Identification of new subtypes and potential genetic signatures in triple-negative breast cancer using weighted gene co-expression network analysis.

OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Here, we used gene expression profiling to define new subtypes of TNBC, which may improve prevention and treatment through personalized medicine. MATERIALS AND METHODS: Gene expression profiles from the public datasets GSE76250, GSE61724, GSE61723, and GES76275 were subjected to co-expression analysis to identify differentially expressed genes (DEGs) between TNBC and non-TNBC tissues. Consistency clustering was used to define TNBC subtypes, whose correlation with gene modules was analyzed. Enrichment analysis was used to identify module genes' biological functions and pathways. Single-sample gene set enrichment analysis was used to assess immune cell infiltration in the different TNBC subtypes, and the ChAMP package was used to examine methylation sites in TNBC. RESULTS: A total of 4,958 DEGs in TNBC were identified, which showed the same expression differences across all datasets as in the dataset GSE76250 and clustered into 9 co-expression modules. TNBC samples clustered into two subtypes based on nine hub genes from the modules. Class I showed the most significant correlation with module 1, whose genes were related mainly to interleukin-1 response, while class II showed the most significant correlation with module 6, whose genes were related mainly to the transforming growth factor-ß pathway. Class I was significantly enriched in cell cycle and DNA replication, and tumors of this subtype showed lower immune cell infiltration than class II tumors. Tumor infiltration by Th2 cells correlated positively with the expression of MCM10 and negatively with the expression of PREX2. A greater methylation of CIDEC, DLC1, EDNRB, EGR2 and SRPK1 correlated with better prognosis. CONCLUSIONS: Class I TNBC, for which a useful biomarker is MCM10, may be associated with a worse prognosis than class II TNBC, for which PREX2 may serve as a biomarker.

Transplantation of bone marrow mesenchymal stem cells alleviates spinal cord injury via inhibiting Notch signaling.

OBJECTIVE: To analyze the mechanism of action by which the bone marrow mesenchymal stem cells (BMMSCs) repair the spinal cord injury (SCI) in rats via the Notch signaling pathway. MATERIALS AND METHODS: A total of 75 male rats aged about 12 weeks old were equally divided into group A (sham operation group), group B (model group), and group C (model group + BMMSCs). The SCI model was established by Allen's method, and the differences in presenilin-1, Hes1 and Notch proteins among the three groups of rats were evaluated via immunohistochemical staining and Western blotting. RESULTS: Group B exhibited a lower Basso, Beattie, and Bresnahan (BBB) score at each time point than group A and group C (p<0.05), and the BBB score in group C was lower than that in group A (p<0.05). According to the average optical density analysis results of the immunohistochemically stained proteins, the optical density of presenilin-1 protein in group A was lower than that in both group B and group C (p<0.05), and group C exhibited a lower optical density of presenilin-1 protein than group B. In group A, the protein expression of Hes1 in the bone marrow tissues of rats was not evident and weakly positive. Compared with that in group A, it was substantially raised (p<0.05), and the strongly positively expressed Hes1 proteins were yellow or dark brown in group B. Compared with that in group B, the color of Hes1 proteins was lighter (p<0.05), and the positive level of Hes1 proteins was lowered in group C. Group A showed inconspicuously positively expressed Notch proteins, group B brown active Notch proteins, while group C several brown Notch proteins. The optical density of Notch proteins in group A was overtly lower than that in group B and group C (p<0.05), and it was significantly lower in group C than that in group B (p<0.05). Additionally, group B had an evidently higher expression level of Notch proteins than the other two groups (p<0.05), and the expression level of Notch proteins in group C was a little higher than that in group A (p<0.05). CONCLUSIONS: BMMSCs inhibit the Notch signals to promote the proliferation and differentiation of rat neurons, thereby repairing spinal neurons.

[Relationships between serum cystatin C, chemerin levels and subclinical atherosclerosis in type 2 diabetes mellitus patients].

Objective: To investigate the relationships between serum cystatin C (Cys C), chemerin levels and subclinical atherosclerosis in type 2 diabetes mellitus (T2DM) patients. Methods: A cross-sectional study was carried out between January 2016 and January 2018, and T2DM patients with carotid intima-media thickness (IMT) less than 1.1 mm were selected as subjects (100 males and 80 females, aged 40-60 years). The brachial-ankle pulse wave velocity (baPWV) ≥ 1 700 cm/s was set as the observation group (subclinical atherosclerosis) and baPWV<1 700 cm/s as the control group (non-subclinical atherosclerosis). Physical and blood examination were performed in both groups. Serum Cys C and chemerin levels were measured and their relationship with subclinical atherosclerosis was analyzed. Results: There was a statistically significant correlation between serum creatinine (r=0.167, P=0.011) and baPWV in the observation group, but not in the control group (r=0.105, P=0.070). Multiple linear regression analysis showed that age, duration of diabetes, serum creatinine, estimated glomerular filtration rate (eGFR), Cys C and chemerin were independently associated with baPWV, while high sensitive C reactive protein (hsCRP) and glycosylated hemoglobin (HbA1c) were not associated with baPWV. The elevation of serum Cys C (ß'=0.393, P=0.003) and chemokine (ß'=0.340, P=0.007) were correlative factors for atherosclerosis. Conclusion: The level of serum Cys C and chemerin is possibly related to the occurrence and development of subclinical atherosclerosis in T2DM patients.

A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients.

BACKGROUND: Human hepatocellular carcinoma (HCC) cells are largely deficient of argininosuccinate synthetase and thus auxotrophic for arginine. This study aims to investigate the efficacy and pharmacodynamics of pegylated arginine deiminase (ADI-PEG 20), a systemic arginine deprivation agent, in Asian HCC patients. METHODS: Patients with advanced HCC who were not candidates for local therapy were eligible and randomly assigned to receive weekly intramuscular injections of ADI-PEG 20 at doses of 160 or 320 IU m(-2). The primary end point was disease-control rate (DCR). RESULTS: Of the 71 accruals, 43.6% had failed previous systemic treatment. There were no objective responders. The DCR and the median overall survival (OS) of the intent-to-treat population were 31.0% (95% confidence interval (CI): 20.5-43.1) and 7.3 (95% CI: 4.7-9.9) months respectively. Both efficacy parameters were comparable between the two study arms. The median OS of patients with undetectable circulating arginine for more than or equal to and <4 weeks was 10.0 (95% CI: 2.1-17.9) and 5.8 (95% CI: 1.4-10.1) months respectively (P=0.251, log-rank test). The major treatment-related adverse events were grades 1-2 local and/or allergic reactions. CONCLUSIONS: ADI-PEG 20 is safe and efficacious in stabilising the progression of heavily pretreated advanced HCC in an Asian population, and deserves further exploration.

Intravenous contrast-enhanced Doppler sonography and intra-arterial carbon dioxide-enhanced sonography in the assessment of hepatocellular carcinoma vascularity before and after treatment.

PURPOSE: To compare i.v. contrast-enhanced sonography (CEUS), power Doppler sonography (PDUS) and i.a. carbon dioxide-enhanced sonography (CO2US) in assessing hepatocellular carcinoma (HCC) vascularities before and after treatment. Differences between PDUS and CEUS with the aid of CO2US were also observed. MATERIAL AND METHODS: In all, 43 patients with 67 histologically proved HCCs were examined with PDUS, CEUS, and CO2US. Among these tumors, 36 were HCCs before treatment and 31 were HCCs treated by transcatheter arterial chemoembolization or percutaneous ethanol injection or a combination of these two treatments. CO2US was used as the gold standard when comparing the PDUS and CEUS. RESULTS: Of the 36 untreated HCC tumors, 20 (55.6%) were hypervascular compared with the liver parenchyma at PDUS, 28 (77.8%) at CEUS, 31 (86.1%) at the early phase of CO2US and 32 (88.9%) at the late phase of CO2US. Of the 31 post-treatment HCCs, 11 (35.5%) showed hypervascularity at PDUS, 25 (80.6%) at CEUS, 25 (80.6%) at the early phase of CO2US and 26 (83.9%) at the late phase of CO2US. CONCLUSION: CO2US was superior to CEUS and CEUS was superior to PDUS for the detection of tumor vascularity in both untreated and treated HCCs. The duration of enhancement at CEUS was shorter than at CO2US. The ability of CO2US to detect additional small tumors was not possible with PDUS and CEUS.

Hepatocellular carcinoma presenting with acquired porphyria: a case report and review of the literature.

Hepatocellular carcinoma (HCC) with acquired porphyria is a very rare condition. It is characterized variably by hyperpigmentation, skin fragility and photodistributed subepidermal vesicles. The serum, urine and/or stool porphyrin levels, usually markedly elevated, can change according to the clinical course. We report here a case of hepatocellular carcinoma presenting with a paraneoplastic syndrome of acquired porphyria. A 73-year-old Chinese woman had the characteristic facial pigmentation of cutaneous porphyria and histologically proven hepatocellular carcinoma. Her serum zinc protoporphyrin was elevated and her urine tested positive for coproporphyrin. Her protoporphyrin and alpha-fetoprotein levels dropped after transarterial chemoembolization treatment. Acquired porphyria in hepatocellular carcinoma occurs exclusively in older persons with huge hepatocellular carcinoma and/or cirrhosis. Before diagnosis, it must be carefully differentiated from inherent porphyrias with HCC, and porphyrias induced by drugs or heavy metal intoxication must be ruled out.

Intra-arterial carbon dioxide-enhanced ultrasonogram of hepatocellular carcinoma treated by transcatheter arterial embolization and percutaneous ethanol injection therapy.

The purpose of this study was to investigate the value of carbon dioxide-enhanced ultrasonography (CO2-US) in the evaluation of viable hepatocellular carcinomas (HCC) which were treated by transcatheter arterial embolization (TAE), percutaneous ethanol injection (PEI), or a combination treatment (TAE and PEI). Forty-one patients with 66 HCC were included in the study. They underwent CO2-US and angiography were performed in all tumours after they were treated by TAE, PEI or a combination treatment. Forty-six tumours were positively enhanced by CO2-US and 40 of them were positive by angiography. These 46 tumours were proved to be viable tumours either by biopsy or by follow-up studies. The positive predictive value was 100% for CO2-US and 87.8% in angiography. Twenty tumours were negative by CO2-US and these were also negative by angiography. Carbon dioxide-enhanced ultrasonography is a more reliable method for detecting the viable portion of the treated HCC compared with conventional angiography.

Alcohol-related problems in Taiwan with particular emphasis on alcoholic liver diseases.

Socioeconomic development has led to a progressive increase of alcohol consumption in Taiwan, with an accompanying increase in alcohol-related psychiatric problems, traffic accidents, and liver disease. The prevalent rates of alcohol dependence for Han Chinese and Fomosan aborigines were 0.1% and 1%, respectively in 1950. The rate of alcohol dependence increased to 23% for aborigines in 1995. The number of cases of death and serious injuries due to alcohol-related traffic accident has decreased, and the number of fatalities resulting from these accidents has decreased from third to eighth since the inception of a program of random traffic stops with alcohol breath test in 1997. Alcohol liver disease (ALD) was defined as daily alcohol consumption of 60 g, for a duration of longer than 5 years. We classified ALD patients into two groups: (1) those whose average daily consumption of alcohol exceeded 120 g for a duration longer than 15 years (group A); and (2) all other patients (group B). The case records of 33 cases of biopsy-confirmed ALD were obtained for study. The average of daily alcohol consumption in these cases was 160 g. All but one of these patients were male, age ranged from 26 to 69 years, with an average of 43.1. Clinically, ill-defined gastrointestinal symptoms were the most common presentation (61%), and hepatomegaly was the main physical sign (73%). The average mean corpuscular volume values of ALD and non-ALD patients were 102.3 +/- 10.94 and 94.5 +/- 8.1, respectively (p < 0.01). The mean corpuscular volume values of group A and group B were 102.9 +/- 9.7 vs. 96.5 +/- 9.11 (p < 0.05). Result from serum SGOT/SGPT and gamma-glutamyltransferase/alkaline phosphatase for ALD and non-ALD revealed statistically significant differences between these groups. Using the avidin-biotin complex technique, tissue IgA deposition for ALD patients was found to be different from that of non-ALD patients. Ten of 13 ALD patients vs. 2 of 13 non-ALD patients had continuous-form IgA deposition. Histologically, 45.5% of ALD patients had alcoholic cirrhosis, whereas alcoholic hepatitis was present in only 9.1% of patients. Overall, 88% of cases showed various severity of fatty metamorphosis.

Truncating the putative membrane association region circumvents the difficulty of expressing hepatitis C virus protein E1 in Escherichia coli.

The putative E1 of hepatitis C virus (HCV) was expressed in Escherichia coli using a glutathione-S-transferase (GST) fusion protein system. The full length E1 protein is difficult to express. A series of E1 DNA fragments was generated and used for expression vector construction. Fusion proteins containing the E1 C-terminal region could not be expressed. When this region was truncated, the fusion proteins were synthesized to high levels. The possibility of this C-terminal region hampering the production of fusion protein was further explored. A construct with this segment directly fused to the C-terminus of GST indeed generated no detectable recombinant protein. According to the predicted structure of E1, this region may have membrane-associating properties. The expression results suggest a general approach to facilitate the production of viral membrane proteins in prokaryotes. Furthermore, these recombinant E1 proteins generated as antigens were used for Western blotting with sera from HCV-infected individuals. It was found that E1 is antigenic during HCV natural infection.