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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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. • The influence of climate on COVID-19 pandemic is suspected but largely enigmatic. • Cold may increase viral infectivity by paralyzing airway defense barriers. • Angiotensin II-mediated vasoconstriction induced by cold promotes hypoxia in cells. • Hypoxia activates aerobic glycolysis promoting SARS-CoV-2 replication. • This cascade may have favored the spread of COVID-19 in European countries in 2020. [ABSTRACT FROM AUTHOR]

We propose that fructose-1,6-bisphosphate (F-1,6-BP) promotes a feedback loop between phosphofructokinase-1 (PFK1), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and PFK2/PFKFB3, which enhances aerobic glycolysis and sustains effector T (T eff) cell activation, while oxidative metabolism is concomitantly downregulated. This regulation, promoted by low citrate and mitochondrial ATP synthesis, also sustains the Warburg effect in cancer cells. [ABSTRACT FROM AUTHOR]

Current mortality due to the Covid-19 pandemic (approximately 1.2 million by November 2020) demonstrates the lack of an effective treatment. As replication of many viruses - including MERS-CoV - is supported by enhanced aerobic glycolysis, we hypothesized that SARS-CoV-2 replication in host cells (especially airway cells) is reliant upon altered glucose metabolism. This metabolism is similar to the Warburg effect well studied in cancer. Counteracting two main pathways (PI3K/AKT and MAPK/ERK signaling) sustaining aerobic glycolysis inhibits MERS-CoV replication and thus, very likely that of SARS-CoV-2, which shares many similarities with MERS-CoV. The Warburg effect appears to be involved in several steps of COVID-19 infection. Once induced by hypoxia, the Warburg effect becomes active in lung endothelial cells, particularly in the presence of atherosclerosis, thereby promoting vasoconstriction and micro thrombosis. Aerobic glycolysis also supports activation of pro-inflammatory cells such as neutrophils and M1 macrophages. As the anti-inflammatory response and reparative process is performed by M2 macrophages reliant on oxidative metabolism, we speculated that the switch to oxidative metabolism in M2 macrophages would not occur at the appropriate time due to an uncontrolled pro-inflammatory cascade. Aging, mitochondrial senescence and enzyme dysfunction, AMPK downregulation and p53 inactivation could all play a role in this key biochemical event. Understanding the role of the Warburg effect in COVID-19 can be essential to developing molecules reducing infectivity, arresting endothelial cells activation and the pro-inflammatory cascade. • Enhanced aerobic glycolysis supports replication of many viruses including MERS-CoV. • PI3K/AKT and MAPK/ERK inhibitors arrest MERS-CoV replication. • This metabolism likely sustains SARS-CoV-2 replication in host cells, in particular airway cells. • The Warburg effect also supports activation of endothelial cells and pro-inflammatory cells. [ABSTRACT FROM AUTHOR]

ACLY links energy metabolism provided by catabolic pathways to biosynthesis. ACLY, which has been found to be overexpressed in many cancers, converts citrate into acetyl-CoA and OAA. The first of these molecules supports protein acetylation, in particular that of histone, and de novo lipid synthesis, and the last one sustains the production of aspartate (required for nucleotide and polyamine synthesis) and the regeneration of NADPH,H+(consumed in redox reaction and biosynthesis). ACLY transcription is promoted by SREBP1, its activity is stabilized by acetylation and promoted by AKT phosphorylation (stimulated by growth factors and glucose abundance). ACLY plays a pivotal role in cancer metabolism through the potential deprivation of cytosolic citrate, a process promoting glycolysis through the enhancement of the activities of PFK 1 and 2 with concomitant activation of oncogenic drivers such as PI3K/AKT which activate ACLY and the Warburg effect in a feed-back loop. Pending the development of specific inhibitors and tailored methods for identifying which specific metabolism is involved in the development of each tumor, ACLY could be targeted by inhibitors such as hydroxycitrate and bempedoic acid. The administration of citrate at high level mimics a strong inhibition of ACLY and could be tested to strengthen the effects of current therapies. [ABSTRACT FROM AUTHOR]

Cell cycle progression and division is regulated by checkpoint controls and sequential activation of cyclin-dependent kinases (CDKs). Understanding of how these events occur in synchrony with metabolic changes could have important therapeutic implications. For biosynthesis, cancer cells enhance glucose and glutamine consumption. Inactivation of pyruvate kinase M2 (PKM2) promotes transcription in G1 phase. Glutamine metabolism supports DNA replication in S phase and lipid synthesis in G2 phase. A boost in glycolysis and oxidative metabolism can temporarily furnish more ATP when necessary (G1/S transition, segregation of chromosomes). Recent studies have shown that a few metabolic enzymes [PKM2, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), GAPDH] also periodically translocate to the nucleus and oversee cell cycle regulators or oncogene expression (c-Myc). Targeting these metabolic enzymes could increase the response to CDK inhibitors (CKIs). The Warburg effect promotes a reductive metabolism that limits the production of ROS, which can be toxic for DNA replication. Aerobic glycolysis actively supports protein synthesis, in G1 phase particularly. Dimeric PKM2 promotes cellular biosynthesis and expression of cyclin D1. PFKFB3 increases ATP production at the G1 restriction checkpoint and promotes activation of cyclins D and E. The upregulation of GLS1 enhances glutaminolysis, which sustains DNA replication in S phase. Some glycolytic enzymes (PKM2, ALDO, GAPDH) periodically translocate to the nucleus upregulating the expression of genes involved in the cell cycle. [ABSTRACT FROM AUTHOR]

Cancer cells employ both conventional oxidative metabolism and glycolytic anaerobic metabolism. However, their proliferation is marked by a shift towards increasing glycolytic metabolism even in the presence of O 2 (Warburg effect). HIF1, a major hypoxia induced transcription factor, promotes a dissociation between glycolysis and the tricarboxylic acid cycle, a process limiting the efficient production of ATP and citrate which otherwise would arrest glycolysis. The Warburg effect also favors an intracellular alkaline pH which is a driving force in many aspects of cancer cell proliferation (enhancement of glycolysis and cell cycle progression) and of cancer aggressiveness (resistance to various processes including hypoxia, apoptosis, cytotoxic drugs and immune response). This metabolism leads to epigenetic and genetic alterations with the occurrence of multiple new cell phenotypes which enhance cancer cell growth and aggressiveness. In depth understanding of these metabolic changes in cancer cells may lead to the development of novel therapeutic strategies, which when combined with existing cancer treatments, might improve their effectiveness and/or overcome chemoresistance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Results of bilobectomy for non-small cell lung cancer have rarely been studied. Methods: Retrospective analysis was conducted on patients with non-small cell lung cancer having undergone bilobectomy from January 1999 to June 2012 at our institution. Analysis aimed at determining perioperative mortality and morbidity, and at studying prognostic factors for long-term survival using the 7th TNM classification. Results: A total of 103 patients (85 males; mean age 62 years) underwent upper-middle bilobectomy (n = 54) or lower-middle bilobectomy (n = 49). Histologic examination revealed 51 adenocarcinomas, 43 squamous cell carcinomas and 9 other cell carcinomas. Perioperative mortality was 0.97%. The overall morbidity rate was 71%, whereas the rate of life-threatening complications was 9.6%. Complications were more frequent in men (p = 0.032), in patients with chronic pulmonary obstructive diseases (p = 0.030) and after lower-middle bilobectomy (p = 0.0016). The overall 5-year Kaplan-Meier survival rate was 57.8%. In univariate analysis, factors associated with increased survival were the following: pathologic stage (stage I 74.9%, stage II 64.1%, stage III 28.8%, p = 0.0018); nodal status (N0 vs N1, p = 0.011; N0 vs N2, p = 0.0015; N0 vs N+, p = 0.0008); R status (R0 vs R1, p = 0.0032), and smoking status (past smoker or nonsmoker vs active smoker, p = 0.00054). Multivariate analysis revealed that active smokers (RR = 3.87, CI 95% [1.83 to 8.21]; p = 0.00042) and increasing stage (stage 0: RR=1; stage I: RR = 1.98, CI 95% [1.38 to 2.83]; stage II: RR = 3.90, CI 95% [1.90 to 8.02]; stage III: RR=7.72, CI 95% [2.62 to 22.73]; stage IV: RR = 15.25, CI 95% [3.61 to 64.40]; p = 0.0042) were significantly associated with poorer survival. Conclusions: Bilobectomy can be performed with low mortality, acceptable morbidity and long term survival in accordance with TNM staging. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

: BackgroundSuperior vena cava syndrome (SVCS) is often seen in the natural history of malignant thoracic diseases. SVCS is characterized by unpleasant symptoms that usually lead to death. The purpose of our study is to show the efficiency of percutaneous stenting in the superior vena cava for relieving SVCS and the possibility of repeated stenting after recurrence.: MethodsTwenty patients with SVCS caused by malignant diseases who had one or more stents placed in the superior vena cava or its main tributaries were evaluated.: ResultsOut of 20 patients, 1 died of myocardial infarction 24 hours after the procedure without any signs of pulmonary embolus, hemorrhage, or malposition of the stent. SVCS was successfully controlled in 94% of patients until death or completion of the study. In 3 patients the procedure was repeated (3 to 20 weeks later) because of the recurrence of symptoms.: ConclusionsPercutaneous venous stent placement in the superior vena cava is a simple and effective technique to relieve rapid SVCS caused by malignancies. When recurrence occurs, repeated stenting can be performed successfully. [Copyright &y& Elsevier]

Posterior intrathoracic neurogenic tumors often have an intraforaminal extension. Ten percent have an extension intraspinal and are called “dumbbell tumors.” The surgically recommended techniques used to treat these conditions may have been applied too systematically, mainly when the diameter of the foramen was obviously enlarged and the possibility of removing the tumor existed. We report two cases to stress the importance of assessing the size of the intervertebral foramina in planning neurinoma cure. [Copyright &y& Elsevier]

The number of clinical protocols testing combined therapies including immune check-point inhibitors and platinum salts is currently increasing in lung cancer treatment, however preclinical studies and rationale are often lacking. Here, we evaluated the impact of cisplatin treatment on PD-L1 expression analyzing the clinicopathological characteristics of patients who received cisplatin-based neoadjuvant chemotherapy followed by surgery and showed that cisplatin-based induction treatment significantly increased PD-L1 staining in both tumor and immune cells from the microenvironment. Twenty-two patients exhibited positive PD-L1 staining variation after neoadjuvant chemotherapy; including 9 (23.1%) patients switching from <50% to ≥50% of stained tumor-cells. We also confirmed the up-regulation of PD-L1 by cisplatin, at both RNA and protein levels, in nude and immunocompetent mice bearing tumors grafted with A549, LNM-R, or LLC1 lung cancer cell lines. The combined administration of anti-PD-L1 antibodies (3 mg/kg) and cisplatin (1 mg/kg) to mice harboring lung carcinoma significantly reduced tumor growth compared to single agent treatments and controls. Overall, these results suggest that cisplatin treatment could synergize with PD-1/PD-L1 blockade to increase the clinical response, in particular through early and sustainable enhancement of PD-L1 expression. [ABSTRACT FROM AUTHOR]