Three-dimensional chromatin landscapes in hepatocellular carcinoma associated with hepatitis B virus.

BACKGROUND: Three-dimensional (3D) chromatin architecture frequently altered in cancer. However, its changes during the pathogenesis of hepatocellular carcinoma (HCC) remained elusive. METHODS: Hi-C and RNA-seq were applied to study the 3D chromatin landscapes and gene expression of HCC and ANHT. Hi-C Pro was used to generate genome-wide raw interaction matrices, which were normalized via iterative correction (ICE). Moreover, the chromosomes were divided into different compartments according to the first principal component (E1). Furthermore, topologically associated domains (TADs) were visualized via WashU Epigenome Browser. Furthermore, differential expression analysis of ANHT and HCC was performed using the DESeq2 R package. Additionally, dysregulated genes associated with 3D genome architecture altered were confirmed using TCGA, qRT-PCR, immunohistochemistry (IHC), etc. RESULTS: First, the intrachromosomal interactions of chr1, chr2, chr5, and chr11 were significantly different, and the interchromosomal interactions of chr4-chr10, chr13-chr21, chr15-chr22, and chr16-chr19 are remarkably different between ANHT and HCC, which resulted in the up-regulation of TP53I3 and ZNF738 and the down-regulation of APOC3 and APOA5 in HCC. Second, 49 compartment regions on 18 chromosomes have significantly switched (A-B or B-A) during HCC tumorigenesis, contributing to up-regulation of RAP2A. Finally, a tumor-specific TAD boundary located on chr5: 6271000-6478000 and enhancer hijacking were identified in HCC tissues, potentially associated with the elevated expression of MED10, whose expression were associated with poor prognosis of HCC patients. CONCLUSION: This study demonstrates the crucial role of chromosomal structure variation in HCC oncogenesis and potential novel biomarkers of HCC, laying a foundation for cancer precision medicine development.

Inequality of opportunity in outpatient expenditure among the elderly with multimorbidity: evidence from China.

BACKGROUND: Inequality of opportunity (IOp) stemming from social circumstances exists in outpatient service utilization for the multimorbid elderly in China. However, little is known regarding the magnitude of the IOp and its composition. Therefore, this study aims to measure the IOp in outpatient expenditure and provide potential pathways for policy reform by assessing the contribution of each circumstance. METHODS: This study included 3527 elderly aged ≥ 65 years with multimorbidity from the Chinese Longitudinal Healthy Longevity Study conducted in 2017-2018. An ordinary least squares regression model was used to analyze the circumstance-influencing factors of outpatient expenditure. The parametric approach was performed to quantify the IOp in outpatient expenditure and the Shapley value decomposition method was employed to determine the contribution of each circumstance. By extracting heterogeneity in the residual of the circumstance-dependent equation of outpatient expenditure across circumstance groups divided based on cluster analysis, we captured the effect of unobserved circumstances. RESULTS: Except for pension and distance to health facilities, all the associations between circumstance and outpatient expenditure were statistically significant. The inequality caused by circumstances accounted for 25.18% of the total inequality. The decomposition results revealed that the reimbursement rate contributed 82.92% of the IOp, followed by education duration (4.55%), household registration (3.21%), household income (3.18%), pension (1.49%), medical insurance (1.26%), physical labor (0.99%), unobserved circumstances (0.86%), distance to health facilities (0.83%) and region (0.71%). CONCLUSIONS: The priority of policy enhancement is to effectively improve the outpatient reimbursement benefit for treating chronic diseases. Additional crucial actions include enhancing the health literacy of the multimorbid elderly to promote the shift from medical needs to demands and accelerating the construction of rural capacity for providing high-quality healthcare to the elderly with multimorbidity.

Robotic Taj Mahal Hepatectomy for Hilar Cholangiocarcinoma.

Hilar cholangiocarcinoma is the most common malignant tumor of the biliary tract. Radical surgical resection is the only effective treatment option. In this study, a 32-year-old male patient with Bismuth Type IVa hilar cholangiocarcinoma underwent radical robotic resection of hepatic S4b, S5, and S1 (Taj Mahal hepatectomy) combined with regional lymphadenectomy, hilar bile duct reconstruction, and hepaticojejunostomy by the robotic surgical system. Postoperative pathological examination showed moderately-differentiated adenocarcinoma of the hilar bile duct. The surgical margins of the liver and bile ducts were negative. Recovery was smooth and the patient was discharged on the 17th postoperative day. The robotic surgical system and associated multiple instruments along with flexible and precise movements is suitable for the local hepatectomy around the porta hepatis, and delicate reconstruction of the hilar bile duct with a smaller diameter. This first clinical application study found that robotic Taj Mahal hepatectomy for hilar cholangiocarcinoma is safe and feasible and needs more experience for the evaluation of its long-term outcomes.

Multivariate Analysis on Development of Lung Adenocarcinoma Lesion from Solitary Pulmonary Nodule.

Objective: To analyze multiple factors developing lung adenocarcinoma lesion from solitary pulmonary nodule (SPN). Methods: A total of 70 patients diagnosed with lung adenocarcinoma after finding SPN by chest CT and treated in our hospital (01, 2018-01, 2021) were selected as the malignant lesion group, and another 70 patients diagnosed with benign lesion after finding SPN by CT in the same period were included in the benign lesion group. All patients had complete medical records. With univariate analysis and multivariate logistic regression, the independent risk factors for developing lung adenocarcinoma lesions from SPN were analyzed. Results: By conducting univariate analysis of patients' general information (age, course of disease, BMI, nodule diameter, and gender), smoking status (smoking history and number of cigarettes smoked per year), medical history (family history of lung cancer, history of extrapulmonary malignant tumor, and history of autoimmune diseases), basic complications (hypertension and diabetes), and laboratory examinations (CEA, NSE, CYFRA21-1, SCC-Ag, and CA125), it was concluded that age, course of disease, nodule diameter, CEA positive, CYFRA21-1 positive, and CA125 positive were significantly different between the two groups (P < 0.05); the logistic regression results showed that high age, increased nodule diameter, and CYFRA21-1 positive were the independent risk factors developing lung adenocarcinoma from SPN (P < 0.05). Conclusion: In patients with SPN, higher age, longer course of disease, greater nodule diameter, and CYFRA21-1 positive imply increased risk for triggering lung adenocarcinoma lesion. Therefore, high attention should be paid in the clinic to such SPN patients for early diagnosis and treatment.

Novel and Specific MRI Features Indicate the Clinical Features of Patients With Rare Hepatic Tumor Epithelioid Hemangioendothelioma.

OBJECTIVE: To investigate the MRI features and clinical significance of hepatic epithelioid hemangioendothelioma (HEHE). METHODS: Clinical records and MRI findings were retrospectively evaluated in nine HEHE patients from May 2010 to January 2020. RESULT: There were 121 lesions in nine patients with a predominantly peripheral distribution. Five lesions (4.13%) in two patients (22.22%) had evidence of capsular retraction, and three patients had lung metastasis (33.33%). Dynamic contrast-enhanced MRI showed progressive enhancement, mainly in two ways: ring enhancement with hypovascularity in four patients (44.44%) and ring enhancement with hypervascularity in five patients (55.56%). Imaging demonstrated a multilayer ring appearance, which was typically observed on T2-weighted imaging (T2WI). The most common appearance consisted of two layers of varying signal, with some images displaying up to four layers. There were significant differences in the size of lesions between different layers of multilayer ring appearance (p < 0.001). All lesions exhibited a two-layer appearance on diffusion-weighted imaging (DWI), with hyperintensity at the periphery and a slightly high signal at the center (except for those with a single layer on T2WI). The "vascular penetration sign" was observed in most lesions, and the blood vessels of 112 lesions (92.56%) were portal vein branches, and five (4.13%) were hepatic vein branches. Pulmonary metastasis was found in three patients with the "vascular penetration sign" of hepatic vein branches. CONCLUSION: The multilayer ring appearance on T2WI, the "vascular penetration sign", and the two enhancement patterns may be of great significance in the diagnosis and treatment of HEHE. The "vascular penetration sign" of hepatic vein branches may indicate extrahepatic metastasis.

Landscapes and dynamic diversifications of B-cell receptor repertoires in COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of coronavirus disease 2019 (COVID-19). Great international efforts have been put into the development of prophylactic vaccines and neutralizing antibodies. However, the knowledge about the B cell immune response induced by the SARS-CoV-2 virus is still limited. Here, we report a comprehensive characterization of the dynamics of immunoglobin heavy chain (IGH) repertoire in COVID-19 patients. By using next-generation sequencing technology, we examined the temporal changes in the landscape of the patient's immunological status and found dramatic changes in the IGH within the patient's immune system after the onset of COVID-19 symptoms. Although different patients have distinct immune responses to SARS-CoV-2 infection, by employing clonotype overlap, lineage expansion, and clonotype network analyses, we observed a higher clonotype overlap and substantial lineage expansion of B cell clones 2-3 weeks after the onset of illness, which is of great importance to B-cell immune responses. Meanwhile, for preferences of V gene usage during SARS-CoV-2 infection, IGHV3-74 and IGHV4-34, and IGHV4-39 in COVID-19 patients were more abundant than those of healthy controls. Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic development as well as mechanistic research.

Integrated gut virome and bacteriome dynamics in COVID-19 patients.

SARS-CoV-2 is the cause of the current global pandemic of COVID-19; this virus infects multiple organs, such as the lungs and gastrointestinal tract. The microbiome in these organs, including the bacteriome and virome, responds to infection and might also influence disease progression and treatment outcome. In a cohort of 13 COVID-19 patients in Beijing, China, we observed that the gut virome and bacteriome in the COVID-19 patients were notably different from those of five healthy controls. We identified a bacterial dysbiosis signature by observing reduced diversity and viral shifts in patients, and among the patients, the bacterial/viral compositions were different between patients of different severities, although these differences are not entirely distinguishable from the effect of antibiotics. Severe cases of COVID-19 exhibited a greater abundance of opportunistic pathogens but were depleted for butyrate-producing groups of bacteria compared with mild to moderate cases. We replicated our findings in a mouse COVID-19 model, confirmed virome differences and bacteriome dysbiosis due to SARS-CoV-2 infection, and observed that immune/infection-related genes were differentially expressed in gut epithelial cells during infection, possibly explaining the virome and bacteriome dynamics. Our results suggest that the components of the microbiome, including the bacteriome and virome, are affected by SARS-CoV-2 infections, while their compositional signatures could reflect or even contribute to disease severity and recovery processes.

The Treatment of Low Leg Nonischemic Ulcers With a Traditional Chinese-Pharmaceutical Medium: A Randomized Controlled Multicenter Clinical Study.

The aim of this study was to observe the curative effect and mechanism of Shengji Yuhong ointment in the healing of chronic ulcer of lower limbs. 400 patients were equally divided into treatment group and control group. The treatment group was covered with a piece of Shengji Yuhong ointment gauze, while the control group was covered with a piece of Vaseline gauze. Both groups changed dressings every other day for 4 weeks. On the 3rd, 7th, 14th, 21st, and 28th days of treatment, the reduction rate of wound area and the growth of wound granulation were observed and the levels of hydroxyproline and hemoglobin in wound granulation tissue were measured. The total effective rate was 99.00% in the treatment group and 71.00% in the control group. The treatment group was significantly better than the control group (P < .01). The ulcer area reduction rate of the treatment group was significantly higher than that of the control group (P < .01). The scores of ulcer depth, granulation color, and coverage area on the 7th, 14th, 21st, and 28th days after treatment in the treatment group were significantly lower than those before treatment (P < .05). After treatment, the levels of hydroxyproline and hemoglobin in granulation tissue of wounds in both groups were significantly higher than those before treatment (P < .01), and the levels in the treatment group were significantly higher than those in the control group (P < .01). Shengji Yuhong ointment can improve the healing rate of chronic ulcer of lower limbs.

SET domain containing 1B gene is mutated in primary hepatic neuroendocrine tumors.

Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare NETs originating from the liver. These tumors are associated with heterogeneous prognosis, and few treatment targets for PHNETs have been identified. Because the major genetic alterations in PHNET are still largely unknown, we performed whole-exome sequencing of 22 paired tissues from PHNET patients and identified 22 recurring mutations of somatic genes involved in the following activities: epigenetic modification (BPTF, MECP2 and WDR5), cell cycle (TP53, ATM, MED12, DIDO1 and ATAD5) and neural development (UBR4, MEN1, GLUL and GIGYF2). Here, we show that TP53 and the SET domain containing the 1B gene (SETD1B) are the most frequently mutated genes in this set of samples (3/22 subjects, 13.6%). A biological analysis suggests that one of the three SETD1B mutants, A1054del, promotes cell proliferation, migration and invasion compared to wild-type SETD1B. Our work unveils that SETD1B A1054del mutant is functional in PHNET and implicates genes including TP53 in the disease. Our findings thus characterize the mutational landscapes of PHNET and implicate novel gene mutations linked to PHNET pathogenesis and potential therapeutic targets.

High­level SETD1B gene expression is associated with unfavorable prognosis in hepatocellular carcinoma.

The SET domain­containing 1B (SETD1B) gene is involved in multiple biological processes, including tumor development and progression. However, the role of SETD1B in hepatocellular carcinoma (HCC) is largely unexplored. The present study, examined the expression of SETD1B in patients with HCC and assessed its clinical significance. Reverse transcriptase quantitative polymerase chain reaction and western blot analysis results revealed that the expression levels of SETD1B mRNA and protein were significantly increased in HCC tumor tissues compared with the adjacent normal tissues. In addition, an analysis of the patient clinical factors indicated that increased levels of SETD1B expression were associated with tumor size, clinical stage and liver cirrhosis. Patients with HCC with decreased levels of SETD1B expression exhibited longer survival times compared with those with increased levels of SETD1B expression. In addition, Cox's regression analysis results implied that the upregulation of SETD1B was an independent prognostic marker in patients with HCC. Taken together, the results demonstrated that SETD1B is essential in the progression of HCC and may be used as a potential prognostic marker and therapeutic target in HCC.

Decreased long intergenic noncoding RNA P7 predicts unfavorable prognosis and promotes tumor proliferation via the modulation of the STAT1-MAPK pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common neoplasm and is a leading cause of cancer-related death. Despite advances in the diagnosis and management of HCC, its prognosis remain unfavorable. Accumulating evidence has shown that long intergenic noncoding RNAs (lincRNAs) play central roles in the development of HCC. In this study, we identified a long intergenic noncoding RNA referred to as lincRNA P7 in HCC and explored its clinical significance and biological functions in HCC. The expression level of lincRNA P7 was significantly aberrantly deceased in HCC cancer tissues and cells lines. Gain- and loss-of-function experiments revealed that overexpression of lincRNA P7 significantly inhibited the proliferation of HCC-derived cancer cells, whereas lincRNA P7 knockdown promoted cell growth. Mechanistically, lincRNA P7 blocked Erk1/2 signaling and repressed activation of the STAT1 pathway. In nude mouse models, we show that overexpression of lincRNA P7 effectively repressed HCC xenograft tumor growth in vivo. Moreover, a clinical investigation demonstrated that down-regulated lincRNA P7 expression correlated with liver cirrhosis, Hepatitis B virus (HBV) infection, clinical stage of the tumor and recurrence. A Kaplan-Meier survival analysis showed that the expression of lincRNA P7 was significantly related to overall survival (P = 0.003) and recurrence-free survival (P = 0.031). Collectively, our findings suggested that the down-regulation of lincRNA P7 predicts poor clinical outcomes for HCC patients and might be a powerful candidate prognostic biomarker and target in HCC.

Downregulation of BRAF-activated non-protein coding RNA in patients with hepatitis B virus-associated hepatocellular carcinoma.

Long non-coding RNAs (lncRNAs) have been investigated as a novel class of regulators of cellular processes, including cell growth, apoptosis and carcinogenesis. lncRNA BRAF-activated non-protein coding RNA (BANCR) has recently been revealed to be involved in tumorigenesis of numerous types of cancer, including papillary thyroid carcinoma, melanoma, non-small cell lung cancer and colorectal cancer. However, the expression profiles and biological relevance of lncRNA BANCR in hepatocellular carcinoma (HCC) has not yet been reported. In the present study, the expression level of BANCR in tumor tissues and para-cancerous tissues was determined by reverse transcription-quantitative polymerase chain reaction in patients with hepatitis B virus (HBV)-associated HCC, and its association with clinicopathological characteristics of patients was analyzed. The results demonstrated that the expression level of BANCR was significantly reduced in tumor tissues in comparison with in para-cancerous tissues (P<0.001). Furthermore, the present study demonstrated that BANCR expression level was closely associated with serum α-fetoprotein levels (P<0.01) and HCC tumor number (P<0.05). To the best of our knowledge, these results revealed for the first time that BANCR downregulated in patients with HBV-associated HCC and BANCR expression level may be a potential valuable diagnosis and therapeutic biomarker in HCC.

Correlations between lncRNA-SOX2OT polymorphism and susceptibility to breast cancer in a Chinese population.

AIM: We evaluated the effect of lncRNA SOX2OT expression and its SNP in tumorigenesis and development of breast cancer (BC) in a case-control study. METHODS: A total of 1106 individuals, 505 newly diagnosed BC patients and 601 age-matched controls (±2 years) were testified. Real-time PCR was adopted for testing tissues' SOX2OT expression. Genotyping of rs9839776 were conducted by using SNaPshot assays. RESULTS: SOX2OT were overexpressed in BC tissues (p < 0.001). SOX2OT SNP rs9839776 was strongly associated with the higher expression of SOX2OT and an increased risk of BC in Chinese women (odds ratio: 1.42; 95% CI: 1.06-1.90; p = 0.018). CONCLUSION: These results confirmed that BC was conspicuously associated with higher SOX2OT expression. SOX2OT SNP rs9839776 was significantly associated with the onset of BC possibly via influencing the expression of SOX2OT.