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Thermal ablation in colorectal liver metastases-the paradox of equipoise

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Hepatobiliary Surgery and Nutrition 2021年第2期10卷 276-278页

作者： Nalinie Joharatnam-Hogan Khurum Khan Department of Gastrointestinal Oncology University College London Hospitals NHS Foundation TrustLondonUK mrc Clinical Trials unit at UCL LondonUK UCL cancer Institute LondonUK Department of Gastrointestinal Oncology North Middlesex University HospitalLondonUK

Approximately 25%of individuals with colorectal cancer(CRC)present with metastatic disease,and it is estimated that throughout the course of the disease,up to 50%of individuals may develop liver metastases,the majority of which are unresectable(1).However,thermal ablation is a treatment modality increasingly used to manage individuals with liver *** Takahashi et *** a comprehensive review of the various approaches to thermal ablation and summarised the recent evidence demonstrating an associated survival benefit supporting its use in the management of metastatic CRC(mCRC)(2).It is however critical to analyse the studies evaluated to ensure the strength of the evidence presented.

关键词： colorectal metastases liver

Arginine in microenvironments remodels the characteristics and function of human CD4+ T cells

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Arginine in microenvironments remodels the characteristics a...

Autophagy in cancer biology and therapy

第十四届全国免疫学学术大会

作者： Meng Xia Mariolina Salio Qian Cheng Andreas Hadjinicolaou Qingqing Wang Vincenzo Cerundolo Institute of Immunology Zhejiang University School of Medicine mrc Human Immunology unit MRC Weatherall Institute of Molecular Medicine University of Oxford mrc Centre for Computational Biology MRC Weatherall Institute of Molecular Medicine University of Oxford mrc cancer unit Hutchison/MRC Research Centre University of Cambridge

Human CD4 T cells are acutely sensitive to changes in microenvironmental arginine and their response to increasing arginine concentrations has been elucidated. However, the metabolic and functional changes of human T cells in arginine-limiting microenvironments, especially during long-term culture, is still unclear. Here we show that with time, the low levels of argininosuccinate synthase(ASS) within arginine-starved T cells could continuously promote arginine synthesis from its precursor, citrulline, impacting on T cell activation and proliferation. A specific condition of low arginine concentration at 20μM Results in T cells attaining a long-term activation capacity, generating a stable proportion of TGF-β-dependent CD25FOXP3 cells and displaying robust mitochondrial respiration and glycolytic activity during a 14-day culture. Moreover, these low-arginine cultured T cells turn to have immunosuppressive properties, with decreased production of IFN-γ, high expression of multiple checkpoint molecules such as CTLA-4, PD-1, GITR and ICOS, and the ability to suppress proliferation of other T cells. These findings improve our understanding of the role of arginine in human T cell biology, essential for immunotherapy strategies targeting arginine metabolism.

关键词： Arginine ASS Human CD4+ T Immunosuppression

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Frontiers in Biology 2014年第1期9卷 35-50页

作者： Noor GAMMOH Simon WILKINSON Edinburgh cancer Research UK Centre MRC Institute of Genetics and Molecular Medicine University of Edinburgh Crewe Road SouthUnited Kingdom EH4 2XR

The role of macroautophagy （hereafter autophagy） in cancer biology and response to clinical intervention is complex. It is clear that autophagy is dysregulated in a wide variety of tumor settings, both during tumor initiation and progression, and in response to therapy. However, the pleiotropic mechanistic roles of autophagy in controlling cell behavior make it difficult to predict in a given tumor setting what the role of autophagy, and, by extension, the therapeutic outcome of targeting autophagy, might be. In this review we summarize the evidence in the literature supporting pro- and anti-tumorigenic and -therapeutic roles of autophagy in cancer. This overview encompasses roles of autophagy in nutrient management, cell death, cell senescence, regulation of proteotoxic stress and cellular homeostasis, regulation of tumor-host interactions and participation in changes in metabolism. We also try to understand, where possible, the mechanistic bases of these roles for autophagy. We specifically expand on the emerging role of genetically- engineered mouse models of cancer in shedding light on these issues in vivo. We also consider how any or all of the above functions of autophagy proteins might be targetable by extant or future classes of pharmacologic agents. We conclude by briefly exploring non-canonical roles for subsets of the key autophagy proteins in cellular processes, and how these might impact upon cancer.

关键词： autophagy cancer inflammation metabolism apoptosis homeostasis

Galectin 3-binding protein(LGALS3BP)depletion attenuates hepatic fibrosis by reducing transforming growth factor-β1(TGF-β1)availability and inhibits hepatocarcinogenesis

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cancer Communications 2024年第10期44卷 1106-1129页

作者： Dae-Hwan Kim Minjeong Sung Myong-Suk Park Eun-Gene Sun Sumin Yoon Kyung Hyun Yoo Kamalakannan Radhakrishnan Sung Yun Jung Woo-Kyun Bae Sang-Hee Cho Ik-Joo Chung Department of Internal Medicine Division of Hematology and OncologyChonnam National University Medical SchoolHwasunSouth Korea Department of Internal Medicine Division of Hematology and OncologyChonnam National University Hwasun HospitalHwasunSouth Korea Combinatorial Tumor Immunotherapy mrc Center Chonnam National University Medical SchoolHwasunSouth Korea National Immunotherapy Innovation Center HwasunSouth Korea BioMedical Sciences Graduate Program Chonnam National UniversityHwasunSouth Korea Department of Biological Science SookmyungWomen’s UniversitySeoulSouth Korea Clinical Vaccine R&D Center Chonnam National UniversityHwasunSouth Korea Department of Biochemistry and Molecular Pharmacology Baylor College of MedicineHoustonTexasUSA

Background:Increased Galectin 3-binding protein(LGALS3BP)serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma(HCC).Considering the crucial role of transforming growth factor-β1(TGF-β1)in the emergence of these diseases,the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling ***:The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis(MASH)and *** omics techniques,such as RNA-sequencing,transposaseaccessible chromatin-sequencing assay,and liquid chromatography-tandem mass spectrometry proteomics,were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 *** effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional LGALS3BP-knockin and LGALS3BP-knockout ***:In patients with MASH and HCC,the levels of LGALS3BP and TGFB1 exhibited positive *** of LGALS3BP by the inflammatory cytokine interferonαin HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of *** fibrosis was observed in the livers of hepatocyte-specific LGALS3BP-knockin mice,with increased TGFB1 ***3BP directly bound to and assembled integrinαV,an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin *** released TGF-β1 activated JunB transcription factor,which in turn promoted the TGF-β1 positive feedback ***3BP deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced ***,LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β***:LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway,making it a promising therapeutic target in TGF-β1-related diseases.

关键词： F-actin FAK hepatic carcinogenesis IntegrinαV Interferonα JunB LGALS3BP metabolic dysfuntion-associated steatohepatitis tensile force TGF-β1

Tale of mitochondria and mitochondria-associated ER membrane in patient-derived neuronal models of Wolfram syndrome

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Neural Regeneration Research 2025年第9期20卷 2587-2588页

作者： Laetitia Aubry Timothy Barrett Sovan Sarkar I-STEM CECSCorbeil-EssonnesFrance UniversitéParis-Saclay Universitéd’EvryINSERMI-STEMUMR861Corbeil-EssonnesFrance Institute of cancer and Genomic Sciences Institute of Biomedical ResearchCollege of Medical and Dental SciencesUniversity of BirminghamEdgbastonBirminghamUK Department of Endocrinology Birmingham Women’s and Children’s HospitalSteelhouse LaneBirminghamUK

Mitochondria and mitochondria-associated endoplasmic reticulum membrane in neurodegenerative diseases:Mitochondria generate most of the chemical energy needed to power the biochemical reactions of cells,and thus are often referred to as the"powerhouse"of the ***,this organelle is also involved in a pleth,ora of different cellular functions such as calcium(Ca^(2+))homeostasis,apoptosis,oxidative stress,and several metabolic pathways including oxidative phosphorylation,tricarboxylic acid cycle,andβ-oxidation of fatty acids.

关键词： oxidative cycle carboxylic

Tetracycline-inducible protein expression in pancreatic cancer cells: Effects of CapG overexpression

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World Journal of Gastroenterology 2011年第15期17卷 1947-1960页

作者： Sarah Tonack Sabina Patel Mehdi Jalali Taoufik Nedjadi Rosalind E Jenkins Christopher Goldring John Neoptolemos Eithne Costello Liverpool CR-UK Centre Department of Molecular and Therapeutic Cancer MedicineUniversity of Liverpool Liverpool L69 3GA United Kingdom mrc Centre forDrug Safety Science Department of Pharmacology and Therapeutics School of Biomedical Sciences University of Liverpool L69 3GA United Kingdom National Institute for Health Research Pancreatic Biomedical Research unit Liverpool L69 3GA United Kingdom

AIM: To establish stable tetracycline-inducible pancreatic cancer cell lines. METHODS: Suit-2, MiaPaca-2, and Panc-1 cells were transfected with a second generation reverse tetracycline-controlled transactivator protein (rtTA2S-M2), under the control of either a cytomegalovirus (CMV) or a chicken β-actin promoter, and the resulting clones were ***: Use of the chicken (β-actin) promoter proved superior for both the production and maintenance of doxycycline-inducible cell lines. The system proved versatile, enabling transient inducible expression of a variety of genes, including GST-P, CYP2E1, S100A6, and the actin capping protein, CapG. To determine the physiological utility of this system in pancreatic cancer cells, stable inducible CapG expressors were established. Overexpressed CapG was localised to the cytoplasm and the nuclear membrane, but was not observed in the nucleus. High CapG levels were associated with enhanced motility, but not with changes to the cell cycle, or cellular proliferation. In CapG-overexpressing cells, the levels and phosphorylation status of other actin-moduating proteins (Cofilin and Ezrin/Radixin) were not altered. However, preliminary analyses suggest that the levels of other cellular proteins, such as ornithine aminotransferase and enolase, are altered upon CapG induction. CONCLUSION: We have generated pancreatic-cancer derived cell lines in which gene expression is fully controllable.

关键词： Pancreatic cancer cells Tetracycline-inducible CapG Suit-2 Panc-1 MiaPaCa-2

Perfusion magnetic resonance imaging of the liver

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World Journal of Gastroenterology 2010年第13期16卷 1598-1609页

作者： Choon Hua Thng Tong San Koh David J Collins Dow Mu Koh Department of Oncologic Imaging National Cancer Centre Department of Radiology Royal Marsden NHS Foundation Trust CR UK-EPSRC cancer Imaging Centre Institute of Cancer Research

Perfusion magnetic resonance imaging (MRI) studies quantify the microcirculatory status of liver parenchyma and liver lesions, and can be used for the detection of liver metastases, assessing the effectiveness of antiangiogenic therapy, evaluating tumor viability after anticancer therapy or ablation, and diagnosis of liver cirrhosis and its severity. In this review, we discuss the basic concepts of perfusion MRI using tracer kinetic modeling, the common kinetic models applied for analyses, the MR scanning techniques, methods of data processing, and evidence that supports its use from published clinical and research studies. Technical standardization and further studies will help to establish and validate perfusion MRI as a clinical imaging modality.

关键词： Magnetic resonance imaging Dynamic contrast-enhanced magnetic resonance imaging Liver Tracer kinetic modeling

Male fertility following childhood cancer: current conceptsand future therapies

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Asian Journal of Andrology 2003年第4期5卷 325-337页

作者： Mark F. H. Brougham Christopher J. H.Kelnar Richard M.Sharpe W.Hamish B.Wallace Royal Hospital for Sick Children Edinburgh United KingdomRoyal Hospital for Sick Children Edinburgh United KingdomMRC Human Reproductive Sciences Unit Centre for Reproductive Biology University of Edinburgh United KingdomRoyal Hospital for Sick Children Edinburgh United Kingdom

Prepubertal boys treated for cancer may exhibit impaired fertility in later life. A number of chemotherapeu tic agents have been identified as being gonadotoxic, and certain treatment regimens, such as that used for Hodgkin's disease, are particularly associated with subsequent infertility. Radiotherapy may also cause gonadal damage, most notably following direct testicular irradiation or total body irradiation. Because of the varied nature of the cytotoxic insult, it can be difficult to predict the likelihood of infertility in later life. Currently it is not possible to detect gonadal damage early due to the lack of a sensitive marker of gonadal function in the prepubertal age *** cryopreservation is currently the only method of preserving fertility in patients receiving gonadotoxic therapy. This is only applicable to postpubertal patients and can be problematic in the adolescent age group. At present there is no provision for the prepubertal boy, although there are a number of experimental methods currently being investigated. By harvesting testicular tissue prior to gonadotoxic therapy, restoration of fertility could be achieved following treatment, either by germ cell transplantation or by in vitro maturation of the germ cells harvested. Alternatively, rendering the testes quiescent during cytotoxic treatment may protect the germ cells from subsequent damage. In addition to the many scientific and technical issues to be overcome prior to clinical application of these techniques, a number of ethical and legal issues must also be addressed to ensure a safe and realistic prospect for future fertility in these patients.

关键词： infertility childhood cancer semen cryopreservation germ cell transplantation In vitro germ cell maturation assisted reproductive techniques

Predictive markers of endocrine response in breast cancer

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World Journal of Experimental Medicine 2018年第1期8卷 1-7页

作者： Duniya Mosly Arran Turnbull Andrew Sims Carol Ward Simon Langdon Applied Bioinformatics of cancer University of Edinburgh Cancer Research Centre MRC Institute of Genetics and Molecular Medicine cancer Research UK Edinburgh Centre and Division of Pathology Laboratory MRC Institute of Genetics and Molecular Medicine University of Edinburgh the Royal (Dick) School of Veterinary Studies and Roslin Institute University of Edinburgh

Ongoing clinical and research efforts seek to optimise the use of endocrine therapy in the treatment of breast cancer. Accurate biomarkers are needed that predict response for individual patients. The presence of the estrogen receptor(ER) as the direct(for tamoxifen and fulvestrant) or indirect(for aromatase inhibitors) target molecule for endocrine therapy remains the foremost biomarker and determinant of response. However, ER expression only poorly predicts outcome and further indicators of response or resistance are required. The development and application of molecular signature assays such as Oncotype Dx, Prosigna, Mammaprint and Endopredict have provided valuable information on prognosis and these are being used to support clinical decision making on whether endocrine therapy alone alongside surgery is sufficient for ER-positive early stage breast cancers or whether combination of endocrine with chemotherapy are also warranted. Ki67, the proliferation marker, has been widely used in the neo-adjuvant(pre-operative) setting to help predict response and long term outcome. Gene expression studies within the same setting have allowed monitoring of changes of potential predictive markers. These have identified frequent changes in estrogenregulated and proliferation genes. Specific molecules such as mutant ER may also prove helpful biomarkers in predicting outcome and monitoring response to treatment.

关键词： Estrogen IL6ST Biomarker Breast cancer Predictive