A barium sulphate-gelatine mixture was injected into the veins in the left lobe of 50 human livers which were then x-rayed. The radiographs were compared with the pathological and anatomical findings ...and enlargements were studied and compared with the histology. A correlation was found between the venogram and the macroscopic and microscopic changes, particularly in various forms of cirrhosis of the liver. The scope and limitations of hepatic venography were studied with respect to solitary and diffuse liver metastase.
Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that ...high-fat diet (HFD)-induced obesity impairs CD8+ T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8+ T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8+ T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8+ T cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8+ T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.
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•Defined a metabolic single-cell atlas of the tumor immune landscape with obesity•Obesity induces a metabolic tug of war between tumor and T cells for lipids•Tumor cells induce fat metabolism and change their microenvironment during obesity•Blocking metabolic adaptations to obesity in cancers restores anti-tumor immunity
High-fat diet compromises anti-tumor immunity by interfering with metabolism in the tumor microenvironment.
Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases ...(2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG-independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.
Immune system activation is essential to thwart the invasion of pathogens and respond appropriately to tissue damage. However, uncontrolled inflammation can result in extensive collateral damage ...underlying a diverse range of auto‐inflammatory, hyper‐inflammatory, and neoplastic diseases. The NF‐κB signaling pathway lies at the heart of the immune system and functions as a master regulator of gene transcription. Thus, this signaling cascade is heavily targeted by mechanisms designed to attenuate overzealous inflammation and promote resolution. Mechanisms associated with the negative regulation of NF‐κB signaling are currently under intense investigation and have yet to be fully elucidated. Here, we provide an overview of mechanisms that negatively regulate NF‐κB signaling through either attenuation of signal transduction, inhibition of posttranscriptional signaling, or interference with posttranslational modifications of key pathway components. While the regulators discussed for each group are far from comprehensive, they exemplify common mechanistic approaches that inhibit this critical biochemical signaling cascade. Despite their diversity, a commonality among these regulators is their selection of specific targets at key inflection points in the pathway, such as TNF‐receptor‐associated factor family members or essential kinases. A better understanding of these negative regulatory mechanisms will be essential to gain greater insight related to the maintenance of immune system homeostasis and inflammation resolution. These processes are vital elements of disease pathology and have important implications for targeted therapeutic strategies.
Review of regulators that negatively modulate NF‐κB signaling to attenuate inflammation and promote resolution.
Crohn's disease and ulcerative colitis are common and debilitating manifestations of inflammatory bowel disease (IBD). IBD is characterized by a radical imbalance in the activation of proinflammatory ...and anti-inflammatory signaling pathways in the gut. These pathways are controlled by NF-κB, which is a master regulator of gene transcription. In IBD patients, NF-κB signaling is often dysregulated resulting in overzealous inflammation. NF-κB activation occurs through 2 distinct pathways, defined as either canonical or noncanonical. Canonical NF-κB pathway activation is well studied in IBD and is associated with the rapid, acute production of diverse proinflammatory mediators, such as COX-2, IL-1β, and IL-6. In contrast to the canonical pathway, the noncanonical or "alternative" NF-κB signaling cascade is tightly regulated and is responsible for the production of highly specific chemokines that tend to be associated with less acute, chronic inflammation. There is a relative paucity of literature regarding all aspects of noncanonical NF-ĸB signaling. However, it is clear that this alternative signaling pathway plays a considerable role in maintaining immune system homeostasis and likely contributes significantly to the chronic inflammation underlying IBD. Noncanonical NF-κB signaling may represent a promising new direction in the search for therapeutic targets and biomarkers associated with IBD. However, significant mechanistic insight is still required to translate the current basic science findings into effective therapeutic strategies.
Introduction: Akt activation is involved in the pathogenesis of inherited thyroid cancer in Cowden’s syndrome and in sporadic thyroid cancers. In cell culture, Akt regulates thyroid cell growth and ...survival; but recent data suggest that Akt also regulates cell motility in non-thyroid cell lines. We therefore sought to evaluate the role of Akt in thyroid cancer progression. Methods: We evaluated 46 thyroid cancer, 20 thyroid follicular adenoma, and adjacent normal tissues samples by immunohistochemistry for activated Akt (pAkt), Akt 1, 2, and 3, and p27 expression. Immunoblots were performed in 14 samples. Results: Akt activation was identified in 10/10 follicular cancers, 26/26 papillary cancers, and 2/10 follicular variant of papillary cancers, but in only 4/66 normal tissue samples and 2/10 typical benign follicular adenomas. Immunoactive pAkt was greatest in regions of capsular invasion; and was localised to the nucleus in follicular cancers and the cytoplasm in papillary cancers, except for invasive regions of papillary cancers where it localised to both compartments. Immunoactive Akt 1, but not Akt 2 or Akt 3, correlated with pAkt localisation, and nuclear pAkt was associated with cytoplasmic expression of p27. In vitro studies using human thyroid cancer cells demonstrated that nuclear translocation of Akt 1 and pAkt were associated with cytoplasmic p27 and cell invasion and migration. Cell migration and the localisation of Akt 1, pAkt, and p27 were inhibited by PI3 kinase, but not MEK inhibition. Discussion: These data suggest an important role for nuclear activation of Akt 1 in thyroid cancer progression.
Abstract Objectives This study aimed to describe the safety and short-term efficacy of the Covered Cheatham-Platinum stent (CCPS) in treating or preventing aortic wall injury (AWI) in patients with ...coarctation of the aorta (CoA). Background The COAST II trial (Covered Cheatham-Platinum Stents for Prevention or Treatment of Aortic Wall Injury Associated with Coarctation of the Aorta Trial) is a multicenter, single-arm trial using the CCPS for the treatment and/or prevention of AWI in patients with CoA and pre-existing AWI or increased risk of AWI. Methods Patients were enrolled if they had a history of CoA with pre-existing AWI (Treatment group) or with increased risk of AWI (Prevention group). Pre/post-implant hemodynamics and angiography were reported. A core laboratory performed standardized review of all angiograms. One-month follow-up was reported. Results A total of 158 patients (male = 65%; median age 19 years) underwent placement of CCPS. Eighty-three patients had pre-existing AWI. The average ascending-to-descending aorta systolic gradient improved from 27 ± 20 mm Hg to 4 ± 6 mm Hg. Complete coverage of pre-existing AWI was achieved in 66 of 71 patients (93%) with AWI who received a single CCPS. Ultimately, complete coverage of AWI was achieved in 76 of 83 patients (92%); 7 patients had minor endoleaks that did not require repeat intervention. Four patients experienced important access site vascular injury. There were no acute AWI, repeat interventions, or deaths. Conclusions The CCPS can effectively treat and potentially prevent AWI associated with CoA. Access site arterial injury is the most common important complication. Longer-term follow-up is necessary to define mid- and late-term outcomes.
Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through ...epigenetic alterations. The cancer cell-intrinsic effects of d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared the oncometabolite d-2HG with its enantiomer, l-2HG, and found that tumor-derived d-2HG was taken up by CD8
T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of d-2HG. d-2HG and inhibition of LDH drive a metabolic program and immune CD8
T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with
mutant gliomas.
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