Elevated TFPI is a prognostic factor in hepatocellular carcinoma: Putative role of miR-7-5p and miR-1236-3p.

BACKGROUND: Primary liver cancer is the third leading cause of cancer related deaths worldwide, and the disease is associated with high incidence rate of thrombosis. Studies indicate that Tissue Factor Pathway Inhibitor (TFPI) plays a role in cancer development. We aimed to study its expression, clinical role and regulation by micro RNAs (miRNAs) in hepatocellular carcinoma (HCC). METHODS: Publically available datasets were used for clinical analysis of TFPI and miRNAs expression by web analysis tools. miRNA mimics targeting TFPIα 3'untranslated region (UTR) were selected from target prediction programs and verified by luciferase reporter assay. In vitro effects of miRNAs overexpression in HCC cell lines on TFPI expression and cell proliferation and apoptosis were analysed. RESULTS: TFPI expression was significantly increased in HCC tumours compared to normal tissue. Low TFPI tumour expression was associated with better survival probability. Four candidate miRNAs were selected from the target prediction programs. miR-7-5p and miR-1236-3p were validated in HepG2 and Huh7 cells to reduce TFPI mRNA and protein levels following overexpression. Furthermore, miR-7-5p and miR-1236-3p reduced TFPIα-3'UTR-controlled luciferase activity. The two validated miRNAs inhibited proliferation of HepG2 cells, and had clinical significance in HCC. CONCLUSIONS: TFPI was increased in HCC tumours compared to normal tissue and high TFPI expression was associated with an unfavorable outcome in HCC patients. miR-7-5p and miR-1236-3p were identified as novel regulators of TFPI in vitro.

Long-term renal preservation in essential hypertension. Angiotensin converting enzyme inhibition is superior to beta-blockade.

Antihypertensive treatment is known to slow down the decline in glomerular filtration rate (GFR) with time. Angiotensin converting enzyme (ACE) inhibition has been shown to be more effective in this regard than conventional antihypertensive therapy. In a recent prospective, randomized, double blind trial in 257 patients with essential hypertension, the loss of GFR, determined with 51Cr-EDTA clearance, was significantly less with an ACE inhibitor (cilazapril) than with a beta-adrenoceptor blocker (atenolol) during the first year of treatment. However, after 2 years, the two therapies were equally effective in this regard, thereby creating doubts about the long-term superiority of ACE inhibition in this regard. In order to elucidate whether the superior renal preservation with the ACE inhibitor was a transient effect, GFR was measured after 1 more year of treatment, i.e., after 36 months. At that time, the decline in GFR was significantly smaller in the ACE inhibitor group as compared to the beta-adrenoceptor blocker group (-3.0 [-5.5, -1.0; 95% CI] v -7.0 [-9.0, -4.5; 95% CI] mL/min x 1.73 m2; P = .026). This demonstrates that in the treatment of essential hypertension ACE inhibition preserves GFR significantly better than beta-adrenoceptor blockade during long-term therapy.

ACE inhibition preserves renal function better than beta-blockade in the treatment of essential hypertension.

Antihypertensive treatment can slow down the decline in glomerular filtration rate (GFR) with time. In patients with diabetic nephropathy, angiotensin converting enzyme (ACE) inhibition has been shown to be more effective in this regard than conventional antihypertensive therapy. Whether this applies to the much larger population of patients with essential hypertension is not yet known. In the present study, the effects of two different antihypertensive therapies on the loss of GFR with time, determined with Cr51-EDTA clearance after 6, 12 and 24 months of treatment, were assessed in a prospective, randomised, double-blind trial in 257 patients with essential hypertension. All had normal renal function and none had diabetes mellitus or glucosuria. Proteinuria (dipstick positive or trace) was detected in 7 patients initially. The two therapeutic modalities were the ACE inhibitor cilazapril and the beta-adrenoceptor blocking agent atenolol. Both therapies were equally effective in lowering systolic blood pressure (e.g. from 168 mmHg to 152 mmHg with cilazapril and from 170 mmHg to 155 mmHg with atenolol after 6 months, p < 0.001 for both). However, atenolol was slightly but significantly more effective in lowering the diastolic blood pressure at 6, 12 and 24 months. The decline in GFR with time was significantly smaller with cilazapril than with atenolol. After 6 months the reduction in GFR was 1.0 vs. 4.0 ml/min x 1.73 m2, p = 0.008 (cilazapril vs. atenolol) and after 12 months the corresponding changes were 2.0 vs. 4.5 ml/min x 1.73 m2, p = 0.04 and after 24 months 3.0 vs. 4.0 ml/min x 1.73 m2, respectively (n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of slow-release piretanide and bendroflumethiazide in the treatment of mild to moderate hypertension.

After 4 weeks of placebo treatment, 76 hypertensive patients were randomly allocated to 6 or 12 mg/day piretanide, or 2.5 mg/day bendroflumethiazide for 12 weeks in a double-blind study. Piretanide was given in a slow-release formulation and bendroflumethiazide as a tablet. All three treatments produced a significant reduction in supine and erect systolic and diastolic blood pressures after 2 weeks, and this effect was maintained throughout the study. Normotension (i.e. supine diastolic pressure less than or equal to 95 mmHg) was achieved in 73% of the patients receiving 12 mg/day piretanide and in 57% receiving 6 mg/day piretanide compared with 72% receiving bendroflumethiazide (not significant). Overall, five patients were withdrawn due to increased diuresis: two patients on each dosage of piretanide and one receiving bendroflumethiazide. Three patients receiving 6 mg/day piretanide were withdrawn due to diastolic blood pressure rising above 120 mmHg. Other side-effects reported were mild and transient. There were no significant changes in serum creatinine, glucose or high-density lipoprotein cholesterol. A small, but non-significant rise in uric acid level was seen in all three groups. Clinically relevant hypokalaemia requiring potassium supplementation occurred in three patients receiving bendroflumethiazide.

Antihypertensive effect of felodipine or hydralazine when added to beta-blocker therapy.

In a double-blind randomized study, hydralazine (n = 59) or the new dihydropyridine calcium antagonist felodipine (n = 61) was added to previous treatment with beta-adrenoceptor blocking agents in a group of 120 patients with essential hypertension. Active treatment with either hydralazine or felodipine was given for 8 weeks after a 4-week placebo run-in period, at the end of which all patients had supine diastolic blood pressures greater than 95 mm Hg. Assessment of the results according to the intention to treat principle showed that felodipine was significantly more effective than hydralazine at the doses employed, reducing systolic blood pressure 10-19 mm Hg more than hydralazine and reducing diastolic blood pressure 5-11 mm Hg more than hydralazine (95% confidence intervals). The number of patients complaining of side effects, the number of complaints, and the number of patients that had to be withdrawn from treatment were numerically higher during treatment with hydralazine than with felodipine, but these differences were not statistically significant. Against this background it is concluded that felodipine is superior to hydralazine when added to an antihypertensive regimen consisting of beta-adrenoceptor blocking agents.

Hyperprolactinaemia and testosterone production. Observations in 2 men on long-term dialysis.

2 men had received maintenance dialysis for more than 5 years because of uraemia. Gradual impairment of libido had led to total impotence of more than 6 months duration. Concurrently hyperprolactinaemia occurred. Bromocriptine was given for 2 and 4 months, respectively. Potency was not restored, but in 1 patient the blood transfusion requirements were halved and general well-being and strength increased. In both men, the serum prolactin levels normalized. Inversely, the low plasma testosterone levels increased during the treatment period.