M00B6400091) and NSF grant (1620457). OLIN: The Olin study was supported by NIH grants R37MH43375 and R01MH074797. Oxford: The Oxford study MRC G0500092. SLF Rome: Support from the Italian Ministry of Health grants RC-12-13-14-15-16-17-18-19/A. RSCZ: RSCZ data collection was supported by RFBR 15-06-05758 grant. SCORE: This study was supported in part by grant 3232BO_119382 from the Swiss National Science Foundation. We thank the FePsy (Frueherkennung von Psychosen; early detection of psychosis) Study Group from the University of Basel, Department of Psychiatry, Switzerland, for the recruitment of the study participants. The FePsy Study was supported in part by grant No. SNF 3200-057216/1, ext./2, ext./3. Singapore: This study was supported by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/11003), and the Singapore Bioimaging Consortium (RP C-009/2006) research grants awarded to KS. SNUH: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (Grant no. 2013R1A2A1A03071089 and 2017M3C7A1029610). UCISZ: The UCISZ study was supported by the National Institutes of Mental Health grant number R21MH097196 to TGMvE. UCISZ data were processed by the UCI High Performance Computing cluster supported by Joseph Farran, Harry Mangalam, and Adam Brenner and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153. UNIBA: The UNIBA study was supported by grant funding from the Italian Ministry of Health (PE-2011-02347951). UNIMAAS: The study was supported by Dutch Organization for Health Research and Development (ZonMw 91112002) and a personal grant to Thérèse van Amelsvoort (ZonMw-VIDI: 91712394). The data was collected in a clinical trial registered in the Dutch clinical trial registry under ID: NTR5094 (http://www.trialregister.nl). UPenn: This study was supported by the National Institute of Mental Health grants MH064045, MH 60722, MH019112, MH085096 (DHW), and R01MH112847 (RTS and TDS). Zurich: This study was supported by the Swiss National Science Foundation (105314_140351 to S.K.). Matthias Kirschner acknowledges support from the National Bank Fellowship (McGill University) and the Swiss National Foundation (P2SKP3_178175). Research reported in this publication was also supported by the following National Institutes of Health grants: U54 EB020403 to PMT, R01 MH116147, U24 RR21992, R21MH097196, and TR000153 to TGMvE, S10 OD023696 and R01EB015611 to PK, T32 AG058507and 5T32 MH073526 to CRKC, R01 MH117601 to NJ, ENIGMA's NIH Big Data to Knowledge (BD2K) initiative U54 EB020403, ENIGMA Sex Differences R01MH116147, and ENIGMA-COINSTAC: Advanced World-wide Transdiagnostic Analysis of Valence System Brain Circuits R01MH121246. A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Most psychiatric disorders are highly heritable and associated with altered brain structural and functional patterns. Data fusion analyses on brain imaging and genetics, one of which is parallel independent component analysis (pICA), enable the link of genomic factors to brain patterns. Due to the small to modest effect sizes of common genetic variants in psychiatric disorders, it is usually challenging to reliably separate disorder-related genetic factors from the rest of the genome with the typical size of clinical samples. To alleviate this problem, we propose sparse parallel independent component analysis (spICA) to leverage the sparsity of individual genomic sources. The sparsity is enforced by performing Hoyer projection on the estimated independent sources. Simulation results demonstrate that the proposed spICA yields improved detection of independent sources and imaging-genomic associations compared to pICA. We applied spICA to gray matter volume (GMV) and single nucleotide polymorphism (SNP) data of 341 unrelated adults, including 127 controls, 167 attention-deficit/hyperactivity disorder (ADHD) cases, and 47 unaffected siblings. We identified one SNP source significantly and positively associated with a GMV source in superior/middle frontal regions. This association was replicated with a smaller effect size in 317 adolescents from ADHD families, including 188 individuals with ADHD and 129 unaffected siblings. The association was found to be more significant in ADHD families than controls, and stronger in adults and older adolescents than younger ones. The identified GMV source in superior/middle frontal regions was not correlated with head motion parameters and its loadings (expression levels) were reduced in adolescent (but not adult) individuals with ADHD. This GMV source was associated with working memory deficits in both adult and adolescent individuals with ADHD. The identified SNP component highlights SNPs in genes encoding long non-coding RNAs and SNPs in genes MEF2C, CADM2, and CADPS2, which have known functions relevant for modulating neuronal substrates underlying high-level cognition in ADHD.

Background Several studies have demonstrated autophagy was involved in the process of esophageal adenocarcinoma (EAC). The aim of this study was to explore autophagy-related genes (ARGs) correlated with overall survival (OS) in EAC patients. Methods Expressions of ARGs in EAC and normal samples were downloaded from TCGA database. GO and KEGG enrichment analyses were used to investigate the ARGs bioinformatics functions. Univariate and multivariate cox regressions were performed to identify prognostic ARGs and the independent risk factors. ROC curve was established to evaluate the feasibility to predict the prognosis. Finally, the correlations between ARGs and clinical features were further explored. In addition, significantly different ARGs were verified in EAC specimens and normal esophageal mucosal tissues. Results Thirty significantly different ARGs were selected from EAC and normal tissues. Functional enrichments showed these ARGs were mainly related apoptosis. Multivariate cox regression analyses demonstrated eight ARGs were significantly associated with OS. Among these eight genes, BECN1 (HR = 0.321, P = 0.046), DAPK1 (HR = 0.636, P = 0.025) and CAPN1 (HR = 0.395, P = 0.004) played protective roles in survival. Gender (HR = 0.225, P = 0.032), stage (HR = 5.841, P = 0.008) and risk score (HR = 1.131, P < 0.001) were independent prognostic risk factors. ROC curves showed better efficacy to predict survival using the risk score. Additionally, we found BECN1, DAPK1, VAMP7 and SIRT1 genes were correlated significantly with survival status, gender, primary tumor and tumor stage (all P < 0.05). The experimental results confirmed the BIRC5 was overexpressed and the ITPR1, PRKN were downregulated in the EAC tissues compared with the normal esophageal mucosal tissues (all P < 0.05). Conclusion Our findings suggested that autophagy was involved in the process of EAC. Several ARGs probably could serve as diagnostic and prognostic biomarkers and may help facilitate therapeutic targets in EAC patients.

Bipolar disorder (BD) is a severe manic-depressive illness. Patients with BD have been shown to have gray matter (GM) deficits in prefrontal, frontal, parietal, and temporal regions; however, the relationship between structural effects and clinical profiles has proved elusive when considered on a region by region or voxel by voxel basis. In this study, we applied parallel independent component analysis (pICA) to structural neuroimaging measures and the positive and negative syndrome scale (PANSS) in 110 patients (mean age 34.9 ± 11.65) with bipolar disorder, to examine networks of brain regions that relate to symptom profiles. The pICA revealed two distinct symptom profiles and associated GM concentration alteration circuits. The first PANSS pICA profile mainly involved anxiety, depression and guilty feelings, reflecting mood symptoms. Reduced GM concentration in right temporal regions predicted worse mood symptoms in this profile. The second PANSS pICA profile generally covered blunted affect, emotional withdrawal, passive/apathetic social withdrawal, depression and active social avoidance, exhibiting a withdrawal or apathy dominating component. Lower GM concentration in bilateral parietal and frontal regions showed worse symptom severity in this profile. In summary, a pICA decomposition suggested BD patients showed distinct mood and apathy profiles differing from the original PANSS subscales, relating to distinct brain structural networks., Highlights • Structural relationships with symptoms in bipolar disorder are complex. • A parallel ICA analysis of PANSS questions and structural images finds two correlated profiles. • The first pair links mood symptoms with right temporal regions. • The second pair highlights social withdrawal and apathy symptoms linked to bilateral frontal and parietal regions.

Highlights • Brain mechanisms behind familial effects and ADHD symptoms are examined in children. • Genetic liability and symptoms are distinctly reflected by structural brain areas. • The cerebellum is negative correlated with inattention across the entire sample. • The insula in siblings and cases showed reduced loadings compared to controls., Gray matter disruptions have been found consistently in Attention-deficit/Hyperactivity Disorder (ADHD). The organization of these alterations into brain structural networks remains largely unexplored. We investigated 508 participants (281 males) with ADHD (N = 210), their unaffected siblings (N = 108), individuals with subthreshold ADHD (N = 49), and unrelated healthy controls (N = 141) with an age range from 7 to 18 years old from 336 families in the Dutch NeuroIMAGE project. Source based morphometry was used to examine structural brain network alterations and their association with symptoms and cognitive performance. Two networks showed significant reductions in individuals with ADHD compared to unrelated healthy controls after False Discovery Rate correction. Component A, mainly located in bilateral Crus I, showed a ADHD/typically developing difference with subthreshold cases being intermediate between ADHD and typically developing controls. The unaffected siblings were similar to controls. After correcting for IQ and medication status, component A showed a negative correlation with inattention symptoms across the entire sample. Component B included a maximum cluster in the bilateral insula, where unaffected siblings, similar to individuals with ADHD, showed significantly reduced loadings compared to controls; but no relationship with individual symptoms or cognitive measures was found for component B. This multivariate approach suggests that areas reflecting genetic liability within ADHD are partly separate from those areas modulating symptom severity.

The effect of a gene's activity can be affected by the existence of another gene, termed as genetic interaction, or intragenic epistasis. Understanding genetic interactions among tumor suppressor genes will undoubtedly facilitate our understanding of the tumorigenesis and metastasis. With the wide-application of the next-generation sequencing of patient tumor samples, we have gained unprecedented resolution on the occurrence of mutations in each patient. Many previous studies have used odds ratio and Fisher's exact test to quantify such genetic interactions among tumor suppressor genes. Here, using the TCGA breast cancer dataset as an example, we have showed a potential problem for previous approaches and propose an approach that corrects for these bias. This study serves as a reminder that the interpretation of such large scale studies of mutational frequency data should proceed with reasonable caution.

While gray matter (GM) anomalies have been reported for attention-deficit/hyperactivity disorder (ADHD), investigating their associations with cognitive deficits and individual symptom domains can help pinpoint the neural underpinnings critical for the pathology of ADHD, particularly the persist form of ADHD. In this work, we performed both independent component analysis and voxel-based morphometry analysis on whole brain GM of 486 adults including 214 patients, 96 unaffected siblings, and 176 healthy controls, in relation to cognition and symptoms. Independent component analysis revealed that higher GM volume in inferior semilunar lobule, inferior frontal gyri, and superior and middle frontal gyri was associated with better working memory performance, and lower GM volume in cerebellar tonsil and culmen was associated with more severe inattention symptoms. Consistently, voxel-based morphometry analysis showed that higher GM volume in multiple regions of frontal lobe, cerebellum and temporal lobe was related to better working memory performance. Focusing on the networks derived from ICA, our results integrated prefrontal regions and cerebellar regions through associations with working memory and inattention symptoms, lending support for the theory of ‘cool’-cognition dysfunction being mediated by inferior fronto-striato-cerebellar networks in ADHD. Siblings showed intermediate cognitive impairments between patients and controls but presented GM anomalies in unique focal regions, suggesting they are a separate group potentially affected by the shared genetic and environmental risks with ADHD patients., Highlights • Frontal and cerebellar regions associated with adult ADHD working memory deficits. • Gray matter reduction in cerebellum related to inattention symptoms in adult ADHD. • Siblings presented intermediate cognitive impairments. • Adult ADHD showed gray matter reduction in middle frontal gyrus.

Early diagnosis of prostate cancer is very crucial to reduce the mortality rate. Multi-parametric magnetic resonance imaging (MRI) can provide detailed visualization of prostate tissues and lesions. Their malignancy can be diagnosed before any necessary invasive approaches, such as needle biopsy, at the risk of damage to or inflammation of the periprostatic nerves, prostate and bladder neck. However, the prostate tissue malignancy on magnetic resonance (MR) images can also be difficult to determine, with often inconclusive results among the clinicians. With the progress in artificial intelligence (AI), research on MR image-based lesion classification with AI tools are being explored increasingly. So far, existing classification approaches heavily rely on manually labelling of lesion areas, which is a labor-intensive and time-consuming process. In this paper, we present a novel two-stage method for fully-automated prostate lesion detection and classification, using input sequences of T2-weighted images, apparent diffusion coefficient (ADC) maps and high b-value diffusion-weighted images. In the first stage, a Mask R-CNN model is trained to automatically segment prostate structures. In the second stage, a weakly supervised deep neural network is developed to detect and classify lesions in a single run. To validate the accuracy of our system, we tested our method on two datasets, one from the PROSTATEx Challenge and the other from our local cohort. Our method can achieve average area-under-the-curve (AUC) of 0.912 and 0.882 on the two datasets respectively. The proposed approach present a promising tool for radiologists in their clinical practices.

This study aims to explore the early response of antidepressant therapy by measuring the voxel-mirrored homotopic connectivity (VMHC) in major depressive disorder (MDD). Eighty-two MDD patients [n=42 treatment-responsive depression (RD) and n=40 non-responding depression (NRD)] and n=50 normal controls (NC) underwent clinical measures and a magnetic resonance imaging scan, and the VMHC values were calculated. Receiver operating characteristic (ROC) curve analysis was applied to determine the capability of altered VMHC to distinguish NRD. The NRD showed significantly decreased VMHC in bilateral precuneus (PCU) and inferior temporal gyrus (ITG), and increased VMHC in middle frontal gyrus (MFG) and caudate nucleus as compared to RD. When compared with NC, the NRD exhibited reduced VMHC in bilateral cerebellum anterior lobe, thalamus and postcentral gyrus. Moreover, VHMC in medial frontal gyrus, postcentral gyrus and precentral gyrus were significantly decreased in RD. Correlation analysis showed that reduced VMHC in PCU was negatively correlated with the baseline HAMD score of the NRD group. The ROC curve indicated that the combined changes of the three regional VMHC (PCU, ITG and MFG) could effectively identify NRD. The current study suggests that interhemispheric asynchrony may represents a novel neural trait underlying the prediction of early therapeutic outcome in MDD.

Background: Asthma is a chronic disease appeared to be associated with depression. But the underpinnings of depression in asthma remain unknown. In order to understand the neural mechanisms of depression in asthma, we used cerebral blood flow (CBF) to probe the difference between depressed asthmatic (DA) and non-depressed asthmatic (NDA) patients. Methods: Eighteen DA patients, 24 NDA patients and 57 healthy controls (HC) received pulsed arterial spin labeling (pASL) scan for measuring CBF, resting-state functional magnetic resonance imaging (rs-fMRI) scan, severity of depression and asthma control assessment, respectively. Results: Compared to NDA, DA patients showed increased regional CBF (rCBF) in the right cerebellum posterior lobe. Compared to HC, DA, and NDA patients all showed significantly decreased rCBF in the right cerebellum posterior lobe. Conclusions: We showed the first evidence of altered rCBF in the right cerebellum posterior lobe in asthma using pASL, which appeared to be involved in the neuropathology in asthma. Clinical Trial Registration: An investigation of therapeutic mechanism in asthmatic patients: based on the results of Group Cognitive Behavioral Therapy (Registration number: ChiCTR-COC-15007442) (http://www.chictr.org.cn/usercenter.aspx).

In the present study, the presence of extracellular matrix components, including collagenous and elastic fibers, and the expression of their key regulating enzymes, were investigated in different stages of hamster tongue carcinoma development. Immunohistochemical and computer-assisted morphological analyses were performed to quantify the staining intensity and area (integral optical density) of matrix metalloproteinase (MMP)-1 and -2, tissue inhibitors of metalloproteinase (TIMP)-1 and -2, and the extent of elastic and collagenous fibers in histological sections. MMP-1, MMP-2, TIMP-1 and TIMP-2 expression levels gradually increased with tongue cancer progression, and were associated with disease pathology staging (r=0.705, 0.633, 0.759 and 0.751, respectively). By contrast, elastic fiber levels gradually decreased with cancer progression and were negatively correlated with disease staging (r=-0.881). The levels of collagenous fibers gradually increased with cancer progression and showed a positive correlation (r=0.619). In summary, the study demonstrated that MMP1/2 and TIMP1/2 expression levels, and collagenous and elastic fiber levels were significantly correlated with disease progression in a hamster model of tongue cancer.

VGF, a non-acronymic neuropeptide, is important in the pathogenesis of major depressive disorder (MDD) and in the functioning and efficacy of some antidepressant drugs. In this study we assessed whether serum VGF levels change in MDD patients and if antidepressant treatments can restore these changes.We measured serum VGF concentrations using sandwich ELISA in drug-free MDD patients before treatment began (n = 26) and at 8 weeks after antidepressant treatment (n = 26) with escitalopram and duloxetine, two common antidepressants. The severity of depression was assessed with the 17-item Hamilton Depression Rating Scale (HDRS).VGF serum levels were significantly lower in MDD patients compared to controls (P = .002), even after controlling for the effects of age and education (P = .037), and they were reversed by 8 weeks of drug treatment (P.0001). Both escitalopram and duloxetine restored the decreased serum VGF levels (P .05). We observed no correlation between VGF levels and HDRS scores in pre-treatment MDD patients (P = .879).The results suggest that VGF may be implicated in the pathophysiology of MDD and in the mechanisms underlying the action of antidepressants, and serum VGF may be regarded as a trait parameter for MDD.

Yingying Yue,1,2 Rui Liu,3 Yin Cao,4 Yanfeng Wu,5 Shining Zhang,6 Huajie Li,7 Jijun Zhu,8 Wenhao Jiang,1,2 Aiqin Wu,9 Yonggui Yuan1,2 1Department of Psychosomatics and Psychiatry, ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, 2Institute of Psychosomatics, Medical school of Southeast university, Nanjing, 3School of Information Science and Engineering, Southeast University, Nanjing, 4Department of Neurology, Changzhou Second People’s Hospital Affiliated to NanjingMedical University, Changzhou, 5Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, 6Department of Psychiatry, Nanjing Brain Hospital of Nanjing Medical University, Nanjing, 7Department of Neurology, Changzhou First People’s Hospital, Changzhou, 8Department of Neurology, Yancheng Third People’s Hospital, Yancheng, 9Department of Psychosomatics, The Affiliated First Hospital of Suzhou University, Suzhou, People’s Republic of China Aim: Poststroke depression (PSD) is the most common complication of stroke. However, some stroke survivors with depression cannot meet the diagnostic criteria of PSD. The aim of this study was to propose the new conception of stroke patients with depression and then make them to receive reasonable diagnosis and treatment. Methods: We first put forward the opinion that the general PSD should consist of PSD disorder (PSDD) and PSD symptoms (PSDS) according to the Diagnostic and Statistical Manual of Mental Disorder – Fifth Edition (DSM-5) and ZhongDa diagnostic criteria – first edition (ZD-1), respectively. The ZD-1 was established based on the suggestions of 65Chinese chief doctors considering that the symptoms of PSDS might be different from those of PSDD and the duration of DSM-5 was too strict. Then, 166 stroke inpatients were recruited, and the study was conducted using the diagnosis and classification of PSD to verify the new concept. Results: A total of 24 (14.46%) and 80 (48.19%) stroke patients were diagnosed with PSDD and PSDS, respectively, according to individual diagnosis criteria. Moreover, patients meeting the diagnostic criteria of PSDD should satisfy the criteria of PSDS first. The distribution frequencies of depressive symptoms were different, which suggested that there might be discrepant depressive symptoms between PSDS and PSDD. Conclusion: The present study proposes new opinion about the classification and diagnosis of depression in stroke survivors. The definition and criteria of PSDS are beneficial to explore phenomenological consistency and provide useful information for early recognition and appropriate interventions. Keywords: poststroke depression, subtypes, diagnostic criteria

Identifying a robust pretreatment neuroimaging marker would be helpful for the selection of an optimal therapy for major depressive disorder (MDD). We recruited 82 MDD patients [n = 42 treatment-responsive depression (RD) and n = 40 non-responding depression (NRD)] and 50 healthy controls (HC) for this study. Based on the thresholded partial correlation matrices of 58 specific brain regions, a graph theory approach was applied to analyse the topological properties. When compared to HC, both RD and NRD patients exhibited a lower nodal degree (Dnodal) in the left anterior cingulate gyrus; as for RD, the Dnodal of the left superior medial orbitofrontal gyrus was significantly reduced, but the right inferior orbitofrontal gyrus was increased (all P

Background Current diagnoses of Schizophrenia (SZ) and related psychiatric disorders are catalogued by phenomenological principles and clinical descriptions. Complicated gene and environmental factor interactions likely play an important role in the onset of SZ and induce great heterogeneity. This unclear etiology and heterogeneity prevent the establishing of accurate subgroups within SZ through clinical observation alone; simultaneously, the boundaries among psychiatric disorders previously drawn by phenomenological findings are merging because there is great overlap, especially in genetic variations and brain imaging findings. By characterizing and quantifying brain regions affected in psychiatric disorders, imaging genetics is a valuable research method to fulfill a new diagnostic system. We review contributions of imaging genetics to SZ diagnosis, limitations, and possible future directions. Methods Among numerous imaging genetic studies, we reviewed recent studies with relatively clear and consistent findings. They were either done in task-phase imaging to indicate certain cognitive impairments of SZ, or the genes included were highlighted in SZ itself or an important cognitive domain related to SZ. Results Some pioneering studies contribute to subtypes and disorder boundaries. The clustering study from Arnedo et al. formed correlations between disjoined networks of symptom groups and Single Nucleotide Polymorphism (SNP) sets, and it may be promising for future SZ subtypes. Bipolar-SZ Network on Intermediate Phenotypes studies combining various clinical biomarkers and brain imaging divided SZ, bipolar disorder and schizoaffective disorder into three different “biotypes” regardless original diagnoses, and it provided meaningful insight into the disorder boundaries. For imaging genetics research, large numbers of associations between functional imaging intermediate phenotypes and genes have been found in working memory, episodic memory, emotion, attention, cognitive control, and theory of mind in SZ or healthy risk allele carriers. Such associations were difficult to identify while using structural brains measures. Discussion Imaging genetics will continue to shape the diagnosis of SZ and related disorders. However, there are still problems to solve. Most importantly, the logic behind imaging genetics has been questioned. Franke et al. reminds us the structural brain deficits believed to be important pathological alterations of SZ may reflect prenatal and later development environmental effects not specific to SZ, or the diagnostic category of SZ may not be uniformly organized. The following aspects need future effort. Firstly, more brain measures need to be introduced, and the criteria of intermediate phenotypes should be carefully checked. The specificity of brain alterations will need careful examination in clinical settings. Secondly, more genetic factors need to be collected. Polygenic risk scores, parallel independent component analysis and other clustering method may be promising. Factors other than SNPs, such as copy number variations and regulatory factors will need to be included. Finally, imaging genetics will need compatible phenomenological assessment scales which need not distinguish current diagnoses but provide a comprehensive scan of clinical features.

Depression is the most disabling disorder worldwide that accounts for the highest proportion of global burden attributable to mental disorders. Major depressive disorder (MDD) is characterized by deep sadness, reduced energy, vegetative nervous system dysregulation, cognitive dysfunction, and even a high suicidal tendency. Although other treatment choices are available, antidepressant medication is the front-line treatment option for MDD. Regarding clinical efficacy, only ~50% of patients respond to frontline antidepressants, and

No effective targeted therapies exist for cancers with somatic KRAS mutations. Here we develop a synthetic lethal chemical screen in isogenic KRAS-mutant and wild-type cells to identify clinical drug pairs. Our results show that dual inhibition of polo-like kinase 1 and RhoA/Rho kinase (ROCK) leads to the synergistic effects in KRAS-mutant cancers. Microarray analysis reveals that this combinatory inhibition significantly increases transcription and activity of cyclin-dependent kinase inhibitor p21WAF1/CIP1, leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21WAF1/CIP1, either by cDNA transfection or clinical drugs, preferentially impairs the growth of KRAS-mutant cells, suggesting a druggable synthetic lethal interaction between KRAS and p21WAF1/CIP1. Co-administration of BI-2536 and fasudil either in the LSL-KRASG12D mouse model or in a patient tumour explant mouse model of KRAS-mutant lung cancer suppresses tumour growth and significantly prolongs mouse survival, suggesting a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers., KRas is frequently mutated in multiple cancer types; identifying drugs to treat such cancers is a good therapeutic strategy. Here, the authors perform a synthetic lethal screen in mice and show that inhibiting Plk1 and ROCK results in the inhibition of tumour growth by increasing expression of the tumour suppressor p21.

Background Anhedonia is a prominent symptom of major depressive disorder (MDD) and schizophrenia. At present, it is believed that hedonic processing rather consists of the anticipatory and consummatory phase. The aim of this research is to explore the different anhedonia components in MDD and schizophrenia in Chinese populations. Methods A Chinese version of the Temporal Experience of Pleasure Scale (TEPS) was used to evaluate 176 MDD patients, 346 schizophrenia patients, and 268 healthy controls. Additionally, the 17-item Hamilton Depression Rating Scale (HAMD-17) was used for MDD patients, while the Positive and Negative Syndrome Scale (PANSS) was applied for schizophrenia. Results The scores of consummatory (TEPS-CON) and anticipatory pleasure (TEPS-ANT) in MDD and schizophrenia were both significantly lower than healthy controls (both P 0.05). There was no significant correlation between TEPS-ANT and any clinical variables (P > 0.05). Conclusions The consummatory and anticipatory pleasures were both impaired in MDD and schizophrenia. Consummatory and anticipatory anhedonia can be considered as a “state” in MDD, but as a “trait” in schizophrenia.

ObjectiveThe potential pattern of regional cerebral blood flow (rCBF) in major depressive disorder (MDD) underlies different response to antidepressants medication remain unclear. This study aimed to investigate the differences of rCBF between patients with different treatment response.MethodsEighty MDD patients [(44 treatment-responsive depression (RD) and 36 non-responding depression (NRD)] and 42 healthy controls (HC) underwent pulsed arterial spin labeling (PASL) scans in magnetic resonance imaging and clinical estimates. The exact rCBF values of each groups were obtained via quantification evaluation.ResultsCompared to NRD, the RD patients showed decreased rCBF values in frontal sensorimotor network (i.e. left paracentral lobule, left medial frontal gyrus, right superior frontal gyrus and right middle frontal gyrus), and further receiver operating curve (ROC) analyses demonstrated that the altered rCBF in these four regions exhibited outstanding performance on distinguishing NRD from RD. The NRD also exhibited reduced rCBF in bilateral cerebellum posterior lobe and right middle occipital gyrus and elevated rCBF in right postcentral gyrus and right middle frontal gyrus as compared to HC.ConclusionsThe decreased rCBF in frontal sensorimotor network appeared to be distinct characteristics for NRD, and might be severed as promising neuroimaging markers to differentiate depressed patients with weak early response to antidepressant medication. These findings expand our understanding of neural substrate underlying the antidepressant efficacy.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Triptolide (TP) has been used in the treatment of rheumatoid arthritis (RA), but its mechanism of action is not understood. T-cell activation and associated release of cytokines appear to be major factors in the pathogenesis of RA. The overexpression of T-cell receptor (TCR) variable gene (V gene) fragments can cause the activation and infiltration of autoreactive T cells. This study examines the effects of TP on rats with collagen-induced arthritis (CIA). The levels of interleukin-10 (IL-10) in the serum were examined with ELISA. Compared to the CIA group, the levels of IL-10 were greater in the TP treatment group. Real-time quantitative polymerase chain reaction confirmed that the expression of TCR V beta (BV) 15 and TCR BV19 was increased in the CIA group, whereas in the TP treatment group, the expression was decreased. In this study, TP was found to enhance IL-10 levels and decrease the expression levels of TCR BV15 and TCR BV19. These changes might help explain the effectiveness of TP in the treatment of RA.

IntroductionEmerging evidences indicate that the alteration of interhemispheric functional coordination may be involved in the pathogenesis of major depressive disorder (MDD). In present study, we aim to explore the potential marker by using the voxel-mirrored homotopic connectivity (VMHC) approach, which may be contributing to predict the clinical prognosis in MDD.MethodsEighty-two MDD patients and 50 normal control (NC) subjects participated in this study. We divided the MDD group into unremitted and remitted group according to the reduction rate of Hamilton Rating Scale for Depression (HAMD) within 2 weeks.ResultsThe study detected significantly decreased VMHC in bilateral precuneus (pCu), inferior temporal gyrus (ITG) and increased VMHC in middle frontal gyrus (MFG) and caudate nucleus when compared remitted depression (RD) group to unremitted depression (URD) group. Meanwhile, when compared with NC group, the URD group presented reduced VMHC in bilateral cerebellum anterior lobe, thalamus and postcentral gyrus. Furthermore, the VHMC in media frontal gyrus, postcentral gyrus and precentral gyrus were significantly decreased in RD group. Correlation analysis suggested that reduced VMHC in bilateral pCu was negatively correlated with the baseline HAMD score of URD (r = −0.325, P = 0.041). Receiver operating characteristic (ROC) curve indicated that three regional VMHC changes could identify depressed patient with poorer treatment response: ITG [area under curve (AUC) = 0.699, P = 0.002, 95% CI = 0.586–0.812], MFG (AUC = 0.692, P = 0.003, 95% CI = 0.580–0.805), pCu (AUC = 0.714, P = 0.001, 95% CI = 0.603–0.825).ConclusionThe current study combined with previous evidence indicates that the subdued intrinsic interhemispheric functional connectivity might represents a novel neural trait involved in the pathophysiology of MDD.Disclosure of interestThe authors have not supplied their declaration of competing interest.