Regulation of DNA synthesis and DNA polymerase in rat pancreas. II. Age-dependent changes in glucocorticoid control.

The effect of glucocorticoid on DNA synthesis and DNA polymerase in the rat pancreas of stable mass has been studied in order to elucidate the mode of control of DNA metabolism in the tissue whose increase in DNA content has reached a steadystate. The DNA synthesis was assessed by the pulse-labeling method using radio-active thymidine as the precursor. The polymerase activity was assayed by measuring the amount of [³H]TTP incorporated in vitro into the acid insoluble fraction in the presence of activated calf thymus DNA. In the pancreas which has ceased to accumulate DNA, the effect of glucocorticoid is monophasic: administration of glucocorticoid inhibits DNA synthesis and DNA polymerase activities, but it does not elicit the subsequent stimulation of DNA synthesis and DNA polymerase activities such as that observed in the actively growing pancreas. The absence of the stimulatory effect in the older animals is an age-dependent alteration in the tissue-response to the steroid observed for the first time.     

Prognostic variables in male breast cancer

The prognostic role of ploidy status, S phase fraction, estrogen and progesterone receptor status, and the expression of p53 and erbB-2 protein in male breast carcinoma (MBC) remains controversial. The primary objective of this study was to determine which of the common prognostic factors for female breast cancer predict prognosis in MBC. A secondary objective was to assess the impact of comorbid illnesses on survival. A retrospective review of demographic data, surgical treatment, pathological staging, adjuvant treatment and follow-up was completed for 16 patients with MBC (1 intraductal and 15 invasive). Formalin-fixed, paraffin-embedded tissue was processed for ploidy, S phase fraction, and immunohistochemical detection of estrogen and progesterone receptors plus expression of p53 and erbB-2 protein. Six of 15 patients with infiltrating ductal carcinoma are currently alive without evidence of disease and a median survival of 61 months. Nine patients died after a median survival of 52 months, with 6 patients having no evidence of recurrent breast cancer. Two of 3 deaths secondary to advanced breast cancer occurred in patients who initially presented with T4 lesions and were staged IIIB. Two of 15 tumors were erbB-2 positive, whereas only 1 tested weakly positive for p53 protein. We observed that MBCs express erbB-2 and p53 proteins infrequently. Neither ploidy status, S phase fraction, nor erbB-2/p53 status provided any apparent improvement in establishing prognosis beyond routine pathological staging. Advanced TNM stage was associated with diminished survival. The majority of MBCs express estrogen and progesterone receptors. Survivals in MBC were reduced in association with comorbid medical conditions.     

Reactive oxygen at the heart of metabolism

During heart development, the progression from a pluripotent, undifferentiated embryonic stem cell to a functional cardiomyocyte in the adult mammalian heart is characterised by profound changes in gene expression, cell structure, proliferative capacity and metabolism. Whilst the precise causal relationships between these processes are not fully understood, it is clear that the availability and cellular ability to utilise oxygen are critical effectors of cardiomyocyte differentiation and function during development. In particular, cardiomyocytes switch from a largely glycolytic-based production of ATP to predominantly β-oxidation of long-chain fatty acids to generate the cellular energy requirements. Whilst this transition occurs progressively during embryonic and foetal development, it is particularly abrupt over the period of birth. In the adult heart, many cardiopathologies are accompanied by a reversal to a more foetal-like metabolic profile. Understanding the mechanistic causes and consequences of the normal metabolic changes that occur during heart development and those in the pathological heart setting is crucial to inform future potential therapeutic interventions. It is becoming clear that reactive oxygen species (ROS) play critical roles in the regulation of redox-mediated molecular mechanisms that control cellular homoeostasis and function. ROS are generated as a consequence of metabolic processes in aerobic organisms. An overproduction of ROS, when not balanced by the cell's antioxidant defence mechanisms (termed “oxidative stress”), results in non-specific oxidation of proteins, lipids and DNA and is cytotoxic. However, the tightly regulated temporal and spatial production of ROS such as H₂O₂ acts to control the activity of proteins through specific post-translational oxidative modifications and is crucial to cellular function. We describe here the metabolic changes that occur in the developing heart and how they can revert in cardiopathologies. They are discussed in the light of what is currently known about the regulation of these processes by changes in the cellular redox state and levels of ROS production.     

Exploration of stilbenoid trimers as potential inhibitors of sirtuin1 enzyme using a molecular docking and molecular dynamics simulation approach

A combination of molecular docking and molecular dynamics simulation (250 ns) has been carried out to study the interaction of stilbenoid trimer compounds with the SIRT1 enzyme as the target protein. SIRT1 expression regulates cellular stress responses that lead to the development of cancer. Redocking showed a good native ligand pose with an RMSD value of 1.40 Å at the receptor active site''s coordinates. The molecular docking score uses a grid score functional (kcal mol⁻¹), which shows results of 1NS: 79.56, TS1: −26.83, TS2: −87.77, and TS3: −83.67. The TS2 and TS3 candidates were chosen for further analysis because they had a lower grid score than the native ligand (1NS). Furthermore, prediction of binding free energy (kcal mol⁻¹) using the Quantum Mechanics/generalized Born Surface Area (QM/MM-GBSA) method shows the results of 1NS: −31.52 ± 0.39, TS2: −58.99 ± 0.34, and TS3: −43.38 ± 0.35. These results indicate that the TS2 and TS3 compounds have good potential as inhibitors of the SIRT1 enzyme. Additionally, the amino acid residues were responsible for the inhibition mechanism through hydrogen bond interactions at the molecular level, including ASP22, PHE91, PRO11, ILE165, ASP166, and VAL230. The observations made in this study provide theoretical information for exploring the stilbenoid trimers as anticancer agents by targeting the SIRT1 enzyme.

A combination of molecular docking and molecular dynamics simulation (250 ns) has been carried out to study the interaction of stilbenoid trimer compounds with the SIRT1 enzyme as the target protein.     

泪道探通对三个年龄组的先天性鼻泪管阻塞患者的疗效(英文)

目的:比较泪道探通治疗对三个年龄组的先天性鼻泪管阻塞患者的成功率。方法:共180例先天性鼻泪管阻塞患者根据年龄分为3组, I组(4 ~6mo), II组(7 ~12mo)和III组(13 ~24mo),均行泪道探通治疗。症状体征均消失为治疗成功的标准。用卡方检验分析结果。结果:I组治疗成功率为100.0%, II组治疗成功率为88.5%,III组治疗成功率为82.3%,总的治愈率为90.7%。结论:泪道探通治疗的有效性随着年龄的增加降低。在6mo时行泪道探通治疗的孩子成功率最高,能完全消除症状。