Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data.

We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We sampled nine different sections from three tumors and seven more sections from the adjacent nontumor tissues. Selected sections were subjected to exon as well as whole-genome sequencing. Putative somatic mutations were then individually validated across all 9 tumor and 7 nontumor sections. Among the mutations validated, 24 were amino acid changes; in addition, 22 large indels/copy number variants (>1 Mb) were detected. These somatic mutations define four evolutionary lineages among tumor cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein-coding mutation. Hence, by using a cell-population genetic definition, this approach identified three coding changes (CCNG1, P62, and an indel/fusion gene) as tumor driver mutations. These three mutations, affecting cell cycle control and apoptosis, are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. These distinct functions of mutations at different stages may reflect the genetic interactions underlying tumor growth.

Association between Cardiac Autonomic Neuropathy and Coronary Artery Lesions in Patients with Type 2 Diabetes.

OBJECTIVE: Cardiac autonomic neuropathy (CAN) is a common and serious complication of diabetes mellitus with various systemic involvements, such as atherosclerotic cardiovascular disease. We aimed to evaluate the association between CAN and coronary artery lesions in patients with type 2 diabetes. Research Design and Methods. We retrospectively reviewed the medical records of 104 patients with type 2 diabetes and coronary artery disease (CAD). We evaluated heart rate variability (HRV) parameters (SDANN, SDNN, and pNN50) to assess cardiac autonomic function. The severity of coronary lesions was assessed by the Gensini scores and the number of affected vessels. Correlation analyses between HRV parameters and the severity of coronary lesions and clinical parameters were performed. RESULTS: Spearman's correlation analysis showed a significant negative correlation between SDANN and Gensini scores (r = -0.22, P = 0.03). Interestingly, this finding remained significant after adjusting for clinical covariates (r = -0.23, P = 0.03). However, there was no association between HRV parameters and the severity of coronary lesions as assessed by the number of affected vessels. Clinical parameters were not significantly correlated with HRV parameters (all P > 0.05). CONCLUSIONS: Cardiac autonomic neuropathy might be related to the degree of coronary atheromatous burden in patients with type 2 diabetes. Screening for cardiac autonomic neuropathy might potentially be beneficial in the risk stratification of patients with type 2 diabetes.

Increased Cathepsin D Correlates with Clinical Parameters in Newly Diagnosed Type 2 Diabetes.

BACKGROUND: Cathepsin D has been recently implicated in insulin resistance and cardiovascular disease. This study was designed to investigate the relationship between cathepsin D and newly diagnosed type 2 diabetes. METHODS: Circulating cathepsin D levels and metabolic variables were measured in 98 cases and 98 controls. Myocardial performance index "Tei index" that reflects both left ventricular systolic and diastolic function was measured with Doppler echocardiography in cases. RESULTS: Newly diagnosed type 2 diabetes demonstrated significantly higher circulating cathepsin D concentrations than controls (median level: 227 ng/ml versus 174 ng/ml, P < 0.01). In newly diagnosed type 2 diabetes, a significant correlation was found between cathepsin D levels and HOMA-IR (homeostatic model assessment of insulin resistance) (r = 0.25, P = 0.01). In contrast, no significant correlation was found between cathepsin D levels and clinical parameters in the control group (all P > 0.05). Interestingly, correlation analysis revealed a positive association between cathepsin D levels and Tei index in type 2 diabetes (r = 0.22, P = 0.03). CONCLUSIONS: Increased levels of circulating cathepsin D are closely linked with the presence of type 2 diabetes, and cathepsin D might serve as a novel biomarker for cardiac dysfunction in newly diagnosed type 2 diabetes.

The relationship between heart rate variability and prostaglandin E2 in patients with renal insufficiencies.

OBJECTIVE: To investigate the relationship between heart rate variability (HRV) and prostaglandin E2 (PGE2) in patients with renal insufficiencies. METHODS: HRV blood and 24-hour urine prostaglandin E2 (PGE2) detection were detected in the following 4 groups of people: group A was a control group comprised of 20 normal individuals; group B had 20 patients with renal disease but exhibiting normal renal function; group C contained 20 patients with renal disease and compensatory renal function; group D had 20 patients demonstrating renal insufficiencies. The indices standard deviation of all NN intervals (SDNN), index of standard deviation of the averages of NN intervals (SDANN), mean of the standard deviation of all NN intervals performed on all 5-minute segments of the entire recording (SDNNindex), square root of the mean of the sum of the squares of differences between adjacent NN intervals (rMSSD) and NN50 count divided by the total number of all NN intervals (PNN50) were used to evaluate HRV, blood and 24-hour urine were determined by specific radioimmunoassay (RIA). RESULTS: PGE2 in blood and urine and HRV exactly within 24 hours in patients with renal insufficiencies, negatively correlated with worsening damage to renal function. There was a slight or moderate correlation between blood and urine PGE2 and the SDNNindex, SDANNindex, SDNN, rMSSD and PNN50 indices (P < 0.05). CONCLUSIONS: HRV and cardiac autonomic regulatory functions are decreased in the patients with renal insufficiencies, while lower levels of PGE2 may be a related factor.

[Effects of atenolol and diltiazem-SR on quality of life in the hypertensive patients].

OBJECTIVE: To compare the efficacy of atenolol and diltiazem-SR and the effects on the quality of life in hypertensive patients. METHODS: Seventy-three patients with mild to moderate hypertension (DBP 90 - 109 mmHg) were allocated randomly to be administered with atenolol 25 mg/d (group A, n=37) and diltiazem-SR 90 mg/d (group B, n=36) for eight weeks. The changes of heart rate, office blood pressure(OBP), ambulatory blood pressure(ABP) and the quality of life were compared before and after treatment. RESULTS: Heart rate, OBP and ABP decreased after treatment in both groups. The effective rate of blood pressure was 88.2% in group A and 93.8% in group B. Twenty four hour mean daytime and nighttime BP,daytime and nighttime BP loads declined in both groups (P<0.05 - 0.01). The quality of life was significantly increased in group B (P<0.05). Side effects were 21.6% in group A and 11.1% in group B, respectively (P>0.05). CONCLUSION: Atenolol and diltiazem-SR are more effective and tolerant in the treatment of the hypertension. Diltiazem improves the quality of life better than atenolol.