A novel synthetic C-1 analogue of 7-deoxypancratistatin induces apoptosis in p53 positive and negative human colorectal cancer cells by targeting the mitochondria: enhancement of activity by tamoxifen

The natural compound pancratistatin (PST), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines. Unlike many other chemotherapeutics, PST is not genotoxic and has minimal adverse effects on non-cancerous cells. However, its availability for preclinical and clinical work is limited due to its low availability in its natural source and difficulties in its chemical synthesis. Several synthetic analogues of 7-deoxypancratistatin with different modifications at C-1 were synthesized and screened for apoptosis inducing activity in human colorectal cancer (CRC) cells. We found that a C-1 acetoxymethyl derivative of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), was effective in inducing apoptosis in both p53 positive (HCT 116) and p53 negative (HT-29) human CRC cell lines, demonstrating similar efficacy to that of natural PST. JCTH-4 was able to decrease mitochondrial membrane potential (MMP), increase levels of reactive oxygen species in isolated mitochondria, cause release of the apoptogenic factor cytochrome c (Cyto c) from isolated mitochondria, and induce autophagy in HCT 116 and HT-29 cells. Interestingly, when JCTH-4 was administered with tamoxifen (TAM), there was an enhanced effect in apoptosis induction, reactive oxygen species (ROS) production and Cyto c release by isolated mitochondria, and autophagic induction by CRC cells. Minimal toxicity was exhibited by a normal human fetal fibroblast (NFF) and a normal colon fibroblast (CCD-18Co) cell line. Hence, JCTH-4 is a novel compound capable of selectively inducing apoptosis and autophagy in CRC cells alone and in combination with TAM and may serve as a safer and more effective alternative to current cancer therapies.     

Staging Neurodegenerative Disorders: Structural, Regional, Biomarker, and Functional Progressions

The notion of staging in the neurodegenerative disorders is modulated by the constant and progressive loss of several aspects of brain structural integrity, circuitry, and neuronal processes. These destructive processes eventually remove individuals?? abilities to perform at sufficient and necessary functional capacity at several levels of disease severity. The classification of (a) patients on the basis of diagnosis, risk prognosis, and intervention outcome, forms the basis of clinical staging, and (b) laboratory animals on the basis of animal model of brain disorder, extent of insult, and dysfunctional expression, provides the components for the clinical staging and preclinical staging , respectively, expressing associated epidemiological, biological, and genetic characteristics. The major focus of clinical staging in the present account stems from the fundamental notions of Braak staging as they describe the course and eventual prognosis for Alzheimer??s disease, Lewy Body dementia, and Parkinson??s disease. Mild cognitive impairment, which expresses the decline in episodic and semantic memory performance below the age-adjusted normal range without marked loss of global cognition or activities of daily living, and the applications of longitudinal magnetic resonance imaging, major instruments for the monitoring of either disease progression in dementia, present important challenges for staging concepts. Although Braak notions present the essential basis for further developments, current staging conceptualizations seem inadequate to comply with the massive influx of information dealing with neurodegenerative processes in brain, advanced both under clinical realities, and discoveries in the laboratory setting. The contributions of various biomarkers of disease progression, e.g., amyloid precursor protein, and neurotransmitter system imbalances, e.g., dopamine receptor supersensitivity and interactive propensities, await their incorporation into the existing staging models thereby underlining the ongoing, dynamic feature of the staging of brain disorders.     

Beating-heart valve surgery: is the introduction of lung perfusion/ventilation the next step?

Myocardial and pulmonary ischemia during cardiopulmonary bypass has been associated with postoperative cardiac and pulmonary dysfunction, as well as poor outcomes. Beating-heart valve surgery utilizing continuous coronary perfusion with warm oxygenated blood via the antegrade/retrograde routes, is a novel strategy for myocardial protection. Conceptually, it is proposed that maintenance of pulmonary perfusion and ventilation during the cardiopulmonary bypass period also might be advantageous. The most current evidence regarding these evolving techniques and further areas of research are discussed in this article.     

Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays

Pancreatic cancer is known to be associated with VTE, but contemporary rates of incidental and symptomatic VTE events and their association with mortality are incompletely understood. We conducted a retrospective cohort study of consecutive pancreatic adenocarcinoma patients at the University of Rochester from 2006-2009. Data were analysed using a Cox model with time-dependent covariates. A total of 1,151 radiologic exams of 135 patients were included. Forty-seven patients (34.8%) experienced VTE including 12 pulmonary emboli (PE), 28 deep-vein thromboses (DVTs) and 47 visceral vein events. Incidental events comprised 33.3% of PEs, 21.4% of DVTs and 100% of visceral VTE. Median (95% CI) conditional survival beyond three months was 233 (162-322) more days for those without VTE, which was significantly greater than 12 (3-60) days for those with DVT as first event (p<0.0001) and 87 (14-322) days with visceral first events (p=0.022). In multivariate analysis, DVT (HR 25, 95% CI 10-63, p <0.0001), PE (HR 8.9, 95% CI 2.5-31.7, p = 0.007) and incidental visceral events (HR 2.6, 95% CI 1.6-4.2, p =0.0001) were all associated with mortality, though anticoagulants reduced these risks by 70% (26-88%, p = 0.009). In conclusion, VTE occurs in over one-third of contemporary pancreatic cancer patients and, whether symptomatic or incidental, is strongly associated with worsened mortality. The role of anticoagulation in treating incidental or visceral VTE warrants further study.