Response to Sharma and Saraya Tosetti, Giulia; Primignani, Massimo
The American journal of gastroenterology,
08/2021, Letnik:
116, Številka:
8
Journal Article
Recenzirano
...a selection bias can confidently be excluded. The baseline LSM of 60 (41%) patients without esophageal varices included in our study was 26.6 kPa (20.2–55.2), and 21 patients only had LSM <25 kPa. ......we are confident that almost all these patients with LSM ≥20 kPa had CSPH at study inclusion. ...all these patients were similarly followed up, and none developed decompensation. ...even if the LSM cutoff for diagnosing CSPH is questioned, our finding that the risk of decompensation is negligible after virological remission in patients without previous decompensation or high-risk varices maintains its validity.
Nonselective β-blockers improve decompensation-free survival in viremic hepatitis C virus compensated cirrhotic patients with clinically significant portal hypertension, but their protective role ...after sustained virological response by direct-acting antiviral (DAA) is undefined. We evaluated the incidence of decompensation in DAA-cured Child-A patients without high-risk varices. During the 49-month (12-60) follow-up, only one of 148 patients decompensated (ascites), with a 4-year cumulative risk of 1%, but decompensation was associated with hepatocellular carcinoma. The risk of decompensation in DAA cured hepatitis C virus compensated Child-A cirrhotic patients with clinically significant portal hypertension but without high-risk varices is negligible; thus, questioning the need for nonselective β-blocker treatment in this setting (see Visual abstract, Supplemental Digital Content, 1, http://links.lww.com/AJG/B861).
Head and neck squamous cell carcinoma (HNSCC) is characterized by high proliferation and limited differentiation. The altered expression of the p53 family members, and specifically of p63, represents ...a pivotal event in the pathogenesis of HNSCC. Physiologically, p63 affects metabolism through the direct transactivation of the enzyme hexokinase 2, and subsequently controls the proliferation of epithelial cells; nonetheless, its role in cancer metabolism is still largely unclear. The high energetic demand of cancer and the consequent needs of a metabolic reshape, also involve the serine and glycine catabolic and anabolic pathways, including the one carbon metabolism (OCM), to produce energetic compounds (purines) and to maintain cellular homeostasis (glutathione and S-adenosylmethionine).
The involvement in serine/glycine starvation by other p53 family members has been reported, including HNSCC. Here, we show that in HNSCC p63 controls the expression of the enzymes regulating the serine biosynthesis and one carbon metabolism. p63 binds the promoter region of genes involved in the serine biosynthesis as well as in the one carbon metabolism. p63 silencing in a HNSCC cell line affects the mRNA and protein levels of these selected enzymes. Moreover, the higher expression of TP63 and its target enzymes, negatively impacts on the overall survival of HNSCC patients.
These data indicate a direct role of p63 in the metabolic regulation of HNSCC with significant clinical effects.
Coronary artery disease (CAD) is associated with perioperative liver transplantation (LT) mortality. In absence of a defined risk algorithm, we aimed to test whether stress echocardiography and ...coronary computed tomography angiography (CCTA) could detect CAD in end-stage liver disease (ESLD) patients without previous evidence of heart disease.
LT candidates ≥30 years underwent a cardiovascular (CV) assessment through stress echocardiography. CCTA was performed in patients ≥50 years with two or more CV risk factors (e.g. diabetes, CAD family history, dyslipidaemia). Coronary angiography (CAG) was scheduled when stress echocardiography and/or CCTA were positive. Sensibility, specificity, positive and negative predictive values of stress echocardiography and CCTA were assessed by numbers of coronary revascularization (true positives) and lack of acute coronary events over a mean follow-up of 3 years (true negatives).
Stress echocardiography was performed in 273 patients, CCTA in 34 and CAG in 41. Eight patients had critical coronary lesions, and 19 not-critical lesions. Sensitivity, specificity, positive and negative predictive values were 50.0%, 90.2%, 13.3% and 98.4% for stress echocardiography and 100%, 76.7%, 36.4% and 100% for CCTA. Among 163 patients who underwent LT (57.6%), 16 died and 5 had major adverse CV events over a mean follow-up of 3 years.
A very low prevalence of CAD in a selected population of ESLD at intermediate to high CV risk was found. A screening based on stress echocardiography and CCTA resulted in low incidence of post-LT acute coronary events in ELSD patients. CAD has no impact on mid-term survival.
Non-melanoma skin cancer (NMSC) is a tumor that arises from human keratinocytes, showing abnormal control of cell proliferation and aberrant stratification. Cutaneous basal cell carcinoma (cBCC) and ...cutaneous squamous cell carcinoma (cSCC) are the most common sub-types of NMSC. From a molecular point of view, we are still far from fully understanding the molecular mechanisms behind the onset and progression of NMSC and to unravel targetable vulnerabilities to leverage for their treatment, which is still essentially based on surgery. Under this assumption, it is still not elucidated how the central cellular metabolism, a potential therapeutical target, is involved in NMSC progression. Therefore, our work is based on the characterization of the serine anabolism/catabolism and/or one-carbon metabolism (OCM) role in NMSC pathogenesis. Expression and protein analysis of normal skin and NMSC samples show the alteration of the expression of two enzymes involved in the serine metabolism and OCM, the Serine Hydroxy-Methyl Transferase 2 (SHMT2) and Methylen-ThetraHydroFolate dehydrogenase/cyclohydrolase 2 (MTHFD2). Tissues analysis shows that these two enzymes are mainly expressed in the proliferative areas of cBCC and in the poorly differentiated areas of cSCC, suggesting their role in tumor proliferation maintenance. Moreover, in vitro silencing of SHMT2 and MTHFD2 impairs the proliferation of epidermoid cancer cell line. Taken together these data allow us to link the central cellular metabolism (serine and/or OCM) and NMSC proliferation and progression, offering the opportunity to modulate pharmacologically the involved enzymes activity against this type of human cancer.
The transcription factor p63 is a renowned master regulator of gene expression of stratified epithelia. While multiple proteins have been identified as p63 bona fide targets, little is known about ...non-coding RNAs (ncRNAs) whose transcription is controlled by p63. Here, we describe a skin-specific non-coding RNA XP33 as a novel target of p63. XP33 levels are increased during keratinocyte differentiation in vitro, while its depletion results in decreased expression of late cornified gene LCE2D. By using publicly available multi-omics data, we show that CTCF and p63 establish an epithelial enhancer to prime XP33 transcription in a tissue-restricted manner. XP33 promoter and enhancer form a chromatin loop exclusively in keratinocytes but not in other cell types. Moreover, the XP33 enhancer is occupied by differentiation-specific factors that control XP33 transcription. Altogether, we identify a tissue-specific non-coding RNA whose expression is epigenetically regulated by p63 and CTCF.
Non selective beta blockers(NSBBs)are used in primary and secondary prophylaxis of portal hypertensionrelated bleeding in patients with cirrhosis.The efficacy of NSBBs treatment is predicted by ...hemodynamic response in term of reduction of the hepatic venouspressure gradient(HVPG)below 12 mm Hg or at least20%of the basal value.Nevertheless a relevant number of patients who do not achieve this HVPG reduction during NSBBs therapy do not bleed during follow up;this evidence suggests an additional non-hemodynamic advantage of NSBBs treatment to modify the natural history of cirrhosis.Recent studies have questioned the efficacy and safety of NSBBs in patients with advanced stage of liver disease characterized by refractory ascites and/or spontaneous bacterial peritonitis.These studies have suggested the existence of a defined and limited period to modify the natural history of cirrhosis by NSBBs:the"window hypothesis".According with this hypothesis,patients with cirrhosis benefit from the use of NSBBs from the appearance of varices up to the development of an advanced stage of cirrhosis.Indeed,in patients with refractory ascites and/or spontaneous bacterial peritonitis the hemodynamic effects of NSBBs may expose to a high risk of further complications such as renal insufficiency and/or death.Methodological concerns and contrasting results counterbalance the evidence produced up to now on this issue and are the main topic of this editorial.
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