Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites.

Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.

Can following the caloric restriction recommendations from the Dietary Guidelines for Americans help individuals lose weight?

BACKGROUND: The Dietary Guidelines for Americans recommend creating an energy deficit of at least 500 kcal a day to facilitate weight loss. This investigation examined the relationship between creating a consistent, self-reported energy deficit of at least 500 kcal a day and weight loss. The relationship between self-monitoring adherence and daily energy intake and expenditure and weight loss was also examined. METHODS: Fifty-four overweight or obese adults (BMI>or=27 kg/m(2)) participating in a 14-week weight loss program were given a 5% total body weight loss goal and instructed to create an energy deficit of at least 500 kcal a day to facilitate weight loss. Participants provided daily records of total energy intake and expenditure, physical activity, and weekly and overall weight loss during treatment. RESULTS: Individuals who averaged an energy deficit in excess of 500 kcal per day lost nearly four times the weight as individuals whose average energy deficit was below 500 kcal per day (p<.01). Individuals who lost 5% of their body weight during the intervention self-monitored more than twice as many days than individuals who failed to lose 5% of their body weight (p<.01). CONCLUSION: Individuals interested in losing weight should continue to be advised to regularly self-monitor energy intake and expenditure as well as to create a consistent daily energy deficit (e.g., 500 kcal day).

Skipping meals and alcohol consumption. The regulation of energy intake and expenditure among weight loss participants.

Research suggests that specific eating patterns (e.g., eating breakfast) may be related to favorable weight status. This investigation examined the relationship between eating patterns (i.e., skipping meals; consuming alcohol) and weight loss treatment outcomes (weight loss, energy intake, energy expenditure, and duration of exercise). Fifty-four overweight or obese adults (BMI> or =27 kg/m(2)) participated in a self-help or therapist-assisted weight loss program. Daily energy intake from breakfast, lunch, dinner, and alcoholic beverages, total daily energy intake, total daily energy expenditure, physical activity, and weekly weight loss were assessed. On days that breakfast or dinner was skipped, or alcoholic beverages were not consumed, less total daily energy was consumed compared to days that breakfast, dinner, or alcoholic beverages were consumed. On days that breakfast or alcohol was consumed, daily energy expenditure (breakfast only) and duration of exercise were higher compared to days that breakfast or alcohol was not consumed. Individuals who skipped dinner or lunch more often had lower energy expenditure and exercise duration than individuals who skipped dinner or lunch less often. Individuals who consumed alcohol more often had high daily energy expenditure than individuals who consumed alcohol less often. Skipping meals or consuming alcoholic beverages was not associated with weekly weight loss. In this investigation, weight loss program participants may have compensated for excess energy intake from alcoholic beverages and meals with greater daily energy expenditure and longer exercise duration.

The failure of therapist assistance and stepped-care to improve weight loss outcomes.

OBJECTIVE: This investigation was designed to examine whether: (i) individuals could successfully lose 5% of their body weight with minimal assistance, (ii) weight loss would be improved by the addition of therapist assistance, and (iii) individuals unsuccessful at losing 5% total body weight during the minimal assistance phase (with or without therapist assistance) would benefit from a weekly weight loss group. METHODS AND PROCEDURES: Fifty-four overweight or obese adults (BMI > 27 kg/m(2)) initially participated in a 14-week self-help (SH) or therapist-assisted SH (TASH) weight loss program. Participants who were unsuccessful at losing 5% total body weight were stepped-up to a 3-month, group-based behavioral weight loss program (BWLP) with weekly weigh-ins. RESULTS: Although approximately 60% of the participants were successful at losing 5% of their total body weight (lb) during the minimal assistance phase (M = 10.6; s.d. = 11.5; P < 0.01), treatment outcome was not improved by the addition of therapist assistance. For individuals who were unsuccessful at losing 5% of total body weight during a minimal assistance phase, the addition of a group-based BWLP did not improve their weight loss. DISCUSSION: While many individuals were quite successful at losing weight with minimal assistance, other individuals evidenced difficulties losing weight, even when participating in a greater intensity intervention (i.e., BWLP group).