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Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs (miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34c-5p on cardiac hypertrophy and the mechanism involved. The expression of miR-34c-5p was proved to be elevated in heart tissues from isoprenaline (ISO)-infused mice. ISO also promoted miR-34c-5p level in primary cultures of neonatal rat cardiomyocytes (NRCMs). Transfection with miR-34c-5p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor (Anf) and β-myosin heavy chain (β-Mhc) in NRCMs. In contrast, treatment with miR-34c-5p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34c-5p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34c-5p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34c-5p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4B (ATG4B) was identified as a direct target of miR-34c-5p, and miR-34c-5p was certified to interact with 3′ untranslated region of Atg4b mRNA by dual-luciferase reporter assay. miR-34c-5p reduced the expression of ATG4B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34c-5p abolished the detrimental effects of ISO by restoring ATG4B and increasing autophagy. In conclusion, our findings illuminate that miR-34c-5p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4B and autophagy. It suggests that regulation of miR-34c-5p may offer a new way for handling hypertrophy-related cardiac dysfunction.

Magnetic resonance guided radiotherapy (MRgRT), enabled by the clinical introduction of the integrated MRI and linear accelerator (MR-LINAC), is a novel technique for prostate cancer (PCa) treatment, promising to further improve clinical outcome and reduce toxicity. The role of prostate MRI has been greatly expanded from the traditional PCa diagnosis to also PCa screening, treatment and surveillance. Diagnostic prostate MRI has been relatively familiar in the community, particularly with the development of Prostate Imaging - Reporting and Data System (PI-RADS). But, on the other hand, the use of MRI in the emerging clinical practice of PCa MRgRT, which is substantially different from that in PCa diagnosis, has been so far sparsely presented in the medical literature. This review attempts to give a comprehensive overview of MRI acquisition techniques currently used in the clinical workflows of PCa MRgRT, from treatment planning to online treatment guidance, in order to promote MRI practice and research for PCa MRgRT. In particular, the major differences in the MRI acquisition of PCa MRgRT from that of diagnostic prostate MRI are demonstrated and explained. Limitations in the current MRI acquisition for PCa MRgRT are analyzed. The future developments of MRI in the PCa MRgRT are also discussed.

Background The overwhelming majority of hangman’s fractures cause anterior dislocation of C2. Hangman’s fracture with C2 posterior dislocation is extremely rare, only one paediatric case was reported in 2018 to date. This kind of injury cannot be catalogued using current classification schemes and no established treatment recommendations exist. The purpose of this article is to report a rare case of a hangman's fracture with C2 posterior dislocation, which does not fit into existing classification systems and discuss management technical notes to avoid pitfalls. Methods Description of case, review of relevant literatures and share our experience. Results A 31-year-old male sustained hangman’s fracture with C2 posterior dislocation after fell into a 50cm deep roadside ditch when riding a motorcycle. Radiograph and computed tomography (CT) on admission showed fractures through both pars of C2 and C2 posterior dislocation. Magnetic resonance imaging (MRI) on admission showed high T2-weighted signal intensity of cervical spinal cord and compression of cervical spinal cord by posterior dislocation of C2 vertebral body. A C2-3 anterior cervical discectomy and fusion (ACDF) was performed. At 6 months after operation, bony fusion was achieved, and MRI showed the T2-weighted signal hyperintensity of cervical spinal cord before surgery disappeared. Conclusion C2–C3 ACDF is recommended for hangman's fractures with C2 posterior dislocation. Traction before surgery is not recommended.

The human body contains more than 100 trillion microorganisms, including the oral cavity, the skin, and the gastrointestinal tract. After the gastrointestinal tract, the oral cavity harbors one of the most diverse microbial communities within the human body and harbors more than 770 species of bacteria. The composition of the oral and gut microbiomes is quite different, but there may be a microbiological link between the two mucosal sites during the course of disease. More studies indicate that oral bacteria can disseminate to the distal gut via enteral or hematogenous routes. This is mostly obvious in periodontitis, where specific bacteria, such as Fusobacterium nucleatum and Porphyromonas gingivalis, show this pathogenic feature. The translocation of oral microbes to the gut may give rise to a variety of gastrointestinal diseases, including colorectal cancer. However, the precise role that oral microbe play in colorectal cancer has not been fully illustrated. Here, we summarize the current researches on possible pathways of ectopic gut colonization by oral bacteria and their possible contribution to the pathogenesis of colorectal cancer. Understanding the correlation of the oral-to-gut microbial axis in the pathogenesis of colorectal cancer will contribute to precise diagnosis and effective treatment.

Whether the definition of hypertension according to 2017 AHA/ACC guidelines and blood pressure (BP) changes was related to the increased risk of chronic kidney disease (CKD) remained debated. This prospective cohort study aimed to investigate the association of BP and long‐term BP change with CKD risk with different glucose metabolism according to the new hypertension guidelines. This study examined 12 951 participants and 11 183 participants derived from the older people cohort study, respectively. Participants were divided into three groups based on blood glucose and the risks were assessmented by the logistic regression model. During a 10 years of follow‐up period, 2727 individuals developed CKD (21.1%). Compared with those with BP

Background Alcohol consumption and smoking are the leading risk factors for laryngeal cancer (LC). Understanding the variations in disease burden of LC attributable to alcohol use and smoking is critical for LC prevention. Methods Disease burden data of LC were retrieved from the Global Burden of Disease Study 2019. We used estimated average percentage change (EAPC) to measure the temporal trends of the age-standardized mortality rate (ASMR) of LC. Results Globally, while the ASMR of LC decreased by 1.49% (95% CI, 1.41–1.57%) per year between 1990 and 2019, the number of deaths from LC has increased 41.0% to 123.4 thousand in 2019. In 2019, 19.4 and 63.5% of total LC-related deaths were attributable to alcohol use and smoking worldwide, respectively. The ASMR of alcohol- and smoking-related LC decreased by 1.78 and 1.93% per year, whereas the corresponding death number has increased 29.2 and 25.1% during this period, respectively. The decreasing trend was more pronounced in developed countries. In some developing countries, such as Guinea and Mongolia, the LC mortality has shown an unfavorable trend. Conclusion The ubiquitous decrease in LC mortality was largely attributed to the smoking control and highlighted the importance of smoking control policies. However, the disease burden of LC remained in increase and more effective strategies are needed to combat the global increase of alcohol consumption.

Background: Acute kidney injury (AKI) is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is currently available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this dilemma. Methods We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model following renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. Results REVs targeted with Kim-1-binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney following I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to chronic kidney disease. Conclusions A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.

Background Urinary sediment messenger RNAs (mRNAs) have been shown as novel biomarkers of kidney disease. We aimed to identify targeted urinary mRNAs in diabetic nephropathy (DN) based on bioinformatics analysis and clinical validation. Methods Microarray studies of DN were searched in the GEO database and Nephroseq platform. Gene modules negatively correlated with estimated glomerular filtration rate (eGFR) were identified by informatics methods. Hub genes were screened within the selected modules. In validation cohorts, a quantitative polymerase chain reaction assay was used to compare the expression levels of candidate mRNAs. Patients with renal biopsy–confirmed DN were then followed up for a median time of 21 months. End-stage renal disease (ESRD) was defined as the primary endpoint. Multivariate Cox proportional hazards regression was developed to evaluate the prognostic values of candidate mRNAs. Results Bioinformatics analysis revealed four chemokines (CCL5, CXCL1, CXLC6 and CXCL12) as candidate mRNAs negatively correlated with eGFR, of which CCL5 and CXCL1 mRNA levels were upregulated in the urinary sediment of patients with DN. In addition, urinary sediment mRNA of CXCL1 was negatively correlated with eGFR (r = −0.2275, P = 0.0301) and CCL5 level was negatively correlated with eGFR (r = −0.4388, P Conclusions Urinary sediment CCL5 and CXCL1 mRNAs were upregulated in DN patients and associated with a decline in renal function and degree of renal interstitial fibrosis. Urinary sediment CCL5 mRNA could be used as a potential prognostic biomarker of DN.

The study aims to compare the efficacies of the immunosuppressants most commonly prescribed for patients with neuromyelitis optica spectrum disorder (NMOSD). The predictors, which might be associated with relapse and disability in NMOSD, were also analyzed. This retrospective study included NMOSD patients treated with azathioprine (AZA), mycophenolate mofetil (MMF), and rituximab (RTX). The annual relapse rate (ARR) and the incidence rates of adverse events were compared. Cox proportional-hazards model calculated the potential predictors of NMOSD relapse and disability. A total of 83 patients were included. The median treatment time of AZA group (n = 34), MMF group (n = 20), and RTX group (n = 29) were 19.5, 15.5, and 12 months, respectively. ARR of the three groups reduced significantly after treatment. In the three groups, 55.9%, 50%, and 79.3% of patients, respectively, were free from relapse. However, the difference among the three groups was of no statistical significance, possibly due to the small sample size. During the treatment, 32.4%, 15%, and 24.1% of patients experienced adverse events in the AZA group, MMF group, and RTX group, respectively. Additionally, the multivariate Cox analyses indicated that history of a severe attack and disease duration were associated with the risk of relapse after immunotherapy. Late-onset (≥ 50 years old) NMOSD patients were probably more susceptible to motor disability, and those with optic neuritis at onset were more likely to develop visual disability. AZA, MMF, and low-dose RTX were all effective in reducing the relapse rate in NMOSD. The age at onset, disease duration, history of severe attacks, and primary syndromes might be significant prognostic predictors in NMOSD.

Background:. Unawareness of stroke symptoms and low income are two barriers that affect the seeking of emergency medical service (EMS). This study aimed to assess the effect of unawareness and low income on seeking EMS and to investigate the regional distribution of the unawareness and low-income status and their associations with failing to call EMS in China. Methods:. A total of 187,723 samples from the China National Stroke Screening Survey was interviewed cross-sectionally. Four status of awareness and annual income were identified: unaware and low-income, unaware-only, low-income-only, and aware and regular income. The outcomes were whether they intended to call EMS or not. The regional distribution of each status and their associations with not calling EMS were presented. Results:. The status of unaware and low-income, unaware-only, and low-income-only accounted for 6.3% (11,806/187,673), 11.9% (22,241/187,673), and 21.5% (40,289/187,673) of the total sample, respectively. Not calling EMS was significantly associated with the status of unaware and low-income (odds ratio [OR]: 3.21, 95% confidence interval [CI]: 3.07–3.35), unaware-only (OR: 2.38, 95% CI: 2.31–2.46), and low-income-only (OR: 1.67, 95% CI: 1.63–1.71), compared with the aware and regular income status. The Midwest regions had higher percentages of people in the unaware and low-income status; the East, South, and Central had higher percentages of unaware-only status; the North and Northeast regions had a higher percentage of low-income-only status, compared with other regions. Conclusion:. The existence of the regional difference in unawareness and low income justifies the specific stroke education strategies for the targeted regions and population.

Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from posttranslational hydroxylation, the mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia-reperfusion-, unilateral ureteral obstruction-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB, which plays a central role in the inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only under hypoxic conditions but also under normoxic conditions. Moreover, the induced HIF-1α by inflammation protected against tubular injury in AKI. Thus, our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.NEW & NOTEWORTHY Here, the mechanism of hypoxia-inducible factor-α (HIF-α) regulation in acute kidney injury (AKI) was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB was involved in the increasing expression of HIF-1α in AKI. Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription. Our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.

Background: Mantle cell lymphoma (MCL) is widely considered an incurable malignancy even with current therapies and relapsed/refractory (R/R) disease to primary treatment remains common. With improved treatment guidelines and the advent of novel agents, patients are increasingly being treated with more lines of regimens. However, outcomes after each line of treatment remain poorly characterized, especially in the Asian population. In this paper, we described the survival outcomes in a group of R/R MCL patients. Methods: We retrospectively studied 35 patients with R/R MCL between 1998 and 2020 at the National Cancer Centre Singapore. Patients were followed longitudinally throughout their disease course. Overall survival (OS) and progression-free survival (PFS) were determined by the Kaplan-Meier method. Results: The median OS and PFS from diagnosis were 105 and 40 months, respectively. After first relapse, the median OS and PFS were 52 and 19 months, post-second relapse 32 and 8 months, and post-third relapse 12 and 6 months, respectively. Patients older than 65 years at first relapse had shorter survival (median OS: 22 vs. 55 months, P = 0.0417; median PFS: 9 vs. 29 months, P = 0.001). Early treatment failure after first line therapy was also associated with worse survival outcomes (median OS: 13 vs. 55 months, P < 0.001; median PFS: 9 vs. 26 months, P < 0.001). Conclusion: With each relapse, survival outcomes for patients with MCL are worse. Novel treatment and contemporary outcomes of R/R MCL are encouraging and support the need for continued research in this area. J Hematol. 2021;10(4):187-195 doi: https://doi.org/10.14740/jh890

Human fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo lipid synthesis. FASN is essential for cancer cell survival and contributes to drug and radiation resistance by up-regulating DNA damage repair but not required for most non-lipogenic tissues. Thus, FASN is an attractive target for drug discovery. However, despite decades of effort in targeting FASN, no FASN inhibitors have been approved due to poor pharmacokinetics or toxicities. Here, we show that the FDA-approved proton pump inhibitors (PPIs) effectively inhibit FASN and suppress breast cancer cell survival. PPI inhibition of FASN leads to suppression of non-homologous end joining repair of DNA damages by reducing FASN-mediated PARP1 expression, resulting in apoptosis from oxidative DNA damages and sensitization of cellular resistance to doxorubicin and ionizing radiation. Mining electronic medical records of 6754 breast cancer patients showed that PPI usage significantly increased overall survival and reduced disease recurrence of these patients. Hence, PPIs may be repurposed as anticancer drugs for breast cancer treatments by targeting FASN to overcome drug and radiation resistance.

Background/Purpose: Recent study suggested that type 2 diabetes (T2DM) attributed to body mass index (BMI) could be influenced by liver aminotransferase. We aim to ascertain the cut-off point of BMI associated with T2DM and the influence of both elevated aminotransferase (AST) and alanine aminotransferase (ALT). Materials and Methods: In our retrospective cohort study, T2DM was diagnosed when FBS ≥ 7.0 mmol/L, BMI of participants with baseline fasting (FBS) < 7.0 mmol/L was divided by percentiles and by aminotransferanse (ALT and AST ≥ 20 U/L, ALT or AST < 20 U/L). Hazard ratios and the turning point of BMI of high T2DM risk was estimated in totality and different aminotransferanse groups. Results: During an average follow-up time of 3.71 years of 33346 participants, 1486 developed T2DM, and the average baseline BMI of participants who developed T2DM was 26.22 kg/m2. Cumulative incidence of T2DM was more than 5% when ALT and AST ≥ 20U/L, age over 44, male sex or BMI over 25.39 kg/m2; The risk of T2DM incidence increased as the BMI grow. The turning point of BMI at high risk of T2DM was 25.0 kg/m2 in totality, 25.1 kg/m2 when ALT or AST < 20 U/L and 26.1 kg/m2 when ALT and AST ≥ 20U/L. Conclusions: BMI of 25.0 kg/m2 was the cutoff point for T2DM development, and there is greater association between BMI and T2DM when ALT or AST < 20 U/L.

Background and aims The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic. Approach and results We report herein that CD69+ CD103+ CD8+ tissue-resident memory T cells (TRM ) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8+ TRM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8+ TRM cells decreased significantly. CD69+ CD8+ and CD69+ CD103+ CD8+ T cells, also known as CD8+ TRM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL-15 and TGF-β on inflammatory cells, and extensive hepatic expression of E-cadherin; these factors likely contribute to the development and localization of CD8+ TRM cells. Based on these data and, in particular, the relationships between disease severity and CD8+ TRM cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8+ TRM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8+ TRM cells induced by IL-15 and TGF-β and with direct down-regulation of the nuclear factor Blimp1 of CD8+ TRM cells. Conclusions Our data suggest that CD8+ TRM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8+ TRM cell expansion.

Objective. Peer support is a concept of substantial significance to health scientists and practitioners today due to its focus shifting from disease treatment to health promotion. Effective incorporation peer relationships in support-enhancing interventions could improve quality care and health outcomes. More and more cases of chronic obstructive pulmonary disease (COPD) have been diagnosed in nonsmokers. In this study, the effects of peer-support nursing intervention on the pulmonary function and quality of life of nonsmoking patients with COPD were investigated. Methods. A total of 100 COPD nonsmoking patients admitted to our hospital from October 2018 to October 2020 were selected as study subjects. All nonsmoking patients were in accordance with the guidelines of COPD diagnosis and treatment issued by the Respiratory Medicine Branch of Chinese Medical Association, and they were not in the habit of smoking. According to the different interventions, the nonsmoking patients were divided into the control group (n = 50) and the observation group (n = 50). Among them, nonsmoking patients in the control group received routine care, and nonsmoking patients in the observation group received routine care and peer-support nursing. The difference on the scores of social support, self-management efficacy, healthy lifestyle, and the distance of six-minute walking were to be compared between the two groups before and after the intervention. Results. There was no significant statistical difference on the general information between the two groups in terms of age, gender, and course of disease ( P > 0.05 ). Before intervention, the social support score involving subjective support, objective support, utilization of support, and total score revealed slight difference between the two groups ( P > 0.05 ). However, after the intervention, the subjective support, utilization of support, and total score remained statistically different between the two groups ( P < 0.05 ), and the objective support showed no significant difference between the two groups ( P > 0.05 ). Before intervention, there was no statistical difference in the self-management efficacy scores such as positive attitude, stress reduction, self-decision-making, and total score between the two groups ( P > 0.05 ). After the intervention, the two groups indicated statistical difference in the self-management efficacy scores ( P < 0.05 ). Before intervention, there was no significant difference between the two groups in the healthy lifestyle score in terms of health responsibility, self-realization, interpersonal support, and stress management ( P > 0.05 ), and the abovementioned outcome measures indicated significant difference between the two groups after intervention ( P < 0.05 ). There was no statistical difference in six-minute walking distance between the two groups before the intervention ( P > 0.05 ), but after the intervention, the observation group revealed a significantly longer distance of six-minute walking compared to the control group ( P < 0.05 ). Conclusion. These data suggest that peer-support nursing intervention can effectively improve pulmonary function and quality of life of nonsmoking patients with COPD.

Objective To explore the changes of proopiomelanocortin (POMC) and Agouti-Related Peptide (AgRP) expression in brain and kidney tissues under insulin intervention at different stages of diabetic nephropathy (DN) rats. Methods The male Sprague-Dawley (SD) rats of DN were treated with high-fat diet for 8 weeks and induced by intraperitoneally injection of streptozotocin (30 mg/kg) for one time. Then DN rats were also injected insulin subcutaneously at 2–5 U/(kg·24 h) from initiation of the streptozotocin. Kidney tissue, blood sample, and 24 h-urine were collected to detect the ratio of kidney/body weight, blood glucose and 24-h urinary albumin excretion rate at different stages (4, 8, 12, and 16 weeks). Immunohistochemistry assay was used to measure the expression of POMC and AgRP at different stages of DN rats. Results The DN rats were established successfully. With the progression of DN, blood glucose, 24-h urinary albumin excretion rate and kidney body weight ratio increased significantly, while decreased when insulin was injected. Immunohistochemistry showed that the expression levels of POMC were decreased gradually in brain and kidney tissues. Conversely, the expression of AgRP in kidney was highest at week 8 and then decreased gradually. The effect of insulin on normalizing POMC and AgRP expression in brain and renal tissues was also observed in DKD rats. Conclusion With the progression of DN, the expression of POMC and AgRP in kidney tissues was observed at different stages of disease, and their expressions were significantly normalized by insulin. The mechanism of in situ expression of POMC and AGRP in kidney to the progression of DN needs further investigations.

Aim Emperipolesis, the cell-in-cell structure, is one of the pathological diagnostic standard of AIH. We have already identified that CD8+ T cells participated in the emperipolesis process in liver tissue of AIH patients. In this study, we aimed to clarify the characteristics and molecular mechanisms of emperipolesis in the patients with AIH in vitro and in mice with α-GalCer-induced acute hepatitis. Methods Peripheral blood mononuclear cell (PBMC) of patients with variant chronic liver diseases and healthy controls were co-cultured with hepatic cell line to induce emperipolesis in vitro. Confocal staining was performed to illustrate the cellular types and potential mechanisms of emperipolesis in AIH. In addition, the mouse model of α-GalCer-induced acute hepatitis which mimics human AIH in several features, was used to confirm the role of CD44/p-ERM/F-actin in the emperipolesis process in vivo. Results In co-culture system with PBMC and hepatic cell line, emperipolesis was observed most common in the patients with AIH. CD8+ T cells were the major cells participated in the emperipolesis process, and penetrated into hepatocytes actively via CD44/p-ERM/F-actin pathway. As a result, most CD8+ T cells engulfed in hepatocytes undergo self-apoptosis. In α-GalCer-induced acute hepatitis model, emperipolesis was observed around the inflammatory foci, and was inhibited by Ezrin phosphorylation inhibitor NSC668394. Similarly, activated murine CD8+ T cells penetrated into primary hepatocytes via CD44/p-ERM/F-actin pathway in vitro. Conclusions CD8+ T cells penetrated into hepatocytes actively via CD44/p-ERM/F-actin signaling pathway and undergo apoptosis, may be a compensative mechanism to attenuate overwhelming immune attack in AIH. This article is protected by copyright. All rights reserved.

Background To investigate the clinical efficacy of the MyoSure hysteroscopic tissue removal system in the treatment of endometrial and cervical polyps in women with an intact hymen. Methods Retrospective analysis was performed on the clinical data of 32 patients treated with the MyoSure hysteroscopic tissue removal system for endometrial and cervical polyps. Results All the patients successfully completed the procedure. No intraoperative complications, such as cervical trauma, uterine perforation or TURP syndrome, were reported. The surgical time ranged from 5 to 35 min, with an average time of 19.3 min, and the intraoperative blood loss ranged from 2 to 50 ml with an average blood loss of 10.8 ml. After surgery, all patients were shown to have intact hymens. No residual polyp tissues were observed under the microscope, and abnormal uterine bleeding was relieved. Conclusions The MyoSure hysteroscopic tissue removal system can be a safe and effective treatment for endometrial and cervical polyps in women with an intact hymen.

Objective: To investigate if routine audiometry in Bell’s palsy patients has prognostic value. Methods: Retrospective case review was conducted on all Bell’s palsy patients (n=191) seen at the tertiary otolaryngology specialist outpatient clinic from 2015 to 2017. Correlation of ipsilesional audiometric thresholds with patients’ time-to-recovery and initial clinical severity (measured by House-Brackmann (HB) scoring) were used for the prognostic outcome measure. Audiometry results were analyzed using three contiguous frequency pure-tone average (1kHz, 2kHz, 4kHz). Statistical analysis was done via Stata (v13.1), significance tests were 2-sided at 5% significance level. Results: There was no significant difference between audiometric thresholds between the ipsilesional ear and the contralateral ear (p=0.87). Time-to-recovery was significantly longer for patients with severe initial presentation as compared to mild and moderate severity (p

Objective: To explore differentially expressed miRNA in type 2 diabetes mellitus and the potential cell function of miRNA. Methods: We examined the plasma miRNA among 113 newly diagnosed untreated diabetic cases and 113 healthy controls by miRNA array screening and Taqman real-time PCR validation. The low-abundance proteins coded by miR-193b-3p target genes were explored in plasma among the same study population. We further investigated the potential cell function of differentially expressed miRNA in HepG2 cells. Results: The miR-193b-3p was differentially expressed (fold change = 2.01, P = 0.006) in diabetic cases compared with healthy controls. The levels of triosephosphate isomerase (TPI1) decreased in plasma of type 2 diabetes (fold change = 1.37, P =0.002). The effect of miR-193b-3p on TPI1 was validated after transfection with miR-193b-3p in HepG2 cells. Additionally, miR-193b-3p suppressed expression of YWHAZ/14-3-3ζ in PI3K-AKT pathway, subsequently altered the FOXO1 and PCK1 expression. When the cells were incubated in glucose free media for another 4h after transfection, the glucose level in media was significantly higher in cells with elevated miR-193b-3p level than negative control cells (P = 0.016). Additionally, elevated miR-193b-3p also decreased glucose uptake by suppressed insulin receptor (IR) and GLUT2 expression. Conclusion: miR-193b-3p was differentially expressed in plasma of patients with type 2 diabetes, and the level of TPI1 was decreased in both plasma and HepG2 cells with elevated miR-193b-3p level. Moreover, miR-193b-3p may impair the glucose metabolism by directly targeting to YWHAZ/14-3-3ζ and up-regulating the transcription factor FOXO1 in the downstream of PI3K-AKT pathway. Funding: This work was supported by the grants from the Program for HUST Academic Frontier Youth Team, the National Natural Science Foundation (grants NSFC-81473051 and 81522040), and the National Key R&D Program of China (2016YFC0900800). Declaration of Interest: None. Ethical Approval: The study protocol was approved by the Ethics and Human Subject Committee of School of Public Health, Tongji Medical College, Huazhong University of Science and Technology and Dongfeng General Hospital, DMC.

Background/Aims Diabetic nephropathy (DN) is one of the main causes of end-stage kidney disease worldwide. Emerging studies have suggested that its pathogenesis is distinct from nondiabetic renal diseases in many aspects. However, it still lacks a comprehensive understanding of the unique molecular mechanism of DN. Methods A total of 255 Affymetrix U133 microarray datasets (Affymetrix, Santa Calra, CA, USA) of human glomerular and tubulointerstitial tissues were collected. The 22 215 Affymetrix identifiers shared by the Human Genome U133 Plus 2.0 and U133A Array were extracted to facilitate dataset pooling. Next, a linear model was constructed and the empirical Bayes method was used to select the differentially expressed genes (DEGs) of each kidney disease. Based on these DEG sets, the unique DEGs of DN were identified and further analyzed using gene ontology and pathway enrichment analysis. Finally, the protein–protein interaction networks (PINs) were constructed and hub genes were selected to further refine the results. Results A total of 129 and 1251 unique DEGs were identified in the diabetic glomerulus (upregulated n = 83 and downregulated n = 203) and the diabetic tubulointerstitium (upregulated n = 399 and downregulated n = 874), respectively. Enrichment analysis revealed that the DEGs in the diabetic glomerulus were significantly associated with the extracellular matrix, cell growth, regulation of blood coagulation, cholesterol homeostasis, intrinsic apoptotic signaling pathway and renal filtration cell differentiation. In the diabetic tubulointerstitium, the significantly enriched biological processes and pathways included metabolism, the advanced glycation end products–receptor for advanced glycation end products signaling pathway in diabetic complications, the epidermal growth factor receptor (EGFR) signaling pathway, the FoxO signaling pathway, autophagy and ferroptosis. By constructing PINs, several nodes, such as AGR2, CSNK2A1, EGFR and HSPD1, were identified as hub genes, which might play key roles in regulating the development of DN. Conclusions Our study not only reveals the unique molecular mechanism of DN but also provides a valuable resource for biomarker and therapeutic target discovery. Some of our findings are promising and should be explored in future work.

Background Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. Method and results This is a national multicenter retrospective observational study involving all consecutive adult COVID-19 patients who required intensive care units (ICU) admission between 23 January 2020 and 30 April 2020 in Singapore. One hundred eleven patients were included and the venous and arterial thrombotic rates in ICU were 1.8% (n = 2) and 9.9% (n = 11), respectively. Major bleeding rate was 14.8% (n = 16). Conclusions Critically ill COVID-19 patients in Singapore have lower venous thromboembolism but higher arterial thrombosis rates and bleeding manifestations than other reported cohorts.

Mesenchymal stem cells-derived exosomes (MSC-exos) have attracted great interest as a cell-free therapy for acute kidney injury (AKI). However, the in vivo biodistribution of MSC-exos in ischemic AKI has not been established. The potential of MSC-exos in promoting tubular repair and the underlying mechanisms remain largely unknown. Methods: Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of human umbilical cord mesenchymal stem cells (hucMSCs) derived exosomes. The biodistribution of MSC-exos in murine ischemia/reperfusion (I/R) induced AKI was imaged by the IVIS spectrum imaging system. The therapeutic efficacy of MSC-exos was investigated in renal I/R injury. The cell cycle arrest, proliferation and apoptosis of tubular epithelial cells (TECs) were evaluated in vivo and in HK-2 cells. The exosomal miRNAs of MSC-exos were profiled by high-throughput miRNA sequencing. One of the most enriched miRNA in MSC-exos was knockdown by transfecting miRNA inhibitor to hucMSCs. Then we investigated whether this candidate miRNA was involved in MSC-exos-mediated tubular repair. Results: Ex vivo imaging showed that MSC-exos was efficiently homing to the ischemic kidney and predominantly accumulated in proximal tubules by virtue of the VLA-4 and LFA-1 on MSC-exos surface. MSC-exos alleviated murine ischemic AKI and decreased the renal tubules injury in a dose-dependent manner. Furthermore, MSC-exos significantly attenuated the cell cycle arrest and apoptosis of TECs both in vivo and in vitro. Mechanistically, miR-125b-5p, which was highly enriched in MSC-exos, repressed the protein expression of p53 in TECs, leading to not only the up-regulation of CDK1 and Cyclin B1 to rescue G2/M arrest, but also the modulation of Bcl-2 and Bax to inhibit TEC apoptosis. Finally, inhibiting miR-125b-5p could mitigate the protective effects of MSC-exos in I/R mice. Conclusion: MSC-exos exhibit preferential tropism to injured kidney and localize to proximal tubules in ischemic AKI. We demonstrate that MSC-exos ameliorate ischemic AKI and promote tubular repair by targeting the cell cycle arrest and apoptosis of TECs through miR-125b-5p/p53 pathway. This study provides a novel insight into the role of MSC-exos in renal tubule repair and highlights the potential of MSC-exos as a promising therapeutic strategy for AKI.

Background Childhood overweight and obesity have become significant public health challenges worldwide. The present study aimed to investigate whether caregivers’ feeding behaviour and children's eating behaviour were associated with the weight status of preschool children in China. Methods A cross‐sectional questionnaire was administered to 912 caregivers of preschool children from April to July 2016. Caregivers’ feeding behaviours were assessed by the Chinese Preschooler's Caregiver Feeding Behaviour Scale. Children's eating behaviours were evaluated using the Chinese Preschooler's Eating Behaviour Questionnaire. After controlling for demographic characteristics, multiple linear regression and logistic regression analyses were performed to evaluate the relationship between caregivers’ feeding behaviour, children's eating behaviour and children's body mass index (BMI). Results The results showed that weight concerns on the part of caregivers (β = 0.53) and food responsiveness on the part of children (β = 0.93) were positively correlated with children's BMI, whereas caregivers’ responsibility for feeding (β = −0.68) and children's external eating (β = −0.53) were negatively correlated with BMI. Among caregiver feeding behaviours, weight concerns [odds ratio (OR) =4.54, p, This study aimed to explore whether caregivers' feeding behavior and children's eating behavior were associated with the weight status of preschool children in China. A cross‐sectional questionnaire was administered to 912 caregivers of preschool children in China. Caregivers' feeding behaviors and children's eating behaviors were assessed respectively by the Chinese Preschooler's Caregiver Feeding Behavior Scale (CPCFBS) and the Chinese Preschooler's Eating Behavior Questionnaire (CPEBQ). The results showed that among Chinese preschool children, caregivers' feeding behavior and children's eating behavior are related to their weight status and behavioral interventions can prevent weight problems of preschool children.

Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal cancer infrequently exhibit IFN and MHC signaling gene mutations and are generally resistant to immunotherapy. In exploring the integrity of IFN and MHC signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways and predicted colorectal cancer patient outcome. Loss of optineurin occurs in early-stage human colorectal cancer. Immunologically, optineurin deficiency was shown to attenuate IFNGR1 and MHC-I expression, impair T-cell immunity, and diminish immunotherapy efficacy in murine cancer models and patients with cancer. Mechanistically, we observed that IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated IFNGR1 lysosomal sorting and degradation, thereby maintaining IFNγ and MHC-I signaling integrity. Furthermore, pharmacologically targeting IFNGR1 palmitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Significance: Loss of optineurin impairs the integrity of both IFNγ and MHC-I signaling pathways via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation, thereby driving immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Our work suggests that pharmacologically targeting IFNGR1 palmitoylation can stabilize IFNGR1, enhance T-cell immunity, and sensitize checkpoint therapy in colorectal cancer. See related commentary by Salvagno and Cubillos-Ruiz, p. 1623. This article is highlighted in the In This Issue feature, p. 1601

NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass spectrometry, we demonstrate a novel role of NSD2 in chromatin remodeling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was noncanonical and independent of the SWI/SNF complex. RNA sequencing identified PTP4A3 as a downstream target of NSD2 and mapped NSD2–SMARCA2 complex on PTP4A3 promoter. This led to a focal increase in the permissive H3K36me2 mark and transcriptional activation of PTP4A3. High levels of PTP4A3 maintained MYC expression and correlated with a 54-gene MYC signature in t(4;14) multiple myeloma. Importantly, this mechanism was druggable by targeting the bromodomain of SMARCA2 using the specific BET inhibitor PFI-3, leading to the displacement of NSD2 from PTP4A3 promoter and inhibiting t(4;14) myeloma cell viability. In vivo, treatment with PFI-3 reduced the growth of t(4;14) xenograft tumors. Together, our study reveals an interplay between histone-modifying enzymes and chromatin remodelers in the regulation of myeloma-specific genes that can be clinically intervened. Significance: This study uncovers a novel, SWI/SNF–independent interaction between SMARCA2 and NSD2 that facilitates chromatin remodeling and transcriptional regulation of oncogenes in t(4;14) multiple myeloma, revealing a therapeutic vulnerability targetable by BET inhibition.

Background Several pharmacological agents, such as chloroquine/hydroxychloroquine, have been promoted for COVID-19 treatment or pre-exposure prophylaxis. However, no comprehensive evaluation of the safety of these possible agents is available, and is urgently needed. Objective The purpose of this study was to investigate the risks of cardiac adverse events associated with the possible pharmacotherapies for COVID-19, including certain antimalarial, antiviral, and antibiotic drugs. Patients and Methods We conduced retrospective pharmacovigilance analyses of the US Food and Drug Administration Adverse Event Reporting System database. The reporting odds ratio (ROR), a data mining algorithm commonly used in pharmacovigilance assessment, was generated to quantify the detection signal of adverse events. Results Among individuals without coronavirus infection from 2015 Q1 to 2020 Q1, increased risks for cardiac disorders were found for antiviral agents such as chloroquine/hydroxychloroquine (ROR: 1.68; 95% confidence interval [CI] 1.66–1.70), lopinavir/ritonavir (ROR: 1.52; 95% CI 1.39–1.66), and antibiotics such as azithromycin (ROR: 1.37; 95% CI 1.30–1.44) and ceftriaxone (ROR: 1.92; 95% CI 1.80–2.05). Increased serious cardiac adverse events, including myocardial infarction, arrhythmia, and cardiac arrest, were also reported for these drugs. Further analyses of individuals with coronavirus infections revealed that 40% of individuals receiving chloroquine/hydroxychloroquine reported serious cardiac adverse events. Two cases resulted in QT prolongations and one case resulted in cardiac arrest. Chloroquine/hydroxychloroquine and azithromycin contributed to all the QT prolongation and cardiac arrest cases. Conclusions The current pharmacotherapies for COVID-19 are associated with increased risks of cardiac adverse events. Variations in the cardiac safety profiles of these pharmacotherapies were also observed. Clinicians should closely monitor patients with COVID-19, especially those at high risk, using chloroquine/hydroxychloroquine and azithromycin.

Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Superenhancers (SEs) are defined as large clusters of enhancers in close genomic proximity, which regulate genes for maintaining cellular identity and promote oncogenic transcription to which cancer cells highly addicted. Here, we analyzed cis-regulatory elements in MM samples with H3K27ac ChIP-seq, to identify novel SE-associated genes involved in the myeloma pathogenesis. SEs and their associated genes in cancerous tissue were compared with the control samples, and we found SE analysis alone uncovered cell-lineage-specific transcription factors and well-known oncogenes ST3GAL6 and ADM. Using a transcriptional CDK7 inhibitor, THZ1, coupled with H3K27ac ChlP-seq, we identified MAGI2 as a novel SE-associated gene of myeloma cells. Elevated MAGI2 was related to myelomagenesis with gradual increased expression from MGUS, SMM to newly diagnosed and relapsed MM. High prevalence of MAGI2 was also associated with poor survival of MM patients. Importantly, inhibition of the SE activity associated with MAGI2 decreased MAGI2 expression, inhibited cell growth and induced cell apoptosis. Mechanistically, we revealed that the oncogenic transcription factor, MAF, directly bound to the SE region and activated gene transcription. In summary, the discoveries of these acquired SEs-associated genes and the novel mechanism by which they are regulated provide new insights into MM biology and MAGI2-MAF-SE regulatory circuit offer potential novel targets for disease treatment.

Background Anemia is one of the common complications in patients with chronic kidney disease (CKD). However, there is no systematic investigation on the prevalence of anemia in CKD patients and its relationship with the quality of life in China. Methods The data for this study comes from baseline data from the Chinese Chronic Kidney Disease Cohort Study (C-STRIDE), which recruited predialysis CKD patients in China. The kidney disease quality of life summary (KDQOL-TM) was used to assess health-related quality of life (HRQoL). Use linear regression model to estimate the relationship between hemoglobin level and quality of life. Results A total of 2921 patients were included in this study. The adjusted prevalence of hemoglobin (Hb) less than 100 g/L was 10.3% (95% confidence interval [CI]: 9.9,11.4%), and showed an increased trend through reduced eGFR levels from 4.0% (95%CI:2.3,5.9%) in the 45-60 ml/min/1.73m2 group to 23.4% (95%CI:20.5,26.2%) in the 15–29 ml/min/1.73m2 group. The prevalence of anti-anemia treatment was 34.0% (95%CI: 28.7,39.3%) and it is shown by reducing eGFR levels from 15.8% (95%CI:0,36.7%) in the 45-60 ml/min/1.73m2 group to 38.2% (95%CI: 30.7,45.2%) in the 15–29 ml/min/1.73m2 group. All five dimensions of the KDQOL scores in patients with CKD decreased as hemoglobin declined. After multivariable adjustments,the degrees of decrease became somewhat blunted. For example, compared with hemoglobin of ≥130 g/L, regression coefficients in the hemoglobin of Conclusions In our cross-sectional analysis of patients with CKD in China, prevalence of both anemia and anti-anemia treatment increased with decreased eGFR. In addition, anemia was associated with reduced HRQoL.

Peripheral nerve injuries occur as the result of sudden trauma and lead to reduced quality of life. The peripheral nervous system has an inherent capability to regenerate axons. However, peripheral nerve regeneration following injury is generally slow and incomplete that results in poor functional outcomes such as muscle atrophy. Although conventional surgical procedures for peripheral nerve injuries present many benefits, there are still several limitations including scarring, difficult accessibility to donor nerve, neuroma formation and a need to sacrifice the autologous nerve. For many years, other therapeutic approaches for peripheral nerve injuries have been explored, the most notable being the replacement of Schwann cells, the glial cells responsible for clearing out debris from the site of injury. Introducing cultured Schwann cells to the injured sites showed great benefits in promoting axonal regeneration and functional recovery. However, there are limited sources of Schwann cells for extraction and difficulties in culturing Schwann cells in vitro. Therefore, novel therapeutic avenues that offer maximum benefits for the treatment of peripheral nerve injuries should be investigated. This review focused on strategies using mesenchymal stem cells to promote peripheral nerve regeneration including exosomes of mesenchymal stem cells, nerve engineering using the nerve guidance conduits containing mesenchymal stem cells, and genetically engineered mesenchymal stem cells. We present the current progress of mesenchymal stem cell treatment of peripheral nerve injuries.

Background Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. Methods Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. Results Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. Conclusion Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

ObjectiveMicrobiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC.Design18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1.ResultsWe have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function.ConclusionF. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.

Most colorectal cancer (CRC) are characterized by allele loss of the genes located on the short arm of chromosome 17 (17p13.1), including the tumor suppressor p53 gene. Although important, p53 is not the only driver of chromosome 17p loss. In this study, we explored the biological and prognostic significance of genes around p53 on 17p13.1 in CRC. The Cancer Genome Atlas (TCGA) were used to identify differentially expressed genes located between 1000 kb upstream and downstream of p53 gene. The function of CLDN7 was evaluated by both in vitro and in vivo experiments. Quantitative real-time PCR, western blot, and promoter luciferase activity, immunohistochemistry were used to explore the molecular drivers responsible for the development and progression of CRC. The results showed that CLDN7, located between 1000 kb upstream and downstream of p53 gene, were remarkably differentially expressed in tumor and normal tissues. CLDN7 expression also positively associated with p53 level in different stages of the adenoma-carcinoma sequence. Both in vitro and in vivo assays showed that CLDN7 inhibited cell proliferation in p53 wild type CRC cells, but had no effects on p53 mutant CRC cells. Mechanistically, p53 could bind to CLDN7 promoter region and regulate its expression. Clinically, high CLDN7 expression was negatively correlated with tumor size, invasion depth, lymphatic metastasis and AJCC III/IV stage, but was positively associated with favorable prognosis of CRC patients. Collectively, our work uncovers the tumor suppressive function for CLDN7 in a p53-dependent manner, which may mediate colorectal tumorigenesis induced by p53 deletion or mutation.

Purpose Glioblastoma (GBM) is the most lethal primary cancer in adult central nervous system, and new strategies are desperately needed. The secretory pathway kinase or kinase-like proteins (SPKKPs) have been shown to mediate multiple physiological functions by phosphorylating extracellular proteins and proteoglycans. However, their roles in cancers, especially GBM, remain poorly defined. Methods The least absolute shrinkage and selection operator (LASSO) regression was employed for establishing the SPKKPs signature for IDH wild type (wt) GBM prognosis. Integrative analyses with multiple datasets were employed to identify the core member of this gene family in glioma. The receiver operator characteristic (ROC) curves and immunohistochemistry were further used for evaluating its association with progressive malignancy in glioma and GBM patients' survival, respectively. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to interpret its functions in GBM, which were further verified in vitro. Results A SPKKPs classifier was constructed with 3 genes of this family. This signature could effectively distinguish IDH wt GBM survival. Family with sequence similarity 20 C (FAM20C) was further identified as the core member of this family in glioma. Elevated FAM20C expression was not only closely correlated with glioma malignancy progression and the mesenchymal subtype of GBM but also indicated unfavorable survival of GBM patients. FAM20C was also found to be associated with the disrupted immune response in GBM microenvironment and was required for the migration of glioma and immune cells. Conclusion These data indicate that the potential of FAM20C serving as a predictive molecule and a therapeutic target for GBM.

Acute ischemic stroke is one of the leading causes of death in developed countries and the most common cause of disability in adults worldwide. Despite advances in the understanding of stroke pathophysiology, therapeutic options remain limited. In this study, we explored the interaction of Shrm4 and the metabotropic gamma-aminobutyric acid (GABA) receptors (GABAB ) in ischemic stroke. A transient middle cerebral artery occlusion (MCAO) model was induced by filament insertion in Shrm4+/+ and wild-type C57BL/6J mice, followed by reperfusion for up to 7 days. Baclofen was administered was used to activate GABAB in vivo during reperfusion. Neurological deficits, motor and memory functions, and infarct volume were determined in the various mouse groups. Furthermore, we also developed an oxygen-glucose deprivation (OGD) cell model in primary neurons to test Shrm4/GABAB interactions in vitro. Shrm4 was observed to decrease infarct volume and neuronal cell loss in penumbra, and rescue neurological deficits in MCAO mice. Notably, Shrm4 also increased pole climbing speed, reduced foot faults, and increased escape latency in the Morris water maze test, while reducing neuron autophagy through an interaction with GABAB receptors. GABAB activation using baclofen further reduced OGD-induced neuron damage in culture and stroke outcomes of MCAO, relative to Shrm4 alone. Taken together, Shrm4-mediated GABAB activation confers neuroprotection by reducing neuronal autophagy in acute ischemic stroke.

Exacerbations are crucial events during bronchiectasis progression.To explore the associations between bacterial, viral, and bacterial plus viral isolations and bronchiectasis exacerbations.In this prospective study, we enrolled 108 patients who were followed up every 3-6 months and at onset of exacerbations between March 2017 and November 2018. Spontaneous sputum was split for detection of bacteria (routine culture) and viruses (quantitative polymerase chain reaction). Symptoms and lung function were assessed during exacerbations.The median exacerbation rate was 2.0 (interquartile range: 1.0-2.5) per patient-year. At any visit, viral isolations (V+) occurred more frequently during onset of exacerbations [odds ratio (OR): 3.28, 95% confidence interval (95%CI): 1.76-6.12], as did isolation of new bacteria (NB+) (OR: 2.52, 95%CI: 1.35-4.71) and bacterial plus viral isolations (OR: 2.24, 95%CI: 1.11-4.55). Whilst coryza appeared more common in exacerbations with V+ than in exacerbations with no pathogen isolations and those with NB+, lower airway symptoms were more severe in exacerbations with NB+ (Viral isolations, isolation of new bacteria and bacterial plus viral isolation are associated with bronchiectasis exacerbations. Symptoms at exacerbations might inform clinicians the possible culprit pathogens.Las exacerbaciones son eventos cruciales durante la progresión de la bronquiectasia.Analizar las asociaciones entre el aislamiento de bacterias, virus y virus y bacterias juntas y las exacerbaciones de las bronquiectasias.En este estudio prospectivo se incluyó a 108 pacientes a los que se siguió cada 3-6 meses y al comienzo de las exacerbaciones entre marzo de 2017 y noviembre de 2018. La muestra de esputo espontáneo se dividió para la detección de bacterias (cultivo de rutina) y virus (reacción en cadena de la polimerasa cuantitativa). Se evaluaron los síntomas y la función pulmonar durante las exacerbaciones.La mediana de la tasa de exacerbación fue de 2,0 (rango intercuartil: 1,0-2,5) por paciente/año. En cualquier visita, los aislamientos de virus (V+) tuvieron lugar con mayor frecuencia durante el inicio de las exacerbaciones (Los aislamientos de virus, el aislamiento de nuevas bacterias y el aislamiento de bacterias y virus juntos están asociados a las exacerbaciones de las bronquiectasias. Los síntomas de las exacerbaciones pueden proporcionar información a los médicos sobre los posibles patógenos responsables.

Objective To explore pharmacogenetic relationships of NRG1 genotypes with neurocognitive performance and clinical symptoms after 12 week treatment of risperidone in Chinese Han first-episode schizophrenia. Methods A cohort of 221 patients with schizophrenia were recruited for this research. Finally 177 untreated first-episode patients were clinically evaluated with the Positive and Negative Syndrome Scale (PANSS), Raven's Standard Progressive Matrices (RSPM), Digit Vigilance Test (DVT), Digit Span (DS), underwent genotyping for five polymorphisms of NRG1, and completed a 12-week prospective study of risperidone monotherapy. Results 1. After risperidone treatment of 12 weeks, the total scores, positive score, negative score and general score of PANSS decreased significantly; the scores of RSPM, DVT and DS increased significantly. 2. No significant association with PANSS scores at baseline or change in scores after 12 weeks'treatment was found with any of the five SNPs. There was also neither significant association of DVT, DS or RSPM at baseline with any of the five SNPs. 3. After risperidone treatment of 12 weeks, rs3924999 and rs35753505 showed significant association with change in DVT and in RSPM in which there were significant differences among different genotype groups. Conclusion This study suggested pharmacogenetic relationships between NRG1 variants and changes in cognition response with exposure to 12 weeks of treatment with risperidone. Two variants, rs3924999 and rs35753505, in the NRG1 gene were associated with the changes in attention and reasoning ability after risperidone treatment of 12 weeks.

Photo-induced hyperthermia possesses great potential in photothermal therapy and thermal-responsive chemotherapy of tumors. However, traditional thermal-triggered drug release requires high tempera...

Background At present, it is well known that many hemogram parameters were related to the prognosis of a variety of cancers. Among them, monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have attracted more and more attention. The purpose of this study was to investigate the prognostic value of MLR, NLR, PLR, especially MLR, in patients with bladder cancer (BC) treated with radical cystectomy (RC). Methods Between January 2009 and October 2018, 203 BC patients who underwent RC participated in the survey, and various clinical and hematological parameters were recorded. The optimal cutoff of MLR, NLR and PLR were determined by X-tile software, and Cox regression analysis was performed to investigated the effect of MLR, NLR and PLR on the overall survival (OS) and disease-free survival (DFS). Results The optimal cutoff values of MLR, NLR and PLR were 0.54, 4.10 and 164.63, respectively. Patients with high MLR (>0.54) predicted shorter OS [hazard ratio (HR): 2.30; 95% confidence interval (CI): 1.36–3.89; P=0.002] and DFS (HR: 2.13; 95% CI: 1.21–3.75; P=0.009) compared with patients with low MLR (≤0.54). Multivariate Cox regression analysis showed that only MLR was an independent risk factor for OS and DFS in MLR, NLR and PLR. In addition, receiver operating characteristic (ROC) analysis showed that at most time points, the area under the curve (AUC) of MLR was greater than that of NLR and PLR used to predict OS and DFS. Conclusions Our results show that MLR can be independently used as a poor prognostic factor for OS and DFS in BC patients with RC. The prognosis of BC patients after RC can be predicted by measuring the level of MLR.

Background. Acinetobacter baumannii (A. baumannii) has become one of the most important opportunistic pathogens inducing nosocomial pneumonia and increasing mortality in critically ill patients recently. The interaction between A. baumannii infection and immune response can influence the prognosis of A. baumannii related pneumonia. The target of the present study was to investigate the role of immunodeficiency in A. baumannii induced pneumonia. Methods. Male BALB/c mice were randomly divided into the normal immunity control (NIC) group, normal immunity infection (NIA) group, immune compromised control (CIC) group, and immune compromised infection (CIA) group (n = 15 for each group). Intraperitoneal injection of cyclophosphamide and intranasal instillation of A. baumannii solution were used to induce compromised immunity and murine pneumonia, respectively. The mice were sacrificed at 6 and 24 h later and the specimens were collected for further tests. Seven-day mortality of mice was also assessed. Results. After A. baumannii stimulation, the recruitment of neutrophils in mice with normal immunity increased sharply (P = 0.030 at 6 h), while there was no significant raise of neutrophil counts in mice with compromised immune condition (P = 0.092 at 6 h, P = 0.772 at 24 h). The Th cell polarization presented with pulmonary interleukin (IL)-4 and interferon (IFN)-γ level in response to the A. baumannii in CIA group were significantly depressed in comparison with in NIA group (IFN-γ: P = 0.003 at 6 h; P = 0.001 at 24 h; IL-4: P

Objectives. By performing an overview of systematic reviews and meta-analyses of the efficacy and safety of oral Chinese patent medicine combined with conventional therapy in the treatment of heart failure, to evaluate the reliability and applicability of the conclusions of the current studies and provide evidence for clinical decision-making. Methods. Systematic reviews and meta-analyses of oral Chinese patent medicine combined with conventional therapy treating heart failure were searched based on standardized search strategy in six electronic databases including PubMed, Embase, Cochrane Library (No. 2 of 2020), China National Knowledge Infrastructure (CNKI), Wanfang Database (Wanfang), and Chinese Scientific Journal Database (VIP) from inception to February 2020. The literature was independently screened and extracted by two researchers. The methodological quality of the included literature was evaluated using the AMSTAR-2 (A Measurement Tool to Assess Systematic Review 2). If necessary, we would summarize the original research data and further perform data synthesis using RevMan software (version 5.3), and the evidence quality of the included literature was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results. A total of 38 systematic reviews and meta-analyses were included, involving 11 kinds of oral Chinese patent medicines, including Qili Qiangxin Capsules (11/38), Qishen Yiqi Dropping Pills (9/38), Shexiang Baoxin Pills (4/38), Wenxin Keli (2/38), Tongxinluo Capsules (2/38), Compound Danshen Dripping Pills (2/38), Zhenyuan Capsules (3/38), Buyi Qiangxin Tablets (2/38), Yangxinshi Tablets (1/38), Xuezhikang (1/38), and Yixinshu Capsules (1/38). The methodological quality of all literature was rated as critically low. The grading of the quality of evidence was 43 moderate, 101 low, and 40 very low. The main reason for the degradation of evidence quality was the risk of bias. In the evaluation of efficacy, there was no statistically significant difference between the two groups in terms of mortality, which is a piece of low-quality evidence. Qili Qiangxin Capsules or Qishen Yiqi Dripping Pills combined with conventional therapy can significantly reduce the hospitalization rate of patients with chronic heart failure, and the quality of the evidence is moderate. The overall efficacy of oral Chinese patent medicine combined with conventional therapy in improving the clinical symptoms, quality of life, exercise endurance, laboratory tests, physical examination, and other indicators of patients with heart failure is confirmed. In the evaluation of safety, there was no significant difference between the two groups. Conclusions. Oral Chinese patent medicine combined with conventional therapy has good clinical efficacy and safety in the treatment of heart failure. However, due to its low level of methodological quality and evidence quality, the current evidence-based conclusions need to be further verified.

Cardiac fibrosis is a typical pathological change in various cardiovascular diseases. Although it has been recognized as a crucial risk factor responsible for heart failure, there is still a lack of effective treatment. Recent evidence shows that microRNAs (miRNAs) play an important role in the development of cardiac fibrosis and represent novel therapeutic targets. In this study we tried to identify the cardiac fibrosis-associated miRNA and elucidate its regulatory mechanisms in mice. Cardiac fibrosis was induced by infusion of angiotensin II (Ang II, 2 mg·kg(−1)·d(−1)) for 2 weeks via osmotic pumps. We showed that Ang II infusion induced cardiac disfunction and fibrosis accompanied by markedly increased expression level of miR-99b-3p in heart tissues. Upregulation of miR-99b-3p and fibrotic responses were also observed in cultured rat cardiac fibroblasts (CFs) treated with Ang II (100 nM) in vitro. Transfection with miR-99b-3p mimic resulted in the overproduction of fibronectin, collagen I, vimentin and α-SMA, and facilitated the proliferation and migration of CFs. On the contrary, transfection with specific miR-99b-3p inhibitor attenuated Ang II-induced fibrotic responses. Similarly, intravenous injection of specific miR-99b-3p antagomir could prevent Ang II-infused mice from cardiac dysfunction and fibrosis. We identified glycogen synthase kinase-3 beta (GSK-3β) as a direct target of miR-99b-3p. In CFs, miR-99b-3p mimic significantly reduced the expression of GSK-3β, leading to activation of its downstream profibrotic effector Smad3, whereas miR-99b-3p inhibitor caused anti-fibrotic effects. GSK-3β knockdown ameliorated the anti-fibrotic role of miR-99b-3p inhibitor. These results suggest that miR-99b-3p contributes to Ang II-induced cardiac fibrosis at least partially through GSK-3β. The modulation of miR-99b-3p may provide a new approach for tackling fibrosis-related cardiomyopathy.

Background Pregnancy is associated with higher incidence of failed endotracheal intubation and is exacerbated by labor. However, the influence of labor on airway outcomes with laryngeal mask airway (LMA) for cesarean delivery is unknown. Methods This is a secondary analysis of a prospective cohort study on LMA use during cesarean delivery. Healthy parturients who fasted > 4 h undergoing Category 2 or 3 cesarean delivery with Supreme™ LMA (sLMA) under general anesthesia were included. We excluded parturients with BMI > 35 kg/m2, gastroesophageal reflux disease, or potentially difficult airway (Mallampati score of 4, upper respiratory tract or neck pathology). Anesthesia and airway management reflected clinical standard at the study center. After rapid sequence induction and cricoid pressure, sLMA was inserted as per manufacturer’s recommendations. Our primary outcome was time to effective ventilation (time from when sLMA was picked up until appearance of end-tidal carbon dioxide capnography), and secondary outcomes include first-attempt insertion failure, oxygen saturation, ventilation parameters, mucosal trauma, pulmonary aspiration, and Apgar scores. Differences between labor status were tested using Student’s t-test, Mann-Whitney U test, or Fisher’s exact test, as appropriate. Quantitative associations between labor status and outcomes were determined using univariate logistic regression analysis. Results Data from 584 parturients were analyzed, with 37.8% in labor. Labor did not significantly affect time to effective ventilation (mean (SD) for labor: 16.0 (5.75) seconds; no labor: 15.3 (3.35); mean difference: -0.65 (95%CI: − 1.49 to 0.18); p = 0.1262). However, labor was associated with increased first-attempt insertion failure and blood on sLMA surface. No reduction in oxygen saturation or pulmonary aspiration was noted. Conclusions Although no significant increase in time to effective ventilation was noted, labor may increase the number of insertion attempts and oropharyngeal trauma with sLMA use for cesarean delivery in parturients at low risk of difficult airway. Future studies should investigate the effects of labor on LMA use in high risk parturients. Trial registration The study was prospectively registered at clinicaltrials.gov (NCT02026882) on 3 January 2014.

To investigate the value of pre-treatment amide proton transfer–weighted (APTw) imaging for predicting survival of patients with nasopharyngeal carcinoma (NPC). Pre-treatment APTw imaging was performed in 77 NPC patients and the mean, 90th percentile, skewness, and kurtosis of APT asymmetry (APTmean, APT90, APTskewness, and APTkurtosis, respectively) were obtained from the primary tumor. Associations of APTw parameters with locoregional relapse–free survival (LRRFS), distant metastasis–free survival (DMFS), and disease-free survival (DFS) after 2 years were assessed by univariable Cox regression analysis and significant APTw parameters, together with age, sex, treatment, and stage as confounding variables, were added to the multivariable model. Kaplan-Meier analysis was used to determine the prognostic significance of patients with high or low APT values based on a threshold value from receiver operating characteristic curve analysis. Locoregional relapse, distant metastases, and disease relapse occurred in 14/77 (18%), 10/77 (13%), and 20/77 (26%) patients, respectively, at a median follow-up of 48.3 (10.6–67.4) months. Univariable analysis showed significant associations of LRRFS with APTskewness (HR = 1.98; p = 0.034), DMFS with APTmean (HR = 2.44; p = 0.033), and APT90 (HR = 1.93; p = 0.009), and DFS with APTmean (HR = 2.01; p = 0.016), APT90 (HR = 1.68; p = 0.009), and APTskewness (HR = 1.85; p = 0.029). In multivariable analysis, the significant predictors for DMFS were APT90 (HR = 3.51; p = 0.004) and nodal stage (HR = 5.95; p = 0.034) and for DFS were APT90 (HR = 1.97; p = 0.010) and age (HR = 0.92; p = 0.014). An APT90 ≥ 4.38% was associated with a significantly poorer DFS at 2 years than APT90 < 4.38% (66% vs. 91%; HR = 4.01; p = 0.005). APTw imaging may potentially predict survival in patients with NPC. • APTw imaging may provide new markers to predict survival in nasopharyngeal carcinoma. • APT90 is an independent predictor of distant metastases–free survival and disease-free survival. • The APThigh group is at higher risk of disease relapse than the APTlow group.

Background: In China, although quite a few bold programmes have been made for HIV/AIDS, the epidemic has still shown an increasing trend. Objectives: The study was aimed to investigate the characteristics of new HIV/AIDS and the major factors of false positives (FP) for HIV testing. Methods: A retrospective review was performed in a teaching hospital in Xi’an between 2013 and 2018. The overall characteristics and trends of new HIV/AIDS were described. Moreover, the major factors of FP were determined by the Pareto analysis. Results: A total of 469 new HIV/AIDS were diagnosed, with an increasing prevalence of the new HIV/AIDS from 0.0626% (41/65503) in 2013 to 0.0827% (115/139046) in 2018. Of them, the majority occurred in the males (88.50%), people aged 21-50 years (76.97%), migrants (60.98%), and sexual contact route (88.70%). There was a rapid increase in the annual number of new HIV/AIDS and increasing trends in groups of young individuals, students, and homosexual mode; however, a downward trend in the percentage of injecting drug use was also observed. Over 50 years old and patients from oncology, obstetrics, hepatobiliary surgery, nephrology, cardiology, and infectious disease constituted the major factors of FP. Conclusions: The HIV/AIDS epidemic in Xi’an is still evolving, therefore, effective strategies, appropriate education and scaling up HIV testing should be developed. In addition, old adults and specific departments were associated with FP.

Background and aims To investigate the safety and efficacy of direct-acting antiviral (DAA) regimens in a cohort of Chinese patients with chronic hepatitis C virus (HCV) infection. Methods A total of 222 adult Chinese patients were enrolled and treated via DAA regimens in accordance with HCV management guidelines. Treatment responses were evaluated 4 weeks after treatment, at the end of treatment (EOT) and 12 weeks post-treatment. Virological responses, biochemical responses, model for end-stage liver disease (MELD) and Child-Pugh (CP) scores were recorded. Results A total of 218 patients (98.2%) achieved sustained virological response 12 weeks post-treatment and 4 patients relapsed. The combined number of rapid virological responses for all six regimens was 170/222 (76.6%), and 221/222 (99.6%) had achieved virological responses by the end of treatment. In decompensated cirrhosis patients the baseline mean CP score was 6.8 ± 1.3 and the mean MELD score was 10.1 ± 3.3. Compared with the mean CP score at baseline, the mean score is significantly lower at the end of treatment (5.7 ± 1.3) and 12 weeks post-treatment (5.6 ± 1.0). Estimated glomerular filtration rates did not differ significantly from baseline during the treatment or 12 weeks post-treatment. The incidence of adverse events in patients with chronic hepatitis C and compensated cirrhosis was 42/172 (24.4%), and in patients with decompensated cirrhosis it was 8/22 (36.4%). The most frequently reported adverse events were elevated indirect bilirubin, fatigue and rash. There were no cases of serious adverse events, death or treatment discontinuation because of adverse events. Conclusion DAA regimens were highly effective and well tolerated irrespective of HCV genotype, cirrhosis, liver or kidney transplantation, hepatocellular carcinoma, HCV/hepatitis B virus co-infection, or renal failure.

Objectives. To systematically evaluate the efficacy and safety of sinomenine preparation (SP) for treating ankylosing spondylitis (AS). Methods. Clinical randomized controlled trials (RCTs) of SP for treating AS were systematically identified in six electronic databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang Databases from the inception up to 31 October 2019. Cochrane’s risk of bias tool was used to assess the methodological quality and Review Manager 5.3 software was used to analyze data. Results. A total of 12 RCTs involving 835 patients were finally included. According to interventions, RCTs were divided into two types. The intervention in 10 RCTs was SP combined with conventional pharmacotherapy (CPT) versus CPT and that in 2 RCTs was SP alone versus CPT. The results of the meta-analysis showed that, compared with CPT alone, SP combined with oral CPT has better improvement in BASDAI (WMD = −1.84, 95% CI [−3.31, −0.37], P=0.01), morning stiffness time (WMD = −13.46, 95% CI [−16.12, −10.79], P<0.00001), the Schober test (WMD = 1.26, 95% CI [0.72, 1.80], P<0.00001), the occipital wall test (WMD = −0.55, 95% CI [−0.96, −0.14], P=0.009), the finger-to-ground distance (WMD = −3.28, 95% CI [−5.64, −0.93], P=0.006), 15 m walking time (WMD = −8.81, 95% CI [−13.42, −4.20], P=0.0002), the C-reactive protein (CRP) (WMD = −1.84, 95% CI [−3.24, −0.45], P=0.01), and the total effective rate (RR = 1.10, 95% CI [1.01, 1.20], P=0.03). Besides, it also showed that oral SP alone may be more effective in improving morning stiffness time (WMD = −31.89, 95% CI [−34.91, −28.87], P<0.00001) compared with CPT alone. However, this study cannot provide evidence that loading the injectable SP based on CPT can significantly increase the efficacy due to the insufficient number of studies included. In terms of adverse events, there was no statistically significant difference between the experimental group and the control group. Conclusions. This study shows that oral SP may be effective and safe in the treatment of AS. Due to the low methodological quality of the included RCTs and the limitations of the meta-analysis, it is still necessary to carry out more multicenter, large-sample, and high-quality RCTs to further verify the conclusions. The review protocol was registered on PROSPERO (CRD42018099170), and the review was constructed following the PRISMA guidelines (Annex 1).

Qiu et al. present a novel deep learning strategy to generate high-resolution visualizations of Alzheimer’s disease risk in humans that are highly interpretable and can accurately predict Alzheimer’s disease status. They then test the model by comparing its performance to that of neurologists and neuropathological data., Alzheimer’s disease is the primary cause of dementia worldwide, with an increasing morbidity burden that may outstrip diagnosis and management capacity as the population ages. Current methods integrate patient history, neuropsychological testing and MRI to identify likely cases, yet effective practices remain variably applied and lacking in sensitivity and specificity. Here we report an interpretable deep learning strategy that delineates unique Alzheimer’s disease signatures from multimodal inputs of MRI, age, gender, and Mini-Mental State Examination score. Our framework linked a fully convolutional network, which constructs high resolution maps of disease probability from local brain structure to a multilayer perceptron and generates precise, intuitive visualization of individual Alzheimer’s disease risk en route to accurate diagnosis. The model was trained using clinically diagnosed Alzheimer’s disease and cognitively normal subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n = 417) and validated on three independent cohorts: the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) (n = 382), the Framingham Heart Study (n = 102), and the National Alzheimer’s Coordinating Center (NACC) (n = 582). Performance of the model that used the multimodal inputs was consistent across datasets, with mean area under curve values of 0.996, 0.974, 0.876 and 0.954 for the ADNI study, AIBL, Framingham Heart Study and NACC datasets, respectively. Moreover, our approach exceeded the diagnostic performance of a multi-institutional team of practicing neurologists (n = 11), and high-risk cerebral regions predicted by the model closely tracked post-mortem histopathological findings. This framework provides a clinically adaptable strategy for using routinely available imaging techniques such as MRI to generate nuanced neuroimaging signatures for Alzheimer’s disease diagnosis, as well as a generalizable approach for linking deep learning to pathophysiological processes in human disease.