Therapeutic exploitation of tumor addiction to fatty acids under acidosis

Acidosis is considered as a hallmark of the tumor microenvironment. Indeed, extracellular pH has been determined in a wide variety of cancers to be significantly more acidic than in normal tissues. Recently, we identified an acidosis-driven metabolic shift from a largely glycolytic metabolism towards significant alterations in fatty acid (FA) metabolism allowing the concomitance of FA oxidation and glutamine-fueled FA synthesis. In this study, we aim to take advantage of this lipid addiction of acidosis-adapted cancer cells to evaluate the possibility to force these cells to take up potentially cytotoxic FA. Growth inhibitory effects were observed with omega-6 (n-6) and omega-3 (n-3) polyunsaturated FA (PUFA) in proportion to the number of unsaturations for both PUFA. More precisely, while short-chain PUFA had only minor effects on cancer cell growth, long-chain PUFA, such as docosapentaenoic acid (DPA n-6) and docosahexaenoic acid (DHA n-3) induced specific cytotoxic effects on acidosis-adapted cells but not on parental cells (at pH 7.4). Furthermore, we found that PUFA are less (rapidly) metabolized than corresponding saturated FA and block respiration fueled by saturated FA in acidosis-adapted cancer cells. Finally, we showed that 3D tumor spheroid growth was severely impaired upon treatment with DPA n-6 and DHA n-3. This growth inhibitory effect was observed only after 4 to 7 days of PUFA administration, which corresponds to the timing for acidosis development. The above effects suggest that PUFA administration could represent a modality to block tumor growth and disease progression in vivo

Metabolic plasticity and adaptive resistance to metabolic inhibitors in tumor cells

Nowadays, tumor metabolism represents an attractive field to develop new anticancer drugs. Cancer cells may however adapt their metabolic preferences to counteract a specific pathway inhibition. Our study aims to identify the optimal combination of metabolism-targeting drugs, in order to prevent a possible escape for cancer cells. The rationale behind our work is, with a first drug, to force cancer cells to become addicted to specific bioenergetic fuels/pathways in order to render a second drug lethal. For the proof of principle, we used 3-bromopyruvate (3-BrPA) as a first metabolism-targeting drug and generated clones resistant to this compound. We showed in three different 3-BrPA-resistant (3-BrPA-R) cell lines that resistance was associated with the downregulation of MCT1, a lactate/H+ membrane co-transporter. Using Seahorse respirometry and metabolite quantification, we confirmed that the induced lack of MCT1 was associated with a deficit of 3-BrPA-R cancer cells to take up extracellular lactate and use it as a fuel. Furthermore, we found that a pre-challenge with 3-BrPA led to the selection of cancer cells with a strict dependence towards MCT4 expression to support glycolytic flux and cell growth. This shift in MCT expression was further associated with an increased resistance of 3-BrPA-R cells to hypoxia and a preferred location of resistant clones within the hypoxic core of 3D tumor spheroids. Our work positions MCT4 inhibitors as attractive drug candidates to be combined with 3BrPA. This hypothesis is currently being tested and if validated, will shed light on how to overcome metabolic plasticity and associated therapy resistance

Intraoperative 3D imaging system in spine surgery: evaluation after 2 years with a retropective analysis of 586 pedicle screws

Purpose : The goals of this paper are to assess the clinical utility and accuracy of a novel intraoperative 3D imaging system for evaluation of pedicle screws positon, and to evaluate and compare the efficacy of this system versus conventional post-operative CT scan. Methods: Intraoperative 2D/3D imaging systems associated or not with navigation system was utilized to place the pedicle screws. An intraoperative 3D cbCT was obtained after all screws were inserted. Two surgeons have retrospectively and independently reviewed all the images to evaluate the position of screw according to breaches classification system. A postoperative CT scan was performed for some patients and was reviewed by a third operator with the same classification to compare the accuracy of these two imaging control. Results: The position of 586 pedicle screws was analysis. Four hundred ninety-six screwsv(84.6%) were grade 1, twenty-four screws (4.1%) were grade 2, twenty-one screws (3.6%) were grade 3, ten screws (1.7%) were grade 4, four screws (0.7%) were grade 5, five screws (0.9%) were grade 6 and twenty-six screws (4.4%) were grade 7. Total percent of breach was 15.4%. Seventeen screws were repositioned intraoperatively after the 3D control, one of us presented at follow-up paresthesia of the big toe. Test of Kappa had showed almost a prefect agreement (0.82) between gold standard (CT scan) and new intraoperative 2D/3D cbCT imaging system. Conclusion: This new intraoperative technic evaluating position of pedicle screws in cbCT images is a feasible and reliable means, and could render the postoperative CT scan control superfluou

Effects of preoperative combined aerobic and resistance exercise training in cancer patients undergoing resection surgery: A systematic review of randomised trials

Background: Surgical management remains the cornerstone of treatment for many cancers, but is associated with a high rate of postoperative complications, which are linked to poor preoperative functional capacity. Prehabilitation may have beneficial effects on functional capacity and postoperative outcomes. Purpose: T he purpose of this study is to evaluate the effects of prehabilitation combining endurance and resistance training (CT) on physical fitness, quality of life (QoL) and postoperative outcomes in cancer patients undergoing tumour resection surgery. Methods: We performed a literature search in PubMe d, PEDro, EMBASE (via Scopus) and the Cochrane library for clinical trials until September 2017. Randomised controlled trials investigating the effects of CT in adult cancer patients undergoing surgery were included when at least one of the following outcomes was reported: physical capacity, muscle strength, QoL, length of stay (LOS), postoperative complications and mortality. Results: Ten studies (360 patients) were r etrieved and included patients with lung, colorectal, bladder and oesophageal cancer. No adverse effects of CT were reported. Compared with the control group, CT improved physical capacity (3 of 5 studies), muscle strength (2 of 3 studies) and some domains of QoL (2 of 4 studies), shortened LOS (1 of 6 studies) and reduced postoperative pulmonary complications (2 of 6 studies). Conclusion(s): The benefits o f CT in cancer population are demonstrated. CT may improve physical fitness and QoL and decrease LOS and postoperative pulmonary complications. However, our conclusions are limited by the heterogeneity of the preoperative CT programs, patient characteristics and measurement tools. Future research is required to determine the optimal composition of CT. Implications: Prehabilitation in cancer patients undergoing tumour resection surgery may be an opportunity to optimize functional capacity before surgery and to improve postoperative recovery and quality of life. This preoperative process makes patients with cancer involved in their treatment and should be encourage by health care providers

PEX1 p.G844D +/+ NMRI mouse: a robust pre-clinical model for mild Zellweger spectrum disorder

Zellweger spectrum disorders (ZSD) form a clinical spectrum of diseases due to a peroxisome biogenesis disorder attributable to mutations in PEX genes. ZSD has an incidence of 1:50.000 live-births. Characteristically elevated levels of phytanic, pristanic, pipecolic, and very long-chain fatty acids, and abnormal bile acid intermediates are observed in the plasma of affected children. Clinical presentation ranges from liver failure and death in infancy to chronic liver disease, neurodevelopmental delay, deafness and blindness among those who survive beyond the first decade of life (mild ZSD). No routine treatment has been shown to arrest or reverse the natural history of this terrible disease. Yet, we previously demonstrated the benefit of liver transplantation or hepatocyte transplantation (HT) on biochemical and clinical outcome in 4 patients with mild ZSD. The aim of this study was to validate a mouse model homozygous for the PEX1 p.G844D hypomorphic mutation as a pre-clinical model for mild ZSD treatment evaluation. We started a colony using 6 PEX1 p.G844D +/- C57BL/6N mice from Jackson Laboratory; +/+ mice (ZSD) are sterile and die within one month. We backcrossed three times the mutation in a NMRI background to get larger litters and more robust homozygous mice. Mice growth and food intake were regularly quantified. We measured mice glycemia before and after a 6 hours fasting test. Mice livers collected at 2 months of age were weighted, fixed, paraffin embedded and stained with periodic-acid Schiff (PAS) ± diastase (as a proxy for glycogen content). ZSD mice exhibited (1) a severe growth retardation associated to an increased food intake/g body weight, (2) lower fed blood glucose levels and (3) a worse fasting resistance. PAS staining on liver sections was severely reduced in fed ZSD mice meaning a low glycogen content. This could be one explanation for their reduced fasting resistance. Scarce peroxisomal ghosts where shown in ZSD mice livers by immunofluorescence staining of the 70-kDa peroxisome membrane protein (PMP70). All the above mentioned classical ZSD metabolites were elevated in ZSD mice compared to their WT siblings. In conclusion, PEX1 p.G844D +/+ NMRI mice are a good and robust pre-clinical model recapitulating liver involvement and growth retardation of mild ZSD. We are currently evaluating HT as a potential therapeutic approach in this model

Pedicle screw placement accuarcy using a new intraoperative cone-beam computed tomography imaging technique: retrospective analysis of 586 pedicle scerws.

Pedicle screws are used for the treatment of various pathologies. Ideally placed screw is fully contained within the pedicle with no breach. The gold standard to assess screw placement is postoperative CT scan. New intraoperative imaging techniques have been adapted to enable direct pedicle breach determination. Artis zeego (Artis zeego, Siemens Healthcare, Forchheim, Germany) is a new intraoperative CBCT imaging technique used in our institution. We aim to firstly assess the accuracy of pedicle screw placement using it and then assess the efficacy of this new CBCT technique for intraoperative assessment of pedicle screw insertion and pedicle breach determination, and to compare it with conventional postoperative CT scan

Risk taking behaviors among HIV­-carriers in Burkina Faso: A population-based survey

The aim of the study was to assess sexual risk behaviors of HIV-positive people in Burkina Faso....Despite nationwide efforts to reduce risk behaviors in the general population, more campaigns should be addressed towards HIV-positive people for safe sex, especially in rural areas and within illiterate people and women. This should contribute to reducing HIV incidence in the country