Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers.

Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. Due to the insidious onset of HCC, at the time of first diagnosis, less than 30% of HCC patients are candidates for radical treatment. Systematic antitumor therapy is the hope for the treatment of patients with middle-advanced HCC. Despite the emergence of new systemic therapies, survival rates for advanced HCC patients remain low. The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets. Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. Research on biomarkers for HCC treatment is also advancing. Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies.

Mononucleosis-like illnesses due to co-infection with severe fever with thrombocytopenia syndrome virus and spotted fever group rickettsia:a case report.

BACKGROUND: We report a mononucleosis-like illnesses case due to co-infection with severe fever with thrombocytopenia syndrome virus (SFTSV) and spotted fever group rickettsia (SFGR), which to the best of our knowledge, has never been reported . CASE PRESENTATION: A 64-year-old male with an 11-day history of fever, sore throat, malaise, nausea, and non-pruritic rash was admitted to our emergency department. Prior to admission, he was bitten by ticks. Laboratory tests revealed a white blood cell count of 24,460 cells/µL with 25% atypical lymphocytes and 20% mononucleosis, thrombocytopenia. Test results were positive for SFTSV RNA, SFTSV-specific IgM antibody, and SFGR-specific IgM antibody. He was diagnosed with mononucleosis-like illnesses due to co-infection with SFTSV and SFGR. After administration of doxycycline, he recovered completely. CONCLUSIONS: The clinical presentation may be atypical in co-infection with SFTSV and SFGR. This finding highlighted the importance of considering SFGR infection, as well as a SFSTV and SFGR co-infection for the differential diagnosis of patients bitten by ticks in SFTSV-endemic areas.

Acute pancreatitis in patients with severe fever with thrombocytopenia syndrome virus infection.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS), a novel tick-borne disease caused by SFTS virus (SFTSV), has been reported in China, Japan, South Korea, and Vietnam since 2009. SFTSV infection can cause multiple organ damage, including acute pancreatitis (AP). We summarize the clinical features, treatment and outcome of AP associated with SFTSV. METHODS: We retrospectively review the clinical manifestations, laboratory tests, treatment, and outcome of AP associated with SFTSV infection from January 2009 to December 2018 in Liaoning Province, China. RESULTS: A total of 418 SFTS patients were reviewed. Fifteen (3.6%) of 418 met the criteria for AP associated with SFTSV infection. The first reported symptom for all SFTS-AP patients was fever. All the SFTS-AP patients presented with thrombocytopenia, and 13 (86.7%) of them presented with leukopenia on admission. Thirteen (86.7%) of 15 SFTS-AP patients were severe SFTS patients, and 9 (60.0%) patients were diagnosed with multiple organ dysfunction syndrome. One SFTS-AP patient died of multiple organ failure. Six (40%) of 15 SFTS-AP patients were not confirmed with SFTSV infection when AP was diagnosed, and the median delay between SFTSV infection and AP diagnosis was 5 days (range, 2-7 days). CONCLUSIONS: AP is not a frequent complication of SFTS, and is more frequently seen in severe SFTS patients. Most patients with SFTS-AP have mild or moderate disease, and can recover with conservative management; however, severe SFTS-AP can be fatal. In SFTS endemic areas, clinicians should be alert to the possibility of SFTS when AP patients with tick exposure, thrombocytopenia, and leukopenia have a fever before abdominal pain.

Epidemiological and genetic investigation of a cluster of cases of severe fever with thrombocytopenia syndrome bunyavirus.

BACKGROUND: To analyze and discuss the transmission route of a cluster of cases of severe fever with thrombocytopenia syndrome bunyavirus (SFTSV). METHOD: We performed an epidemiological investigation and a genetic analysis of patients with severe fever with thrombocytopenia syndrome (SFTS) caused by SFTSV, their close contacts and the surrounding population. RESULTS: We found that all patients had contact with the blood of the first patient. The comparison of gene sequences in the three isolated SFTSV strains showed that the strains were closely related. Six close contacts and nine individuals in the surrounding population were positive for SFTSV IgM antibody. CONCLUSION: We suspect that the cluster outbreak was transmitted via blood and that the natural reservoir host of SFTSV exists in the patients' environment.

Graves' hyperthyroidism accompanied with acute hepatitis B virus infection: an extrahepatic manifestation?

BACKGROUND: Although hepatitis B virus (HBV) primarily affects hepatocytes, it has also been shown to cause complications in the skin, joints, muscles, and kidneys. Thyroid dysfunction is uncommon in cases of acute HBV infection. CASE PRESENTATION: In this report, we describe a case of a 46-year-old woman with incipient acute hepatitis B virus (HBV) infection who presented clinically with Graves' hyperthyroidism. She showed typical symptoms of hyperthyroidism, and laboratory tests revealed high levels of HBV DNA and alanine transaminase (ALT). The patient was not administered with antithyroid medicine or radioiodine, but she was given antiviral therapy and symptomatic treatment with propranolol. Follow-up studies showed that as the HBV DNA levels decreased, the thyroid function recovered. CONCLUSION: Graves' disease maybe an extrahepatic manifestation of acute HBV infection. Antiviral therapy is likely to be beneficial for this condition as without severe thyrotoxicosis.

Atypical primary biliary cholangitis results in vanishing bile duct syndrome with cutaneous xanthomas: a case report.

BACKGROUND: Vanishing bile duct syndrome (VBDS) is a rare but potentially severe acquired chronic cholestatic liver disease. Bile duct deficiency is a reduction of bile ducts in the liver, which can eventually lead to cholestatic liver disease and progress to biliary cirrhosis. Primary biliary cholangitis (PBC) is one of the causes of bile duct deficiency. In addition, 75% of PBC patients may have dyslipidemia, and in case of secondary dyslipidemia, cutaneous xanthomas may occur. A 49-year-old woman was admitted with jaundice and multiple subcutaneous nodules. She received diagnosis of autoimmune liver disease 2 years before. Although she was treated with liver-protecting drugs, such as Essentiale and ursodeoxycholic acid, jaundice occurred repeatedly, and the color of her skin was becoming darker and more yellow. CONCLUSION: This case highlights that the positivity of ANA that in PBC have a well diagnostic and prognostic significance and antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/membranous' pattern scan ca diagnose primary biliary cirrhosis accurately. Since the liver biopsy of PBC alone may not be sufficient to establish the diagnosis, serum antibodies should also be examined. PBC can also lead to intrahepatic cholestasis, which can cause dyslipidemia and cutaneous xanthomas.

Novel Corneal Protein Biomarker Candidates Reveal Iron Metabolic Disturbance in High Myopia Eyes.

Myopia is a major public health concern with increasing global prevalence and is the leading cause of vision loss and complications. The potential role of the cornea, a substantial component of refractive power and the protective fortress of the eye, has been underestimated in the development of myopia. Our study acquired corneal stroma tissues from myopic patients undergoing femtosecond laser-assisted small incision lenticule extraction (SMILE) surgery and investigated the differential expression of circulating proteins between subjects with low and high myopia by means of high-throughput proteomic approaches-the quantitative tandem mass tag (TMT) labeling method and parallel reaction monitoring (PRM) validation. Across all corneal stroma tissue samples, a total of 2,455 proteins were identified qualitatively and quantitatively, 103 of which were differentially expressed between those with low and high myopia. The differentially abundant proteins (DAPs) between the groups of stroma samples mostly demonstrated catalytic activity and molecular function regulator and transporter activity and participated in metabolic processes, biological regulation, response to stimulus, and so forth. Pathway enrichment showed that mineral absorption, ferroptosis, and HIF-1 signaling pathways were activated in the human myopic cornea. Furthermore, TMT analysis and PRM validation revealed that the expression of ferritin light chain (FTL, P02792) and ferritin heavy chain (FTH1, P02794) was negatively associated with myopia development, while the expression of serotransferrin (TF, P02787) was positively related to myopia status. Overall, our results indicated that subjects with low and high myopia could have different proteomic profiles or signatures in the cornea. These findings revealed disturbances in iron metabolism and corneal oxidative stress in the more myopic eyes. Iron metabolic proteins could serve as an essential modulator in the pathogenesis of myopia.

Factors associated with death in hospitalized pneumonia patients with 2009 H1N1 influenza in Shenyang, China.

BACKGROUND: During the spring of 2009, a pandemic influenza A (H1N1) virus emerged and spread globally. We describe the clinical characteristics and factors associated with the death of patients who were hospitalized with 2009 H1N1 influenza pneumonia in Shenyang, China, from November to December 2009. METHODS: We carried out a retrospective chart review of 68 patients who were hospitalized with pneumonia and confirmed to have 2009 H1N1 virus infection by a real time RT-PCR assay of respiratory specimens. RESULTS: Of the 68 patients we studied, 30 (44%) were admitted to an intensive care unit and 10 (14.7%) died. The median age of patients was 41 years (range, 18-66), and only one patient was over 65 years of age. The male to female ratio was 2.78:1 (50:18). Of the 68 patients, 23 (34%) had at least one underlying medical condition, 9 (13%) had a cigarette index > or =400 and 22 (32%) were obese. All patients underwent chest radiography on admission and the findings were consistent with pneumonia in all cases. All patients were treated with oseltamivir and treatment was initiated at a median time of seven days after the onset of illness. The laboratory test results indicated lymphopenia, hypoproteinemia and elevated lactic dehydrogenase and C reactive protein levels. Of the 68 patients, 33 (52%) showed a reduction in CD4 T cell counts. Of the 58 patients who survived, 31 (53%) had lymphopenia and 27 recovered from this condition after five days. Of the 10 patients who died, nine (90%) had lymphopenia and only two patients recovered from this condition after five days. Obesity and recovery from lymphopenia after five days were factors associated with death, as determined by multivariate logistic-regression analysis (obesity, odds ratio = 23.06; lymphocytopenia reversion, odds ration = 28.69). CONCLUSIONS: During the evaluation period in Shenyang, China, 2009 H1N1 influenza caused severe illness requiring hospitalization in 68 patients, 10 (14.7%) of which died. Many of these patients were considered healthy adults and few were elderly (65 years or older). Obesity and lymphopenia, which was not restored after five days of treatment, were factors associated with poor outcomes of 2009 H1N1 influenza infection.

Person-to-person asymptomatic infection of severe fever with thrombocytopenia syndrome virus through blood contact.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease recently discovered in northeastern and central China that is caused by a novel bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV). Humans are primarily infected through tick bites. Four previous reports have discussed SFTS infection from person to person, all cases of which were symptomatic. In this report, we analysed the epidemiological and clinical data for a cluster of cases, including one case of secondary-asymptomatic infection, and review the literature regarding SFTSV transmission from person to person. We conclude that SFTSV caused the asymptomatic infections via person-to-person contact with infected blood.

Association of polymorphisms in the interleukin-4 gene with response to hepatitis B vaccine and susceptibility to hepatitis B virus infection: a meta-analysis.

OBJECTIVE: The aim of this meta-analysis is to evaluate the associations between functional polymorphisms in the interleukin-4 (IL4) gene and individuals' responses to hepatitis B vaccine and their susceptibility to hepatitis B virus (HBV) infection. METHODS: A literature search on articles published before December 1st, 2012 was conducted in PubMed, Embase, Web of Science and China BioMedicine (CBM) databases. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using the STATA 12.0 software. RESULTS: Eight studies were eligible for inclusion in this meta-analysis, including five cross-sectional studies on individual's response to hepatitis B vaccine and three case-control studies on HBV infection risk. The meta-analysis results showed that the T allele of rs2243250, the T allele of rs2070874, and the C allele of rs2227284 in IL4 gene were associated with high responses to hepatitis B vaccine. Further subgroup analysis by ethnicity showed that there was a significant association between IL4 genetic polymorphisms and an individual's responses to hepatitis B vaccine among Asian populations, but similar association was not found among Caucasian populations. However, there was no evidence indicating a correlation between IL4 genetic polymorphism and susceptibility to HBV infection. CONCLUSION: Our current meta-analysis suggests that rs2243250, rs2070874 and rs2227284 polymorphisms in IL4 gene may play an important role in determining the response to hepatitis B vaccine, especially among Asian populations. However, further studies are still needed to evaluate the associations between IL4 genetic polymorphisms and HBV infection risk.

Curcumin protects human keratinocytes against inorganic arsenite-induced acute cytotoxicity through an NRF2-dependent mechanism.

Human exposure to inorganic arsenic leads to various dermal disorders, including hyperkeratosis and skin cancer. Curcumin is demonstrated to induce remarkable antioxidant activity in a variety of cells and tissues. The present study aimed at identifying curcumin as a potent activator of nuclear factor erythroid 2-related factor 2 (NRF2) and demonstrating its protective effect against inorganic arsenite- (iAs(3+)-) induced cytotoxicity in human keratinocytes. We found that curcumin led to nuclear accumulation of NRF2 protein and increased the expression of antioxidant response element- (ARE-) regulated genes in HaCaT keratinocytes in concentration- and time-dependent manners. High concentration of curcumin (20 µM) also increased protein expression of long isoforms of NRF1. Treatment with low concentrations of curcumin (2.5 or 5 µM) effectively increased the viability and survival of HaCaT cells against iAs(3+)-induced cytotoxicity as assessed by the MTT assay and flow cytometry and also attenuated iAs(3+)-induced expression of cleaved caspase-3 and cleaved PARP protein. Selective knockdown of NRF2 or KEAP1 by lentiviral shRNAs significantly diminished the cytoprotection conferred by curcumin, suggesting that the protection against iAs(3+)-induced cytotoxicity is dependent on the activation of NRF2. Our results provided a proof of the concept of using curcumin to activate the NRF2 pathway to alleviate arsenic-induced dermal damage.

Clinical features and factors associated with severity and fatality among patients with severe fever with thrombocytopenia syndrome Bunyavirus infection in Northeast China.

BACKGROUND: In 2009, severe fever with thrombocytopenia syndrome virus (SFTSV) was identified as a novel member of the genus phlebovirus in the Bunyaviridae family in China. The detailed clinical features of cases with SFTSV infection have not been well described, and the risk factors for severity among patients and fatality among severe patients remain to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Clinical and laboratory features of 115 hospitalized patients with SFTSV infection during the period from June 2010 to December 2011 in Northeast China were retrospectively reviewed. We assessed the risk factors associated with severity in confirmed cases and fatality in severe cases by multivariate analysis. One hundred and three (89.6%) of 115 patients presented with multiple organ dysfunction, and 22 (19.1%) of 115 proceeded to the stage of life threatening multiple organ failure. Of the 115 patients, 14 fatalities (12.2%) were reported. Multivariate analysis demonstrated that the independent predictors of risk for severity were: albumin ≤ 30 g/l (OR, 8.09; 95% CI, 2.58-25.32), APTT ≥ 66 seconds (OR, 14.28; 95% CI, 3.28-62.24), sodium ≤ 130 mmol/l (OR, 5.44; 95% CI, 1.38-21.40), and presence of neurological manifestations (OR, 7.70; 95% CI, 1.91-31.12). Among patients with severe disease, presence of acute lung injury/acute respiratory distress syndrome (HR, 4.59; 95% CI, 1.48-14.19) and disseminated intravascular coagulation (HR, 4.24; 95% CI, 1.38-13.03) were independently associated with fatality. CONCLUSIONS/SIGNIFICANCE: SFTSV infection may present with more severe symptoms and laboratory abnormalities than hitherto reported. Due to infection with a novel bunyavirus, the patients may sufferer multiple organ dysfunction and die of multiple organ failure. In the clinical assessment of any case of SFTS, independent factors relating to prognosis need to be taken into account by clinicians.

Novel ATP8B1 mutation in an adult male with progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis type 1 is a rare disease that is characterized by low serum γ-glutamyltransferase levels due to mutation in ATP8B1. We present a 23-year-old male who experienced persistent marked pruritus for eighteen years and recurrent jaundice for thirteen years, in addition to cholestasis that eventually became fatal. Genetic sequencing studies of the entire coding (exon) sequences of ATP8B1 and ABCB11 uncovered a novel heterozygous missense 3035G>T mutation (S1012I) and a synonymous 696T>C mutation in ATP8B1. The patient's progression was associated with not only impaired familial intrahepatic cholestasis 1 (FIC1) function but also impaired bile salt export pump expression due to the impaired FIC1 function. Our findings show that patients with intermittent cholestasis can develop progressive liver disease even after several decades and require regular follow up.

Cytokine and chemokine levels in patients with severe fever with thrombocytopenia syndrome virus.

BACKGROUND: Severe fever with thrombocytopenia syndrome virus (SFTSV), which can cause hemorrhagic fever-like illness, is a newly discovered bunyavirus in China. The pathogenesis of SFTSV infection is poorly understood. However, it has been suggested that immune mechanisms, including cytokines and chemokines, play an important role in disease pathogenesis. In the present study, we investigated host cytokine and chemokine profiles in serum samples of patients with SFTSV infection from Northeast China and explored a possible correlation between cytokine levels and disease severity. METHODS AND PRINCIPAL FINDINGS: Acute phase serum samples from 40 patients, diagnosed with SFTSV infection were included. Patients were divided into two groups--severe or non-severe--based on disease severity. Levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß, interleukin-6, interferon (IFN)-γ, IFN- γ-induced protein (IP)-10 and RANTES were measured in the serum samples with commercial ELISAs. Statistical analysis showed that increases in TNF-α, IP-10 and IFN-γ were associated with disease severity. CONCLUSIONS: We suggest that a cytokine-mediated inflammatory response, characterized by cytokine and chemokine production imbalance, might be in part responsible for the disease progression of patients with SFTSV infection.