Prospective evaluation of weekly concomitant tumor bed boost with three-week hypofractionated whole breast irradiation in early breast cancer

Objectives: A prospective study was conducted to assess the acute and late toxicity of hypofractionated whole breast irradiation with a weekly concomitant boost for women with early breast cancer (EBC). Methods: Women with EBC who underwent breast-conserving surgery were eligible. A dose of 40Gy in 15 fractions over 3 weeks was delivered to the whole breast with a concomitant weekly boost to the post-operative cavity of 3Gy in three fractions. Toxicity was graded using the Radiation Therapy Oncology Group (RTOG) acute toxicity and RTOG/EORTC late toxicity scales. Results: A total of 67 women were enrolled with a median age of 49 years (range 31–69). Median follow-up was 25 months (range 11–34). Acute skin reactions included grade (G) 1 (n = 47, 70%), G2 (n = 10, 13%), and G3 (n = 1, 1.5%). Late skin toxicity was observed in 13 patients (19%), all of whom experienced G1 toxicity only. On multivariable analysis, diabetes mellitus was predictive of acute skin toxicity (p = 0.003), while age less than 50 years (p = 0.029) and diabetes mellitus (p = 0.013) were predictive of late skin toxicity. Conclusions: Whole breast irradiation with concomitant weekly boost appears feasible and safe. Further investigation is required to fully evaluate this schedule as an alternative to conventional whole breast irradiation with a sequential boost

The influence of behavioural and health problems on alcohol and drug use in late adolescence - a follow up study of 2 399 young Norwegians

<p>Abstract</p> <p>Background</p> <p>Both early alcohol debut, behavioural and health problems are reported to enhance adolescence substance use. This prospective study investigate the influence of behavioural and health problems on adolescents' alcohol and drug use.</p> <p>Method</p> <p>Prospective population based cohort study of 2 399 adolescents attending the Young-HUNT study, aged 13-15 at baseline in 1995/97, and 17-19 at follow-up 4 years later. Exposure variables were self reported conduct problems, attention problems, anxiety and depressive symptoms, and muscular pain and tension. Outcome variables at follow-up were frequent alcohol use and initiation of drug use. Associations were estimated by logistic regression models, influence of gender and drinking status at baseline were controlled for by stratification.</p> <p>Results</p> <p>At follow-up 19% of the students drank alcohol once a week or more frequently. Baseline conduct problems (OR 2.2, CI 1.7-3.0) and attention problems (OR 1.5, CI 1.2-2.0) increased the risk for frequent alcohol use at follow-up in the total population. Girls who had experienced alcohol-intoxications at baseline showed strong association between baseline problems and frequent alcohol use at follow-up. Conduct problems (OR 2.5, CI 1.3-4.8), attention problems (OR 2.1, CI 1.2-3.4), anxiety/depressive symptoms (OR 1.9, CI 1.1-3.1) and muscular pain and tension (OR 1.7, CI 1.0-2.9) all were associated with frequent alcohol use among early intoxicated girls.</p> <p>14% of the students had tried cannabis or other drugs at follow-up. Conduct problems at baseline increased the odds for drug use (OR 2.6, CI 1.9-3.6). Any alcohol intoxications at baseline, predicted both frequent alcohol use (boys OR 3.6, CI 2.4-5.2; girls OR 2.8, CI 1.9-4.1), and illegal drug use (boys OR 4.7; CI 3.2-7.0, girls OR 7.7, CI 5.2-11.5) within follow-up.</p> <p>Conclusions</p> <p>Conduct problems in high-school more than doubles the risk for both frequent alcohol use and initiation of drug use later in adolescence. The combination of health problems and alcohol intoxication in early adolescence was closely associated with more frequent drinking later in adolescence among girls.</p> <p>Overall, early alcohol intoxication was closely associated with both frequent alcohol use and drug use at follow up in both genders</p

Both Geography and Ecology Contribute to Mating Isolation in Guppies

Local adaptation to different environments can promote mating isolation – either as an incidental by-product of trait divergence, or as a result of selection to avoid maladaptive mating. Numerous recent empirical examples point to the common influence of divergent natural selection on speciation based largely on evidence of strong pre-mating isolation between populations from different habitat types. Accumulating evidence for natural selection's influence on speciation is therefore no longer a challenge. The difficulty, rather, is in determining the mechanisms involved in the progress of adaptive divergence to speciation once barriers to gene flow are already present. Here, we present results of both laboratory and field experiments with Trinidadian guppies (Poecilia reticulata) from different environments, who do not show complete reproductive isolation despite adaptive divergence. We investigate patterns of mating isolation between populations that do and do not exchange migrants and show evidence for both by-product and reinforcement mechanisms depending on female ecology. Specifically, low-predation females discriminate against all high-predation males thus implying a by-product mechanism, whereas high-predation females only discriminate against low-predation males from further upstream in the same river, implying selection to avoid maladaptive mating. Our study thus confirms that mechanisms of adaptive speciation are not necessarily mutually exclusive and uncovers the complex ecology-geography interactions that underlie the evolution of mating isolation in nature

A prospective investigation of swallowing, nutrition, and patient-rated functional impact following altered fractionation radiotherapy with concomitant boost for oropharyngeal cancer

Altered fractionation radiotherapy for head and neck cancer has been associated with improved locoregional control, overall survival, and heightened toxicity compared with conventional treatment. Swallowing, nutrition, and patient-perceived function for altered fractionation radiotherapy with concomitant boost (AFRT-CB) for T1–T3 oropharyngeal squamous cell carcinoma (SCC) have not been previously reported. Fourteen consecutive patients treated with AFRT-CB for oropharyngeal SCC were recruited from November 2006 to August 2009 in a tertiary hospital in Brisbane, Australia. Swallowing, nutrition, and patient-perceived functional impact assessments were conducted pretreatment, at 4–6 weeks post-treatment, and at 6 months post-treatment. Deterioration from pretreatment to 4–6 weeks post-treatment in swallowing, nutrition, and functional impact was evident, likely due to the heightened toxicity associated with AFRT-CB. There was significant improvement at 6 months post-treatment in functional swallowing, nutritional status, patient-perceived swallowing, and overall function, consistent with recovery from acute toxicity. However, weight and patient perception of physical function and side effects remained significantly worse than pretreatment scores. The ongoing deficits related to weight and patient-perceived outcomes at 6 months revealed that this treatment has a long-term impact on function possibly related to the chronic effects of AFRT-CB

Synergistic interplay of Gβγ and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity.

Kv7.4 channels are key determinants of arterial contractility and cochlear mechanosensation that, like all Kv7 channels, have an obligatory requirement for phosphatidylinositol 4,5-bisphosphate (PIP2). βγ G proteins (Gβγ) have been identified as novel positive regulators of Kv7.4. The present study ascertained whether Gβγ increased Kv7.4 open probability through an increased sensitivity to PIP2. In HEK cells stably expressing Kv7.4, PIP2 or Gβγ increased open probability in a concentration dependent manner. Depleting PIP2 prevented any Gβγ-mediated stimulation whilst an array of Gβγ inhibitors prohibited any PIP2-induced current enhancement. A combination of PIP2 and Gβγ at sub-efficacious concentrations increased channel open probability considerably. The stimulatory effects of three Kv7.2-7.5 channel activators were also lost by PIP2 depletion or Gβγ inhibitors. This study alters substantially our understanding of the fundamental processes that dictate Kv7.4 activity, revealing a more complex and subtle paradigm where the reliance on local phosphoinositide is dictated by interaction with Gβγ