Circadian rhythms of proliferation events in two mouse carcinomas

We studied the index of DNA synthesis (DNAs) of two cellular carcinomas: the hepatocellular ES12a and the mammary TN60 of mice, throughout one circadian cycle. In the results, we observed that both tumors have circadian rhythms (CRs), but the peaks of DNAs vary. Besides, the mean of DNAs along 24 h shows significative differences, the TN60 has higher values than the ES12a. These observed CR in the DNAs index in both carcinomas mean that, at least in partly, the proliferation of cancer cells can be regulated by endocrine factor as it normally occurs in ordinary cells. The big problem we can find for the chronopharmacology is that it is impossible to know in advance the rate of proliferation of each tumor.Fil: Garcia, Marcela. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; ArgentinaFil: Andrini, Laura Beatríz. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; ArgentinaFil: Martinez, Marina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; ArgentinaFil: Inda, Ana. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; ArgentinaFil: Palma, Maria Belen. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Miriuka, Santiago Gabriel. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Errecalde, Ana Lia. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentin

The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma

Background: Clear cell renal cell carcinoma (ccRCC), the most aggressive renal cancer, is characterized by early lymph node metastases and bad prognosis. Most therapies targeting advanced or metastatic ccRCC are based, as first-line treatment, on the administration of the vascular endothelial growth factor (VEGF) neutralizing antibody termed Bevacizumab. Despite proven benefits, the expected results were not obtained for the majority of patients. The possibility that an intricate interplay between angiogenesis and immune-checkpoints might exist lead us to evaluate tumor angiogenesis, by means of VEGF expression together with the immune checkpoint HLA-G/ILT4. Methods: Tumor specimens were obtained from patients from two separate cohorts: One from "Evita Pueblo"Hospital from Berazategui, (Buenos Aires, Argentina) and the second includes patients surgically operated at the Urology Department of Saint-Louis Hospital (Paris, France) with a confirmed ccRCC diagnosis. Immunohistochemistry was performed with specific antibodies directed against HLA-G, VEGF-A, VEGF-C, D240, CD34, ILT4 and Ca-IX. In addition, gene expression levels were measured in a cell line derived from a ccRCC patient by semi-quantitative RT-PCR. Results: Our results show that the highly vascularized tumors of ccRCC patients express high levels of VEGF and the immune-checkpoint HLA-G. In addition, ILT4, one of the HLA-G receptors, was detected on macrophages surrounding tumor cells, suggesting the generation of an immune-tolerant microenvironment that might favor tumorigenesis. Notably, RT-qPCR analysis provided the first evidence on the transcriptional relationship between HLA-G/ILT4 and the VEGF family. Namely, in the presence of HLA-G or ILT4, the levels of VEGF-A are diminished whereas those of VEGF-C are increased. Conclusions: In an effort to find new therapeutic molecules and fight against metastasis dissemination associated with the poor survival rates of ccRCC patients, these findings provide the rationale for co-targeting angiogenesis and the immune checkpoint HLA-G.Fil: García, Marcela. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; ArgentinaFil: Palma, Maria Belen. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Laboratorio de Biología del Desarrollo Celular; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Verine, Jerome. Ap-hp, Saint-louis Hospital; Francia. Research Division in Hematology and Immunology; FranciaFil: Miriuka, Santiago Gabriel. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Laboratorio de Biología del Desarrollo Celular; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Inda, Ana María. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; ArgentinaFil: Errecalde, Ana Lia. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; ArgentinaFil: Desgrandchamps, François. Saint-louis Hospital; FranciaFil: Carosella, Edgardo Delfino. Universite de Paris; FranciaFil: Tronik Le Roux, Diana. Universite de Paris; Franci

HLA-G gene editing in tumor cell lines as a novel alternative in cancer immunotherapy

Cancer immunotherapies based mainly on the blockade of immune-checkpoint (IC) molecules by anti-IC antibodies offer new alternatives for treatment in oncological diseases. However, a considerable proportion of patients remain unresponsive to them. Hence, the development of novel clinical immunotherapeutic approaches and/or targets are crucial.W In this context, targeting the immune-checkpoint HLA-G/ILT2/ILT4 has caused great interest since it is abnormally expressed in several malignancies generating a tolerogenic microenvironment. Here, we used CRISPR/Cas9 gene editing to block the HLA-G expression in two tumor cell lines expressing HLA-G, including a renal cell carcinoma (RCC7) and a choriocarcinoma (JEG-3). Different sgRNA/Cas9 plasmids targeting HLA-G exon 1 and 2 were transfected in both cell lines. Downregulation of HLA-G was reached to different degrees, including complete silencing. Most importantly, HLA-G − cells triggered a higher in vitro response of immune cells with respect to HLA-G + wild type cells. Altogether, we demonstrated for the first time the HLA-G downregulation through gene editing. We propose this approach as a first step to develop novel clinical immunotherapeutic approaches in cancer.Fil: Palma, Maria Belen. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Tronik Le Roux, Diana. Saint-Louis Hospital; Francia. Universite de Paris 1 - Pantheon Sorbonne.; FranciaFil: Amin, Guadalupe. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Castañeda, Sheila Lucia. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Möbbs, Alan Miqueas. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Scarafia, Maria Agustina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: la Greca, Alejandro Damián. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Daouya, Marina. Hôpital Saint-louis; Francia. Universite de Paris 1 - Pantheon Sorbonne.; FranciaFil: Poras, Isabelle. Hôpital Saint-louis; Francia. Universite de Paris 1 - Pantheon Sorbonne.; FranciaFil: Inda, Ana María. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; ArgentinaFil: Moro, Lucía Natalia. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Carosella, Edgardo Delfino. Hôpital Saint-louis; Francia. Universite de Paris 1 - Pantheon Sorbonne.; FranciaFil: García, Marcela Nilda. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; ArgentinaFil: Miriuka, Santiago Gabriel. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997Ł2010

Abstract Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIVinfected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 personyears (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997. Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection

Ten golden rules for optimal antibiotic use in hospital settings: the WARNING call to action

Antibiotics are recognized widely for their benefits when used appropriately. However, they are often used inappropriately despite the importance of responsible use within good clinical practice. Effective antibiotic treatment is an essential component of universal healthcare, and it is a global responsibility to ensure appropriate use. Currently, pharmaceutical companies have little incentive to develop new antibiotics due to scientific, regulatory, and financial barriers, further emphasizing the importance of appropriate antibiotic use. To address this issue, the Global Alliance for Infections in Surgery established an international multidisciplinary task force of 295 experts from 115 countries with different backgrounds. The task force developed a position statement called WARNING (Worldwide Antimicrobial Resistance National/International Network Group) aimed at raising awareness of antimicrobial resistance and improving antibiotic prescribing practices worldwide. The statement outlined is 10 axioms, or “golden rules,” for the appropriate use of antibiotics that all healthcare workers should consistently adhere in clinical practice

CpG-ODN formulated with a nanostructure as adjuvant for anticrotalic serum production. Studies in mice

Antivenom is the only safe and effective treatment to neutralize snake venom. Specific anti-venom used to treat snake bite is usually obtained from horses after hyperimmunization with crude snake venom in combination with Freund´s Adjuvant. Freund´s complete and incomplete adjuvant can cause severe local and systemic acute and chronic inflammation, its potentially severe inflammatory effects have led many researchers to seek alternative immunological adjuvants. CpG-ODN formulated in a 6-O-ascorbyl palmitate nanostructure (Coa-ASC16) was more efficient as adjuvant than CpG-ODN alone using ovalbumin (OVA) as an antigen model. Particularly, immunization of mice with OVA/CpG-ODN/Coa-ASC16 resulted in high OVA specific antibody titers and IFN-γ and IL-17 secretion compared to immunization with OVA/CpG-ODN. First of all, we estimated the effect of Coa-ASC16 nanostructure preparation on venom activity. Additionally, in order to evaluate the immune response induced by this adjuvant strategy using Crotalus durissus terrificus (C. d. terrificus) venom (CdtV), we determined the titer of antibodies (IgG, IgG1 and IgG2) and their specificity. BALB/c mice were subcutaneously immunizated on days 0, 15 and 30 with CdtV/CpG-ODN/Coa-ASC16 or CdtV/Freund´s Adyuvant (complete first and incomplete-booster) (dose/mice: CdtV: 6?10 μg, CpG-ODN: 30 μg). On day 45 mice were sacrificed. The neutralizing ability of serum from animals immunized with CdtV/CpG-ODN/Coa-ASC16 or CdtV/Freund´s adjuvant was tested against PLA2 activity and lethality. In both immunized group mice, the antibody titers in plasma were high (1 × 105), with a similar IgG1/IgG2a ratio. The antibodies recognized phospholipase A2 and thrombin-like proteins, the main toxins from C. d. terrificus venom. Macroscopic and microscopic analysis at the site of injection of mice injected with Freund´s adjuvant showed local damage (with non-infectious abscesses) and hypertrophy of inguinal lymph nodes, whereas mice injected with CpG-ODN/Coa/ASC16 did not. Our results show that CpG-ODN/Coa-ASC16 produces a humoral response as strong and specific as Freund´s adjuvant, with minor or null local deleterious effect, demonstrating the potentiality and advisability of an alternative formulation as a new adjuvant option for future immunizations to produce C. d. terrificus antivenom.Fil: Fusco, Luciano Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; ArgentinaFil: Pascual, Maria Mercedes. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Hernandez, David Roque. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias. Instituto de Ictiología del Nordeste; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Sánchez Vallecillo, María Fernanda. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Arrieta, Maria Belen. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Moron, Victor Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Palma, Santiago Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Maletto, Belkys Angélica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Leiva, Laura Cristina Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentin

RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes

The current standard of care for locally advanced rectal cancer (RC) is neoadjuvant radio-chemotherapy (NRC) with 5-fluorouracil (5Fu) as the main drug, followed by surgery and adjuvant chemotherapy. While a group of patients will achieve a pathological complete response, a significant percentage will not respond to the treatment. The Unfolding Protein Response (UPR) pathway is generally activated in tumors and results in resistance to radio-chemotherapy. We previously showed that RHBDD2 gene is overexpressed in the advanced stages of colorectal cancer (CRC) and that it could modulate the UPR pathway. Moreover, RHBDD2 expression is induced by 5Fu. In this study, we demonstrate that the overexpression of RHBDD2 in CACO2 cell line confers resistance to 5Fu, favors cell migration, adhesion and proliferation and has a profound impact on the expression of both, the UPR genes BiP, PERK and CHOP, and on the cell adhesion genes FAK and PXN. We also determined that RHBDD2 binds to BiP protein, the master UPR regulator. Finally, we confirmed that a high expression of RHBDD2 in RC tumors after NRC treatment is associated with the development of local or distant metastases. The collected evidence positions RHBDD2 as a promising prognostic biomarker to predict the response to neoadjuvant therapy in patients with RC.Fil: Palma, Sabina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Raffa, Carlos Ignacio. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Garcia Fabiani, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Ferretti, Valeria. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Zwenger, Ariel. Grupo Oncologico Cooperativo del Sur; Argentina. Provincia del Neuquén. Hospital Provincial Neuquén "Dr. E. Castro Rendón"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Perez Verdera, P. V.. No especifíca;Fil: Llontop, A.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Rojas Bilbao, E.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Cuartero, V.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; ArgentinaFil: Abba, Martín Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; ArgentinaFil: Lacunza, Ezequiel. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentin

Wound healing treatment by transplantation of umbilical cord mesenchymal stem cell subpopulation

In normal physiological conditions, restoration of a functional epidermal barrier is highly efficient; nevertheless, when it fails, one of the main consequences is a chronic ulcerative skin defect, one of the most frequently recognized complications of diabetes. Most of these chronic venous ulcers do not heal with conventional treatment, leading to the appearance of infections and complications in the patient. Treatments based on the use of autologous mesenchymal stem cells (MSC) have been successful; however, its implementation entails complications. The umbilical cord offers an unlimited source of adult MSC (ucMSC) from the Wharton’s jelly tissue with the same relevant features for clinical applicability and avoiding difficulties. It has recently been characterized by one specific subpopulation derived from ucMSC, the differentiated mesenchymal cells (DMCs). This subpopulation expresses the human leukocyte antigen-G (HLA-G) molecule, a strong immunosuppressive checkpoint, and vascular endothelial growth factor (VEGF), the most potent angiogenic factor. Considering the importance of developing a more effective therapy for wound treatment, especially ulcerative skin lesions, we analyzed DMC safety, efficacy, and therapeutic potential. By immunohistochemistry, umbilical cords HLA-G and VEGF positive were selected. Flow cytometry revealed that 90% of the DMC subpopulation are HLA-G+, CD44+, CD73+, CD29+, CD105+, CD90+, and HLA-DR−. Reverse transcription-polymerase chain reaction revealed the expression of HLA-G in all of DMC subpopulations. Upon co-culture with the DMC, peripheral blood mononuclear cell proliferation was inhibited by 50%. In a xenograft transplantation assay, DMC improved wound healing with no signs of rejection of the transplanted cells in immunocompetent mice. This study confirms that HLA-G allows allogeneic cell transplantation, and VEGF is fundamental for the restoration of the failure in blood supply. DMC population has positive effects on wound healing by promoting local angiogenesis in skin lesions. DMC could play a very important role in regenerative medicine and could be a novel allogeneic cell-therapeutic tool for wound healing.Fil: Palma, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Luzzani, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Andrini, Laura Beatríz. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; ArgentinaFil: Riccillo, Fernando Luis. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Departamento de Ciencias Morfológicas. Cátedra de Citología y Embriología A; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Cátedra de Histología y Embriología Animal; ArgentinaFil: Buero, Guillermo. Sanatorio Mater Dei; ArgentinaFil: Pelinski, Pablo. Hospital Español; ArgentinaFil: Inda, Ana María. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Cátedra de Histología y Embriología Animal; ArgentinaFil: Errecalde, Ana Lia. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Cátedra de Histología y Embriología Animal; ArgentinaFil: Miriuka, Santiago Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Cátedra de Histología y Embriología Animal; ArgentinaFil: Carosella, Edgardo Delfino. Université Paris Diderot - Paris 7; Francia. Commissariat à L?Énergie Atomique et aux Énergies Alternatives; FranciaFil: García, Marcela Nilda. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Cátedra de Histología y Embriología Animal; Argentin