bims-medica 2024-12-08 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–12–08
27 papers selected by
Brett Chrest, Wake Forest University

Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.
Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.
Species differences in glycerol-3-phosphate metabolism reveals trade-offs between metabolic adaptations and cell proliferation.
NMR-based metabolomics combined with metabolic pathway analysis reveals metabolic heterogeneity of colorectal cancer tissue at different anatomical locations and stages.
The liver converts fructose into lipids to fuel tumours.
Indices of healthy and unhealthy plant-based diets and the risk of selected digestive cancers.
Proton Sensing GPCR's: The missing link to Warburg's Oncogenic Legacy?
N-Phenyl ureidobenzenesulfonates, a novel class of human dihydroorotate dehydrogenase inhibitors inducing differentiation and apoptosis in acute myeloid leukemia cells.
Inhibition of LDHB suppresses the metastatic potential of lung cancer by reducing mitochondrial GSH catabolism.
FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML.
Reprogrammed lipid metabolism in advanced resistant cancers: an upcoming therapeutic opportunity.
The impact of a ketogenic diet on weight loss, metabolism, body composition and quality of life.
Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.
Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment.
Respiratory complex II acting as a homeostatic regulatory sensor.
A Review Article: The Relationship Between Obesity and Colorectal Cancer.
Tracking fructose 1,6-bisphosphate dynamics in liver cancer cells using a fluorescent biosensor.
Exploring Consumption of Ultra-Processed Foods and Diet Quality in the Context of Popular Low Carbohydrate and Plant-Based Dietary Approaches.
The Clinical Impact of NPM1 Mutations and the Effect of Concurrent Mutations in Acute Myeloid Leukemia: Unraveling the Prognostic Significance.
FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.
The role of Mediterranean diet in cancer incidence and mortality in the older adults.
Alternative NADH dehydrogenase: A complex I backup, a drug target, and a tool for mitochondrial gene therapy.
Measuring the rate of NADPH consumption by glutathione reductase in the cytosol and mitochondria.
How to improve AML outcomes?
Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
Angiogenesis inhibitors effects on overall survival and progression-free survival in newly diagnosed primary glioblastoma multiforme: a meta-analysis of twelve randomized clinical trials.
Unraveling bidirectional evolution of unstable mitochondrial DNA mutations in hepatocellular carcinoma at single-cell resolution.

ASN Neuro. 2024 ;16(1): 2422268

Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.

Derek C Lee, Linh Ta, Purna Mukherjee, Tomas Duraj, Marek Domin, Bennett Greenwood, Srada Karmacharya, Niven R Narain, Michael Kiebish, Christos Chinopoulos, Thomas N Seyfried.

  Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation is a common metabolic phenotype seen in most cancers including malignant gliomas. This metabolic phenotype is linked to abnormalities in mitochondrial structure and function. A luciferin-luciferase bioluminescence ATP assay was used to measure the influence of amino acids, glucose, and oxygen on ATP content and viability in mouse (VM-M3 and CT-2A) and human (U-87MG) glioma cells that differed in cell biology, genetic background, and species origin. Oxygen consumption was measured using the Resipher system. Extracellular lactate and succinate were measured as end products of the glycolysis and glutaminolysis pathways, respectively. The results showed that: (1) glutamine was a source of ATP content irrespective of oxygen. No other amino acid could replace glutamine in sustaining ATP content and viability; (2) ATP content persisted in the absence of glucose and under hypoxia, ruling out substantial contribution through either glycolysis or oxidative phosphorylation (OxPhos) under these conditions; (3) Mitochondrial complex IV inhibition showed that oxygen consumption was not an accurate measure for ATP production through OxPhos. The glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced ATP content and succinate export in cells grown in glutamine. The data suggests that mitochondrial substrate level phosphorylation in the glutamine-driven glutaminolysis pathway contributes to ATP content in these glioma cells. A new model is presented highlighting the synergistic interaction between the high-throughput glycolysis and glutaminolysis pathways that drive malignant glioma growth and maintain ATP content through the aerobic fermentation of both glucose and glutamine.

Keywords:  Fermentation; glioblastoma; glutaminolysis; mitochondrial substrate level phosphorylation; succinate

DOI:  https://doi.org/10.1080/17590914.2024.2422268
BMC Med. 2024 12 05. 22(1): 578

Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.

Tomás Duraj, Miriam Kalamian, Giulio Zuccoli, Joseph C Maroon, Dominic P D'Agostino, Adrienne C Scheck, Angela Poff, Sebastian F Winter, Jethro Hu, Rainer J Klement, Alicia Hickson, Derek C Lee, Isabella Cooper, Barbara Kofler, Kenneth A Schwartz, Matthew C L Phillips, Colin E Champ, Beth Zupec-Kania, Jocelyn Tan-Shalaby, Fabiano M Serfaty, Egiroh Omene, Gabriel Arismendi-Morillo, Michael Kiebish, Richard Cheng, Ahmed M El-Sakka, Axel Pflueger, Edward H Mathews, Donese Worden, Hanping Shi, Raffaele Ivan Cincione, Jean Pierre Spinosa, Abdul Kadir Slocum, Mehmet Salih Iyikesici, Atsuo Yanagisawa, Geoffrey J Pilkington, Anthony Chaffee, Wafaa Abdel-Hadi, Amr K Elsamman, Pavel Klein, Keisuke Hagihara, Zsófia Clemens, George W Yu, Athanasios E Evangeliou, Janak K Nathan, Kris Smith, David Fortin, Jorg Dietrich, Purna Mukherjee, Thomas N Seyfried.

  Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.

Keywords:  Cancer; Glioblastoma; Glutaminolysis; Metabolism; Precision medicine; Research design; Warburg Effect

DOI:  https://doi.org/10.1186/s12916-024-03775-4
Biochim Biophys Acta Bioenerg. 2024 Dec 02. pii: S0005-2728(24)00500-0. [Epub ahead of print] 149530

Species differences in glycerol-3-phosphate metabolism reveals trade-offs between metabolic adaptations and cell proliferation.

Kateryna Gaertner, Mügen Terzioglu, Craig Michell, Riikka Tapanainen, Jaakko Pohjoismäki, Eric Dufour, Sina Saari.

  The temperate climate-adapted brown hare (Lepus europaeus) and the cold-adapted mountain hare (Lepus timidus) are closely related and interfertile species. However, their skin fibroblasts display distinct gene expression profiles related to fundamental cellular processes. This indicates important metabolic divergence between the two species. Through targeted metabolomics and metabolite tracing, we identified species-specific variations in glycerol 3-phosphate (G3P) metabolism. G3P is a key metabolite of the G3P shuttle, which transfers reducing equivalents from cytosolic NADH to the mitochondrial electron transport chain (ETC), consequently regulating glycolysis, lipid metabolism, and mitochondrial bioenergetics. Alterations in G3P metabolism have been implicated in multiple human pathologies including cancer and diabetes. We observed that mountain hare mitochondria exhibit elevated G3P shuttle activity, alongside increased membrane potential and decreased mitochondrial temperature. Silencing mitochondrial G3P dehydrogenase (GPD2), which couples the conversion of G3P to the ETC, uncovered its species-specific role in controlling mitochondrial membrane potential and highlighted its involvement in skin fibroblast thermogenesis. Unexpectedly, GPD2 silencing enhanced wound healing and cell proliferation rates in a species-specific manner. Our study underscores the pivotal role of the G3P shuttle in mediating physiological, bioenergetic, and metabolic divergence between these hare species.

Keywords:  Glycerol-3-phosphate; Hares; Metabolism; Mitochondria; Mitochondrial membrane potential; Thermogenesis; Wound healing

DOI:  https://doi.org/10.1016/j.bbabio.2024.149530
Int J Cancer. 2024 Dec 04.

NMR-based metabolomics combined with metabolic pathway analysis reveals metabolic heterogeneity of colorectal cancer tissue at different anatomical locations and stages.

Rongzhi Cai, LiXin Ke, Yan Zhao, Jiayun Zhao, Huanian Zhang, Peie Zheng, Lijing Xin, Changchun Ma, Yan Lin.

  Colorectal cancer (CRC) still remains the leading cause of cancer death worldwide. This study aimed to profile the metabolic differences of colorectal cancer tissues (CCT) at different stages and sites, as compared with their distant noncancerous tissues (DNT), to investigate the temporal and spatial heterogeneities of metabolic characterization. Our NMR-based metabolomics fingerprinting revealed that many of the metabolite levels were significantly altered in CCT compared to DNT and esophageal cancer tissues, indicating deregulations of glucose metabolism, one-carbon metabolism, glutamine metabolism, amino acid metabolism, fatty acid metabolism, TCA cycle, choline metabolism, and so forth. A total of five biomarker metabolites, including glucose, glutamate, alanine, valine and histidine, were identified to distinguish between early and advanced stages of CCT. Metabolites that distinguish the different anatomical sites of CCT include glucose, glycerol, glutamine, inositol, succinate, and citrate. Those significant metabolic differences in CRC tissues at different pathological stages and sites suggested temporal and spatial heterogeneities of metabolic characterization in CCT, providing a metabolic foundation for further study on biofluid metabolism in CRC early detection.

Keywords:  NMR‐based metabolomics; anatomical locations; colorectal cancer tissue; metabolic pathways; tumor stages

DOI:  https://doi.org/10.1002/ijc.35273
Nature. 2024 Dec 04.

The liver converts fructose into lipids to fuel tumours.

Hyllana C D Medeiros, Sophia Y Lunt.



Keywords:  Cancer; Metabolism

DOI:  https://doi.org/10.1038/d41586-024-03653-2
Clin Nutr. 2024 Nov 26. pii: S0261-5614(24)00436-9. [Epub ahead of print]44 76-85

Indices of healthy and unhealthy plant-based diets and the risk of selected digestive cancers.

Federica Turati, Silvia Mignozzi, Giovanna Esposito, Francesca Bravi, Angela D'Angelo, Gianfranco Alicandro, Werner Garavello, Livia S A Augustin, Sara Vitale, Attilio Giacosa, Ettore Bidoli, Jerry Polesel, Eva Negri, Monica Ferraroni, Carlo La Vecchia.

   BACKGROUND & AIMS: The relation between various types of plant-based diets and cancer risk is still unclear. We examined the association of the overall plant-based diet index (PDI) and healthy (hPDI) and unhealthy plant-based diet indices (uPDI) with the risk of selected digestive cancers.
METHODS: We used data from a network of hospital-based case-control studies including 942 oral/pharyngeal, 304 esophageal, 230 stomach, 1953 colorectal, and 326 pancreatic cancer cases. We calculated PDI, hPDI, and uPDI from a validated food frequency questionnaire. We used multivariable logistic regression models to estimate the odds ratios (OR) of selected digestive cancers across the three indices (in quintiles, Q, or tertiles, T, and in continuous).
RESULTS: The PDI was significantly inversely associated with oral/pharyngeal (ORQ5 vs Q1=0.63, 95% confidence interval, CI, 0.47-0.84) and esophageal cancer risk (ORT3 vs T1=0.47, 95% CI 0.31-0.72). The inverse associations appeared stronger for the hPDI (oral cavity/pharynx: ORQ5 vs Q1=0.52; 95% CI 0.39-0.70; esophagus: ORT3 vs T1=0.59, 95% CI 0.39-0.91; stomach: ORT3 vs T1=0.42, 95% CI 0.27-0.67; colorectum: ORQ5 vs Q1=0.69; 95% CI 0.57-0.84; pancreas: ORT3 vs T1=0.60; 95% CI 0.41-0.89). In contrast, the uPDI was directly associated with the risk of oral/pharyngeal (ORQ5 vs Q1=1.43, 95% CI 1.06-1.94), colorectal (ORQ5 vs Q1=2.28, 95% CI 1.86-2.81), and pancreatic cancer (ORT3 vs T1=1.74, 95% CI 1.14-2.65). Esophageal and stomach cancer risks were non-significantly increased by 34% and 46% respectively in the highest uPDI quantile.
CONCLUSION: A plant-based diet, especially a healthy plant-based diet, may reduce the risk of various digestive cancers, whereas an unhealthy plant-based diet may increase the risk. The quality of plant-based diets is important for digestive cancer risk evaluation and prevention.

Keywords:  Colorectal cancer; Digestive cancers; Food quality; Plant-based diet; Prevention

DOI:  https://doi.org/10.1016/j.clnu.2024.11.039
J Cancer Biol. 2024 ;5(2): 65-75

Proton Sensing GPCR's: The missing link to Warburg's Oncogenic Legacy?

Jessica Cornell, Samantha Rea, Leif R Neitzel, Charles H Williams, Charles C Hong.

A century after Otto Warburg's seminal discovery of aerobic glycolysis in cancer cells, a phenomenon dubbed the "Warburg effect", the mechanistic links between this metabolic rewiring and tumorigenesis remain elusive. Warburg postulated that this enhanced glucose fermentation to lactate, even in the presence of oxygen, stemmed from an "irreversible respiratory injury" intrinsic to cancer cells. While oxidative phosphorylation yields higher ATP, the Warburg effect paradoxically persists, suggesting that the excess lactate and acid production are worth the deficit. Since Warburg's discovery, it has been demonstrated that the acidic tumor microenvironment activates a myriad of pro-oncogenic phenotypes ranging from therapeutic resistance to immune escape. Here we propose that proton-sensing G-protein-coupled receptors (GPCRs) act as crucial heirs to Warburg's findings by transducing the acid signal from elevated glycolytic lactate into pro-oncogenic signals. The increased lactate production characteristic of the Warburg effect causes extracellular acidification. This acidic tumor microenvironment can activate proton-sensing GPCRs like GPR68, a proton-sensing receptor shown to stimulate proliferation, migration, and survival pathways in cancer cells. Such pH sensing is accomplished through protonation of key residues such as histidine, which causes a conformational change to activate various downstream signaling cascades including the MAPK, PI3K/Akt, Rho, and β-arrestin pathways implicated in tumor progression and therapeutic resistance. By coupling Warburg's "respiratory injury" to potent mitogenic signaling, proton-sensing GPCRs like GPR68 may unveil a longstanding mystery - why forgo efficient ATP generation? As heirs to Warburg's iconic metabolic observations, these proton sensors could represent novel therapeutic targets to disrupt the synergy between the Warburg effect and oncogenic signaling.

DOI: https://doi.org/10.46439/cancerbiology.5.066
Biomed Pharmacother. 2024 Dec 04. pii: S0753-3322(24)01603-2. [Epub ahead of print]181 117717

N-Phenyl ureidobenzenesulfonates, a novel class of human dihydroorotate dehydrogenase inhibitors inducing differentiation and apoptosis in acute myeloid leukemia cells.

Chahrazed Bouzriba, Atziri Corin Chavez Alvarez, Vincent Ouellette, Mathieu Gagné-Boulet, Geneviève Hamel-Côté, Dominic Bastien, Isabelle Laverdière, Sébastien Fortin.

  N-Phenyl ureidobenzensulfonates (PUB-SOs) are a novel family of dihydroorotate dehydrogenase (DHODH) inhibitors. Herein, we investigate the potential of PUB-SOs to induce acute myeloid leukemia (AML) cell differentiation and apoptosis. To that end, we screened our chemolibrary to select the most potent PUB-SOs based on their antiproliferative activity and their ability to arrest the cell progression of AML cells in the S phase. The most promising PUB-SOs show antiproliferative activity in the range of 0.13-23 µM against THP-1, MOLM-13 and HL-60 AML cells. Moreover, those PUB-SOs arrested the cell cycle progression in the S phase. In addition, molecular docking studies evidenced their potential to bind in the brequinar-binding site located on DHODH which was confirmed using the DHODH inhibition assay showing that PUB-SOs are potent DHODH inhibitors (half maximal inhibitory concentration (IC50) = 7.7-1000 nM). Our results also show that selected PUB-SOs induced the differentiation of THP-1 and HL-60 cells into cluster of differentiation (CD) 11b+/CD14+ phenotypes, up to 74 % and 50 %, respectively. They also promoted CD11b+ differentiation in MOLM-13 cells (up to 44 %). Additionally, the prototypical PUB-SOs SFOM-0046 induced lactate dehydrogenase (LDH) release, mitochondrial stress and mitochondrial membrane potential loss in MOLM-13 cell line. Furthermore, SFOM-0046 induced apoptosis in MOLM-13 cells, which was confirmed by the increase of annexin V/propidium iodide (PI) and caspase 3/7 positive cells. In summary, our results highlight PUB-SOs as a novel family of DHODH inhibitors inducing both cell differentiation and apoptosis in AML cells, underscoring their potential as therapeutic agents for AML treatment.

Keywords:  AML; AML cell differentiation; Acute myeloid leukemia; Anticancer agents; DHODH inhibitors; N-Phenyl ureidobenzenesulfonates; PUB-SOs

DOI:  https://doi.org/10.1016/j.biopha.2024.117717
Cancer Lett. 2024 Nov 28. pii: S0304-3835(24)00748-1. [Epub ahead of print] 217353

Inhibition of LDHB suppresses the metastatic potential of lung cancer by reducing mitochondrial GSH catabolism.

Huixiang Ge, Fatlind Malsiu, Yanyun Gao, Tereza Losmanova, Fabian Blank, Julien Ott, Michaela Medová, Ren-Wang Peng, Haibin Deng, Patrick Dorn, Thomas Michael Marti.

  Metastasis, the leading cause of cancer death, is closely linked to lactate metabolism. Our study aimed to investigate the role of lactate dehydrogenase B (LDHB), which mainly catalyzes the conversion of lactate to pyruvate, in the metastatic potential of lung cancer. We found that LDHB silencing reduced the invasion and migration ability of lung cancer cells in vitro. On the molecular level, LDHB silencing decreased the total intracellular levels of the antioxidant glutathione (GSH). Surprisingly, LDHB silencing did not increase cellular or mitochondrial reactive oxygen species (ROS) levels. Furthermore, supplementation with GSH monoethyl ester (GSH-mee), a cell-permeable derivative of GSH, partially restored the reduced in vitro colony formation capacity, the oxygen consumption rate, and the invasion and migration capacity of lung cancer cells after LDHB silencing. Using metabolic inhibitors, we showed that the rescue of colony formation after silencing LDHB by GSH-mee was due to enhanced GSH catabolism by γ-L-Glutamyl transpeptidase (GGT), which was mainly present in the mitochondrial fraction of lung cancer cells. Furthermore, we observed that high GGT expression was a prerequisite for the rescue of migratory capacity by GSH-mee after LDHB silencing. Finally, our in vivo experiments demonstrated that targeting LDHB reduced the metastasis of human and mouse lung cancer cells in immunodeficient and immunocompetent mouse models, respectively. In conclusion, LDHB silencing decreases GSH catabolism mediated by GGT, which is primarily located in the mitochondria of cancer cells. Therefore, targeting LDHB is a promising therapeutic approach for the prevention and treatment of metastatic lung cancer.

Keywords:  glutathione; lactate dehydrogenase; lung cancer; metastasis; mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.canlet.2024.217353
Ann Hematol. 2024 Nov 30.

FLT3 inhibitors and hematopoietic cell transplantation prolong survival in patients with FLT3-ITD-positive AML.

Toshihiro Matsukawa, Masahiro Onozawa, Takeshi Kondo, Minoru Kanaya, Daisuke Hidaka, Shuichi Ota, Akio Mori, Akio Shigematsu, Takuto Miyagishima, Yasutaka Kakinoki, Junichi Hashiguchi, Satoshi Yamamoto, Masayo Yamamoto, Kentaro Wakasa, Mutsumi Takahata, Toshimichi Ishihara, Yoshihito Haseyama, Akihito Fujimi, Tetsuya Igarashi, Takehiro Sarashina, Satoshi Iyama, Ryoji Kobayashi, Hajime Sakai, Katsuya Fujimoto, Junki Inamura, Yuji Kanisawa, Shinsuke Hirabayashi, Tomoyuki Endo, Daigo Hashimoto, Takanori Teshima.

  Acute myeloid leukemia (AML) is an aggressive hematological malignancy with genetic alterations. The FMS-like tyrosine kinase 3 (FLT3) gene is frequently mutated in adult de novo AML, with two types of mutations: internal tandem duplication (ITD) and point mutations in the tyrosine kinase domain. This study aimed to investigate the impact of FLT3 inhibitors and hematopoietic cell transplantation (HCT) on survival outcomes in patients with FLT3-ITD AML in a real-world setting. We retrospectively analyzed 139 patients with FLT3-ITD-positive AML between 2012 and 2021. The median age was 63 years. In the propensity score-matched cohort, FLT3 inhibitors improved overall survival (OS) compared with patients treated without FLT3 inhibitors (3-year OS: 33.7% vs. 25.8%, p = 0.021). Patients who underwent HCT had superior outcomes to those without HCT (3-year OS: 45.3% vs. 2.2%, p < 0.0001). The combination of FLT3 inhibitors and HCT resulted in the highest OS and relapse-free survival (RFS) rates (3-year OS: 62.4%; 3-year RFS: 44.4%). Disease status before transplantation did not predict the prognosis, but use of FLT3 inhibitors increased survival in patients without complete remission before HCT. These results demonstrate the clinical impact of FLT3 inhibitors on survival outcomes in patients with FLT3-ITD-positive AML, particularly when combined with HCT. FLT3 inhibitors can improve the prognosis of AML with FLT3 mutations, especially in patients who undergo HCT.

Keywords:   FLT3-ITD; Acute myeloid leukemia; FLT3 inhibitor; Hematopoietic cell transplantation

DOI:  https://doi.org/10.1007/s00277-024-06125-9
Cancer Drug Resist. 2024 ;7 45

Reprogrammed lipid metabolism in advanced resistant cancers: an upcoming therapeutic opportunity.

Mario Cioce, Mariamena Arbitrio, Nicoletta Polerà, Emanuela Altomare, Antonia Rizzuto, Carmela De Marco, Vito Michele Fazio, Giuseppe Viglietto, Maria Lucibello.

  Resistance of cancer to therapy is the main challenge to its therapeutic management and is still an unsolved problem. Rearranged lipid metabolism is a strategy adopted by cancer cells to counteract adversity during their evolution toward aggressiveness and immune evasion. This relies on several mechanisms, ranging from altered metabolic pathways within cancer cells to evolved dynamic crosstalk between cancer cells and the tumor microenvironment (TME), with some cell populations at the forefront of metabolic reprogramming, thereby contributing to the resistance of the whole ecosystem during therapy. Unraveling these mechanisms may contribute to the development of more effective combinatorial therapy in resistant patients. This review highlights the alterations in lipid metabolism that contribute to cancer progression, with a focus on the potential clinical relevance of such findings for the management of therapy resistance.

Keywords:  Metabolic signaling; immune evasion; metastasis; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.20517/cdr.2024.131
iScience. 2024 Dec 20. 27(12): 111291

The impact of a ketogenic diet on weight loss, metabolism, body composition and quality of life.

Simon Hirschberger, David Effinger, Polina Yoncheva, Annika Schmid, Mara-Noel Weis, Lesca-Miriam Holdt, Daniel Teupser, Simone Kreth.

  A ketogenic diet (KD) is increasingly debated as a countermeasure against nutrition-related modern diseases. While being immunologically beneficial, KD is still suspected of having severe metabolic side effects and negatively impacting general well-being, which prevents its widespread clinical use. We conducted a prospective pre-post interventional study investigating the effects of an eucaloric KD on metabolism, weight loss, body composition, diet adherence, and quality of life. The study had two stages: first, feasibility was tested in healthy, normal-weight participants over three weeks. After positive results, the KD period was expanded to three months, enrolling adults with overweight. Significant weight loss was observed in both groups, reducing body fat without affecting muscle or bone mass and without adverse metabolic changes. Quality of life improved, and fatigue symptoms in subjects with overweight decreased. These findings may help to overcome reservations about KD, encouraging its use as a medical tool for treating nutrition-related disorders.

Keywords:  Diet; Human metabolism

DOI:  https://doi.org/10.1016/j.isci.2024.111291
Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2412157121

Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.

Graham P Lobel, Nanumi Han, William A Molina Arocho, Michal Silber, Jason Shoush, Michael C Noji, Tsun Ki Jerrick To, Li Zhai, Nicholas P Lesner, M Celeste Simon, Malay Haldar.

  Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDCs) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets-cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.

Keywords:  dendritic cells; glutamine; tumor microenvironment

DOI:  https://doi.org/10.1073/pnas.2412157121
Oncogene. 2024 Dec 06.

Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment.

Ming Li Chia, Flaviu Bulat, Adam Gaunt, Susana Ros, Alan J Wright, Ashley Sawle, Luca Porcu, Maria Vias, James D Brenton, Kevin M Brindle.

High grade serous ovarian cancer displays two metabolic subtypes; a high OXPHOS subtype that shows increased expression of genes encoding electron transport chain components, increased oxygen consumption, and increased chemosensitivity, and a low OXPHOS subtype that exhibits glycolytic metabolism and is more drug resistant. We show here in patient-derived organoids and in the xenografts obtained by their subcutaneous implantation that the low OXPHOS subtype shows higher lactate dehydrogenase activity and monocarboxylate transporter 4 expression than the high OXPHOS subtype and increased lactate labeling in 13C magnetic resonance spectroscopy (MRS) measurements of hyperpolarized [1-13C]pyruvate metabolism. There was no difference between the subtypes in PET measurements of 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([18F]FDG) uptake. Both metabolic imaging techniques could detect the early response to Carboplatin treatment in drug-sensitive high OXPHOS xenografts and no response in drug-resistant in low OXPHOS xenografts. 13C magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate metabolism has the potential to be used clinically to distinguish low OXPHOS and high OXPHOS tumor deposits in HGSOC patients and to detect their differential responses to treatment.

DOI: https://doi.org/10.1038/s41388-024-03231-w
Phys Chem Chem Phys. 2024 Dec 02.

Respiratory complex II acting as a homeostatic regulatory sensor.

Muhammad A Hagras.

The succinate-ubiquinone oxidoreductase (SQR) complex connects two of the cell's most vital energy-producing metabolic processes: the tricarboxylic acid cycle and the electron transport chain. Hence, the SQR complex is essential in cell metabolism, and its malfunction leads to the progression of multiple metabolic disorders and other diseases, such as cancer. In the current study, we calculated the electron tunneling (ET) pathways between the different redox systems in the SQR complex, including the SQR ligands and the distant heme b redox center, using the broken-symmetry semi-empirical ZINDO method. Interestingly, we discovered a water channel running from the mitochondrial matrix, filling the space between Fe3S4 and heme b redox centers. To investigate the physiological function of the water channel, we performed extensive molecular dynamics (MD) simulations of the membrane-embedded SQR complex in small and large water boxes, representing regular (MDA) and extended (MDB) volume states, respectively. We found that under regular volume conditions (MDA), the ET reaction is conducted through both the iron-sulfur cluster chain (i.e., pathway A) and through heme b (i.e., pathway B). Hence, the SQR complex encompasses an internal interferometer similar to the Mach-Zender interferometer, such that the tunneling electron experiences a self-interference effect through pathways A and B, enhancing the SQR complex's overall ET thermodynamics and favoring the forward ET direction of oxidizing succinate to fumarate and reducing ubiquinone to ubiquinol. On the other hand, we found that under extended volume conditions (MDB), the internal water channel of the SQR complex "senses" the expansion in the mitochondrial volume, pushing the heme b and Fe4S3 redox centers apart and hence lowering the SQR equilibrium constant to almost unity. Therefore, the SQR complex could be driven to work in the reverse direction, catalyzing the production of ubiquinone molecules essential for the physiological function of respiratory complexes I and III and restoring the inner-mitochondrial membrane potential, which leads to restoring the function of the H-K anti-porter, pumping K+ outward from the matrix and restoring the regular mitochondrial volume.

DOI: https://doi.org/10.1039/d4cp03552f
Curr Diab Rep. 2024 Dec 02. 25(1): 8

A Review Article: The Relationship Between Obesity and Colorectal Cancer.

Lily Nguyen, Skandan Shanmugan.

   PURPOSE OF REVIEW: This article aims to review the recent literature assessing the relationship between obesity and colorectal carcinogenesis, the effect of obesity on the treatment of colorectal cancer (CRC), tools available to help augment the increased risk, and outcomes for patients who are affected by both obesity and colorectal cancer.
RECENT FINDINGS: The biochemical mechanisms contributing to CRC carcinogenesis are not well understood but are suspected to be related to adipose tissue leading to a pro-inflammatory state and changes in the gut microbiome. Individuals with obesity are at higher risk for CRC development, worse oncologic outcomes, and increased rates of post-operative complications. Bariatric surgery decreases CRC risk but results with GLP-1 agonists are heterogeneous. Prehabilitation is the only weight loss method that has been demonstrated to decrease risks of post-operative morbidity in this population. Obesity augments CRC risk and outcomes. There are persistent knowledge gaps in etiology and epidemiology for the increased CRC risk in obese patients and more research is required to identify the therapeutic advantage of weight loss on CRC risk.

Keywords:  Bariatric surgery; Colorectal cancer; Colorectal cancer surgery; Obesity; Prehabilitation; Rectal cancer

DOI:  https://doi.org/10.1007/s11892-024-01556-0
iScience. 2024 Dec 20. 27(12): 111336

Tracking fructose 1,6-bisphosphate dynamics in liver cancer cells using a fluorescent biosensor.

Israel Pérez-Chávez, John N Koberstein, Julia Malo Pueyo, Eduardo H Gilglioni, Didier Vertommen, Nicolas Baeyens, Daria Ezeriņa, Esteban N Gurzov, Joris Messens.

  HYlight is a genetically encoded fluorescent biosensor that ratiometrically monitors fructose 1,6-bisphosphate (FBP), a key glycolytic metabolite. Given the role of glucose in liver cancer metabolism, we expressed HYlight in human liver cancer cells and primary mouse hepatocytes. Through in vitro, in silico, and in cellulo experiments, we showed HYlight's ability to monitor FBP changes linked to glycolysis, not gluconeogenesis. HYlight's affinity for FBP was ∼1 μM and stable within physiological pH range. HYlight demonstrated weak binding to dihydroxyacetone phosphate, and its ratiometric response was influenced by both ionic strength and phosphate. Therefore, simulating cytosolic conditions in vitro was necessary to establish a reliable correlation between HYlight's cellular responses and FBP concentrations. FBP concentrations were found to be in the lower micromolar range, far lower than previous millimolar estimates. Altogether, this biosensor approach offers real-time monitoring of FBP concentrations at single-cell resolution, making it an invaluable tool for the understanding of cancer metabolism.

Keywords:  biochemistry methods; cancer; metabolomics

DOI:  https://doi.org/10.1016/j.isci.2024.111336
Food Sci Nutr. 2024 Nov;12(11): 9651-9663

Exploring Consumption of Ultra-Processed Foods and Diet Quality in the Context of Popular Low Carbohydrate and Plant-Based Dietary Approaches.

Kayla-Anne Lenferna De La Motte, Jessica L Campbell, Caryn Zinn.

  This study investigates diet quality across four popular dietary patterns: Ketogenic Diet, Low-Carbohydrate Healthy-Fat, Vegetarian, and Vegan, employing the NOVA and Human Interference Scoring System (HISS) classification systems. Utilizing a modified Food Frequency Questionnaire (FFQ) and analyzing 168 participants' dietary habits, the research identifies notable differences in dietary quality among the dietary patterns. While all groups reported lower consumption of UPFs than the general population, plant-based diets demonstrated higher UPF consumption than ketogenic and low carbohydrate diets. The study reveals that both NOVA and HISS effectively identify UPFs, with significant differences observed at various processing levels, except for UPFs where both systems showed similarity. This research contributes to the detailed understanding of diet quality within popular dietary patterns, highlighting the importance of considering food processing in dietary choices and the need for ongoing research to further elucidate the health implications of different types of UPFs.

Keywords:  food quality; food‐classification systems; low carbohydrate; plant‐based; ultra‐processed foods

DOI:  https://doi.org/10.1002/fsn3.4496
Health Sci Rep. 2024 Dec;7(12): e70231

The Clinical Impact of NPM1 Mutations and the Effect of Concurrent Mutations in Acute Myeloid Leukemia: Unraveling the Prognostic Significance.

Faten Moassass, Yahia Moualla, Bassel Al-Halabi, Atieh Khamis, Walid Al-Achkar.

   Background and Aims: Nucleophosmin (NPM1) gene mutations occur in approximately 30%-35% of individuals with an initial diagnosis of acute myeloid leukemia (AML). Mutations in this gene have been reported in 50%-60% of AML patients with a normal karyotype. These mutations help to distinguish clinicopathological and molecular features, setting them apart as a unique subset within the heterogeneous landscape of AML. In the present study, we investigated the frequency and clinical impact of NPM1 mut in 100 newly diagnosed adult Syrian patients with AML-normal karyotype (NK) using direct sequencing.
Methods: We analyzed 100 AML-NK patients using direct sequencing to assess the prevalence and clinical impact of NPM1 mutations, as well as the co-occurrence of FLT3-ITD and DNMT3A mutations.
Results: Our results revealed that the prevalence of NPM1 mut was 22% among the patients; 86.4% of these mutations were type A (NM_002520.5:c.860-863dupTCTG), while 13.6% were de novo mutations (c.863_864insCCTG, p.Trp288CysfsTer12), (c.861_862dup, p.Trp288SerfsTer13), and (c.863_864insCCGG, p.Trp288CysfsTer12). Among our patients, 22% exhibited NPM1 mut, with 7% also harboring FLT3-ITD mut and 2% having DNMT3A mut. The presence of NPM1 mut was correlated with a statistically significant increase in bone marrow blast percentage (p = 0.017). Notably, patients with NPM1 mut displayed significantly higher mortality rates, with 72.7% succumbing to the disease compared to 29.5% of patients without NPM1 mut (p < 0.001). Furthermore, our results showed that when the overall survival (OS) time exceeded 8.35 months, the likelihood of NPM1 wild-type status was greater.
Conclusion: The evaluation of NPM1 mut and co-mutation has consistently demonstrated remarkable prognostic significance in AML, suggesting the potential for improved response rates, extended disease-free periods, and OS. Our findings provide valuable insights for understanding molecular leukemogenesis in AML-NK patients and will aid in clinical diagnosis, prognostic implications, and the development of targeted therapy strategies for Syrian AML patients.

Keywords:  NPM1; Syria; acute myeloid leukemia (AML); normal karyotype; prognostic factors

DOI:  https://doi.org/10.1002/hsr2.70231
FEBS J. 2024 Dec 06.

FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.

Elia Cappuccio, Max Holzknecht, Michèle Petit, Anne Heberle, Yana Rytchenko, Athanasios Seretis, Ciro L Pierri, Hubert Gstach, Pidder Jansen-Dürr, Alexander K H Weiss.

  This review consolidates a decade of research on fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1), a mitochondrial oxaloacetate tautomerase and decarboxylase with profound implications in cellular metabolism. Despite its critical role as a regulator in mitochondrial metabolism, FAHD1 has remained an often-overlooked enzyme in broader discussions of mitochondrial function. After more than 12 years of research, it is increasingly clear that FAHD1's contributions to cellular metabolism, oxidative stress regulation, and disease processes such as cancer and aging warrant recognition in both textbooks and comprehensive reviews. The review delves into the broader implications of FAHD1 in mitochondrial function, emphasizing its roles in mitigating reactive oxygen species (ROS) levels and regulating complex II activity, particularly in cancer cells. This enzyme's significance is further highlighted in the context of aging, where FAHD1's activity has been shown to influence cellular senescence, mitochondrial quality control, and the aging process. Moreover, FAHD1's involvement in glutamine metabolism and its impact on cancer cell proliferation, particularly in aggressive breast cancer subtypes, underscores its potential as a therapeutic target. In addition to providing a comprehensive account of FAHD1's biochemical properties and structural insights, the review integrates emerging hypotheses regarding its role in metabolic reprogramming, immune regulation, and mitochondrial dynamics. By establishing a detailed understanding of FAHD1's physiological roles and therapeutic potential, this work advocates for FAHD1's recognition in foundational texts and resources, marking a pivotal step in its integration into mainstream metabolic research and clinical applications in treating metabolic disorders, cancer, and age-related diseases.

Keywords:  FAHD1; ODx; ROS; TCA cycle; aging and cellular senescence; cancer metabolism; glutamine metabolism; mitochondrial dysfunction; mitochondrial metabolism

DOI:  https://doi.org/10.1111/febs.17345
NPJ Aging. 2024 Dec 05. 10(1): 61

The role of Mediterranean diet in cancer incidence and mortality in the older adults.

Giulia Giordano, Luca Mastrantoni, Roberta Terranova, Giuseppe Ferdinando Colloca, Giuseppe Zuccalà, Francesco Landi.

The magnitude of benefit of Mediterranean diet in cancer prevention and mortality in older adults is still unclear, therefore we conducted a systematic review and meta-analysis. Outcomes considered were cancer incidence and cancer mortality. In studies evaluating cancer incidence as a time-to-event endpoint and adherence as quantiles, HR was 0.885 (95% CI 0.773-1.013, I2 = 44%). Including ORs, exploratory pooled effect size was 0.876 (0.794-0.966, I2 = 34%), consistently with results of studies evaluating ORs for adherence as one-point increase (OR 0.744, 0.570-0.972, I2 = 90%). No clear benefit was observed on cancer mortality, with pooled HR of 0.935 (0.800-1.093, I2 = 0%). Significant differences were observed for ORs according to cancer type but not between medium and high adherence for both outcomes. Certainty of evidence was low. Our findings suggest that MD could play a protective role in cancer incidence in advanced age, but no clear effect on cancer mortality was observed.

DOI: https://doi.org/10.1038/s41514-024-00186-w
Biochim Biophys Acta Bioenerg. 2024 Nov 28. pii: S0005-2728(24)00499-7. [Epub ahead of print]1866(2): 149529

Alternative NADH dehydrogenase: A complex I backup, a drug target, and a tool for mitochondrial gene therapy.

Dmytro V Gospodaryov.

  Alternative NADH dehydrogenase, also known as type II NADH dehydrogenase (NDH-2), catalyzes the same redox reaction as mitochondrial respiratory chain complex I. Specifically, it oxidizes reduced nicotinamide adenine dinucleotide (NADH) while simultaneously reducing ubiquinone to ubiquinol. However, unlike complex I, this enzyme is non-proton pumping, comprises of a single subunit, and is resistant to rotenone. Initially identified in bacteria, fungi and plants, NDH-2 was subsequently discovered in protists and certain animal taxa including sea squirts. The gene coding for NDH-2 is also present in the genomes of some annelids, tardigrades, and crustaceans. For over two decades, NDH-2 has been investigated as a potential substitute for defective complex I. In model organisms, NDH-2 has been shown to ameliorate a broad spectrum of conditions associated with complex I malfunction, including symptoms of Parkinson's disease. Recently, lifespan extension has been observed in animals expressing NDH-2 in a heterologous manner. A variety of mechanisms have been put forward by which NDH-2 may extend lifespan. Such mechanisms include the activation of pro-longevity pathways through modulation of the NAD+/NADH ratio, decreasing production of reactive oxygen species (ROS) in mitochondria, or then through moderate increases in ROS production followed by activation of defense pathways (mitohormesis). This review gives an overview of the latest research on NDH-2, including the structural peculiarities of NDH-2, its inhibitors, its role in the pathogenicity of mycobacteria and apicomplexan parasites, and its function in bacteria, fungi, and animals.

Keywords:  Hypoxia/reoxygenation; Mitochondrial diseases; Quinolones; Rossmann fold; Type II NADH dehydrogenase; iron‑sulfur clusters

DOI:  https://doi.org/10.1016/j.bbabio.2024.149529
PLoS One. 2024 ;19(12): e0309886

Measuring the rate of NADPH consumption by glutathione reductase in the cytosol and mitochondria.

Kenneth K Y Ting, Eric Floro, Riley Dow, Jenny Jongstra-Bilen, Myron I Cybulsky, Jonathan V Rocheleau.

BACKGROUND: NADPH is an essential co-factor supporting the function of enzymes that participate in both inflammatory and anti-inflammatory pathways in myeloid cells, particularly macrophages. Although individual NADPH-dependent pathways are well characterized, how these opposing pathways are co-regulated to orchestrate an optimized inflammatory response is not well understood. To investigate this, techniques to track the consumption of NADPH need to be applied. Deuterium tracing of NADPH remains the gold standard in the field, yet this setup of mass-spectrometry is technically challenging and not readily available to most research groups. Furthermore, NADPH pools are compartmentalized in various organelles with no known membrane transporters, suggesting that NADPH-dependent pathways are regulated in an organelle-specific manner. Conventional methods such as commercial kits are limited to quantifying NADPH in whole cells and not at the resolution of specific organelles. These limitations reflect the need for a novel assay that can readily measure the consumption rate of NADPH in different organelles.
METHODS: We devised an assay that measures the consumption rate of NADPH by glutathione-disulfide reductase (GSR) in the mitochondria and the cytosol of RAW264.7 macrophage cell lines. RAW264.7 cells were transfected with Apollo-NADP+ sensors targeted to the mitochondria or the cytosol, followed by the treatment of 2-deoxyglucose and diamide. Intravital imaging over time then determined GSR-dependent NADPH consumption in an organelle-specific manner.
DISCUSSION: In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, cytosolic and mitochondrial NADPH was consumed by GSR in a time-dependent manner. This finding was cross validated with a commercially available NADPH kit that detects NADPH in whole cells. Loading of RAW264.7 cells with oxidized low-density lipoprotein followed by LPS stimulation elevated GSR expression, and this correlated with a more rapid drop in cytosolic and mitochondrial NADPH in our assay. The current limitation of our assay is applicability to transfectable cell lines, and higher expression of plasmid-encoded sensors relative to endogenous glucose-6-phosphate dehydrogenase.

DOI: https://doi.org/10.1371/journal.pone.0309886
Blood Res. 2024 Dec 02. 59(1): 39

How to improve AML outcomes?

Taner Tan, Sinem Civriz Bozdag.

  Understanding the intricacies of the pathophysiology and genomic landscape has enhanced the long-term outcomes for patients with acute myeloid leukemia (AML). The identification of novel molecular targets has introduced new therapeutic strategies that attempt to surpass the dominance of the "7 + 3 regimen" established in the 1970s. In 2022, the World Health Organization and International Consensus Classification revised their definitions and approaches to AML, reflecting the current and evolving changes at the molecular level. The guidelines are now grounded in a definition of the disease that emphasizes genetic characteristics. Today, we recognize AML as a genetically diverse disease; a retrospective study identified 5234 driver mutations across 76 genes or genomic regions, with two or more drivers observed in 86% of patients (Papaemmanuil et al., N Engl J Med 374:2209-21, 2016).

Keywords:  AML; Mutations; Outcome; Relapsed; Targeted; Treatment

DOI:  https://doi.org/10.1007/s44313-024-00041-7
Nature. 2024 Dec 04.

Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.

Xueqian Zhuang, Qing Wang, Simon Joost, Alexander Ferrena, David T Humphreys, Zhuxuan Li, Melissa Blum, Klavdija Krause, Selena Ding, Yuna Landais, Yingqian Zhan, Yang Zhao, Ronan Chaligne, Joo-Hyeon Lee, Sebastian E Carrasco, Umeshkumar K Bhanot, Richard P Koche, Matthew J Bott, Pekka Katajisto, Yadira M Soto-Feliciano, Thomas Pisanic, Tiffany Thomas, Deyou Zheng, Emily S Wong, Tuomas Tammela.

Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.

DOI: https://doi.org/10.1038/s41586-024-08285-0
J Neurooncol. 2024 Dec 05.

Angiogenesis inhibitors effects on overall survival and progression-free survival in newly diagnosed primary glioblastoma multiforme: a meta-analysis of twelve randomized clinical trials.

Ali Motamed-Sanaye, Ali Mortezaei, Amir R Afshari, Zahra Saadatian, Amir H Faraji, Jason P Sheehan, Ali Mohammad Mokhtari.

   BACKGROUND: Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Typically treated with initial surgical resection, and chemoradiotherapy, despite current treatments, patients typically survive only 12-14 months, necessitating new therapeutic approaches. Our meta-analysis evaluates combining antiangiogenic medications with chemoradiotherapy versus using chemoradiotherapy alone in treating newly diagnosed GBM.
METHODS: A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus, Cochrane and the Web of Science databases. The search aimed to identify studies reporting overall survival (OS), progression-free survival (PFS), and hazard ratio (HR) with corresponding confidence intervals (CIs) in patients with newly diagnosed GBM. We employed random-effect meta-analysis.
RESULTS: Twelve randomized clinical trials (RCTs) involved 3,309 patients included in the study. The findings showed that angiogenesis inhibitors significantly prolonged PFS [HR 0.85, 95% CI (0.73, 0.99), p-value = 0.04], while there was no significant difference on OS [HR 1.014, 95%CI (0.89, 1.15), p-value = 0.84]. Bevacizumab (BEV) exhibited the highest [HR 0.67, 95% CI (0.56, 0.79), p-value < 0.0001] and thalidomide exhibited the lowest [HR 1.46, 95% CI (1.004, 2.1), p-value = 0.048] improvements of PFS. Meta-regression revealed that age, white race, study sample size, infection, vascular disease complications, KPS > 60, biopsy, gross and subtotal resection can significantly influenced the PFS, while only the year of publication affected OS.
CONCLUSIONS: The current study showed that improve the PFS with no significant effect on OS. Our findings may provide some evidence for decision-making regarding the utilization of angiogenesis inhibitors for the treatment of adult patients with newly diagnosed GBM.

Keywords:  Angiogenesis inhibitors; Glioblastoma multiforme; Overall survival; Progression-free survival

DOI:  https://doi.org/10.1007/s11060-024-04865-2
Hepatology. 2024 Oct 11.

Unraveling bidirectional evolution of unstable mitochondrial DNA mutations in hepatocellular carcinoma at single-cell resolution.

Kaixiang Zhou, Zhenni Wang, Wenjie Guo, Fanfan Xie, Qing Yuan, Shanshan Guo, Huanqin Zhang, Yang Liu, Xiwen Gu, Wenjie Song, Xu Guo, Jinliang Xing.

BACKGROUND AND AIMS: Somatic mutations in mitochondrial DNA (mtDNA) are abundant in HCC and directly affect metabolic homeostasis and tumor progression. The mixed population of mutant and wild-type mtDNA alleles within a cell, termed heteroplasmy, can vary from cell-to-cell and orchestrate tumorigenesis. However, the systematic evolutionary dynamics of somatic mtDNA mutations in HCC tissues remain to be delineated at single-cell resolution.
APPROACH AND RESULTS: We established the single-cell capture-based mtDNA sequencing approach for accurately detecting somatic mtDNA mutations at single-cell resolution. Based on single-cell capture-based mtDNA sequencing, the single-cell somatic mtDNA mutational landscape, intratumor heterogeneity (ITH), and spatiotemporal clonal evolution were systematically investigated in 1641 single cells from 11 patients with HCC and 528 single cells from 2 patient-derived xenografts mouse models. Our data revealed the presence of 2 distinct categories of mtDNA mutation at single-cell resolution, including stable mutations exhibiting similar heteroplasmy levels and unstable mutations exhibiting remarkable cell-to-cell variability of heteroplasmy levels. Furthermore, the proportion of unstable mtDNA mutations was positively associated with the ITH of patients with HCC, with high ITH reflecting the proliferative and aggressive clinicopathological features of HCC cells. In addition, reconstruction of the evolutionary history classified HCC evolution patterns as linear or branched. Notably, spatiotemporal lineage tracing in patient-derived xenograft mouse models and multifocal lesions revealed bidirectional evolution of unstable mtDNA mutations during HCC progression.
CONCLUSIONS: Our study unravels the landscape of single-cell somatic mtDNA mutations in HCC tissues and reveals the bidirectional evolution of unstable mtDNA mutations, with potential implications for HCC stratification and therapeutic intervention.

DOI: https://doi.org/10.1097/HEP.0000000000001113