IBtkα Activates the β‐Catenin‐Dependent Transcription of MYC through Ubiquitylation and Proteasomal Degradation of GSK3βin Cancerous B Cells

The IBTK gene encodes the IBtkα protein that is a substrate receptor of E3 ubiquitin ligase, Cullin 3. We have previously reported the pro‐tumorigenic activity of Ibtk in MYC‐dependent B‐ lymphomagenesis observed in Eμ‐myc transgenic mice. Here, we provide mechanistic evidence of the functional interplay between IBtkα and MYC. We show that IBtkα, albeit indirectly, activates the β‐catenin‐dependent transcription of the MYC gene. Of course, IBtkαassociates with GSK3β and promotes its ubiquitylation, which is associated with proteasomal degradation. This event increases the protein level of β‐catenin, a substrate of GSK3β, and results in the transcriptional activation of the MYC and CCND1 target genes of β‐catenin, which are involved in the control of cell division and apoptosis. In particular, we found that in Burkitt’s lymphoma cells, IBtkα silencing triggered the downregulation of both MYC mRNA and protein expression, as well as a strong decrease of cell survival, mainly through the induction of apoptotic events, as assessed by using flow cytometry‐based cell cycle and apoptosis analysis. Collectively, our results shed further light on the complex puzzle of IBtkα interactome and highlight IBtkα as a potential novel therapeutic target to be employed in the strategy for personalized therapy of B cell lymphoma

The expression of inhibitor of bruton's tyrosine kinase gene is progressively up regulated in the clinical course of chronic lymphocytic leukaemia conferring resistance to apoptosis.

Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy with a variable clinical outcome. Biomarkers of CLL progression are required for optimising prognosis and therapy. The Inhibitor of Bruton's tyrosine kinase-isoform α (IBTKα) gene encodes a substrate receptor of Cullin 3-dependent E3 ubiquitin ligase, and promotes cell survival in response to the reticulum stress. Searching for novel markers of CLL progression, we analysed the expression of IBTKα in the peripheral blood B-cells of CLL patients, before and after first line therapy causing remission. The expression of IBTKα was significantly increased in disease progression, and decreased in remission after chemotherapy. Consistently with a pro-survival action, RNA interference of IBTKα increased the spontaneous and Fludarabine-induced apoptosis of MEC-1 CLL cells, and impaired the cell cycle of DeFew B-lymphoma cells by promoting the arrest in G0/G1 phase and apoptosis. Consistently, RNA interference of IBTKα up regulated the expression of pro-apoptotic genes, including TNF, CRADD, CASP7, BNIP3 and BIRC3. Our results indicate that IBTKα is a novel marker of CLL progression promoting cell growth and resistance to apoptosis. In this view, IBTKα may represent an attractive cancer drug target for counteracting the therapy-resistance of tumour cells

Insights into Thymus Development and Viral Thymic Infections

T-cell development in the thymus is a complex and highly regulated process, involving a wide variety of cells and molecules which orchestrate thymocyte maturation into either CD4+ or CD8+ single-positive (SP) T cells. Here, we briefly review the process regulating T-cell differentiation, which includes the latest advances in this field. In particular, we highlight how, starting from a pool of hematopoietic stem cells in the bone marrow, the sequential action of transcriptional factors and cytokines dictates the proliferation, restriction of lineage potential, T-cell antigen receptors (TCR) gene rearrangements, and selection events on the T-cell progenitors, ultimately leading to the generation of mature T cells. Moreover, this review discusses paradigmatic examples of viral infections affecting the thymus that, by inducing functional changes within this lymphoid gland, consequently influence the behavior of peripheral mature T-lymphocytes

Monitoring multiple myeloma by idiotype-specific peptide binders of tumor-derived exosomes.

Abstract Tumor-derived exosomes (TDEs) play a pivotal role in tumor establishment and progression, and are emerging biomarkers for tumor diagnosis in personalized medicine. To date, there is a lack of efficient technology platforms for exosome isolation and characterization. Multiple myeloma (MM) is an incurable B-cell malignancy due to the rapid development of drug-resistance. MM-released exosomes express the immunoglobulin B-cell receptor (Ig-BCR) of the tumor B-cells, which can be targeted by Idiotype-binding peptides (Id-peptides). In this study, we analyzed the production of MM-released exosomes in the murine 5T33MM multiple myeloma model as biomarkers of tumor growth. To this end, we selected Id-peptides by screening a phage display library using as bait the Ig-BCR expressed by 5T33MM cells. By FACS, the FITC-conjugated Id-peptides detected the MM-released exosomes in the serum of 5T33MM-engrafted mice, levels of which are correlated with tumor progression at an earlier time point compared to serum paraprotein. These results indicate that Id-peptide-based recognition of MM-released exosomes may represent a very sensitive diagnostic approach for clinical evaluation of disease progression

Towards a genetic AIDS vaccine

We discuss a recent Nature Medicine publication by Philip Johnson and co-workers (Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nat. Med. 2009, 15: 901-906) in which an effective HIV-1 vaccine was designed that is based on gene therapy. The introduced gene produces an antibody-like immunoadhesin in the blood that neutralizes the virus

HIV vaccine: it may take two to tango, but no party time yet

A press conference on Thursday September 24 in Bangkok, Thailand, released data that an experimental vaccine provided mild protection against HIV-1 infection. This is the first positive signal of any degree of vaccine efficacy in humans, more than a quarter-century after scientists discovered the virus that causes AIDS. The research was conducted by a team including Thai researchers, the U.S. Army and the U.S. National Institutes of Health. The RV144 Phase III clinical trial, which began in 2003, had been disparaged by many critics as a waste of time and money because each of the two components had been shown to produce no benefit as individual vaccines and because the scientific rationales behind the immunogens were just wrong. It was nevertheless speculated that using them together in the prime-boost scenario could be more effective, with the aim to induce heightened CD4+ cellular immune responses against the viral Envelope protein. This optimism seems to have been validated. In fact, this would not be the first time that the discovery of an effective vaccine relied as much on serendipity as opposed to scientific rationale. On the other hand, many questions remain about the RV144 trial, and these issues will be addressed in this editorial

Prevalência e implicações da circunferência abdominal alterada, sobrepeso e obesidade em adolescentes de ensino médio

A obesidade é uma doença crônica caracterizada pelo acúmulo excessivo de tecido adiposo, principalmente na região abdominal, sob etiologias variadas (WHO, 2016). O diagnóstico é feito pela associação de diferentes técnicas, como o cálculo do IMC e a medida da circunferência abdominal (ABESO, 2016). De modo geral, o tratamento para obesidade pode ser pautado com metas para emagrecer e alternativas medicamentosas, mas, especialmente, intervenções integrais em estilo de vida são essenciais nos casos em população jovem (TAYLOR, 2016; TYSON, 2018). A prevenção abrange várias estratégias, desde a reeducação alimentar, junto a estímulos escolares e familiares, e o incentivo à prática de esportes (TYSON, 2018). Seguindo a tendência mundial, a prevalência da doença em jovens vem aumentando, e incorpora hoje 25% dos adolescentes de 10 a 19anos, acarretando, principalmente, em desfechos cardiovasculares, metabólicos e articulares em curto e longo prazo (IBGE, 2010; PASQUALI et al., 2020). Dentro disso, o objetivo do trabalho visa identificar a prevalência de circunferência abdominal alterada, sobrepeso e obesidade em adolescentes escolares de ensinomédio e avaliar os principais fatores predisponentes ao excesso de peso. Trata-se de um estudo epidemiológico, observacional, descritivo e transversal de natureza quantitativa para avaliar a prevalência da obesidade e suas consequências a curto e longo prazo em estudantes do ensino médio de Anápolis, Goiás no período de 2020 e 2021

Dermatite atópica em crianças e o papel da microbiota intestinal na fisiopatologia da doença

A dermatite atópica é uma doença crônica de etiologia multifatorial que afeta hoje 15 a 20% das crianças pelo mundo. Por se tratar de uma doença altamente prugirinosa, as manifestações na infância podem afetar fortemente o curso de desenvolvimento da criança e, consequentemente, a sua qualidade de vida e de todos os envolvidos. Assim, surge a necessidade de uma maior atenção sobre as possíveis formas de prevenção, tratamento e, primariamente, à etiologia por trás dos distúrbios cutâneos. Nessa linha, a relação entre a dermatite atópica infantil e a microbiota intestinal vem ganhando força em meio a hipóteses e teorias ainda pouco conhecidas. Considerando a relevância do assunto, o presente estudo tem por objetivo relacionar a dermatite atópica infantil com a atuação na microbiota intestinal e destacar as principais condutas frente à doença. Tratando-se, portanto, de uma revisão integrativa de literatura embasada em 28 artigos científicos e dados epidemiológicos entre 2011 e 2019, mediante busca nas de dados PubMed e Bireme com os descritores: “atopic eczema”, “etiology”, microbiota gastrointestinal, “probiotic supplement”. Dessa forma, foi possível, não só esclarecer a fisiopatologia da doença, como também evidenciar tópicos a serem aprofundados e chamar a atenção da comunidade científica atual