Lactate Upregulates the Expression of DNA Repair Genes, Causing Intrinsic Resistance of Cancer Cells to Cisplatin

Intrinsic or acquired drug resistance is one of the major problems compromising the success of antineoplastic treatments. Several evidences correlated some therapeutic failures with changes in cell metabolic asset and in line with these findings, hindering the glycolytic metabolism of cancer cells via lactate dehydrogenase (LDH) inhibition was found to overcome the resistance to chemotherapeutic agents. Lactate, the product of LDH reaction, was shown to be involved in epigenetic regulation of gene expression. The experiments described in this paper were aimed at highlighting a possible direct effect of lactate in modifying the response of cancer cells to a chemotherapeutic treatment. To discriminate between the effects potentially caused by glycolytic metabolism from those directly referable to lactate, we selected cancer cell lines able to grow in glucose deprived conditions and evaluated the impact of lactate on the cellular response to cisplatin-induced DNA damage. In lactate-exposed cells we observed a reduced efficacy of cisplatin, which was associated with reduced signatures of DNA damage, enhanced DNA recombination competence and increased expression of a panel of genes involved in DNA repair. The identified genes take part in mismatch and nucleotide excision repair pathways, which were found to contribute in restoring the cisplatin-induced DNA damage. The obtained results suggest that this metabolite could play a role in reducing the efficacy of antineoplastic treatments

The activation of lactate dehydrogenase induced by mTOR drives neoplastic change in breast epithelial cells

mTOR kinase and the A isoform of lactate dehydrogenase (LDH-A) are key players controlling the metabolic characteristics of cancer cells. By using cultured human breast cells as a \u201cmetabolic tumor\u201d model, we attempted to explore the correlation between these two factors. \u201cMetabolic tumors\u201d are defined as neoplastic conditions frequently associated with features of the metabolic syndrome, such as hyper-insulinemia and hyper-glycemia. MCF-7 cells (a well differentiated carcinoma) and MCF-10A cells (a widely used model for studying normal breast cell transformation) were used in this study. These cells were exposed to known factors triggering mTOR activation. In both treated cultures, we evaluated the link between mTOR kinase activity and the level of LDH expression / function. Furthermore, we elaborated the metabolic changes produced in cells by the mTOR-directed LDH-A up-regulation. Interestingly, we observed that in the non-neoplastic MCF-10A culture, mTOR-directed up-regulation of LDH-A was followed by a reprogramming of cell metabolism, which showed an increased dependence on glycolysis rather than on oxidative reactions. As a consequence, lactate production appeared to be enhanced and cells began to display increased self-renewal and clonogenic power: signals suggestive of neoplastic change. Enhanced clono-genicity of cells was abolished by rapamycin treatment, and furthermore heavily reduced by LDH enzymatic inhibition. These results highlighted a mechanistic link between metabolic alterations and tumorigenesis, whereby suggesting LDH inhibition as a possible chemo-preventive measure to target the metabolic alterations driving neoplastic change

Endocannabinoids and cardiovascular prevention: real progress?

The prevalence of obesity continues to increase and represents one of the principal causes of cardiovascular morbidity and mortality. After the discovery of a specific receptor of the psychoactive principle of marijuana, the cannabinoid receptors and their endogenous ligands, several studies have demonstrated the role of this system in the control of food intake and energy balance and its overactivity in obesity. Recent studies with the CB1 receptor antagonist rimonabant have demonstrated favorable effects such as a reduction in body weight and waist circumference and an improvement in metabolic factors (cholesterol, triglycerides, glycemia etc). Therefore, the antagonism of the endocannabinoid (EC) system, if recent data can be confirmed, could be a new treatment target for high risk overweight or obese patients. Obesity is a growing problem that has epidemic proportions worldwide and is associated with an increased risk of premature death (1–3). Individuals with a central deposition of fats have elevated cardiovascular morbidity and mortality (including stroke, heart failure and myocardial infarction) and, because of a growing prevalence not only in adults but also in adolescents, it was reclassified in AHA guidelines as a “major modifiable risk factor” for coronary heart disease (4, 5). Although first choice therapy in obesity is based on correcting lifestyle (diet and physical activity) in patients with abdominal obesity and high cardiovascular risk and diabetes, often it is necessary to use drugs which reduce the risks. The EC system represents a new target for weight control and the improvement of lipid and glycemic metabolism (6, 7)

Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey

Background: There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. Methods: The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group - KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients' outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. Results: One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p < 0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%; p < 0.0001). Short-term follow data showed minor complications. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data. Conclusion: Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths

The Multi-Vehicle Traveling Purchaser Problem with Pairwise Incompatibility Constraints and Unitary Demands: A Branch-and-Price Approach

In this work we study a suppliers selection and routing problem where a fleet of homogeneous vehicles with a predefined capacity is available for procuring different products from different suppliers with the aim to minimize both the traveling and the purchasing costs. Decisions are further complicated by the presence of pairwise incompatibility constraints among products, implying the impossibility of loading two incompatible products on the same vehicle. The problemis known as the Multi-Vehicle Traveling Purchaser Problem with Pairwise Incompatibility Constraints.We study a variant in which products demand is unitary and propose a column generation approach based on a Dantzig-Wolfe reformulation of the problem, where each column represents a feasible vehicle route associated with a compatible purchasing plan.Two different procedures are introduced to solve the pricing problem, namely a labeling algorithm solving a Resource-Constrained Elementary Shortest Path Problem on an expanded graph, and a tailored branch-and-cut algorithm. Due to the integrality request on variables, we embed the column generation in a branch-and-bound framework and propose different branching rules, thus obtaining a branch-and-price procedure. Extensive tests, carried out on a large set of instances, show that our branch-and-price method performs well, improving on average, both in quality and in computational time, solutions obtained by a branch-and-cut approach existing in the literature that relies on a three-index connectivity constraints based formulation

The Multi-Vehicle Traveling Purchaser Problem with Pairwise Incompatibility Constraints and Unitary Demands: A Branch-and-Price Approach

In this work we study a suppliers selection and routing problem where a fleet of homogeneous vehicles with a predefined capacity is available for procuring different products from different suppliers with the aim to minimize both the traveling and the purchasing costs. Decisions are further complicated by the presence of pairwise incompatibility constraints among products, implying the impossibility of loading two incompatible products on the same vehicle. The problemis known as the Multi-Vehicle Traveling Purchaser Problem with Pairwise Incompatibility Constraints.We study a variant in which products demand is unitary and propose a column generation approach based on a Dantzig-Wolfe reformulation of the problem, where each column represents a feasible vehicle route associated with a compatible purchasing plan.Two different procedures are introduced to solve the pricing problem, namely a labeling algorithm solving a Resource-Constrained Elementary Shortest Path Problem on an expanded graph, and a tailored branch-and-cut algorithm. Due to the integrality request on variables, we embed the column generation in a branch-and-bound framework and propose different branching rules, thus obtaining a branch-and-price procedure. Extensive tests, carried out on a large set of instances, show that our branch-and-price method performs well, improving on average, both in quality and in computational time, solutions obtained by a branch-and-cut approach existing in the literature that relies on a three-index connectivity constraints based formulation

A branch-and-price algorithm for the Multi-Vehicle Travelling Purchaser Problem with Pairwise Incompatibility Constraints and Unitary Demands

In this work we study a suppliers selection and routing problem where a fleet of homogeneous vehicles with a predefined capacity is available for procuring different products from different suppliers with the aim to minimize both the traveling and the purchasing costs. Decisions are further complicated by the presence of pairwise incompatibility constraints among products, implying the impossibility of loading two incompatible products on the same vehicle. The problemis known as the Multi-Vehicle Traveling Purchaser Problem with Pairwise Incompatibility Constraints.We study a variant in which products demand is unitary and propose a column generation approach based on a Dantzig-Wolfe reformulation of the problem, where each column represents a feasible vehicle route associated with a compatible purchasing plan.Two different procedures are introduced to solve the pricing problem, namely a labeling algorithm solving a Resource-Constrained Elementary Shortest Path Problem on an expanded graph, and a tailored branch-and-cut algorithm. Due to the integrality request on variables, we embed the column generation in a branch-and-bound framework and propose different branching rules, thus obtaining a branch-and-price procedure. Extensive tests, carried out on a large set of instances, show that our branch-and-price method performs well, improving on average, both in quality and in computational time, solutions obtained by a branch-and-cut approach existing in the literature that relies on a three-index connectivity constraints based formulation