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Background Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Magnetic resonance imaging (MRI) is one of the most effective imaging methods for the early diagnosis of HCC. However, the current MR contrast agents are still facing challenges in the early diagnosis of HCC due to their relatively low sensitivity and biosafety. Thus, the development of effective MR agents is highly needed for the early diagnosis of HCC. Results Herein, we fabricated an HCC-targeted nanocomplexes containing SPIO-loaded mesoporous polydopamine (MPDA@SPIO), sialic acid (SA)-modified polyethyleneimine (SA-PEI), and alpha-fetoprotein regulated ferritin gene (AFP-Fth) which was developed for the early diagnosis of HCC. It was found that the prepared nanocomplexes (MPDA@SPIO/SA-PEI/AFP-Fth) has an excellent biocompatibility towards the liver cells. In vivo and in vivo studies revealed that the transfection of AFP-Fth gene in hepatic cells significantly upregulated the expression level of ferritin, thereby resulting in an enhanced contrast on T2-weighted images via the formed endogenous MR contrast. Conclusions The results suggested that MPDA@SPIO/SA-PEI/AFP-Fth had a superior ability to enhance the MR contrast of T2-weighted images of tumor region than the other preparations, which was due to its HCC-targeted ability and the combined T2 contrast effect of endogenous ferritin and exogenous SPIO. Our study proved that MPDA@SPIO/SA-PEI/AFP-Fth nanocomplexes could be used as an effective MR contrast agent to detect HCC in the early stage.

X-linked ubiquitin-specific peptidase 9 (USP9X) serves important roles in the development and progression of various human cancers. However, its role and molecular mechanism in liver cancer require further elucidation. In the present study, USP9X was found to be upregulated in liver cancer tissues. At the same time, overexpression of USP9X promoted the proliferation, invasiveness and migration of liver cancer cells, which were subsequently suppressed by USP9X silencing. On a molecular level, the results revealed that USP9X knockdown suppressed elements of the Janus kinase 2 (JAK2)/STAT3 signaling pathway, including JAK2, STAT3, matrix metalloproteinase-2 and c-Myc. By contrast, overexpression of USP9X had the opposite effect. In conclusion, the results of the present study suggest that USP9X is upregulated in patients with liver cancer, which may accelerate the proliferation, invasiveness and migration of liver cancer cells by regulating the JAK2/STAT3 signaling pathway.

Jinyu Zhu,1,2,&ast; Bufu Tang,1,3,&ast; Yang Gao,1,4 Suqin Xu,5 Jianfei Tu,1,4 Yajie Wang,4 Weibin Yang,1,4 Shiji Fang,4 Qiaoyou Weng,4 Zhongwei Zhao,1,4 Min Xu,1,4 Yang Yang,1,4 Minjiang Chen,1,4 Chenying Lu,1,4 Jiansong Ji1,4 1Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui, 323000, People’s Republic of China; 2Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China; 3Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of China; 4Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, People’s Republic of China; 5Clinical Laboratory, Fuyuan Hospital of Yiwu, Jinhua, 321000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiansong Ji; Chenying Lu Email jijiansong@zju.edu.cn; luchenying@zju.edu.cnIntroduction: Hepatocellular carcinoma (HCC) is a heterogeneous molecular disease with complex molecular pathogenesis that influences the efficacy of therapies. Exosomes play a crucial role in tumorigenesis and poor disease outcomes in HCC.Objective: The aim of this study was to identify the optimal gene set derived from exosomes in HCC with substantial predictive value to construct models for determining prognosis, recurrence risk and diagnosis and to identify candidates suitable for immunotherapy and chemotherapy, thereby providing new ideas for the individualized treatment of patients and for improving prognosis.Methods: Weighted correlation network analysis (WGCNA) and univariate and multivariate Cox PH regression analyses were applied to identify exosome-related signatures in the TCGA and exoRbase databases associated with clinical relevance, immunogenic features and tumor progression in HCC. Cell experiments were performed to further confirm the oncogenic effect of MYL6B and THOC2.Results: The models for prognosis and recurrence risk prediction were built based on two exosomal genes (MYL6B and THOC2) and were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC datasets, namely, the TCGA cohort (HR=2.5, P< 0.001), the ICGC cohort (HR=3.15, P< 0.001) and the GSE14520 cohort (HR=1.85, P=0.004). A higher recurrence probability was found in HCC patients with high recurrence risk than in HCC patients with low recurrence risk in the TCGA cohort (HR=2.44, P< 0.001) and the GSE14520 cohort (HR=1.54, P=0.025). High prognostic risk patients had higher expression of immune checkpoint genes, such as PD1, B7H3, B7H5, CTLA4 and TIM3 (P< 0.05). Diagnostic models based on the same two genes were able to accurately distinguish HCC patients from normal individuals and HCC from dysplastic nodules.Conclusion: Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.Keywords: exosome, hepatocellular carcinoma, HCC, immune checkpoint, prognosis

BACKGROUND Breast cancer, a common malignant tumor, has been considered as the leading cause of cancer-related death in women. Collagen type X alpha 1 (COL10A1) is overexpressed in breast cancer. The current study was designed to determine the functional involvement and regulatory mechanism of COL10A1 on the growth and metastasis of breast cancer. MATERIAL AND METHODS COL10A1 and Prolyl 4-hydroxylase beta polypeptide (P4HB) expressions in normal tissues and tumor tissues of breast cancer patients were obtained from the GEPIA dataset. COL10A1 and P4HB levels in breast cancer cell lines were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Furthermore, the interaction between COL10A1 and P4HB was confirmed by co-immunoprecipitation (Co-IP) assay. Cell Counting Kit-8 (CCK-8) and colony formation assay were applied to evaluate cell proliferation and clone-forming abilities of breast cancer cells. In addition, wound healing assay and transwell assay were performed to measure cell migration and invasion capabilities, respectively, in breast cancer. RESULTS The GEPIA dataset presented overexpressed COL10A1 and P4HB in tumor tissues of breast cancer patients. COL10A1 and P4HB expression levels were greatly upregulated in breast cancer cell lines. In addition, COL10A1 could directly interact with P4HB. Functionally, overexpressed COL10A1 boosted the proliferation and metastasis of breast cancer cells and silenced COL10A1 impeded the progression of breast cancer. More importantly, knockdown of P4HB weakened the promoting effects of overexpressed COL10A1 on cell proliferation, migration, and invasion in breast cancer. CONCLUSIONS COL10A1 promotes the malignant progression of breast cancer by upregulating P4HB expression, indicating that COL10A1 functions as an oncogene in breast cancer.

The outbreak of novel coronavirus disease 2019 (COVID-19) has become the largest health threat worldwide, with more than 34.40 million positive cases and over 1.02 million deaths confirmed. In this study, we confirmed that significantly differentially expressed genes in COVID-19 patients were mainly involved in the regulation of immune and inflammation-related signaling pathways. It is worth noting that many infected COVID-19 patients have malignant tumors, and their prognosis is poor. To explore the susceptibility factors of cancer patients, we assessed the expression of ACE2, TMPRSS2, and the endocytic regulator AAK1 in lung adenocarcinoma (LUAD) patients and explored their effects on immune infiltration. We found that the expression of ACE2 and TMPRSS2 in LUAD patients was significantly increased, which may explain why LUAD patients are susceptible to SARS-CoV-2, and the patients with high-expression genes presented increased infiltration of immune cells such as B cells and CD4 T cells. In addition, we also identified miR-432-5p as a potential targeted molecule and bexarotene as a potential targeted drug of the three genes through bioinformatic analysis and further verified the anti-inflammatory effect of bexarotene, providing new ideas for the treatment of COVID-19.

Hepatocellular carcinoma (HCC) is the fifth common cause of tumor-related death worldwide. ZFP36, a RNA-binding protein, decreases in many cancers and its role in HCC remains unclear. This study aimed to investigate the underlying mechanisms by which ZFP36 inhibited HCC progression and increased fluorouracil (5-Fu) sensitivity. We found that ZFP36 was downregulated and PRC1 was upregulated in HCC tissues compared with adjacent non-tumor tissues. In vitro investigation presented that ZFP36 acted as a tumor suppressor, while overexpression of PRC1 increased cell proliferation, colony formation and invasion. Further investigations demonstrated that overexpression of ZFP36 inhibited tumor growth and promoted 5-Fu sensitivity in xenograft tumor mice model, which could be reversed when PRC1 overexpressed simultaneously. Luciferase reporter assays and Ribonucleoprotein immunoprecipitation analysis indicated that ZFP36 could bind to adenylate uridylate-rich elements located in PRC1 mRNA 3′UTR to downregulate PRC1 expression. Taken together, our findings identified that ZFP36 regulated PRC1 to exert anti-tumor effect, which suggested a potential therapeutic strategy for treating HCC by exploiting ZFP36/PRC1 axis.

Background: In this study, we performed a comprehensive analysis to identify the optimal gene set derived from exosomes in hepatocellular carcinoma (HCC) with great prognostic value to construct prognostic, recurrence and diagnostic models and predicted therapeutic response for hepatocellular carcinoma.Methods: Differential expression analysis and Weighted Gene Co-Expression Network Analysis (WGCNA) of RNA-sequencing were used to identify differentially expressed exosome-derived genes related to HCC. Univariate and multivariate Cox regression analyses were performed to determine exosome-derived genes associated with prognosis of HCC to construct a prognostic model, and recurrence and diagnostic models were built based on the same genes. Results: MYL6B and THOC2 were determined to be closely related to prognosis in HCC. The prognostic and recurrence models built based on these two genes were confirmed to be independent predictive factors with superior predictive performance. Patients with high prognostic risk had poorer prognosis than patients with low prognostic risk in all HCC sets, namely, the TCGA cohort (HR=2.5, PConclusions: Prognostic, recurrence, and diagnostic models based on the two exosome-derived genes (MYL6B and THOC2) were proven superior predictive performance. Our findings lay the foundation for identifying molecular markers to increase the early detection rate of HCC, improve disease outcomes, and determine more effective individualized treatment options for patients.

Fluid percussion (FP) injury model is a popular animal model of traumatic brain injury (TBI), but still there are some issues need to be addressed. To increase the validity and reliability of this technique, we adapted the FP device using electromagnetic protractor, stainless-steel cylinder, changing pressure transducer position, and foam pads to adjust the parameters of FP pulse. Besides, the adjusted FP device is more automatic. The FP pulse is promptly measured and displayed in a graphic user interface software. The modified device resulted in reliable FP pulse. The accuracy of the pendulum leveling was improved with using the electromagnetic protractor with slots. We then collected behavioral, cognition, electrophysiological, and immunohistochemical data to verify the percussion effects in TBI mice. Lateral fluid percussion injury (FPI) or sham treatment was administered at the right frontal motorsensory region of male C57BL/6J mice. TBI mice showed evident motor, cognitive, and functional impairments, characterized by evaluation of neurological, righting, geotaxis and cliff aversion reflexes, limb asymmetrical use, rotarod running, and Morris water maze testing. The neurobehavioral damages were scaled with histopathological findings. Further, the overall firing rates and theta powers in hippocampal CA1 were significantly reduced in TBI mice compared to sham mice at Days 2 and 3 after electrode implanting. The adapted device induced effects on behavior and biology in mice that agree with existing models. These findings confirmed the validity of adjustments, and the modified device may boost the interest in TBI studies.

Background: Early diagnostic of COVID-19 pneumonia remains a dilemma We aimed to investigate the importance of early stage chest CT imaging features in the ear

Activated oncogenes and loss of tumor suppressors contribute to reprogrammed energy metabolism and induce aerobic glycolysis, also known as Warburg effect. MicroRNAs are profoundly implicated in human malignancies by inhibiting translation of multiple mRNA targets. Using hepatocellular carcinoma (HCC) molecular profiles from The Cancer Genome Atlas (TCGA), we identified a handful of dysregulated microRNA in HCC glycolysis, especially miR-34c-3p. Antagonization of miR-34c-3p inhibited the lactate production, glucose consumption, extracellular acidification rate (ECAR), and aggressive proliferation in HCC cells. Hijacking glycolysis by 2-deoxy-d-glucose or galactose largely abrogated the suppressive effects of miR-34c-3p inhibition in HCC. Membrane associated guanylate kinase, WW, and PDZ domain containing 3 (MAGI3) is then identified as a direct functional target of miR-34c-3p in regulating HCC glycolysis and oncogenic activities. Mechanistically, MAGI3 physically interacted with β-catenin to regulate its transcriptional activity and c-Myc expression, which further facilitates the Warburg effect by increasing expression of glycolytic genes including HK2, PFKL, and LDHA. Moreover, overexpressed miR-34c-3p and reduced MAGI3 predicted poor clinical outcome and was closely associated with the maximum standard uptake value (SUVmax) in HCC patients who received preoperative 18 F-FDG PET/CT. Our findings elucidate critical several microRNAs implicated in HCC glycolysis and reveal a novel function of miR-34c-3p/MAGI3 axis in Warburg effect through regulating β-catenin activity.

Background Recent evidence suggests early screening of preeclampsia and small-for-gestational-age (SGA) would benefit pregnancies followed by subsequent prophylactic use of aspirin. Multi-marker models have shown capability of predicting preeclampsia and SGA in first trimester. Yet the clinical feasibility of combined screening model for Chinese pregnancies has not been fully assessed. The aim of this study is to evaluate the applicability of a multi-marker screening model to the prediction of preeclampsia and SGA in first trimester particularly among Chinese population. Methods Three thousand two hundred seventy pregnancies meeting the inclusion criteria took first-trimester screening of preeclampsia and SGA. A prior risk based on maternal characteristics was evaluated, and a posterior risk was assessed by combining prior risk with multiple of median (MoM) values of mean arterial pressure (MAP), serum placental growth factor (PLGF) and pregnancy associated plasma protein A (PAPP-A). Both risks were calculated by Preeclampsia PREDICTOR™ software, Perkin Elmer. Screening performance of prior and posterior risks for early and late preeclampsia by using PREDICTOR software was shown by Receiver Operating Characteristics (ROC) curves. The estimation of detection rates and false positive rates of delivery with both preeclampsia and SGA was made. Results Eight cases developed early preeclampsia (0.24%) and 35 were diagnosed as late preeclampsia (1.07%). Five with early preeclampsia and ten with late preeclampsia later delivered SGA newborns (0.46%); 84 without preeclampsia gave birth to the SGAs (2.57%). According to ROC curves, posterior risks performed better than prior risks in terms of preeclampsia, especially in early preeclampsia. At 10% false positive rate, detection rates of early and late preeclampsia were 87.50 and 48.57%, detection rates of early and late SGA were 41.67 and 28.00%, respectively. For SGA, detection rates in cases with preeclampsia were much higher than those in absence of it. Conclusions This study demonstrates that combined screening model could be useful for predicting early preeclampsia in Chinese pregnancies. Furthermore, the performance of SGA screening by same protocol is strongly associated with preeclampsia. Electronic supplementary material The online version of this article (10.1186/s12884-019-2455-8) contains supplementary material, which is available to authorized users.

Background: The present study aimed to explore the changes in the hepatic metabolic profile during the evolution of diabetes mellitus (DM) and verify the key metabolic pathways. Methods: Liver samples were collected from diabetic rats induced by streptozotocin (STZ) and rats in the control group at 1, 5, and 9 weeks after STZ administration. Proton nuclear magnetic resonance spectroscopy (1H NMR)-based metabolomics was used to examine the metabolic changes during the evolution of DM, and partial least squares-discriminate analysis (PLS-DA) was performed to identify the key metabolites. Results: We identified 40 metabolites in the 1H NMR spectra, and 11 metabolites were further selected by PLS-DA model. The levels of α-glucose and β-glucose, which are two energy-related metabolites, gradually increased over time in the DM rats, and were significantly greater than those of the control rats at the three-time points. The levels of choline, betaine, and methionine decreased in the DM livers, indicating that the protective function in response to liver injury may be undermined by hyperglycemia. The levels of the other amino acids (leucine, alanine, glycine, tyrosine, and phenylalanine) were significantly less than those of the control group during DM development. Conclusions: Our results suggested that the hepatic metabolic pathways of glucose, choline-betaine-methionine, and amino acids were disturbed during the evolution of diabetes, and that choline-betaine-methionine metabolism may play a key role.

The systemic investigation of the metabolic pathways associated with the hepatic tumorigenesis is important to discover novel biomarkers and identify the potential pathogenesis. Here, the 1H nuclear magnetic resonance- (1H NMR-) based metabolomic analysis was used to monitor the whole process of rat diethylnitrosamine-induced HCC. Intraperitoneal administration of diethylnitrosamine (DEN) was used to induce primary HCCs in male Sprague-Dawley rats. Magnetic resonance imaging (MRI) examinations were performed to follow the tumor formation and growth in the liver and H&E staining was used to confirm MR imaging findings. The rats with DEN treatment and control rats without DEN were euthanized at the time points of 3, 8, and 15 weeks after the start of modeling. 1H NMR-based metabolomic analysis was used to explore hepatic metabolite changes and certify key metabolic pathways in the process of tumor tumorigenesis. Our MRI results depicted the formation of HCC nodules in ten rats 14 weeks after DEN injection which were confirmed by histology. Twenty-four different metabolites were identified and quantified by 1H NMR spectroscopy; OPLS-DA models and corresponding VIP plots analysis further identified ten metabolites associated with the abnormal metabolism. The aberrant glucose, lipid, and glutathione-glutamine-glutamate metabolism could be detected involving in the process of hepatic tumorigenesis, which provides an important evidence for the in-depth study of subsequent molecular mechanisms, especially the glutathione-glutamine-glutamate metabolism.

Chronic pain can develop from numerous conditions and is one of the most widespread and disabling health problems today. Unfortunately, the pathophysiology of chronic pain in most of these conditions, along with consistently effective treatments, remain elusive. However, recent advances in neuroimaging and neurophysiology are rapidly expanding our understanding of these pain syndromes. It is now clear that substantial functional and structural changes, or plasticity, in the central nervous system (CNS) are associated with many chronic pain syndromes. A group of cortical and subcortical brain regions, often referred to as the "pain matrix," often show abnormalities on functional imaging studies in persons with chronic pain, even with different pain locations and etiologies. Changes in the motor and sensory homunculus also are seen. Some of these CNS changes return to a normal state with resolution of the pain. It is hoped that this knowledge will lead to more effective treatments or even new preventative measures. The purpose of this article is to review recent advances in the understanding of the CNS changes associated with chronic pain in a number of clinical entities encountered in the field of physical medicine and rehabilitation. These clinical entities include nonspecific low back pain, fibromyalgia, complex regional pain syndrome, postamputation phantom pain, and chronic pain after spinal cord injury.

Objective: To investigate whether the provision of power mobility would have an effect on body weight in adults who were first-time qualifiers for power mobility. Design: This was a retrospective observational study of consecutive subjects, who served as their own controls. The medical records of 468 subjects who were approved for power mobility during a 17-mo period were reviewed. Three weight groups (12 mos before, at, and 12 mos after the power mobility evaluation) were evaluated with repeated-measures analysis of variance (ANOVA). The weight changes on subjects in different age groups (45-54, 55-64, 65-74, and >74), in geriatric vs. nongeriatric groups, and in different body mass index (BMI) groups were analyzed. Results: Eighty-nine subjects met the inclusion criteria. They were obese (49.4%), and most of them were geriatric (64%). Congestive heart failure (30.34%) and chronic obstructive pulmonary disease (22.47%) were the two main presenting diagnoses. The repeated-measures ANOVA showed no significant weight change in the three studied weight groups. Similar results were seen in the age and BMI subgroups. Conclusions: There was no statistically significant weight change in adults who were first-time qualifiers and who used power mobility for 1 yr.

Background Transmetatarsal amputation (TMA) is an operation designed to remove a limited area of irremediable tissue ischemia and/or infection and preserve limb function. Patients are selected for TMA based on degree of tissue loss/infection, adequacy of tissue perfusion at the transmetatarsal level, current ambulatory status, and estimation of the likelihood of postprocedure ambulation. The purpose of this study was to assess the validity of these selection criteria. Methods An institutional review board–approved retrospective review was conducted of all patients undergoing TMA from January 1, 1997, until January 1, 2006. Information was collected on patient demographics, medical comorbidity, and clinical and surgical variables. Outcome measures included the proportion of patients requiring amputation revision to a more proximal level and ambulatory status at last follow-up. Results Fifty-two TMAs were performed. In 35 procedures, the skin was left open, and in 17 TMA was closed primarily. Primary indications for the procedure were vascular insufficiency or infection in 50 of 52 patients, whereas 2 patients required amputation for malignancy. The majority (46/52, 89%) of patients were diabetic. After the index TMA, 85 additional operations were required. Only 9 patients (18%) underwent a single operation. Revision of the TMA to a more proximal level was required in 29 of 52 (56%) patients, resulting in 4 Syme, 20 transtibial, and 5 transfemoral amputations. Non–insulin-dependent diabetes was associated with an increased likelihood of revision to a more proximal amputation (odds ratio [OR] = 5.4; 95% confidence interval [CI], 1.2–24). At the time of last follow-up (median 18 months), 37 of 50 (74%) patients were ambulatory (83% for TMAs and 67% for more proximal amputations, P = 0.18). Prior vascular procedures were associated with a significantly decreased likelihood of ambulation (OR = 14; 95% CI, 1.9–103). Conclusions Although most patients retain the ability to ambulate after TMA, multiple operations should be anticipated in the majority of patients and revision of a TMA to a more proximal level may be required. These data suggest that current selection criteria for TMA may be inadequate.

Zolpidem is an imidazopyridine agent indicated for the short-term treatment of insomnia. Sleepwalking is a rare side effect of zolpidem. A review of the literature produced only 2 cases. We report a case of a male rehabilitation inpatient in his mid fifties with a history of alcoholism and traumatic brain injury who had undergone a right hip hemiarthroplasty. He had no history of somnambulism or insomnia but walked in his sleep on 2 nonconsecutive nights after taking zolpidem. He had exhibited no such behavior before taking zolpidem, on the intervening night that was he was not given medication, and after the medication was discontinued. We conclude that zolpidem can cause sleepwalking, and patients who have suffered a brain injury may be more susceptible to this side effect. Here we describe the clinical presentation and review the relevant literature on zolpidem and sleepwalking.