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Background: Ovarian carcinoma is the leading cause of death from gynecological cancer because there is risk of chemoresistance. As previously demonstrated in our laboratory, Alpha-lipoic acid (LA), a co-factor for metabolic enzymes, suppresses the tumor growth. In this study, we have researched the mechanisms that are responsible for the activity of LA. Methods: We have studied the mechanisms of LA in two ovarian cancer cell lines, a cisplatin sensitive one, IGROV1 and its resistant counterpart, IGROV1-R10. These cells have been exposed to lipoic acid at various concentrations. Cell proliferation, cell cycle repartition and nuclear staining with DAPI were recorded. Western blot analyses were performed to detect various proteins implied in apoptotic cell death pathways. To investigate the formation of ROS, the oxidation of CM-DCFH2-DA were also determined. Findings: LA suppressed growth proliferation and induced apoptosis in both ovarian cell lines. Moreover, LA provoked a down regulation of two anti-apoptotic proteins, Mcl-1 and Bcl-xL protein and a strong induction of the BH3-only protein Bim. Furthermore, LA induced ROS generation which could be involved in the CHOP induction which is known to activate the Bim translation. Conclusions: Our results reveal novel actions of LA which could explain the anti-tumoral effects of the LA. Therefore, LA seems to be a promising compound for ovarian cancer treatment. [ABSTRACT FROM AUTHOR]

The inhibition of two major anti-apoptotic proteins, Bcl-xL and Mcl-1, appears essential to destroy chemoresistant cancer cells. We have studied their concomitant inhibition, using ABT 737 or siRNA targeting XL1 and citrate, a molecule which reduces the expression level of Mcl-1. Two cisplatin-chemoresistant ovarian cell lines (SKOV3 and IGROV1-R10) were exposed to ABT 737 or siRNA targeting XL1 and citrate at various individual concentrations, or combined. Cell proliferation, cell cycle repartition and nuclear staining with DAPI were recorded. Western blot analyses were performed to detect various proteins implied in apoptotic cell death pathways. Mcl-1 expression was barely reduced when cells were exposed to citrate alone, whereas a mild reduction was observed after ABT 737 treatment. Concomitant inhibition of Bcl-xL and Mcl-1 using ABT 737 or siXL1 associated with citrate was far more effective in inhibiting cell proliferation and inducing cell death than treatment alone. Given that few, if any, specific inhibitors of Mcl-1 are currently available, anti-glycolytic agents such as citrate could be tested in association with synthetic inhibitors of Bcl-xL [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to compare 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and 99mTc-depreotide single-photon emission computed tomography (SPECT) in the diagnosis of malignancy of solitary pulmonary nodules (SPNs). Methods: Twenty-eight patients without any history of cancer and presenting an SPN (0.8-3 cm in size) underwent FDG PET and depreotide SPECT. Depreotide SPECT and FDG PET were performed on a double-head gamma camera and a dedicated PET scanner respectively. Twenty-five out of 28 lesions were removed by thoracotomy or assessed by biopsy (n=1) and histologically examined. A strategy of serial CT scanning was adopted in the three remaining patients. Results: Histological findings revealed 18 malignant nodules and seven benign lesions. Stability over a 2-year period indicated a benign process in the remaining three cases. Both techniques yielded true positive results in 15 of the 18 cancers. FDG PET identified two additional adenocarcinomas not detected by depreotide SPECT. A carcinoid tumour not visualised on FDG PET was identified by depreotide SPECT. Seven of the ten benign lesions did not reveal tracer uptake on either depreotide SPECT or FDG PET. Both techniques showed false positive results for the same two lesions. One more false positive was seen on FDG PET. FDG PET and depreotide SPECT had a sensitivity of 94.4% and 88.9% respectively; this difference was not significant. In our experience, depreotide SPECT and FDG PET are equally sensitive (92.3%) for large (>1.5 cm) and equally specific (85.7%) for small (up to 1.5 cm) SPNs suspicious for malignancy. Conclusion: This study showed 18F-FDG PET to be more sensitive than 99mTc-depreotide SPECT in the diagnosis of malignancy of SPNs. However, the combination of both techniques may provide additional accuracy. [ABSTRACT FROM AUTHOR]

Gao-Min Liu and Yao-Ming Zhang recently published a review entitled «Targeting FBPase is an emerging novel approach for cancer therapy» (Liu and Zhang in Cancer Cell Int 18:36, 2018). In this paper, the authors highlighted how the down regulation or inactivation of FBPase, a rate limiting enzyme of gluconeogenesis, can promote the Warburg effect and cancer growth. In contrast, activation of this enzyme demonstrates anti-cancer effects and may appear as emerging novel approach for cancer therapy. Among the potential activators of FBP listed by Liu and Zhang, citrate was surprisingly not mentioned although it is an activator of FBPase, also demonstrating various anti-cancer effects in pre-clinical studies. Thus, citrate should be tested as a new therapeutic strategy, in particular in clinical studies. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the second most common cancer in the world. Despite advances in therapies, the mechanisms of resistance remain the underlying cause of morbidity and mortality. Lipoic acid (LA) is an antioxidant and essential cofactor in oxidative metabolism. Its potential therapeutic effects have been well documented, but its mechanisms of action (MOA) are not fully understood.Methods: The aim of this study is to validate the inhibitory LA effect on the proliferation of various breast cancer cell lines and to investigate the MOA that may be involved in this process. We tested LA effects by ex vivo studies on fresh human mammary tumour samples.Results: We demonstrate that LA inhibits the proliferation and Akt and ERK signalling pathways of several breast cancer cells. While searching for upstream dysregulations, we discovered the loss of expression of IGF-1R upon exposure to LA. This decrease is due to the downregulation of the convertase, furin, which is implicated in the maturation of IGF-1R. Moreover, ex vivo studies on human tumour samples showed that LA significantly decreases the expression of the proliferation marker Ki67.Conclusion: LA exerts its anti-proliferative effect by inhibiting the maturation of IGF-1R via the downregulation of furin. [ABSTRACT FROM AUTHOR]

Purpose: Respiratory complications are the leading causes of morbidity and mortality after lung cancer surgery. We hypothesized that oropharyngeal and nasopharyngeal decontamination with chlorhexidine gluconate (CHG) would be an effective method to reduce these complications as reported in cardiac surgery.Methods: In this multicenter parallel-group randomized double-blind placebo-controlled trial, we enrolled consecutive adults scheduled for anatomical pulmonary resection for lung cancer. Perioperative decontamination consisted in oropharyngeal rinse solution (0.12% CHG) and nasopharyngeal soap (4% CHG) or a placebo. The primary outcome measure was the proportion of patients requiring postoperative invasive and/or noninvasive mechanical ventilation (MV). Secondary outcome measures included occurrence of respiratory and non-respiratory healthcare-associated infections (HAIs) and outcomes within 90 days.Results: Between July 2012 and April 2015, 474 patients were randomized. Of them, 24 had their surgical procedure cancelled or withdrew consent. The remaining 450 patients were included in a modified intention-to-treat analysis: 226 were allocated to CHG and 224 to the placebo. Proportions of patients requiring postoperative MV were not significantly different [CHG 14.2%; placebo 15.2%; relative risks (RRs) 0.93; 95% confidence interval (CI) 0.59-1.45; P = 0.76]. Neither of the proportions of patients with respiratory HAIs were different (CHG 13.7%; placebo 12.9%; RRs 1.06; 95% CI 0.66-1.69; P = 0.81). The CHG group had significantly decreased incidence of bacteremia, surgical-site infection and overall Staphylococcus aureus infections. However, there were no significant between-group differences for hospital stay length, change in tracheal microbiota, postoperative antibiotic utilization and outcomes by day 90.Conclusions: CHG decontamination decreased neither MV requirements nor respiratory infections after lung cancer surgery. Additionally, CHG did not change tracheal microbiota or postoperative antibiotic utilization.Trial Registration: This study is registered on ClinicalTrials.gov, number NCT01613365. [ABSTRACT FROM AUTHOR]

Concerns remain over the risk of cancer following differentiated thyroid carcinoma and its causes. Iodine-131 (131I) and external irradiation are known to have potential carcinogenic effects. Thyroid carcinoma is a polygenic disease which may be associated with other malignancies. We investigated the incidence of second cancer and its aetiology in a cohort of 875 patients (146 men, 729 women) with differentiated thyroid carcinoma originating from Basse-Normandie, France. Cancer incidence was compared with that of the general population of the Département du Calvados matched for age, gender and period. The cumulative proportion of second cancer was estimated using the life-table method. Factors that correlated with the risk of second cancer were studied using the Cox model. After a median follow-up of 8 years, 58 second cancers had been observed. Compared with general population incidence rates, there was an overall increased risk of second cancer in women [standardised incidence ratio (SIR)=1.52; P<0.01], but not in men (SIR=1.27; P>0.20). Increased risk related to cancers of the genitourinary tract (SIR=3.31; P<0.001), and particularly to cancer of the kidney (SIR=7.02; P<0.01). Multivariate analysis showed that age above 40 years (P<0.01) and a history of previous primary cancer (P<0.001) correlated with risk. In contrast, neither cervical irradiation nor cumulative activity of 131I was related to the risk. These data confirm that women with differentiated thyroid carcinoma are at risk of developing a second cancer of the genitourinary tract and kidney. Only age and medical history of primary cancer before thyroid carcinoma are risk factors for second cancer. Common environmental or genetic factors as well as long-term carcinogenic effects of primary cancer therapy should be considered. [ABSTRACT FROM AUTHOR]

Lung scedosporiosis is an opportunistic fungus in humans that rarely affects the lung. It may give clinical presentations that are similar to aspergillosis. However, it must be detected because of its frequent resistance to medical treatment. Two cases of pulmonary scedosporiosis that were surgically treated are reported herein. [Copyright &y& Elsevier]

The ability of CD8 + T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8 + T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8 + T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8 + T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8 + T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors., (© 2024. The Author(s).)

Citrate is a key metabolite of the Krebs cycle that can also be exported in the cytosol, where it performs several functions. In normal cells, citrate sustains protein acetylation, lipid synthesis, gluconeogenesis, insulin secretion, bone tissues formation, spermatozoid mobility, and immune response. Dysregulation of citrate metabolism is implicated in several pathologies, including cancer. Here we discuss how cancer cells use citrate to sustain their proliferation, survival, and metastatic progression. Also, we propose two paradoxically opposite strategies to reduce tumour growth by targeting citrate metabolism in preclinical models. In the first strategy, we propose to administer in the tumor microenvironment a high amount of citrate, which can then act as a glycolysis inhibitor and apoptosis inducer, whereas the other strategy targets citrate transporters to starve cancer cells from citrate. These strategies, effective in several preclinical in vitro and in vivo cancer models, could be exploited in clinics, particularly to increase sensibility to current anti-cancer agents., Competing Interests: Declaration of Competing Interest MEM is an inventor on the Patent Application no. EP15767532.3 and US15/514,255 (status patent pending) “The plasma membrane citrate transporter for use in the diagnosis and treatment of cancer” owned by the University Hospital Regensburg. GZ is an employee and shareholder of Eternygen GmbH. PI, MA and LS have no conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Epigenetic drugs induce ATP depletion, promoting a glycolysis-to-oxidative phosphorylation (OXPHOS) shift which sometimes favors tumor growth by promoting necroptosis over apoptosis. To restore effective apoptosis in tumors, we propose that the administration of citrate could inhibit ATP production, activate caspase-8 (a key necroptosis inhibitor), and downregulate key anti-apoptotic proteins (Bcl-xL and MCL1)., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We discuss how metabolism changes during different phases of the cell cycle to sustain biosynthesis and replication in normal and cancer cells. We also highlight how several master regulators of cell cycle, such as cyclin-cyclin-dependent kinases (cyc-CDK complexes) and E3 proteasome ligases, modulate key metabolic enzymes to support cell-cycle progression., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

NSCLC is the leading cause of cancer mortality and represents a major challenge in cancer therapy. Intrinsic and acquired anticancer drug resistance are promoted by hypoxia and HIF-1α. Moreover, chemoresistance is sustained by the activation of key signaling pathways (such as RAS and its well-known downstream targets PI3K/AKT and MAPK) and several mutated oncogenes (including KRAS and EGFR among others). In this review, we highlight how these oncogenic factors are interconnected with cell metabolism (aerobic glycolysis, glutaminolysis and lipid synthesis). Also, we stress the key role of four metabolic enzymes (PFK1, dimeric-PKM2, GLS1 and ACLY), which promote the activation of these oncogenic pathways in a positive feedback loop. These four tenors orchestrating the coordination of metabolism and oncogenic pathways could be key druggable targets for specific inhibition. Since PFK1 appears as the first tenor of this orchestra, its inhibition (and/or that of its main activator PFK2/PFKFB3) could be an efficacious strategy against NSCLC. Citrate is a potent physiologic inhibitor of both PFK1 and PFKFB3, and NSCLC cells seem to maintain a low citrate level to sustain aerobic glycolysis and the PFK1/PI3K/EGFR axis. Awaiting the development of specific non-toxic inhibitors of PFK1 and PFK2/PFKFB3, we propose to test strategies increasing citrate levels in NSCLC tumors to disrupt this interconnection. This could be attempted by evaluating inhibitors of the citrate-consuming enzyme ACLY and/or by direct administration of citrate at high doses. In preclinical models, this "citrate strategy" efficiently inhibits PFK1/PFK2, HIF-1α, and IGFR/PI3K/AKT axes. It also blocks tumor growth in RAS-driven lung cancer models, reversing dedifferentiation, promoting T lymphocytes tumor infiltration, and increasing sensitivity to cytotoxic drugs., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated striking efficacy for the treatment of several hematological malignancies, including B-cell lymphoma, leukemia, and multiple myeloma. However, many patients still do not respond to this therapy or eventually relapse after an initial remission. In most solid tumors for which CAR T-cell therapy has been tested, efficacy has been very limited. In this context, it is of paramount importance to understand the mechanisms of tumor resistance to CAR T cells. Possible factors contributing to such resistance have been identified, including inherent CAR T-cell dysfunction, the presence of an immunosuppressive tumor microenvironment, and tumor-intrinsic factors. To control tumor growth, CAR T cells have to migrate actively enabling a productive conjugate with their targets. To date, many cells and factors contained within the tumor microenvironment have been reported to negatively control the migration of T cells and their ability to reach cancer cells. Recent evidence suggests that additional determinants, such as immune checkpoint proteins, cellular metabolism, and adhesion molecules, may modulate the motility of CAR T cells in tumors. Here, we review the potential impact of these determinants on CAR T-cell motility, and we discuss possible strategies to restore intratumoral T-cell migration with a special emphasis on approaches targeting these determinants.

PI3K/AKT is one of the most frequently altered signaling pathways in human cancers, supporting the activation of many proteins sustaining cell metabolism, proliferation, and aggressiveness. Another important pathway frequently altered in cancer cells is the one regulating the YAP/TAZ transcriptional coactivators, which promote the expression of genes sustaining aerobic glycolysis (such as WNT, MYC, HIF-1), EMT, and drug resistance. Of note, the PI3K/AKT pathway can also regulate the YAP/TAZ one. Unfortunately, although PI3K and YAP inhibitors are currently tested in highly resistant cancers (both solid and hematologic ones), several resistance mechanisms may arise. Resistance mechanisms to PI3K inhibitors may involve the stimulation of alternative pathways (such as RAS, HER, IGFR/AKT), the inactivation of PTEN (the physiologic inhibitor of PI3K), and the expression of anti-apoptotic Bcl-xL and MCL1 proteins. Therefore, it is important to improve current therapeutic strategies to overcome these limitations. Here, we want to highlight how the glycolytic enzyme PFK1 (and its product F-1,6-BP) promotes the activation of both PI3K/AKT and YAP/TAZ pathways by several direct and indirect mechanisms. In turn, PI3K/AKT and YAP/TAZ can promote PFK1 activity and F-1,6-BP production in a positive feedback loop, thus sustaining the Warburg effect and drug resistance. Thus, we propose that the inhibition of PFK1 (and of its key activator PFK2/PFKFB3) could potentiate the sensitivity to PI3K and YAP inhibitors currently tested. Awaiting the development of non-toxic inhibitors of these enzymes, we propose to test the administration of citrate at a high dosage, because citrate is a physiologic inhibitor of both PFK1 and PFK2/PFKFB3. Consistently, in various cultured cancer cells (including melanoma, sarcoma, hematologic, and epithelial cancer cells), this "citrate strategy" efficiently inhibits the IGFR1/AKT pathway, promotes PTEN activity, reduces Bcl-xL and MCL1 expression, and increases sensitivity to standard chemotherapy. It also inhibits the development of sarcoma, pancreatic, mammary HER + and lung RAS-driven tumors in mice without apparent toxicities.

Hepatocellular carcinoma (HCC) represents the third cause of cancer death in men worldwide, and its increasing incidence can be explained by the increasing occurrence of non-alcoholic steatohepatitis (NASH). HCC prognosis is poor, as its 5-year overall survival is approximately 18 % and most cases are diagnosed at an inoperable advanced stage. Moreover, tumor sensitivity to conventional chemotherapeutics (particularly to cisplatin-based regimen), trans-arterial chemoembolization (cTACE), tyrosine kinase inhibitors, anti-angiogenic molecules and immune checkpoint inhibitors is limited. Oncogenic signaling pathways, such as HIF-1α and RAS/PI3K/AKT, may provoke drug resistance by enhancing the aerobic glycolysis ("Warburg effect") in cancer cells. Indeed, this metabolism, which promotes cancer cell development and aggressiveness, also induces extracellular acidity. In turn, this acidity promotes the protonation of drugs, hence abrogating their internalization, since they are most often weakly basic molecules. Consequently, targeting the Warburg effect in these cancer cells (which in turn would reduce the extracellular acidification) could be an effective strategy to increase the delivery of drugs into the tumor. Phosphofructokinase-1 (PFK1) and its activator PFK2 are the main regulators of glycolysis, and they also couple the enhancement of glycolysis to the activation of key signaling cascades and cell cycle progression. Therefore, targeting this "Gordian Knot" in HCC cells would be of crucial importance. Here, we suggest that this could be achieved by citrate administration at high concentration, because citrate is a physiologic inhibitor of PFK1 and PFK2. As shown in various in vitro studies, including HCC cell lines, administration of high concentrations of citrate inhibits PFK1 and PFK2 (and consequently glycolysis), decreases ATP production, counteracts HIF-1α and PI3K/AKT signaling, induces apoptosis, and sensitizes cells to cisplatin treatment. Administration of high concentrations of citrate in animal models (including Ras-driven tumours) has been shown to effectively inhibit cancer growth, reverse cell dedifferentiation, and neutralize intratumor acidity, without apparent toxicity in animal studies. Citrate may also induce a rapid secretion of pro-inflammatory cytokines by macrophages, and it could favour the destruction of cancer stem cells (CSCs) sustaining tumor recurrence. Consequently, this "citrate strategy" could improve the tumor sensitivity to current treatments of HCC by reducing the extracellular acidity, thus enhancing the delivery of chemotherapeutic drugs into the tumor. Therefore, we propose that this strategy should be explored in clinical trials, in particular to enhance cTACE effectiveness., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

COVID-19 pandemic has been characterized by a pattern of consecutive declines and regrowth in European countries in 2020. After being partially regressed during the summer, the reappearance of the infection during fall 2020 in many temperate countries strongly suggests that temperature and cold may play a role in influencing the infectivity and virulence of SARS-CoV-2. While promoting medicine as an art, Hippocrates interpreted with logical reasoning the occurrence of diseases such as epidemics, as a consequence of environmental factors, in particular climatic variations. During the Renaissance, Sanctorius was one of the first to perform quantitative measurements, and Harvey discovered the circulation of blood by performing experimental procedures in animals. We think that a reasoning mixing various observations, measurements and experiments is fundamental to understand how cold increases infectivity and virulence of SARS-CoV-2. By this review, we provide evidence linking cold, angiotensin-II, vasoconstriction, hypoxia and aerobic glycolysis (the Warburg effect) to explain how cold affects the epidemiology of COVID-19. Also, a low humidity increases virus transmissibility, while a warm atmosphere, a moderate airway humidity, and the production of vasodilator angiotensin 1-7 by ACE2 are less favorable to the virus entry and/or its development. The meteorological and environmental parameters impacting COVID-19 pandemic should be reintegrated into a whole perspective by taking into account the different factors influencing transmissibility, infectivity and virulence of SARS-CoV-2. To understand the modern enigma represented by COVID-19, an interdisciplinary approach is surely essential., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Background: Infection of the pleural cavity invariably leads to hospitalisation, and a fatal outcome is not uncommon. Our aim was to study the epidemiology of pleural empyema on a nationwide basis in the whole population and in three subgroups of patients, namely post-lung resection, associated cancer and those with no surgery and no cancer., Methods: Data from patients aged ≥18 years hospitalised with a diagnosis of pleural infection in France between January 2013 and December 2017 were retrieved from the medical-administrative national hospitalisation database and retrospectively analysed. Mortality, length of stay and costs were assessed., Results: There were 25 512 hospitalisations for pleural empyema. The annual rate was 7.15 cases per 100 000 habitants in 2013 and increased to 7.75 cases per 100 000 inhabitants in 2017. The mean age of patients was 62.4±15.6 years and 71.7% were men. Post-lung resection, associated cancer and no surgery-no cancer cases accounted for 9.8%, 30.1% and 60.1% of patients, respectively. These groups were significantly different in terms of clinical characteristics, mortality and risk factors for length of stay, costs and mortality. Mortality was 17.1% in the whole population, 29.5% in the associated cancer group, 17.7% in the post-lung resection group and 10.7% in the no surgery-no cancer group. In the whole population, age, presence of fistula, higher Charlson Comorbidity Index ( > 3), alcohol abuse, arterial hypertension, hyperlipidaemia, atheroma, atrial fibrillation, performance status > 3 and three subgroups of pleural empyema independently predicted mortality., Conclusions: Empyema is increasing in incidence. Factors associated with mortality are recent lung resection and associated diagnosis of cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)