Открытое контролируемое исследование клинических эффектов препарата Лаеннек® у пациентов с неалкогольным стеатогепатитом или циррозом печени

Objective: to evaluate the efficacy and safety of human placenta hydrolysate (HPH) Laennec® in the treatment of nonalcoholic fatty liver disease (NAFLD) in a clinical trial.Material and methods. The study involved hospitalized NAFLD patients (with non-alcoholic steatohepatitis, cirrhosis) (n=34, mean age 53±14 years). In the therapy group (n=17), patients received Laennec® HPH (4 ml intravenous drip infusion in a solution of 5% glucose 5 times a week for 2 weeks). In the control group (n=17), patients hospitalized in other departments of the clinic did not receive any therapy for NAFLD. The effectiveness of therapy was assessed after 2 and 3 weeks by subjective NAFLD symptoms (fatigue, anorexia, bloating, constipation, nausea, and pain in hypochondrium) and biochemical indicators of liver function: levels of blood serum aspartate aminotrans-ferase (AST), alanine notransferase (ALT), gamma-glutamyltransferase (GGT).Results. At the start of the study, there were no significant differences between the groups in the values of the studied indicators of liver function: blood levels of AST, ALT, GGT, etc. By the end of Week 1, a significant decrease in AST levels was registered in the group receiving Laennec® (–35 U/l; control: –8 U/l; p<0.001), ALT (–45 U/l; control: –10 U/l; p<0.001), and GGT (–23 U/l; control: –8 U/l; p=0.084; trend). At the end of the study (Week 3), the decrease in AST, ALT and GGT levels towards the normal range was even more pronounced for all three biomarkers: AST (–62 U/l; control: –23 U/l; p<0.001), ALT (–78 U/l; control: –20 U/l; p<0.001), GGT (–40 U/l; control: –15 U/l; p=0.005). Subjective NAFLD symptoms significantly improved after 3 weeks. No adverse effects were identified with the use of HPH. Conclusion. Laennec® is an effective and safe treatment for NAFLD.Цель: оценка эффективности и безопасности гидролизата плаценты человека (ГПЧ) Лаеннек® при лечении неалкогольной жировой болезни печени (НАЖБП) в рамках клинического исследования.Материал и методы. В исследовании приняли участие госпитализированные пациенты с НАЖБП (неалкогольный стеатогепатит, цирроз) (n=34, средний возраст 53±14 лет). В группе терапии (n=17) больные получали ГПЧ Лаеннек® (4 мл внутривенная капельная инфузия в растворе 5% глюкозы 5 раз в неделю в течение 2 нед). В контрольной группе (n=17) пациенты, госпитализированные в другие отделения клиники, не получали никакой терапии в связи с НАЖБП. Эффективность лечения оценивали через 2 и 3 нед по субъективным симптомам НАЖБП (утомляемость, анорексия, вздутие живота, запор, тошнота и боль в подреберье) и биохимическим показателям функции печени: уровням аспартатаминотрансферазы (АСТ), аланинаминотрансферазы (АЛТ), гамма-глутамилтрансферазы (ГГТ) в сыворотке крови.Результаты. На момент начала исследования между группами не было достоверных различий в значениях исследованных показателей функции печени: уровни АСТ, АЛТ, ГГТ и др. К концу 1-й недели в группе получавших Лаеннек® зарегистрировано достоверное снижение уровней АСТ (–35 Ед/л; контроль: –8 Ед/л; р<0,001), АЛТ (–45 Ед/л; контроль: –10 Ед/л; р<0,001) и ГГТ (–23 Ед/л; контроль: –8 Ед/л; р=0,084; тренд). На момент окончания исследования (3-я неделя) снижение уровней АСТ, АЛТ и ГГТ в сторону интервала нормы было еще более выраженно для всех трех биомаркеров: АСТ (–62 Ед/л; контроль: –23 Ед/л; р<0,001), АЛТ (–78 Ед/л; контроль: –20 Ед/л; р<0,001), ГГТ (–40 Ед/л; контроль: –15 Ед/л; р=0,005). Субъективная симптоматика НАЖБП достоверно улучшилась через 3 нед. Не было установлено каких-либо нежелательных эффектов при применении ГПЧ.Заключение. Лаеннек® – эффективное и безопасное средство лечения НАЖБП

DNA Methylation Profiles of Primary Colorectal Carcinoma and Matched Liver Metastasis

BACKGROUND: The contribution of DNA methylation to the metastatic process in colorectal cancers (CRCs) is unclear. METHODS: We evaluated the methylation status of 13 genes (MINT1, MINT2, MINT31, MLH1, p16, p14, TIMP3, CDH1, CDH13, THBS1, MGMT, HPP1 and ERα) by bisulfite-pyrosequencing in 79 CRCs comprising 36 CRCs without liver metastasis and 43 CRCs with liver metastasis, including 16 paired primary CRCs and liver metastasis. We also performed methylated CpG island amplification microarrays (MCAM) in three paired primary and metastatic cancers. RESULTS: Methylation of p14, TIMP3 and HPP1 in primary CRCs progressively decreased from absence to presence of liver metastasis (13.1% vs. 4.3%; 14.8% vs. 3.7%; 43.9% vs. 35.8%, respectively) (P<.05). When paired primary and metastatic tumors were compared, only MGMT methylation was significantly higher in metastatic cancers (27.4% vs. 13.4%, P = .013), and this difference was due to an increase in methylation density rather than frequency in the majority of cases. MCAM showed an average 7.4% increase in DNA methylated genes in the metastatic samples. The numbers of differentially hypermethylated genes in the liver metastases increased with increasing time between resection of the primary and resection of the liver metastasis. Bisulfite-pyrosequencing validation in 12 paired samples showed that most of these increases were not conserved, and could be explained by differences in methylation density rather than frequency. CONCLUSIONS: Most DNA methylation differences between primary CRCs and matched liver metastasis are due to random variation and an increase in DNA methylation density rather than de-novo inactivation and silencing. Thus, DNA methylation changes occur for the most part before progression to liver metastasis

Study of p53 gene alteration as a biomarker to evaluate the malignant risk of Lugol-unstained lesion with non-dysplasia in the oesophagus

Mutations of the p53 gene are detected frequently in oesophageal dysplasia and cancer. It is unclear whether Lugol-unstained lesions (LULs) with non-dysplastic epithelium (NDE) are precursors of oesophageal squamous cell carcinoma (ESCC). To study the genetic alterations of NDE in the multistep process of oesophageal carcinogenesis, we determined the relationship between p53 mutations and LULs-NDE. Videoendoscopy with Lugol staining was performed prospectively in 542 oesophageal cancer-free subjects. Lugol-unstained lesions were detected in 103 subjects (19%). A total of 255 samples, including 152 LULs (NDE, 137; dysplasia, 15) and 103 paired samples of normal staining epithelium, were obtained from 103 subjects. After extraction of DNA and polymerase chain reaction analysis, direct sequencing method was applied to detect mutations of the p53 gene. The p53 mutation was detected in five of 137 samples with LULs-NDE (4%) and in five of 15 samples with dysplasia (33%). A hotspot mutation was found in 20% of LULs-NDE with p53 mutation and in 40% of dysplasia with p53 mutation. In contrast, no p53 mutations were found in 103 paired NDE samples with normal Lugol staining. In biopsy samples from oesophageal cancer-free individuals, the p53 missense mutations containing a hotspot mutation were found in NDE, which was identified as an LUL. These findings suggest that some LULs-NDE may represent the earliest state of oesophageal squamous cell carcinoma in Japanese individuals

The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress

To survive proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by the transcription factor heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive therapeutic target. As developing inhibitors against transcriptional regulators, such as HSF1 is challenging, the identification and targeting of upstream regulators of HSF1 present a tractable alternative strategy. Here we demonstrate that in triple-negative breast cancer (TNBC) cells, the dual specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. These findings identify DYRK2 as a key modulator of the HSF1 transcriptional programme and a potential therapeutic target

BRAF mutations and phosphorylation status of mitogen-activated protein kinases in the development of flat and depressed-type colorectal neoplasias

Although some molecular differences between flat-depressed neoplasias (FDNs) and protruding neoplasias (PNs) have been reported, it is uncertain if the BRAF mutations or the status of phosphorylated mitogen-activated protein kinase (p-MAPK) are different between theses two groups. We evaluated the incidence of BRAF and KRAS mutations, high-frequency microsatellite instability (MSI-H), and the immunohistochemical status of p-MAPK in the nonserrated neoplasias (46 FDNs and 57 PNs). BRAF mutations were detected in four FDNs (9%) and none of PNs (P=0.0369 by Fisher's exact test). KRAS mutations were observed in none of FDNs and in 14 PNs (25%; P=0.0002 by Fisher's exact test). MSI-H was detected in seven out of 44 FDNs (16%) and in one out of 52 of PNs (2%) (P=0.022 by Fisher's exact test). Type B and C immunostaining for p-MAPK was observed in 34 out of 46 FDNs (72%), compared with 24 out of 55 PNs (44%; P=0.0022 by χ2 test). There was no significant difference in the type B and C immunostaining of p-MAPK between FDNs with and without BRAF mutations. BRAF and KRAS mutations are mutually exclusive in the morphological characteristics of colorectal nonserrated neoplasia. Abnormal accumulation of p-MAPK protein is more likely to be implicated in the tumorigenesis of FDNs than of PNs. However, this abnormality in FDNs might occur via the genetic alteration other than BRAF or KRAS mutation

Correlation between serum HCV RNA and aminotransferase levels in patients with chronic HCV infection

Cross-sectional studies on the correlation between serum hepatitis C virus (HCV) RNA and alanine aminotransferase (ALT) levels in patients with chronic hepatitis C have yielded conflicting results. We conducted a longitudinal study to examine the correlation between HCV viremia and serum ALT levels in individual patients over time. Serial samples (mean 9) from 25 patients with chronic HCV infection, including interferon-treated and untreated immunocompetent and immunosuppressed patients, collected over a period of 1–4.8 years (mean 2.6 years) were tested for HCV RNA and ALT levels using a highly reproducible quantitative (bDNA) assay. A significant correlation was found between serum HCV RNA and ALT levels in the patients who received IFN therapy, but no correlation was observed in the untreated patients. Among the untreated patients, the immunosuppressed patients had significantly higher HCV RNA levels (39±4 vs 3.6±8 Meq/ml, P <0.0001) but significantly lower ALT (56±11 vs 97±12 units/liter, P =0.03) levels when compared to the immunocompetent ones. In summary, we found no correlation between serum HCV RNA and ALT levels in chronic hepatitis C patients who are not receiving interferon therapy. Immunosuppression results in higher HCV RNA but lower ALT levels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44425/1/10620_2005_Article_BF02071402.pd