Evaluation of thyroid congestion in patients with heart failure using shear wave elastography: An observational study.

Shear wave elastography (SWE) is a noninvasive method for measuring organ stiffness. Liver stiffness measured using SWE reflects hepatic congestion in patients with heart failure (HF). However, little is known about the use of SWE to assess other organ congestions. This study aimed to evaluate the utility of SWE for assessing not only the liver but also thyroid congestion in patients with HF. This prospective study included 21 patients with HF who have normal thyroid lobes (age: 77.0 ±â€…11.0, men: 14). Thyroid and liver stiffness were measured by SWE using the ARIETTA 850 ultrasonography system (Fujifilm Ltd., Tokyo, Japan). SWE of the thyroid was performed on B-mode ultrasonography; a target region was identified within a region of interest. SWE was performed in each lobe of the thyroid gland. Five measurements were taken at the same location and the averages were recorded for comparison. We investigated the relationship between SWE for evaluating thyroid stiffness and the clinical characteristics of patients with HF. SWE of the thyroid was significantly correlated with SWE of the liver (R = 0.768, P < .001), thyroid stimulation hormone (R = 0.570, P = .011), free thyroxine (R = 0.493, P = .032), estimated right atrial pressure (RAP; R = 0.468, P = .033), and composite congestion score (R = 0.441, P = .045). SWE may be useful for evaluating thyroid stiffness and assessing the degree of thyroid congestion. Thyroid congestion may reflect the elevation of RAP and cause thyroid dysfunction through organ congestion.

Prognostic role of apolipoproteins on long-term major adverse cardiac events after percutaneous coronary intervention.

BACKGROUND/PURPOSE: Apolipoprotein (apo) levels are associated with coronary risk. However, the relationship between apo levels after percutaneous coronary intervention (PCI) and long-term major adverse cardiac events (MACEs) remains unclear. We aimed to investigate the association between lipid levels, including apo, at follow-up, and long-term MACEs in patients undergoing PCI. METHODS/MATERIALS: In total, 241 patients who underwent PCI between January 2004 and August 2008 were included in this study. MACEs were defined as cardiac death, acute coronary syndrome, or coronary revascularization of new lesions. The primary endpoint was MACE, and the secondary endpoint was a composite of cardiac death and acute coronary syndrome. RESULTS: During a mean follow-up period of 2079 days, the following cardiovascular events occurred in 78 patients: cardiovascular death (n = 1), non-fatal acute myocardial infarctions (n = 10), and revascularizations of new lesions (n = 67). Multivariate cox's proportional hazards analysis showed that the apo B level was an independent risk factor for MACEs (hazard ratio 1.11, 95 % confidence interval 1.03-1.20; P = 0.009). In the Kaplan-Meier estimation for primary endpoints, significant differences were observed in the apo B level and apo B/apo A1 ratio (P = 0.04 and P = 0.004, respectively). However, there was no difference in the LDL-C level and LDL-C/HDL-C ratio. At the secondary endpoint, only the apo B/apo A1 ratio was a prognostic factor (P = 0.007). CONCLUSIONS: In the long-term cardiovascular events of patients undergoing PCI, the apo B level and apo B/apo A1 ratio were more valuable prognostic factors for cardiovascular events compared to the LDL-C level and LDL-C/HDL-C ratio.

Identification of Plasma Proteins as Biomarkers for Mild Cognitive Impairment and Alzheimer's Disease Using Liquid Chromatography-Tandem Mass Spectrometry.

Blood proteins can be used for biomarkers to monitor the progression of cognitive decline, even in the early stages of disease. In this study, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based blood test to identify plasma proteins that can be used to detect mild cognitive impairment (MCI) and Alzheimer's disease (AD). Using this system, we quantified plasma proteins using isotope-labeled synthetic peptides. A total of 192 patients, including 63 with AD, 71 with MCI, and 58 non-demented controls (NDCs), were analyzed. Multinomial regression and receiver operating characteristic (ROC) analyses were performed to identify specific combinations of plasma protein panels that could differentiate among NDCs, those with MCI, and those with AD. We identified eight plasma protein biomarker candidates that can be used to distinguish between MCI and AD. These biomarkers were associated with coagulation pathways, innate immunity, lipid metabolism, and nutrition. The clinical potential to differentiate cognitive impairment from NDC was assessed using area under the curve values from ROC analysis, which yielded values of 0.83 for males and 0.71 for females. This LC-MS-based plasma protein panel allows the pathophysiology of AD to be followed through detection of cognitive decline and disease progression markers.

Graves' disease after exposure to the SARS-CoV-2 vaccine: a case report and review of the literature.

BACKGROUND: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is characterized by immune system dysregulation after exposure to adjuvants, such as aluminum. Although cases of autoimmune thyroid diseases caused by ASIA have been reported, Graves' disease is one of the rarer diseases. There are some reports that vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause ASIA. Here, we describe a case of Graves' disease following SARS-CoV-2 vaccination and a review of the literature. CASE PRESENTATION: A 41-year-old woman was admitted to our hospital because of palpitations and fatigue. Two weeks after receiving the second SARS-CoV-2 vaccine (BNT162b2, Coronavirus Modified Uridine messenger RNA (mRNA) Vaccine, Pfizer), she developed fatigue and gradually worsened. On admission, she exhibited thyrotoxicosis (thyroid-stimulating hormone (TSH) < 0.01 mIU/L (0.08-0.54), free triiodothyronine (FT3) 33.2 pmol/L (3.8-6.3), and free thyroxine (FT4) 72.1 pmol/L (11.6-19.3)) and palpitations associated with atrial fibrillation. TSH receptor antibody (TRAb) was positive (TRAb 5.0 IU/L (< 2.0)), and 99mTc scintigraphy showed diffuse uptake in the thyroid gland, suggesting that the thyrotoxicosis in this case was caused by Graves' disease. Thiamazole was prescribed to correct her condition, and soon after this treatment was initiated, her symptoms and thyroid hormone levels were significantly reduced. CONCLUSIONS: This case report reinforces the potential correlation between ASIA affecting the thyroid and SARS-CoV-2 mRNA vaccines. The clinical course suggests that it is essential to consider the possibility of developing ASIA, such as Graves' disease, after exposure to the SARS-CoV-2 vaccine.

Gallbladder Wall Thickness-Based Assessment of Organ Congestion in Patients With Heart Failure.

Background: Diffuse gallbladder (GB) wall thickening is caused by elevated systemic venous pressure, such as heart failure (HF). This study investigated the relationship between GB wall thickness (WT) and HF, and the prognostic impact of GBWT. Methods and Results: This prospective study included 116 patients with HF and 11 healthy controls. Among the 116 patients, 30 with GBWT measurements in the postprandial state or a history and/or signs of GB disease were excluded. The remaining 86 patients had significantly higher GBWT than the controls (median [interquartile range {IQR}] 2.0 [1.7-2.4] vs. 1.3 [1.1-1.6] mm, respectively; P<0.001). GBWT was significantly correlated with B-type natriuretic peptide (r=0.386, P<0.001), left atrial volume index (r=0.452, P<0.001), and tricuspid annular plane systolic excursion (r=-0.311, P=0.006). GBWT also exhibited a stepwise increasing relationship with increasing HF stage (Stage B, 22 patients, median [IQR] 1.8 [1.7-2.1] mm; Stage C, 60 patients, 2.0 [1.8-2.5] mm; and Stage D, 4 patients: 4.0 [3.5-4.5] mm). In Stage C or D HF patients, 11 hospitalizations for HF were observed over a median follow-up of 303 days (IQR 125-394 days). Furthermore, the rate of hospitalization events for HF was significantly higher in the high (≥3 mm) than low GBWT group (P=0.007). Conclusions: GBWT can be used to assess organ congestion in patients with HF.

Waste Clearance in the Brain and Neuroinflammation: A Novel Perspective on Biomarker and Drug Target Discovery in Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial disease with a heterogeneous etiology. The pathology of Alzheimer's disease is characterized by amyloid-beta and hyperphosphorylated tau, which are necessary for disease progression. Many clinical trials on disease-modifying drugs for AD have failed to indicate their clinical benefits. Recent advances in fundamental research have indicated that neuroinflammation plays an important pathological role in AD. Damage- and pathogen-associated molecular patterns in the brain induce neuroinflammation and inflammasome activation, causing caspase-1-dependent glial and neuronal cell death. These waste products in the brain are eliminated by the glymphatic system via perivascular spaces, the blood-brain barrier, and the blood-cerebrospinal fluid barrier. Age-related vascular dysfunction is associated with an impairment of clearance and barrier functions, leading to neuroinflammation. The proteins involved in waste clearance in the brain and peripheral circulation may be potential biomarkers and drug targets in the early stages of cognitive impairment. This short review focuses on waste clearance dysfunction in AD pathobiology and discusses the improvement of waste clearance as an early intervention in prodromal AD and preclinical stages of dementia.

Structural brain network correlations with amyloid burden in elderly individuals at risk of Alzheimer's disease.

Alzheimer's disease (AD) has a long preclinical phase during which beta-amyloid accumulates in the brain without cognitive impairment. However, the pattern of brain network alterations in this early stage of the disease remains to be clarified. In this study we examined the relationships between regional brain network indices and beta-amyloid deposits. Twenty-four elderly subjects with the APOE4 allele underwent both a 1.5-Tesla magnetic resonance imaging (MRI) scan and a positron emission tomography (PET) scan using [18F]Florbetapir. We computed network metrics such as the degree, betweenness centrality, and clustering coefficient, and examined the relationships between the beta-amyloid accumulation and these regional brain network connectivity metrics. We found a significant positive correlation between the global standardized uptake value ratio (SUVR) of [18F]Florbetapir and the betweenness centrality in the left parietal region. However, there were no significant correlations between the SUVR score and other network indices or the regional gray matter volume. Our data suggest a relationship between the beta-amyloid accumulation and the regional brain network connectivity in subjects at risk of AD. The brain connectome may provide an adjunct biomarker for the early detection of AD.

A Novel Cognitive Function Scale Using Functional Near-Infrared Spectroscopy for Evaluating Cognitive Dysfunction.

BACKGROUND: Maintaining cognitive function is integral to a healthy social life in the aged. Although neuropsychological tests and brain imaging methods can assess cognitive dysfunction, these techniques are subjective, psychologically burdensome, and cannot be conducted easily. OBJECTIVE: We sought to develop an objective, low-burden novel cognitive function scale based on functional near-infrared spectroscopy (fNIRS) of hemodynamic changes in the cerebral cortex during daily task performance. METHODS: A total of 63 participants (aged 60-80 years) identified as non-dementia controls (NDC) or with mild cognitive impairment (MCI) were recruited and randomly assigned to training and test data sets. Explanatory variables were hemodynamic responses during low-burden sensory and simple tasks without higher-order brain functioning. RESULTS: A logistic regression analysis of the fNIRS index in NDCs and MCI patients revealed area under the curve, sensitivity, specificity, and holdout results of 0.98, 94%, 88%, and 62% respectively. Correlation between fNIRS index and MCI odds showed positive linearity (R2 = 0.96). CONCLUSION: Positive correlation between the fNIRS index and MCI odds indicated effectiveness of this fNIRS measurement. Although additional experiments are necessary, the fNIRS index representing degree of cognitive decline can be an onsite monitoring tool to assess cognitive status.

Kinetochore stretching-mediated rapid silencing of the spindle-assembly checkpoint required for failsafe chromosome segregation.

The spindle-assembly checkpoint facilitates mitotic fidelity by delaying anaphase onset in response to microtubule vacancy at kinetochores. Following microtubule attachment, kinetochores receive microtubule-derived force, which causes kinetochores to undergo repetitive cycles of deformation; this phenomenon is referred to as kinetochore stretching. The nature of the forces and the relevance relating this deformation are not well understood. Here, we show that kinetochore stretching occurs within a framework of single end-on attached kinetochores, irrespective of microtubule poleward pulling force. An experimental method to conditionally interfere with the stretching allowed us to determine that kinetochore stretching comprises an essential process of checkpoint silencing by promoting PP1 phosphatase recruitment after the establishment of end-on attachments and removal of the majority of checkpoint-activating kinase Mps1 from kinetochores. Remarkably, we found that a lower frequency of kinetochore stretching largely correlates with a prolonged metaphase in cancer cell lines with chromosomal instability. Perturbation of kinetochore stretching and checkpoint silencing in chromosomally stable cells produced anaphase bridges, which can be alleviated by reducing chromosome-loaded cohesin. These observations indicate that kinetochore stretching-mediated checkpoint silencing provides an unanticipated etiology underlying chromosomal instability and underscores the importance of a rapid metaphase-to-anaphase transition in sustaining mitotic fidelity.

Prolonged mitosis causes separase deregulation and chromosome nondisjunction.

During mitotic chromosome segregation, the protease separase severs cohesin between sister chromatids. A probe for separase activity has shown that separase undergoes abrupt activation shortly before anaphase onset, after being suppressed throughout metaphase; however, the relevance of this control remains unclear. Here, we report that separase activates precociously, with respect to anaphase onset, during prolonged metaphase in multiple types of cancer cell lines. The artificial extension of metaphase in chromosomally stable diploid cells leads to precocious activation and, subsequently, to chromosomal bridges in anaphase, which seems to be attributable to incomplete cohesin removal. Conversely, shortening back of a prolonged metaphase restores the activation of separase and ameliorates anaphase bridge formation. These observations suggest that retarded metaphase progression affects the separase activation profile and its enzymatic proficiency. Our findings provide an unanticipated etiology for chromosomal instability in cancers and underscore the relevance of swift mitotic transitions for fail-safe chromosome segregation.

Drosophila melanogaster as a model for understanding polyADP-ribosylation.

PolyADP-ribosylation is a post-translational modification which is involved in various physiological processes including maintenance of genome stability through DNA repair, regulation of transcription, and development. This process is also involved in pathological events such as cell death. Here, we review the effect of polyADP-ribosylation in signal transduction pathways in Drosophila melanogaster system. It is hoped that such an insight paves the way to develop therapeutics for human diseases.

Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology.

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as-yet-unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2 S)/polysulfide-producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst-deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst-transgenic (Tg) mice showed deteriorated PPI, suggesting that "sulfide stress" may be linked to PPI impairment. Analysis of human samples demonstrated that the H2 S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst-Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H2 S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H2 S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H2 S/polysulfides production.

Cdk1-mediated DIAPH1 phosphorylation maintains metaphase cortical tension and inactivates the spindle assembly checkpoint at anaphase.

Animal cells undergo rapid rounding during mitosis, ensuring proper chromosome segregation, during which an outward rounding force abruptly increases upon prometaphase entry and is maintained at a constant level during metaphase. Initial cortical tension is generated by the actomyosin system to which both myosin motors and actin network architecture contribute. However, how cortical tension is maintained and its physiological significance remain unknown. We demonstrate here that Cdk1-mediated phosphorylation of DIAPH1 stably maintains cortical tension after rounding and inactivates the spindle assembly checkpoint (SAC). Cdk1 phosphorylates DIAPH1, preventing profilin1 binding to maintain cortical tension. Mutation of DIAPH1 phosphorylation sites promotes cortical F-actin accumulation, increases cortical tension, and delays anaphase onset due to SAC activation. Measurement of the intra-kinetochore length suggests that Cdk1-mediated cortex relaxation is indispensable for kinetochore stretching. We thus uncovered a previously unknown mechanism by which Cdk1 coordinates cortical tension maintenance and SAC inactivation at anaphase onset.

Systemic transduction of p16INK4a antitumor peptide inhibits lung metastasis of the MBT-2 bladder tumor cell line in mice.

p16INK4a (p16) is a key molecule in bladder tumor (BT) development. We previously reported that a p16 antitumor peptide inhibited the growth of subcutaneous BT grafts in mice through restoration of p16 function using a Wr-T peptide transporter system. In the present study, the efficacy of mouse p16 peptide administration in a mouse lung metastasis model for BT and also the toxicity of peptides by cardiac peptide injection were evaluated. Mouse lung metastases were developed by tail vein injection of a p16-deficient MBT-2 cell line. Six-week-old C3H/He female mice were divided into three groups: A control group (n=12) receiving no treatment; a group treated once on the 3rd experimental day (n=12); and a group treated three times on the 3rd, 5th and 7th experimental days (n=10) with an injection of a mixture of 80 nmol mouse p16 peptide and 50 nmol Wr-T into the tail vein. At the 14th experimental day, the lung metastases were histologically evaluated. Lung metastases were observed in 100% (12/12), 41.7% (5/12) and 30% (3/10) of the aforementioned three groups, respectively. The number and area of metastatic lung tumors were significantly different between control and treatment groups (control vs. triple treatment group for the number and area, P=0.0029 and P=0.0296, respectively). Immunohistochemistry demonstrated that phosphorylated retinoblastoma (Rb) protein was decreased in lung tumors of the treatment groups, compared with the control group. The toxicity of p16 peptide transduction was evaluated by using low-dose treatment (three dosages) and high-dose treatment (two dosages) on three male and three female C3H/He mice in early and late experimental phases. In low and high dose groups, no notable change was determined in body weight or blood analyses in early or late phases following mouse p16 peptide administration. In addition, no notable change was observed histologically in bone marrow of treatment groups. To conclude, systemic p16 peptide administration decreased lung tumor development in a mouse metastatic BT model without severe adverse events, as assessed by blood analyses and histological evaluation.

Serum levels of proteins involved in amyloid-ß clearance are related to cognitive decline and neuroimaging changes in mild cognitive impairment.

INTRODUCTION: Amyloid-ß (Aß) clearance is important for damage prevention in Alzheimer's disease. We investigated the utility of Aß clearance proteins as biomarkers for mild cognitive impairment (MCI). METHODS: Serum apolipoprotein (apo) A-I, compliment protein C3 (C3), transthyretin, and cholesterol levels were measured in 273 subjects, and we analyzed the relationship between these levels and brain atrophy and cerebral blood flow in 63 clinically diagnosed mild cognitive impairment, Alzheimer's disease, and nondemented disease control subjects. RESULTS: ApoA-I and transthyretin levels and the active form of C3:native form of C3 ratio achieved an area under the curve of 0.89 (sensitivity: 83%, specificity: 90%) for detecting late mild cognitive impairment. Atrophy was associated with decreased apoA-I and high-density lipoprotein levels. Subjects with reduced cerebral blood flow had lower levels of active form of C3, apoA-I, high-density lipoprotein, and total cholesterol. Low native form of C3 and high active form of C3 levels were found in the hippocampi of patients with Alzheimer's disease. DISCUSSION: Aß clearance proteins in the serum are potential biomarkers for mild cognitive impairment evaluation.

HP1-Assisted Aurora B Kinase Activity Prevents Chromosome Segregation Errors.

Incorrect attachment of kinetochore microtubules is the leading cause of chromosome missegregation in cancers. The highly conserved chromosomal passenger complex (CPC), containing mitotic kinase Aurora B as a catalytic subunit, ensures faithful chromosome segregation through destabilizing incorrect microtubule attachments and promoting biorientation of chromosomes on the mitotic spindle. It is unknown whether CPC dysfunction affects chromosome segregation fidelity in cancers and, if so, how. Here, we show that heterochromatin protein 1 (HP1) is an essential CPC component required for full Aurora B activity. HP1 binding to the CPC becomes particularly important when Aurora B phosphorylates kinetochore targets to eliminate erroneous microtubule attachments. Remarkably, a reduced proportion of HP1 bound to CPC is widespread in cancers, which causes an impairment in Aurora B activity. These results indicate that HP1 is an essential modulator for CPC function and identify a molecular basis for chromosome segregation errors in cancer cells.

Amyloid-ß sequester proteins as blood-based biomarkers of cognitive decline.

INTRODUCTION: There are no blood-based biomarkers for cognitive decline in aging, or mild cognitive impairment (MCI) and Alzheimer's disease (AD). Cumulative evidence suggests that apolipoproteins, complement system, and transthyretin are involved in AD pathogenesis by sequestration of amyloid ß. However, there is no clinical study to assess the utility of "sequester proteins" in risk assessment and/or diagnosis of MCI and AD. METHODS: Serum levels of sequester proteins and their clinical potential in cognitive decline assessment were analyzed by longitudinal and cross-sectional studies using independent cohorts and were confirmed by a prospective study. RESULTS: A combination of apolipoprotein A1, complement C3, and transthyretin achieved an area under the curve of 0.89 (sensitivity 91% and specificity 80%) in MCI versus healthy controls and also discriminated individuals with mild cognitive decline from healthy controls. DISCUSSION: A set of sequester proteins could be blood-based biomarkers for assessment of early stages of cognitive decline.

Genetic and environmental determinants of risk for cholangiocarcinoma in Thailand.

Cholangiocarcinoma (CCA) is a difficult cancer to diagnose in the early stage and to treat by curative resection. The incidence of CCA in the northeast of Thailand is the highest in the world. To make progress in detecting a high risk group and in the prevention and detection of CCA, we have been analyzing the risk factors for CCA. Although liver fluke infection is known to be a risk factor, there are patients who are not infected with the liver fluke and not all people infected with the liver fluke will suffer from the disease. Therefore, it is of the utmost importance to analyze the risk factors and the mechanism to prevent the disease and also to detect the disease in its early stage to save patients' lives. Through collaboration among Thai and Japanese researchers, we analyzed the genetic and environmental determinants of risks for CCA. Also, we have been trying to develop methods to detect the disease in a non-invasive way. Without repeating findings reported in various reviews on CCA, we will first discuss the environmental and genetic determinants of the risks for CCA. Second, we will discuss the properties of CCA, including the etiological agents and the mechanism of cholangiocarcinogenesis, and finally, we will discuss future approaches to prevent and cure CCA from the standpoint of evidence-based medicine. We will discuss these points by including the data from our laboratories. We would like to emphasize the importance of the genetic data, especially whole genome approaches, to understand the properties of CCA, to find a high risk population for CCA and to develop effective preventative methods to stop the carcinogenic steps toward CCA in the near future. In addition, it is of the upmost importance to develop a non-invasive, specific and sensitive method to detect CCA in its early stage for the application of modern medical approaches to help patients with CCA.

Five-year cohort study: emphysematous progression of indium-exposed workers.

BACKGROUND: Dose-dependent adverse lung effects due to indium exposure have been reported in a cross-sectional study. This is a 5-year longitudinal cohort study of indium-exposed and unexposed workers, assessing indium exposure levels and its clinical lung effects. METHODS: From 2008 to 2011, a 5-year follow-up study was conducted on 40 unexposed and 240 workers formerly or currently exposed to indium at 11 factories. Indium exposure was assessed by serum indium (In-S) (µg/L). Lung effects were assessed by subjective symptoms, serum biomarkers, spirometry, and chest high-resolution CT scan. Effect biomarkers used were Krebs von den Lungen and surfactant protein D. RESULTS: Mean values of In-S, Krebs von den Lungen, and surfactant protein D among the workers exposed to indium at baseline declined during the 5-year follow-up by 29.8%, 27.2%, and 27.5%, respectively. Of the exposed subjects with In-S levels > 20 µg/L, 26.3% experienced emphysematous progression on high-resolution CT scan. Ninety percent (18 of 20) of workers with emphysematous progression during follow-up were current smokers at baseline, and a trend of increasing incidence of emphysematous progression at higher In-S levels was observed among the smokers (P = .005). Emphysematous changes among subjects with In-S levels > 20 µg/L were likely to progress, after adjusting for age, mean duration since initial indium exposure, and smoking history (OR = 10.49, 95% CI = 1.54-71.36). CONCLUSIONS: Long-term adverse effects on emphysematous changes were observed. The results suggest workers exposed to indium with In-S levels > 20 µg/L should be immediately removed from exposure.

Collagen triple helix repeat containing 1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation and motility.

Although several therapeutic options are available for hepatocellular carcinoma (HCC), the outcome is still very poor. One reason is the complexity of signal transduction in the pathogenesis of HCC. The aim of this study was to identify new HCC-related genes and to investigate the functions of these genes in the pathogenesis and progression of HCC. Whole genomes of 15 surgically resected HCC specimens were examined for copy number alterations with comparative genomic hybridization. Gene expression was compared between HCC and normal liver tissues. The roles of the new genes in the progression of HCC were studied using cultured cell lines. Copy number gain in chromosome 8q was detected in 53% of HCC tissues examined. The gene that coded for collagen triple helix repeat containing 1 (CTHRC1), located at chromosome 8q22.3, was overexpressed in HCC compared with normal or liver cirrhosis tissues and identified as a new HCC-related gene. CTHRC1 deletion with short hairpin RNA significantly reduced proliferation, migration and invasion of HepG2 and Huh7 cells. In addition, mRNA of integrins ß-2 and ß-3 was downregulated, with deletion of CTHRC1 in these cells. Immunohistochemical staining on resected HCC tissues showing positive staining areas for CTHRC1 was significantly greater in poorly-differentiated HCC compared with well­differentiated HCC. Moreover, some cases showed strong staining for CTHRC1 in invasive areas of HCC. CTHRC1 has the potential to be a new biomarker for the aggressive HCC, and to be a new therapeutic target in treating HCC.