Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

[Strategies and recommendations to face respiratory syncytial virus disease in 2024]. / Estrategias y recomendaciones para enfrentar la enfermedad por virus respiratorio sincicial el año 2024.

During the winter of 2023, Chile faced a complex situation related to the respiratory syncytial virus (RSV). After experiencing a decline in RSV circulation during the years of the SARS-CoV-2 pandemic, a late outbreak was observed in the spring of 2022 and an early onset of the outbreak in 2023, with a significant increase in the number of serious cases. The ineffectiveness of strategic planning and risk communication contributed to the complexity of the situation. To avoid the above next winter, measures such as active surveillance, unification of definitions for acute respiratory infections, identification of RSV variants, public education about infections and advance preparation regarding hospital beds and health personnel are suggested. The importance of immunization and intersectoral collaboration to acquire new preventive alternatives is highlighted, as well as the need for early communication about the importance of immunization and identification of high-risk groups, improvement in training of medical personnel and strategic planning of the Ministry of Health. seeking a proactive and collaborative approach to address the complex RSV situation in future winters. The Chilean Immunization Advisory Committee has already carried out an analysis and recommendation on a new prevention alternative. This working group will support any decision of the Ministry of Health in public policies that attempt a change in the paradigm of control of this disease for the health of the children of our country.

Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia.

Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling.

Gold Nanorods with Mesoporous Silica Shell: A Promising Platform for Cisplatin Delivery.

The versatile combination of metal nanoparticles with chemotherapy agents makes designing multifunctional drug delivery systems attractive. In this work, we reported cisplatin's encapsulation and release profile using a mesoporous silica-coated gold nanorods system. Gold nanorods were synthesized by an acidic seed-mediated method in the presence of cetyltrimethylammonium bromide surfactant, and the silica-coated state was obtained by modified Stöber method. The silica shell was modified first with 3-aminopropyltriethoxysilane and then with succinic anhydride to obtain carboxylates groups to improve cisplatin encapsulation. Gold nanorods with an aspect ratio of 3.2 and silica shell thickness of 14.74 nm were obtained, and infrared spectroscopy and ζ potential studies corroborated surface modification with carboxylates groups. On the other hand, cisplatin was encapsulated under optimal conditions with an efficiency of ~58%, and it was released in a controlled manner over 96 h. Furthermore, acidic pH promoted a faster release of 72% cisplatin encapsulated compared to 51% in neutral pH.

BH3 mimetics and TKI combined therapy for Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) was considered for a long time one of the most hostile leukemia that was incurable for most of the patients, predominantly due to the extreme resistance to chemotherapy. Part of the resistance to cell death (apoptosis) is the result of increased levels of anti-apoptotic and decreased levels of pro-apoptotic member of the BCL-2 family induced by the BCR-ABL1 oncoprotein. BCR-ABL1 is a constitutively active tyrosine kinase responsible for initiating multiple and oncogenic signaling pathways. With the development of specific BCR-ABL1 tyrosine kinase inhibitors (TKIs) CML became a much more tractable disease. Nevertheless, TKIs do not cure CML patients and a substantial number of them develop intolerance or become resistant to the treatment. Therefore, novel anti-cancer strategies must be developed to treat CML patients independently or in combination with TKIs. Here, we will discuss the mechanisms of BCR-ABL1-dependent and -independent resistance to TKIs and the use of BH3-mimetics as a potential tool to fight CML.

Batroxin I: a novel Bradykinin-potentiating peptide with Cytotoxic activity isolated from Bothrops atrox snake venom

Venom peptides are interesting molecular models for the development of biotechnological strategies applicable in generating therapeutic agents and/or experimental tools for basic and applied research. The present study aimed to search for peptides from Bothrops atrox snake venom with anticancer potential activity against HepG2 liver tumor cell line, determine their cytotoxic action, and analyze the structure–function relationship. The novel peptide Batroxin I (M.W. 1.38 kDa) was isolated by molecular exclusion and reversed phase chromatography methods. The Batroxin I presented a selective cytotoxicity towards tumor cells, reducing the viability of HepG2 cells by 94.6% with IC50 of 0.72 μg/mL, and showing a low toxicity against peripheral blood mononuclear cells. Analysis of the apoptotic and necrotic peptide effects revealed that it induced apoptosis by intrinsic pathway activation. The amino acid sequence of Batroxin I was determined by de novo sequencing as < EKWPRPDAPIPP (where < E = pyroglutamic acid); hence, it is an unpublished peptide that belongs to the class of bradykinin-enhancing peptides and cell penetration peptide. This is one of the first reports on the cytotoxic antitumor activity of a bradykinin-enhancing peptide. Our results indicate that this peptide could serve not only as a template for the development of new drugs, but also as an adjuvant to less effective marketed drugs to treat cancer and other diseases.

Philadelphia-negative myeloproliferative neoplasms display alterations in monocyte subpopulations frequency and immunophenotype.

Philadelphia-negative myeloproliferative neoplasms (MPN) are clonal hematological diseases associated with driver mutations in JAK2, CALR, and MPL genes. Moreover, several evidence suggests that chronic inflammation and alterations in stromal and immune cells may contribute to MPN's pathophysiology. We evaluated the frequency and the immunophenotype of peripheral blood monocyte subpopulations in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). Peripheral blood monocytes from PV (n = 16), ET (n = 16), and MF (n = 15) patients and healthy donors (n = 10) were isolated and submitted to immunophenotyping to determine the frequency of monocyte subpopulations and surface markers expression density. Plasma samples were used to measure the levels of soluble CD163, a biomarker of monocyte activity. PV, ET, and MF patients presented increased frequency of intermediate and non-classical monocytes and reduced frequency of classical monocytes compared to controls. Positivity for JAK2 mutation was significantly associated with the percentage of intermediate monocytes. PV, ET, and MF patients presented high-activated monocytes, evidenced by higher HLA-DR expression and increased soluble CD163 levels. The three MPN categories presented increased frequency of CD56+ aberrant monocytes, and PV and ET patients presented reduced frequency of CD80/86+ monocytes. Therefore, alterations in monocyte subpopulations frequency and surface markers expression pattern may contribute to oncoinflammation and may be associated with the pathophysiology of MPN.

Hippo pathway-related genes expression is deregulated in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are hematological disorders characterized by increased proliferation of precursor and mature myeloid cells. MPN patients may present driver mutations in JAK2, MPL, and CALR genes, which are essential to describe the molecular mechanisms of MPN pathogenesis. Despite all the new knowledge on MPN pathogenesis, many questions remain to be answered to develop effective therapies to cure MPN or impair its progression to acute myeloid leukemia. The present study examined the expression levels of the Hippo signaling pathway members in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), as well as the role that they play in disease pathogenesis. The Hippo pathway is a tumor suppressor pathway that participates in the regulation of cell proliferation, differentiation, and death. Our main finding was that the expression of tumor suppressor genes from Hippo pathway were downregulated and seemed to be associated with cell resistance to apoptosis and increased proliferation rate. Therefore, the decreased expression of Hippo pathway-related genes may contribute to the malignant phenotype, apoptosis resistance, and cell proliferation in MPN pathogenesis.

Bioactive Lipids as Chronic Myeloid Leukemia's Potential Biomarkers for Disease Progression and Response to Tyrosine Kinase Inhibitors.

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that expresses the Philadelphia chromosome and constitutively activated Bcr-Abl tyrosine kinase in hematopoietic progenitor cells. Bcr-Abl tyrosine-kinase inhibitors (TKI) do not definitively cure all CML patients. The efficacy of TKI is reduced in CML patients in the blastic phase-the most severe phase of the disease-and resistance to this drug has emerged. There is limited knowledge on the underlying mechanisms of disease progression and resistance to TKI beyond BCR-ABL1, as well as on the impact of TKI treatment and disease progression on the metabolome of CML patients. The present study reports the metabolomic profiles of CML patients at different phases of the disease treated with TKI. The plasma metabolites from CML patients were analyzed using liquid chromatography, mass spectrometry, and bioinformatics. Distinct metabolic patterns were identified for CML patients at different phases of the disease and for those who were resistant to TKI. The lipid metabolism in CML patients at advanced phases and TKI-resistant patients is reprogrammed, as detected by analysis of metabolomic data. CML patients who were responsive and resistant to TKI therapy exhibited distinct enriched pathways. In addition, ceramide levels were higher and sphingomyelin levels were lower in resistant patients compared with control and CML groups. Taken together, the results here reported established metabolic profiles of CML patients who progressed to advanced phases of the disease and failed to respond to TKI therapy as well as patients in remission. In the future, an expanded study on CML metabolomics may provide new potential prognostic markers for disease progression and response to therapy.

Hepatobiliary manifestations in inflammatory bowel disease: A practical approach.

Inflammatory bowel diseases (IBD) are associated with various hepatobiliary disorders. They can occur at any moment in the course of the disease or associated with the treatment. The prevalence of liver dysfunction can reach up to 50% in different studies. Nonalcoholic fatty liver disease is considered the most common hepatobiliary complication in IBD, while primary sclerosing cholangitis is the most specific. Management of hepatic manifestations in IBD involves a multidisciplinary approach that includes a high index of suspicion and joint management with hepatologists. The medical confrontation with abnormal liver tests must include an exhaustive study to determine if these patterns can be related to IBD, associated diseases or to the therapies used.

Donor-derived TB after kidney transplantation: a case report / TB derivada do doador após transplante renal: um relato de caso

Abstract Introduction: Tuberculosis (TB) is a possible serious complication of solid organ transplantation, associated with high mortality and morbidity. Post-transplant TB has varied pathogenesis with many approaches to its prevention, which is the most important way to reduce its incidence. Treatment of TB in organ recipients is challenging because of drug toxicity and interaction with immunosuppressants. Case report: an 18-year-old woman that underwent kidney transplantation from a deceased donor and was discharged with fair renal function was readmitted at 37th postoperative day with fever. CT showed signs of miliary TB and fluid collection besides graft fistulization through the skin. The patient presented positive BAAR in the drained fluid and Koch's bacillus in the urine. She was treated with a four-drug regimen (rifampicin, isoniazid, pyrazinamide, and etambutol), with great response and preserved graft function. We were informed that the recipient of the contralateral kidney also presented post-transplant TB, implying in a donor-derived origin. Conclusion: TB is an important differential diagnosis for infectious complications in patients after solid-organ transplantation, especially in endemic regions. Its initial clinical presentation can be unspecific and it should be suspected in the presence of fever or formation of fluid collections. The suspicion of TB is the key to early diagnosis and satisfactory outcomes in post-transplant TB.

Resumo Introdução: A tuberculose (TB) é uma possível complicação grave do transplante de órgãos sólidos, associada à alta mortalidade e morbidade. A TB pós-transplante tem patogênese variada com muitas abordagens para sua prevenção, que é a forma mais importante de reduzir sua incidência. O tratamento da TB em receptores de órgãos é um desafio devido à toxicidade dos medicamentos e à interação com imunossupressores. Relato de caso: uma mulher de 18 anos que foi submetida a transplante renal de um doador falecido e recebeu alta com função renal adequada foi readmitida no 37º dia de pós-operatório com febre. A TC mostrou sinais de TB miliar e coleção de fluidos além de fistulização do enxerto através da pele. A paciente apresentou BAAR positivo no fluido drenado e bacilo de Koch na urina. Ela foi tratada com um esquema de quatro medicamentos (rifampicina, isoniazida, pirazinamida e etambutol), com ótima resposta e função de enxerto preservada. Fomos informados de que o receptor do rim contralateral também apresentou TB pós-transplante, implicando em uma origem derivada do doador. Conclusão: A TB é um importante diagnóstico diferencial para complicações infecciosas em pacientes após transplante de órgãos sólidos, especialmente em regiões endêmicas. Sua apresentação clínica inicial pode não ser específica e deve ser suspeitada na presença de febre ou formação de coleções de fluidos. A suspeita de TB é a chave para o diagnóstico precoce e desfechos satisfatórios na TB pós-transplante.

Drug-Induced Liver Injury Used in the Treatment of Inflammatory Bowel Disease.

Therapeutic options for the management of inflammatory bowel disease [IBD] have been expanding in recent decades. New biological and small molecule therapies have been incorporated into the pharmacological arsenal, allowing a more personalized management, and seeking increasingly strict remission goals. However, the fear of developing adverse events represents one of the most important limitations in deciding its use by patients and by a multidisciplinary team. Despite the risk of hepatotoxicity of thiopurines and methotrexate, these drugs are still used either as monotherapy or as combined therapy with anti-tumour necrosis factor [anti-TNF] biological agents. Although drug-induced liver injury [DILI] appears to be less frequent with anti-TNF agents, newer biologics and small molecules, liver tests should be considered in the follow-up of these patients, especially regarding future combined therapy of biologics or of these drugs with small molecules. The objective of this review is to show data on the risk of developing DILI in patients with IBD who are undergoing treatment with traditional therapy or new drugs, whether biological or small molecules.

Donor-derived TB after kidney transplantation: a case report.

INTRODUCTION: Tuberculosis (TB) is a possible serious complication of solid organ transplantation, associated with high mortality and morbidity. Post-transplant TB has varied pathogenesis with many approaches to its prevention, which is the most important way to reduce its incidence. Treatment of TB in organ recipients is challenging because of drug toxicity and interaction with immunosuppressants. CASE REPORT: an 18-year-old woman that underwent kidney transplantation from a deceased donor and was discharged with fair renal function was readmitted at 37th postoperative day with fever. CT showed signs of miliary TB and fluid collection besides graft fistulization through the skin. The patient presented positive BAAR in the drained fluid and Koch's bacillus in the urine. She was treated with a four-drug regimen (rifampicin, isoniazid, pyrazinamide, and etambutol), with great response and preserved graft function. We were informed that the recipient of the contralateral kidney also presented post-transplant TB, implying in a donor-derived origin. CONCLUSION: TB is an important differential diagnosis for infectious complications in patients after solid-organ transplantation, especially in endemic regions. Its initial clinical presentation can be unspecific and it should be suspected in the presence of fever or formation of fluid collections. The suspicion of TB is the key to early diagnosis and satisfactory outcomes in post-transplant TB.

Resumen ejecutivo: Enfermedad por hígado graso no alcohólico en sujetos con diabetes mellitus tipo 2: Postura conjunta de la Asociación Chilena de Hepatología (ACHHEP) y la Sociedad Chilena de Diabetología (SOCHIDIAB) / Non-alcoholic fatty liver disease in type 2 diabetes: a joint statement of the Chilean Hepatology and Diabetology Societies

Non-alcoholic fatty liver disease (NAFLD) has a high prevalence and risk of progression to cirrhosis and other complications in patients with type 2 diabetes mellitus (T2DM). Likewise, the presence of NAFLD implies a high risk of developing T2DM, determining a bidirectional relationship between them. The diabetology and hepatology societies, developed a joint initiative aiming to unify criteria, reviewing the definitions, diagnostic criteria, risk stratification, treatment, and follow-up of patients with NAFLD and T2DM. The key questions to be discussed were defined by a panel of specialists in diabetology and hepatology. The Delphi methodology was used to reach consensus on the respective recommendations. Based on the discussion generated among the experts, diagnostic and treatment algorithms were proposed, as well as an indication for referral and the role of the different specialists involved in the management of these patients. Strengthening multidisciplinary work with patients with NAFLD and T2DM will allow the early recognition of the disease, the prevention of the progression to cirrhosis, and reducing the associated complications.

Bone Marrow Soluble Mediator Signatures of Patients With Philadelphia Chromosome-Negative Myeloproliferative Neoplasms.

BACKGROUND: Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are clonal hematological diseases classified as Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). MPN pathogenesis is associated with the presence of somatic driver mutations, bone marrow (BM) niche alterations, and tumor inflammatory status. The relevance of soluble mediators in the pathogenesis of MPN led us to analyze the levels of cytokines, chemokines, and growth factors related to inflammation, angiogenesis and hematopoiesis regulation in the BM niche of MPN patients. METHODS: Soluble mediator levels in BM plasma samples from 17 healthy subjects, 28 ET, 19 PV, and 16 PMF patients were determined using a multiplex assay. Soluble mediator signatures were created from categorical analyses of high mediator producers. Soluble mediator connections and the correlation between plasma levels and clinic-laboratory parameters were also analyzed. RESULTS: The soluble mediator signatures of the BM niche of PV patients revealed a highly inflammatory and pro-angiogenic milieu, with increased levels of chemokines (CCL2, CCL5, CXCL8, CXCL12, CXCL10), and growth factors (GM-CSF M-CSF, HGF, IFN-γ, IL-1ß, IL-6Ra, IL-12, IL-17, IL-18, TNF-α, VEGF, and VEGF-R2). ET and PMF patients presented intermediate inflammatory and pro-angiogenic profiles. Deregulation of soluble mediators was associated with some clinic-laboratory parameters of MPN patients, including vascular events, treatment status, risk stratification of disease, hemoglobin concentration, hematocrit, and red blood cell count. CONCLUSIONS: Each MPN subtype exhibits a distinct soluble mediator signature. Deregulated production of BM soluble mediators may contribute to MPN pathogenesis and BM niche modification, provides pro-tumor stimuli, and is a potential target for future therapies.

Bothrops moojeni L-amino acid oxidase induces apoptosis and epigenetic modulation on Bcr-Abl+ cells.

BACKGROUND: Resistance to apoptosis in chronic myeloid leukemia (CML) is associated with constitutive tyrosine kinase activity of the Bcr-Abl oncoprotein. The deregulated expression of apoptosis-related genes and alteration in epigenetic machinery may also contribute to apoptosis resistance in CML. Tyrosine kinase inhibitors target the Bcr-Abl oncoprotein and are used in CML treatment. The resistance of CML patients to tyrosine kinase inhibitors has guided the search for new compounds that may induce apoptosis in Bcr-Abl+ leukemic cells and improve the disease treatment. METHODS: In the present study, we investigated whether the L-amino acid oxidase isolated from Bothrops moojeni snake venom (BmooLAAO-I) (i) was cytotoxic to Bcr-Abl+ cell lines (HL-60.Bcr-Abl, K562-S, and K562-R), HL-60 (acute promyelocytic leukemia) cells, the non-tumor cell line HEK-293, and peripheral blood mononuclear cells (PBMC); and (ii) affected epigenetic mechanisms, including DNA methylation and microRNAs expression in vitro. RESULTS: BmooLAAO-I induced ROS production, apoptosis, and differential DNA methylation pattern of regulatory apoptosis genes. The toxin upregulated expression of the pro-apoptotic genes BID and FADD and downregulated DFFA expression in leukemic cell lines, as well as increased miR-16 expression - whose major predicted target is the anti-apoptotic gene BCL2 - in Bcr-Abl+ cells. CONCLUSION: BmooLAAO-I exerts selective antitumor action mediated by H2O2 release and induces apoptosis, and alterations in epigenetic mechanisms. These results support future investigations on the effect of BmooLAAO-I on in vivo models to determine its potential in CML therapy.