Vimentin is required for tumor progression and metastasis in a mouse model of non-small cell lung cancer.

Vimentin is highly expressed in metastatic cancers, and its expression correlates with poor patient prognoses. However, no causal in vivo studies linking vimentin and non-small cell lung cancer (NSCLC) progression existed until now. We use three complementary in vivo models to show that vimentin is required for the progression of NSCLC. First, we crossed LSL-KrasG12D; Tp53fl/fl mice (KPV+/+) with vimentin knockout mice (KPV-/-) to demonstrate that KPV-/- mice have attenuated tumor growth and improved survival compared with KPV+/+ mice. Next, we therapeutically treated KPV+/+ mice with withaferin A (WFA), an agent that disrupts vimentin intermediate filaments (IFs). We show that WFA suppresses tumor growth and reduces tumor burden in the lung. Finally, luciferase-expressing KPV+/+, KPV-/-, or KPVY117L cells were implanted into the flanks of athymic mice to track cancer metastasis to the lung. In KPVY117L cells, vimentin forms oligomers called unit-length filaments but cannot assemble into mature vimentin IFs. KPV-/- and KPVY117L cells fail to metastasize, suggesting that cell-autonomous metastasis requires mature vimentin IFs. Integrative metabolomic and transcriptomic analysis reveals that KPV-/- cells upregulate genes associated with ferroptosis, an iron-dependent form of regulated cell death. KPV-/- cells have reduced glutathione peroxidase 4 (GPX4) levels, resulting in the accumulation of toxic lipid peroxides and increased ferroptosis. Together, our results demonstrate that vimentin is required for rapid tumor growth, metastasis, and protection from ferroptosis in NSCLC.

TGF-ß/SMAD Pathway Is Modulated by miR-26b-5p: Another Piece in the Puzzle of Chronic Lymphocytic Leukemia Progression.

Clinical and molecular heterogeneity are hallmarks of chronic lymphocytic leukemia (CLL), a neoplasm characterized by accumulation of mature and clonal long-lived CD5 + B-lymphocytes. Mutational status of the IgHV gene of leukemic clones is a powerful prognostic tool in CLL, and it is well established that unmutated CLLs (U-CLLs) have worse evolution than mutated cases. Nevertheless, progression and treatment requirement of patients can evolve independently from the mutational status. Microenvironment signaling or epigenetic changes partially explain this different behavior. Thus, we think that detailed characterization of the miRNAs landscape from patients with different clinical evolution could facilitate the understanding of this heterogeneity. Since miRNAs are key players in leukemia pathogenesis and evolution, we aim to better characterize different CLL behaviors by comparing the miRNome of clinically progressive U-CLLs vs. stable U-CLLs. Our data show up-regulation of miR-26b-5p, miR-106b-5p, and miR-142-5p in progressive cases and indicate a key role for miR-26b-5p during CLL progression. Specifically, up-regulation of miR-26b-5p in CLL cells blocks TGF-ß/SMAD pathway by down-modulation of SMAD-4, resulting in lower expression of p21-Cip1 kinase inhibitor and higher expression of c-Myc oncogene. This work describes a new molecular mechanism linking CLL progression with TGF-ß modulation and proposes an alternative strategy to explore in CLL therapy.

Complete Blood Count and Derived Indices: Evolution Pattern and Prognostic Value in Adult Burned Patients.

Certain parameters of complete blood count (CBC) such as red cell distribution width (RDW) and mean platelet volume, as well as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and RDW-to-platelet ratio (RPR) have been associated with inflammatory status and outcome in diverse medical conditions. The aim of this study was to describe the evolution pattern of these parameters in adult burned patients. Adult burned patients admitted to the National Burn Center in Uruguay between May 2017 and February 2018 (discovery cohort) and between March 2018 and August 2019 (validation cohort) were included. Patients' characteristics and outcomes were recorded, as well as CBC parameters on days 1, 3, 5, and 7 after thermal injury. Eighty-eight patients were included in the discovery cohort. Total body surface area burned was 14 [7-23]% and mortality was 15%. Nonsurvivors presented higher RDW and mean platelet volume (P < .01). NLR decreased after admission in all patients (P < .01), but was higher in nonsurvivors (P < .01). Deceased patients also presented higher RPR on days 3, 5, and 7 (P < .001). On the contrary, PLR was reduced in nonsurvivors (P < .05). There was a significant correlation between NLR on admission and burn extension and severity. Kaplan-Meier analysis revealed that NLR, PLR, and RPR could identify patients with increased mortality. These findings were confirmed in the validation cohort (n = 95). Basic CBC parameters and derived indices could be useful as biomarkers to determine prognosis in adults with thermal injuries.

Vimentin regulates activation of the NLRP3 inflammasome.

Activation of the NLRP3 inflammasome and subsequent maturation of IL-1ß have been implicated in acute lung injury (ALI), resulting in inflammation and fibrosis. We investigated the role of vimentin, a type III intermediate filament, in this process using three well-characterized murine models of ALI known to require NLRP3 inflammasome activation. We demonstrate that central pathophysiologic events in ALI (inflammation, IL-1ß levels, endothelial and alveolar epithelial barrier permeability, remodelling and fibrosis) are attenuated in the lungs of Vim(-/-) mice challenged with LPS, bleomycin and asbestos. Bone marrow chimeric mice lacking vimentin have reduced IL-1ß levels and attenuated lung injury and fibrosis following bleomycin exposure. Furthermore, decreased active caspase-1 and IL-1ß levels are observed in vitro in Vim(-/-) and vimentin-knockdown macrophages. Importantly, we show direct protein-protein interaction between NLRP3 and vimentin. This study provides insights into lung inflammation and fibrosis and suggests that vimentin may be a key regulator of the NLRP3 inflammasome.

The inflammasome in lung diseases.

Inflammation, the process aimed at restoring homeostasis after an insult, can be more damaging than the insult itself if uncontrolled, excessive, or prolonged. The inflammasome is an intracellular multimeric protein complex that regulates the maturation and release of proinflammatory cytokines of the IL-1 family in response to pathogens and endogenous danger signals. Growing evidence indicates that the inflammasome plays a key role in the pathogenesis of acute and chronic respiratory diseases. The inflammasome can be activated by the pathogens that account for the most prevalent infectious diseases of the respiratory tract, such as influenza A virus, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. The inflammasome also plays a role in the chronic inflammation of the airways of patients with asthma and chronic obstructive pulmonary disease, as well as in the initiation and progression of the inflammatory process in pulmonary fibrosis. The aim of this review is to summarize the most relevant points of inflammasome activation in lung diseases.

Hemangioendotelioma epitelioide hepático diseminado: a propósito de un caso / A case of hepatic epithelioid hemangioendo thelioma

Introducción: el hemangioendotelioma epiteloide es un tumor mesenquinal de causa desconocida y en general diseminado al diagnóstico. Se describen alrededor de 400 casos en el mundo a la fecha. Material y método: se presenta el caso de una paciente joven que consulta por dolor en hipocondrio derecho constatándose hepatomegalia y esplenomegalia tumoral que seconfirman imagenológicamente y lesión lítica costal y vertebral. La biopsia hepática demuestra hemangioendotelioma epiteloide de alto grado. Se realiza revisión bibliográficadel tema, particularmente su presentación hepática. Resultados: se inicia radioterapia analgésica de columna, la paciente presenta un rápidodeterioro del estado general y fallece de sepsis de origen respiratorio. Conclusión: el hemangioendotelioma epiteloide debe ser considerado en el diagnóstico diferencial de los pacientes en estudio por tumoración hepática y es la cirugía el tratamiento de elección.

Introduction: epitheloid hemangiothelioma is a mesenchymaltumour of unknown etiology and typically disseminated for diagnosis. Until today, 400 cases have beendescribed around the world. Method: the case of a young woman who consultedfor pain in the right hypochondrium is presented. She presented tumoral hepatomegaly and splenomegaly that were imagenologically confirmed, and costal and vertebral lytic lesion. Hepatic biopsy shows high-grade epitheloidhemangiothelioma. A bibliographic review of the conditions is conducted, in particular regarding its hepatic presentation. Results: radiotherapy to the spine for pain was initiated and the patient presented a rapid deterioration of her general condition and died as a result of sepsis of respiratory origin.Conclusion: epitheloid emangiothelioma must be considered in the differential diagnosis for patients seen for hepatic tumors, and surgery is the best choice of treatment.

Introdução: o hemangioendotelioma epitelióide é um tumor mesenquimal de etiologia desconhecida geralmentedisseminado no momento de seu diagnóstico. Cerca de 400 casos foram descritos no mundo até o momento.Material e método: apresenta-se o caso de uma paciente jovem que consulta por dor no hipocôndrio direito constatando-se hepatomegalia e esplenomegalia tumoral confirmadas imagenológicamente e lesão lítica costal e vertebral. A biópsia hepática mostra hemangioendotelioma epitelióide de alto grau. Faz-se uma revisão da bibliografia sobre o tema, especialmente sobre a apresentação hepática. Resultados: a paciente foi submetida a radioterapiaanalgésica de coluna, mas apresentou um rápido deterioro do estado general e falece por sepse de origem respiratória.Conclusão: o hemangioendotelioma epitelióide deve ser considerado no diagnóstico diferencial de pacientesestudados por tumoraçao hepática sendo a cirurgia o tratamento de escolha.