Epigenetic approach for angiostatic therapy: promising combinations for cancer treatment

Cancer cells are often dependent on epigenetic pathways for their survival. Consequently, drugs that target the epigenome, rather than the underlying DNA sequence, are currently attracting considerable attention. In recent years, the first epigenetic drugs have been approved for cancer chemotherapy, mainly for hematological applications. Limitations in single-drug efficacies have thus far limited their application in the treatment of solid tumors. Nevertheless, promising activity for these compounds has been suggested when combined with other, distinctly targeted agents. In this review, we discuss the anti-angiogenic activity of histone deacetylase and DNA methyltransferase inhibitors and their combinations with other targeted (anti-angiogenic) therapeutics in treatment of solid tumors. The role that these inhibitors play in the inhibition of tumor angiogenesis, particularly in combination with other targeted agents, and the advantages they present over broad acting anticancer agents, are critically discussed.     

Categorization of major and minor complications in the treatment of patients with resectable rectal cancer using short-term pre-operative radiotherapy and total mesorectal excision: a Delphi round

Background To properly balance the benefit (reduction of local recurrence) of short‐term pre‐operative radiotherapy for resectable rectal cancer against its harm (complications), a consensus concerning the severity of complications is required. The aim of this study was to reach consensus regarding major and minor complications after short‐term radiotherapy followed by total mesorectal excision in the treatment of rectal carcinoma, using the Delphi technique. Methods A Delphi round was performed in cooperation with 21 colo‐rectal surgeons from the Netherlands, United Kingdom and Sweden. The key‐question was: ‘Which of the predefined complications, caused or substantially aggravated by radiotherapy, are so important (major) that they might lead to the decision to abandon short‐term pre‐operative radiotherapy (5 × 5Gy) when treating patients with resectable rectal cancer (T_1?3N_0?2M₀)?’ Results After three rounds, consensus was reached for 37 (68%) of 54 complications of which 13 were considered major and 24 considered minor. The following complications were considered to be major: mortality, anastomotic leakage managed by relaparotomy, anastomotic leakage resulting in persisting fistula, postoperative haemorrhage managed by relaparotomy, intra‐abdominal abscess without healing tendency, sepsis, pulmonary embolism, myocardial infarction, compartment syndrome of the lower legs, long‐term incontinence for solid stool, long‐term problems with voiding, pelvic fracture with persisting pain, and neuropathy with persisting pain (legs). Three of 17 complications without consensus showed a tendency to be considered as major: perineal wound dehiscence managed by surgical treatment, small bowel obstruction leading to relaparotomy and long‐term incontinence for liquid stool. Conclusion The 13 major and three ‘accepted as major’ complications can be used to properly balance the benefit and harm of short‐term pre‐operative radiotherapy in resectable rectal cancer. This may eventually lead to improved treatment strategies for these patients.     

Corticosteroid induced decoupling of the amygdala in men

The amygdala is a key regulator of vigilance and heightens attention toward threat. Its activity is boosted upon threat exposure and contributes to a neuroendocrine stress response via the hypothalamic-pituitary-adrenal (HPA) axis. Corticosteroids are known to control brain activity as well as HPA activity by providing negative feedback to the brain. However, it is unknown how corticosteroids affect the neural circuitry connected to the amygdala. Implementing a randomized, double-blind, placebo-controlled design, we here investigated the effects of 10-mg hydrocortisone on amygdala-centered functional connectivity patterns in men using resting state functional magnetic resonance imaging. Results showed generally decreased functional connectivity of the amygdala by corticosteroids. Hydrocortisone reduced "positive" functional coupling of the amygdala to brain regions involved in the initiation and maintenance of the stress response; the locus coeruleus, hypothalamus, and hippocampus. Furthermore, hydrocortisone reduced "negative" functional coupling of the amygdala to the middle frontal and temporal gyrus; brain regions known to be involved in executive control. A control analysis did not show significant corticosteroid modulation of visual cortex coupling, indicating that the amygdala decoupling was not reflecting a general reduction of network connectivity. These results suggest that corticosteroids may reduce amygdala's impact on brain processing in the aftermath of stress in men.     

Private peer group settings as an environmental determinant of alcohol use in Dutch adolescents: results from a representative survey in the region of Twente

This study supports the hypothesis that the drinking setting can be an environmental risk factor for hazardous alcohol use. In a survey of Dutch adolescents (n = 1516), alcohol consumption and participation in private peer group settings (PPSs), environments where adolescents meet and drink alcohol without direct adult supervision, were measured. After controlling for demographic variables, adolescents visiting PPSs as compared to non-visitors, appeared to have a significantly higher lifetime prevalence of alcohol use, average weekly consumption, and frequency of heavy episodic drinking. Moreover, accounting for school clustering, the frequency of PPS visits was associated with increased alcohol consumption.     

Micro-level economic factors and incentives in Children’s energy balance related behaviours - findings from the ENERGY European cross-section questionnaire survey

Women who are physically active during early pregnancy have notably lower odds of developing gestational diabetes than do inactive women. The purpose of the intervention was to examine whether intensified physical activity (PA) counseling in Finnish maternity care is feasible and effective in promoting leisure-time PA (LTPA) among pregnant women at risk of gestational diabetes. Fourteen municipalities were randomized to intervention (INT) and usual care group (UC). Nurses in INT integrated five PA counseling sessions into routine maternity visits and offered monthly group meetings on PA instructed by physiotherapists. In UC conventional practices were continued. Feasibility evaluation included safety (incidence of PA-related adverse events; questionnaire), realization (timing and duration of sessions, number of sessions missed, attendance at group meetings; systematic record-keeping of the nurses and physiotherapists) and applicability (nurses’ views; telephone interview). Effectiveness outcomes were weekly frequency and duration of total and intensity-specific LTPA and meeting PA recommendation for health self-reported at 8-12 (baseline), 26-28 and 36-37 weeks’ gestation. Multilevel analysis with adjustments was used in testing for between-group differences in PA changes. The decrease in the weekly days of total and moderate-to-vigorous-intensity LTPA was smaller in INT (N = 219) than in UC (N = 180) from baseline to the first follow-up (0.1 vs. -1.2, p = 0.040 and −0.2 vs. -1.3, p = 0.016). A similar trend was seen in meeting the PA recommendation (−11%-points vs. -28%-points, p = 0.06). INT did not experience more adverse events classified as warning signs to terminate exercise than UC, counseling was implemented as planned and viewed positively by the nurses. Intensified counseling had no effects on the duration of total or intensity-specific weekly LTPA. However, it was able to reduce the decrease in the weekly frequency of total and moderate-to-vigorous-intensity LTPA from baseline to the end of second trimester and was feasibly embedded into routine practices. ISRCTN 33885819 ( http://www.isrctn.org )     

Why did patients with cardiovascular disease in the Netherlands accept Q fever vaccination?

This study examines patient's reasons for accepting Q fever vaccination, including risk perception, feelings of doubt, social influence, information-seeking behavior, preventive measures taken, and perceptions regarding received information and governmental action. Data was obtained from exit interviews conducted after Q fever vaccination, between January and April 2011. A total of 413 patients with specific cardiovascular conditions in the Netherlands participated in exit interviews; 70% were older than 60 years. Most reported reasons for accepting Q fever vaccination were: "I am at an increased risk for developing (chronic) Q fever" (69%) and "my general practitioner recommends Q fever vaccination for me" (34%). The majority (86%) reported a high perceived severity of Q fever, and only 6% felt vulnerable to Q fever after vaccination. One-third had doubts about getting vaccinated, primarily related to fears of side effects and practical barriers. Fifty-two percent solicited advice from their social networks; of these, 67% reported influence on their vaccination decision. General practitioners and family were the most reported sources of advice. Thirty percent actively sought information about Q fever vaccination. Twenty-two percent of all respondents had taken other preventive measures, such as avoiding contact with goats and sheep (74%), and cancelling or postponing visits to Q fever-affected areas (36%). Almost one-half of all respondents reported negative feelings regarding governmental action to control Q fever. Significant differences were observed regarding feelings of doubt, information-seeking behavior, perceived vulnerability, preventive measures taken, and perceptions regarding received information and governmental action regarding gender, age, educational level, and/or employment status. Vaccination decision-making may differ among socio-demographic subgroups. When preparing future vaccination campaigns, it is important to obtain greater insight into these differences and take these aspects into account in risk communication strategies by tailoring information to specific target groups.