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Background: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor was licensed for the treatment of ALK-positive metastatic non-small cell lung cancer in 2016. However, real-world evidence on the safety and effectiveness of brigatinib in Latin America remains limited., Objective: The aim of this study was to assess the safety and effectiveness of brigatinib in the real world in Argentina., Methods: We conducted a non-interventional cohort study of adult patients (aged ≥  18 years) with a diagnosis of ALK-positive metastatic non-small cell lung cancer not previously treated (first line) or previously treated (second line) with an ALK inhibitor and who received at least one dose of brigatinib between November 2020 and March 2023. The primary outcome was the incidence of treatment-emergent adverse events. Secondary outcomes at the 24-week follow-up were the percentage of patients with an overall best objective response rate of complete or partial response; intracranial objective response rate; progression-free survival; and overall survival., Results: Of the 39 patients included in the study (n = 22 [first line]; n = 17 [second line]), 12 patients (30.7%) experienced treatment-emergent adverse events, with the most frequent being increased levels of transaminases (7.6%), increased level of blood creatine phosphokinase (5%) and hypokalaemia (5%). Most adverse events (85.7%) were mild to moderate. Effectiveness outcomes at 24 weeks in patients treated with brigatinib first line or second line, respectively, were as follows: overall objective response rate: 81.8% and 70.5%; intracranial objective response rate (in patients with brain metastases at baseline): 66.6% and 88.8%; progression-free survival: 93.8% and 82.4%; overall survival: 100% and 87.5%., Conclusions: Brigatinib was demonstrated to be a safe and effective treatment option for ALK-positive metastatic non-small cell lung cancer in routine clinical practice in Argentina., Clinical Trial Registration: NCT04887519., Competing Interests: Declarations. Funding: This study was supported by Takeda Argentina S.A. Conflicts of Interest/Competing Interests: Claudio Martin received consulting fees from Pfizer, Astra Zeneca, Takeda, Boehringer Ingelheim and Roche. Gabriela Ileana Malcervelli received travel support and consulting fees from Takeda. Lucas Gastón Martinengo has no conflict of interest that are directly relevant to the content of this article. Patricio Servienti received travel support from Raffo, GSK, Takeda, Merck, BMS and Pfizer; lecture fees from GSK and Raffo; and consulting fees from Pfizer. Patricio Levit received lectures fees from Roche, Takeda and AstraZeneca, and consulting fees from Tuteur. Elisa Malaver, Laura Brion, Vanesa Patronella and Andrea Zumarrága are employees of Takeda Argentina S.A. Jose Zarba received travel support from MSD, BMS and Takeda; lecture fees from Novartis, BMS and MSD; and consulting fees from MSD, Takeda and AstraZeneca. Ethics Approval: The study protocol (Brigatinib-5008) was approved by an independent ethics committee (Fundación de Estudios Farmacológicos y Medicamentos, FEFyM) on 21 October, 2020. All patients were required to provide mandatory written informed consent. Good pharmacoepidemiology practice guidelines, local applicable regulations and the Declaration of Helsinki were followed. Furthermore, this study conformed to all regulations concerning the use of personal data. The study was incorporated in the clinical study registry of the city of Buenos Aires, Argentina (PRIISA-BA #3201) and in ClinicalTrials.gov (NCT04887519). Consent to Participate: To receive brigatinib during the post-marketing surveillance study period, eligible patients were required to provide a written inform consent in the presence of the treating physician. The patients were informed about the medication and the scope of the study before providing their consent. Consent for Publication: Not applicable. Availability of Data and Material: The datasets, including the redacted study protocol, redacted statistical analysis plan and individual participant data supporting the results reported in this article, will be made available within 3 months from initial request to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization. Code Availability: Not applicable. Authors’ Contributions: CM, GIM, LGM, PS, PL and JZ participated in patient recruitment and data collection. EM, LB, VP, AZ and JZ participated in study design. All authors participated in the analysis and interpretation of data and contributed to writing and critical revision of all drafts., (© 2025. The Author(s).)

Objective: To report the progress in Peru, since June 2019, in the implementation of the World Health Organization Global Initiative for Childhood Cancer using the Cure All framework, which can be replicated in low- and middle-income countries., Methods: A mixed method was used of participatory and documentary evaluation. The participatory evaluation included stakeholders from various government institutions, nonprofit organizations, and international partners. The documentary aspect consisted of a review of data on the regulatory environment, national projects, and interventions implemented. The Ministry of Health engaged more than 150 participants to form working committees, which have developed policy and regulatory documents to strengthen care services., Results: Achievements include a decrease in the national treatment abandonment rate from 18.6% to 8.5%, the approval of the Childhood Cancer Law, improvements in the management of patients with febrile neutropenia, and a reduction in rates of events of clinical deterioration and mortality of hospitalized patients. The Cure All implementation framework allows local teams to implement specific strategies and monitor early outcomes in pediatric oncology., Conclusions: The results obtained reflect the teamwork, the leadership of the authorities, the technical support of professionals, and the support of involved organizations. Further actions will be needed to guarantee sustainability, and monitoring tools are needed to assure success in the planned activities.

Nitric oxide (NO) is a diffusible, short-lived, diatomic free radical ubiquitously produced by mammalian cells. The generation of NO from L-arginine is enzymatically regulated by three different isoforms of NO synthases. The NO signaling pathway involves mainly the activation of soluble guanylyl cyclase to produce cyclic GMP (cGMP) as a second messenger and downstream mediator. In addition, the free radical activity of NO can cause cellular damage through a phenomenon known as nitrosative stress. NO is a pleiotropic biomodulator in several systems, including the cardiovascular, nervous and immune systems. In the hematopoietic system, NO is thought to be an autocrine or paracrine messenger but also an intracellular effector molecule. Megakaryopoiesis and subsequent thrombopoiesis occur through complex biologic steps that involve hematopoietic stem cell commitment to megakaryocytic lineage, megakaryocyte maturation and finally, platelet release. Here, we summarize the current knowledge regarding the role of exogenous and endogenous NO in hematopoietic stem cell biology, megakaryocyte development and platelet biogenesis as well as relevance of platelet-derived NO generation on platelet function. Dysregulation of NO synthesis has been observed in several diseases, and the evaluation of a series of pharmacological agents with the ability to modulate the NO/cGMP pathway in platelets will also be discussed.

Cell adhesion molecules (CAMs) are surface receptors present in eukaryotic cells that mediate cell-cell or cell-extracellular matrix interactions. Vascular endothelium stimulation in vitro that lead to the upregulation of CAMs was reported for the pathogenic spirochaetes, including rLIC10365 of Leptospira interrogans. In this study, we report the cloning of LIC10507, LIC10508, LIC10509 genes of L. interrogans using Escherichia coli as a host system. The rational for selecting these sequences is due to their location in L. interrogans serovar Copenhageni genome that has a potential involvement in pathogenesis. The genes encode for predicted lipoproteins with no assigned functions. The purified recombinant proteins were capable to promote the upregulation of intercellular adhesion molecule 1 (ICAM-1) and E-selectin on monolayers of human umbilical vein endothelial cells (HUVECS). In addition, the coding sequences are expressed in the renal tubules of animal during bacterial experimental infection. The proteins are probably located at the outer membrane of the bacteria since they are detected in detergent-phase of L. interrogans Triton X-114 extract. Altogether our data suggest a possible involvement of these proteins during bacterial infection and provide new insights into the role of this region in the pathogenesis of Leptospira.

Platelet activation is a critical process during inflammation, thrombosis, and cancer. Here, we show that galectin-1, an endogenous lectin with immunoregulatory properties, plays a key role in human platelet activation and function. Galectin-1 binds to human platelets in a carbohydrate-dependent manner and synergizes with ADP or thrombin to induce platelet aggregation and ATP release. Furthermore, galectin-1 induces F-actin polymerization, up-regulation of P-selectin, and GPIIIa expression; promotes shedding of microvesicles; and triggers conformational changes in GPIIb/IIIa. In addition, exposure to this lectin favors the generation of leukocyte-platelet aggregates. A further mechanistic analysis revealed the involvement of Ca(2+) and cyclic nucleotide-dependent pathways in galectin-1-mediated control of platelet activation. Finally, expression of endogenous galectin-1 in human platelets contributes to ADP-induced aggregation. Our study reveals a novel unrecognized role for galectin-1 in the control of platelet physiology with potential implications in thrombosis, inflammation, and metastasis.

During inflammation, polymorphonuclear leukocyte (PMN) apoptosis can be delayed by different proinflammatory mediators. Classically, it has been accepted that the widely used anti-inflammatory drug acetyl salicylic acid (ASA) exerts its action through inhibition of cyclooxygenases and subsequent prostaglandin synthesis. We hypothesized that another anti-inflammatory action of ASA could be the shortening of PMN survival. We found that at therapeutic concentrations (1-3 mM), ASA and its metabolite salicylate (NaSal), but not indomethacin or ibuprofen, counteracted the prolonged PMN survival mediated by lipopolysaccharide (LPS) through inhibition of nuclear factor-kappaB (NF-kappaB) activation. Both salicylates also inhibited interleukin (IL)-1alpha or acidic conditions antiapoptotic activity. Higher concentrations of both drugs had a direct apoptotic effect. Salicylates were not effective when PMN apoptosis delay was induced by granulocyte macrophage-colony-stimulating factor (GM-CSF), a NF-kappaB-independent cytokine. Promotion of PMN survival by the combination of IL-1alpha and LPS was also reversed by salicylates, but higher concentrations were required. ASA concentrations that did not trigger PMN death increase the zymosan- or tumor necrosis factor-alpha-mediated proapoptotic effect. The LPS- and IL-1alpha- but not GM-CSF-mediated antiapoptotic effect was markedly reduced in PMNs from donors who had ingested ASA. Using a thioglycolate-induced peritonitis model, we showed that in ASA- or NaSal-treated mice there was not only a decrease in the number of cells recruited but also an increase in the percentage of apoptotic PMNs as well as an enhancement of phagocytosis compared with controls. Our findings demonstrate that acceleration of PMN apoptosis by turning off the NF-kappaB-mediated survival signals elicited by proinflammatory stimuli is another anti-inflammatory action of ASA and NaSal.

Objective: Although cAMP is involved in a number of physiologic functions, its role in hematopoietic cell fate decision remains poorly understood. We have recently demonstrated that in CD34(+)-derived megakaryocytes, cAMP-related agents prevent apoptosis. In this study we addressed the question of whether cAMP also regulates survival of their precursors, CD34(+) cells., Methods: Apoptosis was evaluated by fluorescence microscopy, and detection of hypodiploid or annexin V(+) cells by flow cytometry. Mitochondrial membrane potential and bcl-xL or caspase-3 expression were assessed by flow cytometry. Colony-forming units were studied by clonogenic assays in methylcellulose., Results: We found that two different cAMP analogs such as Dibutiril-cAMP and sp-5,6-DCl-BIMPS (BIMPS) promoted survival of human umbilical cord-derived CD34(+) cells by suppressing apoptosis induced by either nitric oxide (NO) or serum deprivation. Involvement of PKA and PI3K pathway was demonstrated by the ability of their specific inhibitors Rp-cAMP and Wortmannin or LY294002 respectively to reverse the antiapoptotic effect of BIMPS. Treatment of CD34(+) cell with BIMPS not only restrained the bcl-xL downregulation but also suppressed the loss of mitochondrial membrane potential and caspase-3 activation induced by serum starvation. While thrombopoietin (TPO), granulocyte colony-stimulating factor (G-CSF) or stem cell factor (SCF) were not able to increase cAMP levels, the antiapoptotic activity exerted by these growth factors was blocked by inhibition of the adenylate cyclase and synergized by BIMPS. Cyclic AMP analogs suppressed the decreased colony formation in cells exposed to NO or serum deprivation., Conclusion: Altogether, our results strongly suggest that cAMP appears to be not only a key pathway controlling CD34(+) survival, but also a mediator of the TPO-, G-CSF- and SCF-mediated cytoprotection.