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https://hdl.handle.net/10171/18928
2024-03-28T19:51:50ZComprehensive analysis of epigenetic and epitranscriptomic genes’ expression in human NAFLD
https://hdl.handle.net/10171/69181
Title: Comprehensive analysis of epigenetic and epitranscriptomic genes’ expression in human NAFLD
Abstract: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with a complex etiology. Its incidence is increasing globally in parallel with the obesity epidemic, and it is now considered the most common liver disease in Western countries. The precise mechanisms underlying the development and progression of NAFLD are complex and still poorly understood. The dysregulation of epigenetic and epitranscriptomic mechanisms is increasingly recognized to play pathogenic roles in multiple conditions, including chronic liver diseases. Here, we have performed a comprehensive analysis of the expression of epigenetic and epitranscriptomic genes in a total of 903 liver tissue samples corresponding to patients with normal liver, obese patients, and patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), advancing stages in NAFLD progression. We integrated ten transcriptomic datasets in an unbiased manner, enabling their robust analysis and comparison. We describe the complete landscape of epigenetic and epitranscriptomic genes’ expression along the course of the disease. We identify signatures of genes significantly dysregulated in association with disease progression, particularly with liver fibrosis development. Most of these epigenetic and epitranscriptomic effectors have not been previously described in human NAFLD, and their altered expression may have pathogenic implications. We also performed a comprehensive analysis of the expression of enzymes involved in the metabolism of the substrates and cofactors of epigenetic and epitranscriptomic effectors. This study provides novel information on NAFLD pathogenesis and may also guide the identification of drug targets to treat this condition and its progression towards hepatocellular carcinoma.2023-01-01T00:00:00ZMetabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment
https://hdl.handle.net/10171/69160
Title: Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment
Abstract: Metabolic dysfunction-associated fatty liver disease (MAFLD) is nowadays considered the liver manifestation of metabolic syndrome. Its prevalence is increasing worldwide in parallel to the epidemic of diabetes and obesity. MAFLD includes a wide spectrum of liver injury including simple steatosis and non-alcoholic steatohepatitis (NASH) that may lead to serious complications such as liver cirrhosis and liver cancer. The complexity of its pathophysiology and the intricate mechanisms underlying disease progression explains the huge variety of molecules targeting diverse biological mechanisms that have been tested in preclinical and clinical settings in the last two decades. Thanks to the large number of clinical trials of the last few years, most of them still ongoing, the pharmacotherapy scenario of MAFLD is rapidly evolving. The three major components of MAFLD, steatosis, inflammation, and fibrosis seem to be safely targeted with different agents at least in a large proportion of patients. Likely, in the next few years more than one drug will be approved for the treatment of MAFLD at different disease stages. The aim of this review is to synthesize the characteristics and the results of the most advanced clinical trials for the treatment of NASH to evaluate the recent advances of pharmacotherapy in this disease.2023-01-01T00:00:00ZArtificial intelligence-based pathology as a biomarker of sensitivity to atezolizumab–bevacizumab in patients with hepatocellular carcinoma: a multicentre retrospective study
https://hdl.handle.net/10171/69002
Title: Artificial intelligence-based pathology as a biomarker of sensitivity to atezolizumab–bevacizumab in patients with hepatocellular carcinoma: a multicentre retrospective study
Abstract: Background Clinical benefits of atezolizumab plus bevacizumab (atezolizumab–bevacizumab) are observed only in a
subset of patients with hepatocellular carcinoma and the development of biomarkers is needed to improve therapeutic
strategies. The atezolizumab–bevacizumab response signature (ABRS), assessed by molecular biology profiling
techniques, has been shown to be associated with progression-free survival after treatment initiation. The primary
objective of our study was to develop an artificial intelligence (AI) model able to estimate ABRS expression directly
from histological slides, and to evaluate if model predictions were associated with progression-free survival.
Methods In this multicentre retrospective study, we developed a model (ABRS-prediction; ABRS-P), which was
derived from the previously published clustering-constrained attention multiple instance learning (or CLAM)
pipeline. We trained the model fit for regression analysis using a multicentre dataset from The Cancer Genome Atlas
(patients treated by surgical resection, n=336). The ABRS-P model was externally validated on two independent series
of samples from patients with hepatocellular carcinoma (a surgical resection series, n=225; and a biopsy series, n=157).
The predictive value of the model was further tested in a series of biopsy samples from a multicentre cohort of
patients with hepatocellular carcinoma treated with atezolizumab–bevacizumab (n=122). All samples in the study
were from adults (aged ≥18 years). The validation sets were sampled between Jan 1, 2008, to Jan 1, 2023. For the
multicentre validation set, the primary objective was to assess the association of high versus low ABRS-P values,
defined relative to cross-validation median split thresholds in the first biopsy series, with progression-free survival
after treatment initiation. Additionally, we performed spatial transcriptomics and matched prediction heatmaps with
in situ expression profiles.
Findings Of the 840 patients sampled, 641 (76%) were male and 199 (24%) were female. Across the development and
validation datasets, hepatocellular carcinoma risk factors included alcohol intake, hepatitis B and C virus infections,
and non-alcoholic steatohepatitis. Using cross-validation in the development series, the mean Pearson’s correlation
between ABRS-P values and ABRS score (mean expression of ABRS genes) was 0·62 (SD 0·09; mean p<0·0001,
SD<0·0001). The ABRS-P generalised well on the external validation series (surgical resection series, r=0·60 [95% CI
0·51–0·68], p<0·0001; biopsy series, r=0·53 [0·40–0·63], p<0·0001). In the 122 patients treated with
atezolizumab–bevacizumab, those with ABRS-P-high tumours (n=74) showed significantly longer median
progression-free survival than those with ABRS-P-low tumours (n=48) after treatment initiation (12 months [95% CI
7–not reached] vs 7 months [4–9]; p=0·014). Spatial transcriptomics showed significantly higher ABRS score, along
with upregulation of various other immune effectors, in tumour areas with high ABRS-P values versus
areas with low ABRS-P values.
Interpretation Our study indicates that AI applied on hepatocellular carcinoma digital slides is able to serve as a
biomarker for progression-free survival in patients treated with atezolizumab–bevacizumab. This approach could be
used in the development of inexpensive and fast biomarkers for targeted therapies. The combination of AI heatmaps
with spatial transcriptomics provides insight on the molecular features associated with predictions. This methodology
could be applied to other cancers or diseases and improve understanding of the biological mechanisms that drive
responses to treatments.2023-01-01T00:00:00ZIs a Technetium-99m Macroaggregated Albumin Scan Essential in the Workup for Selective Internal Radiation Therapy with Yttrium-90? An Analysis of 532 Patients
https://hdl.handle.net/10171/68984
Title: Is a Technetium-99m Macroaggregated Albumin Scan Essential in the Workup for Selective Internal Radiation Therapy with Yttrium-90? An Analysis of 532 Patients
Abstract: Purpose: To determine if baseline patient, tumor, and pretreatment evaluation characteristics could help identify patients who require technetium-99m (99mTc) macroaggregated albumin (99mTc MAA) imaging before selective internal radiation therapy (SIRT).
Materials and methods: In this retrospective analysis, 532 consecutive patients with primary (n = 248) or metastatic (n = 284) liver tumors were evaluated between 2006 and 2015. Variables were compared between patients in whom 99mTc MAA imaging results contraindicated/modified SIRT administration with yttrium-90 (90Y) resin microspheres and those who were treated as initially planned. The 99mTc MAA findings that contraindicated/modified SIRT were a lung shunt fraction (LSF) > 20%, gastrointestinal 99mTc MAA uptake, or a mismatch between 99mTc MAA uptake and intrahepatic tumor distribution.
Results: LSF > 20% and gastrointestinal MAA uptake were observed in 7.5% and 3.9% of patients, respectively, and 11% presented a mismatch. Presence of a single lesion (odds ratio [OR] = 2.4) and vascular invasion (OR = 5.5) predicted LSF > 20%, and GI MAA uptake was predicted by the presence of liver metastases (OR = 3.7) and 99mTc MAA injection through the common/proper hepatic artery (OR = 4.7). Vascular invasion (OR = 4.1) was the only predictor of LSF > 20% and/or GI MAA uptake (sensitivity = 49.2%, specificity = 80.3%, negative predictive value = 92.4%). Previous antiangiogenic treatment (OR = 2.4) and presence of a single lesion (OR = 2.6) predicted mismatch.
Conclusions: Imaging with 99mTc MAA is essential in SIRT workup because baseline characteristics may not adequately predict 99mTc MAA results. Nevertheless, the absence of vascular invasion potentially identifies a group of patients at low risk of SIRT contraindication/modification in whom performing SIRT in a single session (ie, pretreatment evaluation and SIRT on the same day) should be explored.2017-01-01T00:00:00Z