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La enfermedad hepática crónica y sus complicaciones, la cirrosis y el carcinoma hepatocelular, presentan una elevada mortalidad. Los tratamientos curativos, como la hepatectomía parcial o el trasplante hepático, tienen una aplicación limitada en pacientes con cirrosis, por su escasa capacidad de regeneración hepática. Son necesarias otras alternativas diagnósticas y terapéuticas para prevenir la progresión de la enfermedad y mejorar la supervivencia. Diversos estudios preclínicos demuestran el importante papel de la proteína quinasa B(Akt) en la disfunción hepática, aunque aún se desconoce el estado de Akt y sus dianas en las patologías hepáticas crónicas. El principal objetivo es determinar el estado de activación de la vía Akt y su relación con la función hepática en pacientes cirróticos.

Chronic liver disease and related complications, cirrhosis and hepatocellular carcinoma, are associated with high mortality. Curative treatments, partial hepatectomy or liver transplantation, have limited applicability in patients with cirrhosis due to the poor liver regenerative capacity. Thus, we need to find new diagnostic and therapeutic alternatives, to block the disease progression and to improve the survival of patients. In this context, preclinical studies have demonstrated the key role of the protein kinase B (Akt) in liver dysfunction, but the status of Akt and its targets in patients with chronic hepatopathy remains unknown. Aims: To determine the activation status of the Akt pathway and their association with liver functionality in cirrhotic patients.

Simple Summary: Adult B-cell acute lymphoblastic leukemia (B-ALL) is characterized by genetic heterogeneity and high relapse rate. Forty-four adult B-ALL patients were studied at both diagnosis and relapse by next-generation sequencing (NGS) in order to identify genetic alteration driving relapse. Four main genetic pathways leading to relapse in adults were identified: IKZF1plus genetic profile, RAS mutations and TP53 alterations in Philadelphia chromosome (Ph)-negative B-ALL and acquisition of ABL1 mutations in Ph-positive patients. In addition, three clonal evolution patterns were identified: the persistent clone trajectory (25%), the expanding clone trajectory (11%) and the therapy-boosted trajectory (48%). Our results reveal the presence of preferential biological pathways leading to relapse in adult B-ALL. Adult B-cell acute lymphoblastic leukemia (B-ALL) is characterized by genetic heterogeneity and a high relapse rate, affecting over 40% of adults. However, the mechanisms leading to relapse in adults are poorly understood. Forty-four adult B-ALL patients were studied at both diagnosis and relapse by next-generation sequencing (NGS). Four main genetic pathways leading to relapse in adults were identified: IKZF1plus genetic profile, RAS mutations and TP53 alterations in Ph-negative B-ALL and acquisition of ABL1 mutations in Ph-positive patients. The most frequently deleted gene at diagnosis was IKZF1 (52%), and 70% of these patients had IKZF1plus profile. Notably, 88% of patients with IKZF1plus at diagnosis retained this genetic profile at relapse. Conversely, the acquisition of RAS mutations or the expansion of subclones (normalized variant allele frequency < 25%) present from diagnosis were observed in 24% of Ph-negative patients at relapse. In addition, 24% of relapses in the Ph-negative cohort could potentially be driven by TP53 alterations. Of these cases, five presented from diagnosis, and four emerged at relapse, mostly as "double-hit" events involving both TP53 deletion and mutation. In Ph-positive B-ALL, the main genetic finding at relapse was the acquisition of ABL1 mutations (86%). Three clonal evolution patterns were identified: the persistent clone trajectory (25%), the expanding clone trajectory (11%) and the therapy-boosted trajectory (48%). Our results reveal the presence of preferential biological pathways leading to relapse in adult B-ALL. These findings underscore the need for personalized therapeutic strategies to improve clinical outcomes in adult patients with B-ALL. [ABSTRACT FROM AUTHOR]

This article discusses the genetic characteristics and evolution of intrachromosomal amplification of chromosome 21 (iAMP21) in childhood B‐cell acute lymphoblastic leukemia (ALL). iAMP21 is associated with poor prognosis and high relapse rates, but intensive treatment has improved outcomes. The article highlights the complexity and variability of iAMP21, including common amplified regions and secondary genetic abnormalities. The case report presented in the article describes a unique scenario where the copy number state of iAMP21 decreases at relapse, suggesting the emergence of subclones with evolving genomic alterations. The study emphasizes the importance of comprehensive genomic analyses to understand the clonal evolution of leukemia and develop tailored treatment strategies. [Extracted from the article]

Background & Aims: Transcription co‐activator factor 20 (TCF20) is a regulator of transcription factors involved in extracellular matrix remodelling. In addition, TCF20 genomic variants in humans have been associated with impaired intellectual disability. Therefore, we hypothesized that TCF20 has several functions beyond those described in neurogenesis, including the regulation of fibrogenesis. Methods: Tcf20 knock‐out (Tcf20−/−) and Tcf20 heterozygous mice were generated by homologous recombination. TCF20 gene genotyping and expression was assessed in patients with pathogenic variants in the TCF20 gene. Neural development was investigated by immufluorescense. Mitochondrial metabolic activity was evaluated with the Seahorse analyser. The proteome analysis was carried out by gas chromatography mass‐spectrometry. Results: Characterization of Tcf20−/− newborn mice showed impaired neural development and death after birth. In contrast, heterozygous mice were viable but showed higher CCl4‐induced liver fibrosis and a differential expression of genes involved in extracellular matrix homeostasis compared to wild‐type mice, along with abnormal behavioural patterns compatible with autism‐like phenotypes. Tcf20−/− embryonic livers and mouse embryonic fibroblast (MEF) cells revealed differential expression of structural proteins involved in the mitochondrial oxidative phosphorylation chain, increased rates of mitochondrial metabolic activity and alterations in metabolites of the citric acid cycle. These results parallel to those found in patients with TCF20 pathogenic variants, including alterations of the fibrosis scores (ELF and APRI) and the elevation of succinate concentration in plasma. Conclusions: We demonstrated a new role of Tcf20 in fibrogenesis and mitochondria metabolism in mice and showed the association of TCF20 deficiency with fibrosis and metabolic biomarkers in humans. [ABSTRACT FROM AUTHOR]

This study shows that the clinical and biologic characteristics of adult patients with BL and BLL were similar to those of patients from the BL-IPI cohort. Consequently, the BL-IPI was validated in our series of patients with BL and BLL. Keywords: Burkitt lymphoma; prognosis; International Prognostic Index; validation EN Burkitt lymphoma prognosis International Prognostic Index validation 1993 1996 4 08/22/22 20220801 NES 220801 Chemoimmunotherapy including rituximab and high-dose or infusional chemotherapy constitute the standard treatment for patients with Burkitt's lymphoma (BL) or Burkitt's lymphoma and leukemia (BLL) [[1], [3]]. [Extracted from the article]

These two models end up creating binary constructions of the body realities, then produce normalised bodies and a-normalised bodies, bodies that are within the normal canons and bodies who live beyond the borders of bodily canonisation. There is no doubt that too often we limit ourselves to thinking and understanding the body as flesh, as something that only has and only offers an anatomical dimension. This is why we should speak of the bodies that also need to be flesh; perhaps we could speak of flesh-and-body as something united.[5] The demand for flesh goes beyond (or maybe before) the claim to the body, from the metaphorisation, enculturation or poeticisation of that flesh, from the raw materials that we bring to our interactions with the world that surrounds us. The Christian vision of the body splintered from the soul is enhanced with the Cartesian distinction of the res cogitans and res extensa.[7] It is a body that later would be seen and understood as a machine body, a controlled body, a medicalised body, a rehabilitated body or a body without organs. [Extracted from the article]

Summary: The prognosis of t(1;19)(q23;p13)/transcription factor 3‐pre‐B‐cell leukaemia homeobox 1 (TCF3‐PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)‐oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric‐inspired trials. The patients with TCF3‐PBX1 showed similar MRD clearance and did not have different survival compared with other B‐cell precursor ALL patients. However, patients with TCF3‐PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation). [ABSTRACT FROM AUTHOR]

Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinicalbiological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5- year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.