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Background: Low-carbohydrate diets have become increasingly popular for weight loss. However, evidence from individual trials about benefits and risks of these diets to achieve weight loss and modify cardiovascular risk factors is preliminary. Methods: We used the Cochrane Collaboration search strategy to identify trials comparing the effects of lowcarbohydrate diets without restriction of energy intake vs low-fat diets in individuals with a body mass index (calculated as weight in kilograms divided by the square of height in meters) of at least 25. Included trials had to report changes in body weight in intention-to-treat analysis and to have a follow-up of at least 6 months. Two reviewers independently assessed trial eligibility and quality of randomized controlled trials. Results: Five trials including a total of 447 individuals fulfilled our inclusion criteria. After 6 months, individuals assigned to low-carbohydrate diets had lost more weight than individuals randomized to low-fat diets (weighted mean difference,-3.3 kg; 95% confidence interval [CI], −5.3 to −1.4 kg). This difference was no longer obvious after 12 months (weighted mean difference, −1.0 kg; 95% CI, −3.5 to 1.5 kg). There were no differences in blood pressure. Tri-glyceride and high-density lipoprotein cholesterol values changed more favorably in individuals assigned to lowcarbohydrate diets (after 6 months, for triglycerides, weighted mean difference, −22.1 mg/dL [−0.25 mmol/L]; 95% CI, −38.1 to −5.3 mg/dL [−0.43 to −0.06 mmol/L]; and for high-density lipoprotein cholesterol, weighted mean difference, 4.6 mg/dL [0.12 mmol/L]; 95% CI, 1.5-8.1 mg/dL [0.04-0.21 mmol/L]), but total cholesterol and lowdensity lipoprotein cholesterol values changed more favorably in individuals assigned to low-fat diets (weighted mean difference in low-density lipoprotein cholesterol after 6 months, 5.4 mg/dL [0.14 mmol/L]; 95% CI, 1.2-10.1 mg/dL [0.03-0.26 mmol/L]). Conclusions: Low-carbohydrate, non-energy-restricted diets appear to be at least as effective as low-fat, energyrestricted diets in inducing weight loss for up to 1 year. However, potential favorable changes in triglyceride and highdensity lipoprotein cholesterol values should be weighed against potential unfavorable changes in low-density lipoprotein cholesterol values when low-carbohydrate diets to induce weight loss are considered.

Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility. We directly validated this Doxycycline-induced glycolytic phenotype, by using metabolic flux analysis and label-free unbiased proteomics. Next, we identified two natural products (Vitamin C and Berberine) and six clinically-approved drugs, for metabolically targeting the Doxycycline-resistant CSC population (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol). This new combination strategy allows for the more efficacious eradication of CSCs with Doxycycline, and provides a simple pragmatic solution to the possible development of Doxycycline-resistance in cancer cells. In summary, we propose the combined use of i) Doxycycline (Hit-1: targeting mitochondria) and ii) Vitamin C (Hit-2: targeting glycolysis), which represents a new synthetic-lethal metabolic strategy for eradicating CSCs. This type of metabolic Achilles' heel will allow us and others to more effectively "starve" the CSC population.

Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

Serum visceral proteins such as albumin and prealbumin have traditionally been used as markers of the nutritional status of patients. Prealbumin is nowadays often preferred over albumin due to its shorter half live, reflecting more rapid changes of the nutritional state. However, recent focus has been on an appropriate nutrition-focused physical examination and on the patient’s history for diagnosing malnutrition, and the role of inflammation as a risk factor for malnutrition has been more and more recognized. Inflammatory signals are potent inhibitors of visceral protein synthesis, and the use of these proteins as biomarkers of the nutritional status has been debated since they are strongly influenced by inflammation and less so by protein energy stores. The current consensus is that laboratory markers could be used as a complement to a thorough physical examination. Other markers of the nutritional status such as urinary creatinine or 3-methylhistidine as indicators of muscle protein breakdown have not found widespread use. Serum IGF-1 is less influenced by inflammation and falls during malnutrition. However, its concentration changes are not sufficiently specific to be useful clinically as a marker of malnutrition, and serum IGF-1 has less been used in clinical trials. Nevertheless, biomarkers of malnutrition such as prealbumin may be of interest as easily measurable predictors of the prognosis for surgical outcomes and of mortality in severe illnesses.

Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.

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