Impairing energy metabolism in solid tumors through agents targeting oncogenic signaling pathways

Cell metabolic reprogramming is one of the main hallmarks of cancer and many oncogenic pathways that drive the cancer-promoting signals also drive the altered metabolism. This review focuses on recent data on the use of oncogene-targeting agents as potential modulators of deregulated metabolism in different solid cancers. Many drugs, originally designed to inhibit a specific target, then have turned out to have different effects involving also cell metabolism, which may contribute to the mechanisms underlying the growth inhibitory activity of these drugs. Metabolic reprogramming may also represent a way by which cancer cells escape from the selective pressure of targeted drugs and become resistant. Here we discuss how targeting metabolism could emerge as a new effective strategy to overcome such resistance. Finally, accumulating evidence indicates that cancer metabolic rewiring may have profound effects on tumor-infiltrating immune cells. Modulating cancer metabolic pathways through oncogene-targeting agents may not only restore more favorable conditions for proper lymphocytes activation, but also increase the persistence of memory T cells, thereby improving the efficacy of immune-surveillance

An update on hepatocellular carcinoma in chronic kidney disease

Chronic kidney disease is a major public health issue globally and the risk of cancer (including HCC) is greater in patients on long-term dialysis and kidney transplant compared with the general population. According to an international study on 831,804 patients on long-term dialysis, the standardized incidence ratio for liver cancer was 1.2 (95% CI, 1.0–1.4) and 1.5 (95% CI, 1.3–1.7) in European and USA cohorts, respectively. It appears that important predictors of HCC in dialysis population are hepatotropic viruses (HBV and HCV) and cirrhosis. 1-, 3-, and 5-year survival rates are lower in HCC patients on long-term dialysis than those with HCC and intact kidneys. NAFLD is a metabolic disease with increasing prevalence worldwide and recent evidence shows that it is an important cause of liver-related and extra liver-related diseases (including HCC and CKD, respectively). Some longitudinal studies have shown that patients with chronic hepatitis B are aging and the frequency of comorbidities (such as HCC and CKD) is increasing over time in these patients; it has been suggested to connect these patients to an appropriate care earlier. Antiviral therapy of HBV and HCV plays a pivotal role in the management of HCC in CKD and some combinations of DAAs (elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir-based regimens) are now available for HCV positive patients and advanced chronic kidney disease. The interventional management of HCC includes liver resection. Some ablative techniques have been suggested for HCC in CKD patients who are not appropriate candidates to surgery. Transcatheter arterial chemoembolization has been proposed for HCC in patients who are not candidates to liver surgery due to comorbidities. The gold standard for early-stage HCC in patients with chronic liver disease and/or cirrhosis is still liver transplant.Fil: Fabrizi, Fabrizio. No especifíca;Fil: Cerutti, Roberta. No especifíca;Fil: Alfieri, Carlo M.. Università degli Studi di Milano; ItaliaFil: Ridruejo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentin

Fighting tertiary mutations in EGFR-driven lung-cancers: Current advances and future perspectives in medicinal chemistry

Third-generation inhibitors of the epidermal growth factor receptor (EGFR), best exemplified by osimertinib, have been developed to selectively target variants of EGFR bearing activating mutations and the mutation of gatekeeper T790 in patients with EGFR-mutated forms of Non-Small Cell Lung Cancer (NSCLC). While the application of third-generation inhibitors has represented an effective first- and second-line treatment, the efficacy of this class of inhibitors has been hampered by the novel, tertiary mutation C797S, which may occur after the treatment with osimertinib. More recently, other point mutations, including L718Q, G796D, G724S, L792 and G719, have emerged as mutations mediating resistance to third-generation inhibitors. The challenge of overcoming newly developed and recurrent resistances mediated by EGFR-mutations is thus driving the search of alternative strategies in the design of new therapeutic agents able to block EGFR-driven tumor growth. In this manuscript we review the recently emerged EGFR-dependent mechanisms of resistance to third-generation inhibitors, and the achievements lately obtained in the development of next-generation EGFR inhibitors

A multilevel data integration resource for breast cancer study

BACKGROUND: Breast cancer is one of the most common cancer types. Due to the complexity of this disease, it is important to face its study with an integrated and multilevel approach, from genes, transcripts and proteins to molecular networks, cell populations and tissues. According to the systems biology perspective, the biological functions arise from complex networks: in this context, concepts like molecular pathways, protein-protein interactions (PPIs), mathematical models and ontologies play an important role for dissecting such complexity. RESULTS: In this work we present the Genes-to-Systems Breast Cancer (G2SBC) Database, a resource which integrates data about genes, transcripts and proteins reported in literature as altered in breast cancer cells. Beside the data integration, we provide an ontology based query system and analysis tools related to intracellular pathways, PPIs, protein structure and systems modelling, in order to facilitate the study of breast cancer using a multilevel perspective. The resource is available at the URL http://www.itb.cnr.it/breastcancer. CONCLUSIONS: The G2SBC Database represents a systems biology oriented data integration approach devoted to breast cancer. By means of the analysis capabilities provided by the web interface, it is possible to overcome the limits of reductionist resources, enabling predictions that can lead to new experiments

Towards a systems biology approach to mammalian cell cycle: modeling the entrance into S phase of quiescent fibroblasts after serum stimulation

Background: The cell cycle is a complex process that allows eukaryotic cells to replicate chromosomal DNA and partition it into two daughter cells. A relevant regulatory step is in the G0/G1phase, a point called the restriction (R) point where intracellular and extracellular signals are monitored and integrated. Results: Subcellular localization of cell cycle proteins is increasingly recognized as a major factor that regulates cell cycle transitions. Nevertheless, current mathematical models of the G1/S networks of mammalian cells do not consider this aspect. Hence, there is a need for a computational model that incorporates this regulatory aspect that has a relevant role in cancer, since altered localization of key cell cycle players, notably of inhibitors of cyclin-dependent kinases, has been reported to occur in neoplastic cells and to be linked to cancer aggressiveness. Conclusion: The network of the model components involved in the G1to S transition process was identified through a literature and web-based data mining and the corresponding wiring diagram of the G1to S transition drawn with Cell Designer notation. The model has been implemented in Mathematica using Ordinary Differential Equations. Time-courses of level and of sub-cellular localization of key cell cycle players in mouse fibroblasts re-entering the cell cycle after serum starvation/re-feeding have been used to constrain network design and parameter determination. The model allows to recapitulate events from growth factor stimulation to the onset of S phase. The R point estimated by simulation is consistent with the R point experimentally determined. The major element of novelty of our model of the G1to S transition is the explicit modeling of cytoplasmic/nuclear shuttling of cyclins, cyclin-dependent kinases, their inhibitor and complexes. Sensitivity analysis of the network performance newly reveals that the biological effect brought about by Cki overexpression is strictly dependent on whether the Cki is promoting nuclear translocation of cyclin/Cdk containing complexes. © 2009 Alfieri et al; licensee BioMed Central Ltd

Small airway dysfunction predicts excess ventilation and dynamic hyperinflation during exercise in patients with COPD

Introduction: Small airway dysfunction (SAD) is a pathophysiological characteristic of chronic obstructive pulmonary disease (COPD). Excess ventilation and dynamic hyperinflation (DH) are two main pathophysiological traits and limiting factors of COPD patients while exercising. We aimed to ascertain whether or not SAD, assessed by the multiple breath nitrogen washout (MBNW), may predict exercise ventilatory inefficiency and DH. Methods: Fifty stable COPD patients were prospectively studied and underwent MBNW and incremental cardio-pulmonary exercise test (CPET). Indices of conductive (Scond) and acinar (Sacin) ventilation heterogeneity as well as minute ventilation/CO2 production (VE/VCO2) linear relationship and the change in inspiratory capacity (IC) were analyzed. Results: Sacin was significantly and directly related to VE/VCO2 slope and inversely related to IC change and to peak O2 uptake (p < 0.01 for all correlations). No significant correlation was found between Scond and CPET parameters. The regression equation generated by stepwise multiple regression analysis for the VE/VCO2 slope and IC change, as dependent variables, included only Sacin, as independent variable. This model accounted for 31% and 36% of the total variance for the VE/VCO2 slope and IC change, respectively. Conclusion: Our study shows the value of the SAD as determinant of the excess ventilation and DH during exercise in patients with stable COPD

Hypertonic Stress and Amino Acid Deprivation Both Increase Expression of mRNA for Amino Acid Transport System A

Amino acid transport system A (SNAT2) in Chinese hamster ovary (CHO-K1) cells was stimulated when the cells were depleted of amino acids or subjected to hypertonic stress. Each of these stresses also caused increases in the abundance of SNAT2 mRNA in these cells. Similar results were obtained with Madin-Darby canine kidney (MDCK) cells, porcine pulmonary artery endothelial cells and human WI-38 fibroblasts. We conclude that the cellular signal transduction pathways for hypertonic stress and amino acid starvation must converge at or before transcription of the message for SNAT2

Ankle electromyography among the young and the elderly

O envelhecimento altera a função musculoesquelética prejudicando a marcha e a manutenção do equilíbrio corporal. Objetivo: Verificar e comparar a atividade eletromiográfica (EMG) da região do tornozelo de idosos e jovens fisicamente ativos. Método: Participaram deste ensaio 40 indivíduos de ambos os sexos considerados fisicamente ativos mediante o Questionário Internacional de Atividade Física - IPAQ (formato curto). Não participaram do estudo aqueles com algum tipo de condição clínica que afetasse o equilíbrio e contração muscular. Avaliou-se a atividade eletromiográfica (EMG) dos músculos tibial anterior e tríceps sural na posição bipodal (BA) e unipodal (UA), com olhos abertos. Para a captação dos sinais EMG foram utilizados eletrodos monopolares de superfície Ag/AgCl da KENDALL (MEDITRACETM 200). O teste t de Student foi utilizado para a comparação entre os grupos. O nível de significância adotado foi p &lt; 0,05. Resultados: Os idosos exibiram valores superiores quanto a frequência de potenciais de ação em 3 das 4 condições avaliadas. Conclusão: Os idosos deste estudo exibiram maior frequência de disparos e recrutamento de unidades motoras dos músculos do tornozelo para a manutenção das posturas unipodal e bipodal, em comparação aos jovens.Aging changes the musculoskeletal function and affects gait and body balance. Objective: To compare the electromyographic activity (EMG) of the ankles of physically active older and younger people. Method: Forty subjects of both genders considered physically active through the International Physical Activity Questionnaire - IPAQ (short format) participated in this study. Those with some kind of medical condition that could affect balance and muscle contraction did not participate in the study. We evaluated the electromyographic activity (EMG) of the tibialis anterior and triceps surae in bipedal stance (BS) and single-leg (US) with eyes open. To capture the EMG, monopolar Ag/AgCl surface electrodes from KENDALL (MEDITRACETM 200) were used. The Student t test was used for comparison between groups. The level of significance adopted was p &lt; 0.05. Results: Elderly individuals exhibited higher values regarding the frequency of action potentials in 3 of the 4 conditions assessed. Conclusion: The older volunteers in this study exhibited a higher firing rate and recruitment of motor units of the ankle muscles to maintain the bipedal and unipedal stance, as compared to the younger