Spontaneous Osteoclastogenesis, a risk factor for bone metastasis in advanced luminal A-type breast cancer patients

Introduction: Osteolytic bone metastasis in advanced breast cancer stages are a major complication for patient´s quality life and a sign of low survival prognosis. Permissive microenvironments which allow cancer cell secondary homing and later proliferation are fundamental for metastatic processes. The causes and mechanisms behind bone metastasis in breast cancer patients are still an unsolved puzzle. Therefore, in this work we contribute to describe bone marrow pre-metastatic niche in advanced breast cancer patients. Results: We show an increase in osteoclasts precursors with a concomitant imbalance towards spontaneous osteoclastogenesis which can be evidenced at bone marrow and peripheral levels. Pro-osteoclastogenic factors RANKL and CCL-2 may contribute to bone resorption signature observed in bone marrow. Meanwhile, expression levels of specific microRNAs in primary breast tumors may already indicate a pro-osteoclastogenic scenario prior to bone metastasis. Discussion: The discovery of prognostic biomarkers and novel therapeutic targets linked to bone metastasis initiation and development are a promising perspective for preventive treatments and metastasis management in advanced breast cancer patients.Fil: Fernández Vallone, Valeria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Borzone, Francisco Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Giorello, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Choi, Hosoon. No especifíca;Fil: Dimase, Federico. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Feldman, Leonardo. Universidad Nacional del Centro de la Provincia de Buenos Aires; ArgentinaFil: Bordenave, Raúl Horacio. Hospital Iriarte; ArgentinaFil: Chudzinski Tavassi, Ana Marisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Batagelj, Emilio. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Spontaneous Osteoclastogenesis, a risk factor for bone metastasis in advanced luminal A-type breast cancer patients

Introduction: Osteolytic bone metastasis in advanced breast cancer stages are a major complication for patient ' s quality life and a sign of low survival prognosis. Permissive microenvironments which allow cancer cell secondary homing and later proliferation are fundamental for metastatic processes. The causes and mechanisms behind bone metastasis in breast cancer patients are still an unsolved puzzle. Therefore, in this work we contribute to describe bone marrow pre-metastatic niche in advanced breast cancer patients. Results: We show an increase in osteoclasts precursors with a concomitant imbalance towards spontaneous osteoclastogenesis which can be evidenced at bone marrow and peripheral levels. Pro-osteoclastogenic factors RANKL and CCL-2 may contribute to bone resorption signature observed in bone marrow. Meanwhile, expression levels of specific microRNAs in primary breast tumors may already indicate a pro-osteoclastogenic scenario prior to bone metastasis. Discussion: The discovery of prognostic biomarkers and novel therapeutic targets linked to bone metastasis initiation and development are a promising perspective for preventive treatments and metastasis management in advanced breast cancer patients

Early high-titer plasma therapy to prevent severe Covid-19 in older adults

BACKGROUND: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness. METHODS We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible. RESULTS A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. CONCLUSIONS Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.).Fil: Libster, Romina Paula. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Pérez Marc, Gonzalo. Hospital Militar Central, Buenos Aires; ArgentinaFil: Wappner, Diego. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Coviello, Silvina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Bianchi, Alejandra. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Braem, Virginia. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Esteban, Ignacio. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Caballero, Mauricio Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Wood, Cristian. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Berrueta, Mabel. Hospital Militar Central; ArgentinaFil: Rondan, Aníbal. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Lescano, Gabriela Mariel. Hospital Dr. Carlos Bocalandro; ArgentinaFil: Cruz, Pablo. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Ritou, Yvonne. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Fernández Viña, Valeria Silvina. Hospital Simplemente Evita; ArgentinaFil: Álvarez Paggi, Damián Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Esperante, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ferreti, Adrián. Hospital Dr. Carlos Bocalandro; ArgentinaFil: Ofman, Gaston. University of Oklahoma; Estados UnidosFil: Ciganda, Álvaro. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal Especializado de Agudos y Cronicos San Juan de Dios.; ArgentinaFil: Rodriguez, Rocío. Hospital Simplemente Evita; ArgentinaFil: Lantos, Jorge. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Valentini, Ricardo. No especifíca;Fil: Itcovici, Nicolás. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Hintze, Alejandra. No especifíca;Fil: Oyarvide, M. Laura. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Etchegaray, Candela. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Neira, Alejandra. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Name, Ivonne. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Alfonso, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Swiss Medical Group; ArgentinaFil: López Castelo, Rocío. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; ArgentinaFil: Caruso, Gisela. Hospital Militar Central; ArgentinaFil: Rapelius, Sofía. Hospital Militar Central; ArgentinaFil: Alvez, Fernando. Hospital Militar Central; ArgentinaFil: Etchenique, Federico. Hospital Militar Central; ArgentinaFil: Dimase, Federico. Hospital Militar Central; ArgentinaFil: Alvarez, Darío. Hospital Militar Central; ArgentinaFil: Aranda, Sofía S.. Hospital Militar Central; ArgentinaFil: Sánchez Yanotti, Clara Inés. Hospital Militar Central; ArgentinaFil: De Luca, Julián. Hospital Militar Central; ArgentinaFil: Jares Baglivo, Sofía. Hospital Militar Central; ArgentinaFil: Laudanno, Sofía. Fundación Hematológica Sarmiento; ArgentinaFil: Nowogrodzki, Florencia. Swiss Medical Group; ArgentinaFil: Larrea, Ramiro. Hospital Municipal San Isidro; ArgentinaFil: Silveyra, María. Hospital Militar Central; ArgentinaFil: Leberzstein, Gabriel. No especifíca;Fil: Debonis, Alejandra. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Molinos, Juan. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: González, Miguel. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Perez, Eduardo. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Kreplak, Nicolás. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Pastor Argüello, Susana. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Gibbons, Luz. Hospital Municipal de San Isidro; ArgentinaFil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Bergel, Eduardo. Sanatorio Sagrado Corazón; ArgentinaFil: Polack, Fernando Pedro. Provincia de Buenos Aires. Ministerio de Salud; Argentin

Circulating miRNAs as potential biomarkers for the early diagnosis of prostate cancer

.Prostate cancer (PCa) is the most common type of cancer and the third cause of death by cancer in Argentinian men. miRNAs are small non-coding RNA molecules that regulate gene expression. miRNAs can be secreted by tumor cells and circulate in the bloodstream. Our aim was to identify circulating miRNAs as candidate biomarkers for the diagnosis of PCa. GeneChip® miRNA 4.0 Arrays (Affymetrix) were hybridized with circulating RNA obtained from serum of PCa patients or healthy donors. Diagnosed PCa patients, free of treatment, were divided into subcategories according to Gleason grade. After data normalization, we identified a list of miRNAs (miR-4668-5p, miR 2277-5p, miR-3613-3p, miR-101-3p, miR-320e-5p, miR-6750- 5p, miR-548x-3p, miR-320a, miR-4532, miR-21-5p) that were increased in PCa patients serum compared to healthy donors. To validate these results, NSG mice were inoculated s.c. with PC3 or 22Rv1 PCa cell lines. After tumor growth, mice with tumors and a non-tumor mice group (control) were sacrificed. Blood and tumor samples were collected for RNA isolation. miRNA expression levels were assessed by stem-loop RT-qPCR. miR-4668-5p, miR 2277-5p, miR-3613-3p and miR-21-5p were significantly increased in the circulation of mice inoculated with PC3 cells compared to control. Also, miR-101-3p and miR-3613-3p were significantly upregulated in the plasma of mice that were inoculated with 22Rv1 compared to control. miR-2277-5p was not detected in the plasma of 22Rv1 injected mice. Interestingly, miR-101-3p was increased in circulation of 22Rv1 compared to PC3 injected mice, while miR-4668-5p was increased in plasma of PC3 compared to 22Rv1 injected mice. Additionally, miR-101- 3p was upregulated in 22Rv1 compared to PC3 xenografts. In summary, our work defines novel candidate biomarkers for PCa diagnosis based on circulating miRNAs from human serum samples. These biomarkers were also detected in xenografts and plasma from mice.Fil: Duca, Rocío Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Farré, Paula Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Graña, Karen Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Massillo, Cintia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Garcia, Nicolas. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Dimase, Federico. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Gandini, Norberto Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Dalton, Guillermo Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaReunión Anual de Sociedades de BiocienciaMar del PlataArgentinaSociedad Argentina de Investigación ClínicaAsociación Argentina de Farmacología ExperimentalSociedad Argentina de BiologíaSociedad Argentina de ProtozoologíaAsociación Argentina de NanomedicinasAsociación Argentina de Ciencia y Tecnología de Animales de LaboratorioThe Histochemical Societ

Behaviour of mesenchymal stem cells from bone marrow of untreated advanced breast and lung cancer patients before bone osteolytic metastasis

Tumour cells can find in bone marrow (BM) a niche rich in growth factors and cytokines that promote their self-renewal, proliferation and survival. In turn, tumour cells affect the homeostasis of the BM and bone, as well as the balance among haematopoiesis, osteogenesis, osteoclastogenesis and bone-resorption. As a result, growth and survival factors normally sequestered in the bone matrix are released, favouring tumour development. Mesenchymal stem cells (MSCs) from BM can become tumour-associated fibroblasts, have immunosuppressive function, and facilitate metastasis by epithelial-to-mesenchymal transition. Moreover, MSCs generate osteoblasts and osteocytes and regulate osteoclastogenesis. Therefore, MSCs can play an important pro-tumorigenic role in the formation of a microenvironment that promotes BM and bone metastasis. In this study we showed that BM MSCs from untreated advanced breast and lung cancer patients, without bone metastasis, had low osteogenic and adipogenic differentiation capacity compared to that of healthy volunteers. In contrast, chondrogenic differentiation was increased. Moreover, MSCs from patients had lower expression of CD146. Finally, our data showed higher levels of Dkk-1 in peripheral blood plasma from patients compared with healthy volunteers. Because no patient had any bone disorder by the time of the study we propose that the primary tumour altered the plasticity of MSCs. As over 70 % of advanced breast cancer patients and 30–40 % of lung cancer patients will develop osteolytic bone metastasis for which there is no total cure, our findings could possibly be used as predictive tools indicating the first signs of future bone disease. In addition, as the MSCs present in the BM of these patients may not be able to regenerate bone after the tumour cells invasion into BM/bone, it is possible that they promote the cycle between tumour cell growth and bone destruction.Fil: Fernández Vallone, Valeria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Hofer, Erica L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Choi, Hosoon. Texas A&M Health Science Center; Estados UnidosFil: Bordenave, Raúl H.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Zonal General de Agudos "Dr. Isidoro G. Iriarte" Quilmes; ArgentinaFil: Batagelj, Emilio. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Feldman, Leonardo. Fundacion Favaloro; ArgentinaFil: La Russa, Vincent. Memorial Sloan Kettering Cancer Center; Estados UnidosFil: Caramutti, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Dimase, Federico. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Labovsky, Vivian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin

Changes in the peripheral blood and bone marrow from untreated advanced breast cancer patients that are associated with the establishment of bone metastases

Bone metastasis is an incurable complication of breast cancer affecting 70-80 % of advanced patients. It is a multistep process that includes tumour cell mobilisation, intravasation, survival in the circulation, extravasation, migration and proliferation in the bone marrow/bone. Although novel findings demonstrate the bone marrow microenvironment significance in bone metastatic progression, a majority of studies have focused on end-stage disease and little is known about how the pre-metastatic niche arises in the bone marrow/bone tissues. We demonstrated a significant increase in patients´ peripheral blood plasma ability to induce transendothelial migration of MCF-7 cells compared with healthy volunteers. Moreover, high RANKL, MIF and OPG levels in patients´ peripheral blood could play a role in the intravasation, angiogenesis, survival and epithelial-mesenchymal transition of circulating tumour cells. Also, we observed a significant increase in patients´ bone marrow plasma capacity to induce transendothelial migration of MDA-MB231 and MCF-7 cells compared with healthy volunteers. Furthermore, patients´ bone marrow mesenchymal stem cells could control the recruitment of tumour cells, modifying the MCF-7 and MDA-MB231 cell migration. In addition, we found a significantly higher MDA-MB231 cell proliferation when we used patients´ bone marrow plasma compared with healthy volunteers. Interestingly, PDGF-AB, ICAM-1 and VCAM-1 levels in patients´ bone marrow were significantly higher than the values of healthy volunteers, suggesting that they could be involved in the cancer cell extravasation, bone resorption and cancer cell proliferation. We believe that these results can reveal new information about what alterations happen in the bone marrow of advanced breast cancer patients before bone colonisation, changes that create optimal soil for the metastatic cascade progression.Fil: Martinez, Leandro Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Fernández Vallone, Valeria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Labovsky, Vivian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Choi, Hosoon. Medicine Institute for Regenerative Medicine. Texas A&M University Health Science Center; Estados UnidosFil: Hofer, Erica Leonor. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Feldman, Leonardo. Fundacion Favaloro; ArgentinaFil: Bordenave, Raúl Horacio. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Zonal General de Agudos "Dr. Isidoro G. Iriarte" (Quilmes); ArgentinaFil: Batagelj, Emilio. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Dimase, Federico. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Rodriguez Villafañe, Ana. Ministerio de Defensa. Ejercito Argentino. Hospital Militar Central Cirujano Mayor "Cosme Argerich"; ArgentinaFil: Chasseing, Norma Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin