CD28 costimulation augments CAR signaling in NK cells via the LCK/CD3Z/ZAP70 signaling axis.

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3Z creates a platform that recruits critical kinases, such as LCK and ZAP70, initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy.

Navigating the Immunological Crossroads: Mesenchymal Stem/Stromal Cells as Architects of Inflammatory Harmony in Tissue-Engineered Constructs.

In the dynamic landscape of tissue engineering, the integration of tissue-engineered constructs (TECs) faces a dual challenge-initiating beneficial inflammation for regeneration while avoiding the perils of prolonged immune activation. As TECs encounter the immediate reaction of the immune system upon implantation, the unique immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) emerge as key navigators. Harnessing the paracrine effects of MSCs, researchers aim to craft a localized microenvironment that not only enhances TEC integration but also holds therapeutic promise for inflammatory-driven pathologies. This review unravels the latest advancements, applications, obstacles, and future prospects surrounding the strategic alliance between MSCs and TECs, shedding light on the immunological symphony that guides the course of regenerative medicine.

Health care professionals under programmes for addictions. Personality characteristics of the patients, barriers to treatment and challenges / Programas de atención a los profesionales de la salud con trastornos por uso de sustancias. Idiosincrasias de los usuarios, barreras de accesibilidad y desafíos.

Physicians have privileged information regarding the importance of leading a healthy and drug-free lifestyle, but in everyday reality, they are subject to extreme stressors (work stress, compassion fatigue, burnout syndrome) that have a profound emotional impact. As a result, it is not uncommon for physicians to present substance use disorders and dependencies. Recently, greater attention has been paid to specific factors that may lead to substance use disorder. Despite these efforts, there is a lack of prevention policies and substance use disorders are excluded in the list of occupational diseases. The idiosyncrasies of the tasks and particularities of the behavior of health care workers create a major challenge for the design of effective and safe programs for the health care professional with addictions and their patients. The objective of this work is to carry out an analytical review of the existing literature related to the implementation of specific treatments for health professionals to address SUD. After a tour of the mental health programs in place for health workers in different regions of the world and local resources, a discussion of current information on mental health disorders, as well as prevention and occupational health policies, is presented. In this population, the challenges that must be faced in our reality to create a specific treatment for this population are summarized.

Los médicos cuentan con información privilegiada respecto a la importancia de llevar una vida saludable y libre de drogas, pero la realidad cotidiana señala que están sujetos a estresores extremos (estrés laboral, desgaste por empatía, síndrome de burnout) que producen un impacto emocional profundo. Por ello, no es infrecuente que los médicos presenten trastornos por uso de sustancias y dependencias. Recientemente se ha prestado mayor atención a factores profesionales de las distintas especialidades médicas que puedan propiciar el trastorno por uso de sustancias, aunque faltan políticas de prevención en grupos de mayor riesgo y la incorporación de estos trastornos al listado de enfermedades profesionales por la medicina laboral. La idiosincrasia de las tareas y particularidades de la conducta de trabajadores de la salud generan un desafío mayor para el diseño de programas efectivos y seguros para el profesional con adicciones y sus propios pacientes. El presente trabajo tiene por objetivo realizar una revisión analítica de la bibliografía existente relacionada a la implementación de tratamientos específicos para profesionales de la salud para el abordaje de los trastornos por uso de sustancias. Luego de un recorrido por los programas de salud mental en marcha para trabajadores de la salud en distintas regiones del mundo y los recursos locales, se presenta una discusión de la información actual sobre trastornos de salud mental, así como las políticas de prevención y salud laboral en esta población, se resumen los desafíos con los cuales se deben afrontar en nuestra realidad para el armado de un tratamiento específico para esta población.

Intervenciones facilitadoras para las mujeres en el tratamiento por consumos problemáticos desde un enfoque de género / Facilitating interventions for women in treatment for problematic drug use from a gender perspective

RESUMEN INTRODUCCIÓN: Existen barreras para la atención y permanencia de las mujeres en los tratamientos por consumos problemáticos. Se relacionan con los espacios y el diseño de programas donde no se tienen en cuenta las necesidades específicas para un trabajo con enfoque de género. El objetivo fue explorar las intervenciones que funcionan como facilitadoras para alojar y escuchar a las mujeres a partir de la experiencia de un grupo de ellas en el marco de un tratamiento por consumo problemático de sustancias. MÉTODOS: Se utilizó un diseño mixto, tomando como referencia empírica la implementación de un grupo de mujeres. Se trabajó con una muestra de 33 mujeres de la población de 79 pacientes atendidas en un dispositivo ambulatorio para el tratamiento de consumos problemáticos en la ciudad de Buenos Aires entre julio de 2020 y julio de 2022. RESULTADOS: Los datos relevados describen un aumento en la población de mujeres desde la creación del grupo, mientras que el análisis de las experiencias permite distinguir cuatro categorías de intervenciones: las que vinculan los consumos con el rol social de las mujeres; las destinadas a mejorar el apoyo mutuo entre las compañeras; las que permiten construir un espacio de apertura para el trabajo de situaciones de violencia; y las que nacen de la creación del grupo de mujeres para trabajar la accesibilidad. DISCUSIÓN: El presente trabajo refleja la importancia de abordar la perspectiva de género al interior de los tratamientos de un modo transversal.

ABSTRACT INTRODUCTION: There are barriers for women's care and staying in treatment for problematic drug use. They are related to spaces and design of programs that do not consider the specific needs for gender perspective work. The objective was to explore the interventions that work as facilitators to support and listen to women, based on the experience of a group of women in the context of a treatment for problematic substance use. METHODS: A mixed design was used, taking as empirical reference the implementation of a women's group. The study worked with a sample of 33 women from a population of 79 patients in an outpatient facility for the treatment of problematic substance use in the city of Buenos Aires from July 2020 to July 2022. RESULTS: The collected data show an increase in the population of women since the creation of the group, while the analysis of the experiences allows to distinguish four categories of interventions: the ones that link drug use with women's social role; the ones aimed at improving mutual support among partners; the ones that allow building a space of openness to tackle situations of violence; and the ones arising from the creation of a women's group to work on accessibility. DISCUSSION: This work reflects the importance of addressing gender perspective in the treatment in a cross-sectional way.

CAR T-Cells for the Treatment of Refractory or Relapsed Large B-Cell Lymphoma: A Single-Center Retrospective Canadian Study.

BACKGROUND: Chimeric antigen receptor (CAR) T-cells are an important new third-line treatment option for large B-cell lymphoma (LBCL). The objective response rates in pivotal early phase clinical trials with CAR T-cells were very promising. The objective of this study was to describe the efficacy results obtained with CAR T-cells infusions in our institution and to compare the toxicities of our cohort with those of pivotal trials and studies conducted in a real-life setting. PATIENTS AND METHODS: Efficacy and safety data were retrospectively collected from 25 patients with LBCL treated with CAR T-cells therapy at CHU de Québec-Université Laval. A literature search was then performed to identify other efficacy or safety data from a real-life setting. RESULTS: At 3 months post infusion, the objective response rate (ORR) in our population with tisagenlecleucel and axicabtagene-ciloleucel were 20% and 47%, respectively. Bulky disease was the only negative predictor of poor response at 3 months (0% vs. 53%, P = .03). Bulky disease was associated with a median PFS of 2 months compared to 5 months for non-bulky disease (P = .0009). Grade ≥ 3 hematological toxicities were greater in patients treated with axi-cel (60% vs. 20%, P = .048), without bone marrow involvement (55% vs. 0%, P =.046), without stage IV disease (72% vs. 21%, P =.02), with refractory disease (67% vs. 10%, P =.01) or having been affected by cytokine release syndrome (58% vs. 0%, P =.02). CONCLUSION: The poor response rate at 3 months after infusion in our cohort was influenced mainly by bulky disease. Further studies are needed to better characterize the loss of efficacy of CAR T-cells because the majority of patients will relapse over time.

Abstracts of the Cell Therapy Transplant Canada 2022 Annual Conference.

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2022 Annual Conference. The conference was held in-person 15-18 June 2022, in Niagara Falls, Ontario. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 16 June, and oral abstract authors were featured during the oral abstract session in the afternoon on Friday, 17 June 2022. Thirty-three (33) abstracts were selected for presentation as posters and six (6) as oral presentations. The top abstracts in each of four (4) categories, (1) Basic/Translational sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support, received awards for both the oral and poster presentations. All of these were marked as "Award Recipient" with the relevant category. We congratulate all the presenters on their research and contribution to the field.

Engineered cord blood megakaryocytes evade killing by allogeneic T-cells for refractory thrombocytopenia.

The current global platelet supply is often insufficient to meet all the transfusion needs of patients, in particular for those with alloimmune thrombocytopenia. To address this issue, we have developed a strategy employing a combination of approaches to achieve more efficient production of functional megakaryocytes (MKs) and platelets collected from cord blood (CB)-derived CD34+ hematopoietic cells. This strategy is based on ex-vivo expansion and differentiation of MKs in the presence of bone marrow niche-mimicking mesenchymal stem cells (MSCs), together with two other key components: (1) To enhance MK polyploidization, we used the potent pharmacological Rho-associated coiled-coil kinase (ROCK) inhibitor, KD045, resulting in liberation of increased numbers of functional platelets both in-vitro and in-vivo; (2) To evade HLA class I T-cell-driven killing of these expanded MKs, we employed CRISPR-Cas9-mediated ß-2 microglobulin (ß2M) gene knockout (KO). We found that coculturing with MSCs and MK-lineage-specific cytokines significantly increased MK expansion. This was further increased by ROCK inhibition, which induced MK polyploidization and platelet production. Additionally, ex-vivo treatment of MKs with KD045 resulted in significantly higher levels of engraftment and donor chimerism in a mouse model of thrombocytopenia. Finally, ß2M KO allowed MKs to evade killing by allogeneic T-cells. Overall, our approaches offer a novel, readily translatable roadmap for producing adult donor-independent platelet products for a variety of clinical indications.

Cannabidiol pharmacotherapy for delta-9-tetrahidrocannabinol dependence / Cannabis de grado médico para el tratamiento de la dependencia a Δ-9-Tetrahidrocannabinol.

Addictions are one of the most important health problems worldwide. Within these disorders, cannabis is one of the psychoactive substances with more burden of morbidity and mortality worldwide. The actual knowledge about the effectiveness of treatments for cannabis use disorders is unsatisfactory. This review aims to explore the evidence on cannabidiol for the treatment of cannabis use disorder. There are several clinical pharmacotherapy trials researching cannabis use disorders with limited evidence. A smaller number of trials in animal models and humans on the use of cannabinoids, especially Cannabidiol and Tetrahydrocannabinol to treat cannabis dependence show evidence of reduction in days of use, withdrawal symptoms and craving. New trials are under development, and there is an urgent need for trials with larger numbers of patients and longer treatment periods to support possible indications in the near future.

Las adicciones son uno de los problemas de salud más importantes a nivel mundial. Dentro de estos trastornos, el cannabis es una de las sustancias psicoactivas que provoca mayor morbimortalidad a nivel mundial. La efectividad documentada de los tratamientos para los trastornos por uso de cannabis no es satisfactoria. Esta revisión tiene por objetivo explorar las evidencias sobre la implementación de tratamientos con cannabinoides para el abordaje de estos trastornos. La bibliografía actual cuenta con muchos ensayos sobre el uso de neuropsicofármacos en los trastornos por uso de cannabis con limitada evidencia a favor; mientras que un número más reducido de ensayos en modelos animales y en pacientes sobre el uso de cannabinoides, en especial Cannabidiol y Tetrahidrocannabinol para tratar dicha dependencia muestran evidencias de reducción en días de consumo, síntomas de abstinencia y craving. Se encuentran en desarrollo nuevos ensayos clínicos, estos son una necesidad imperiosa para proveer mayor número de pacientes y con períodos de tratamiento más prolongados y así poder explorar más a fondo su posible indicación en un futuro cercano.

Multilocus sequence typing of Treponema pallidum pallidum in children with acquired syphilis by nonsexual contact.

Background: There are scarce data of Treponema pallidum subsp. pallidum (TPA) characterization in children with syphilis. Nonsexually acquired transmission (NSAT) of TPA is possible in infants through close contact. Methods: A descriptive study in five families with NSAT of syphilis was conducted. Polymerase chain reaction detection of TPA in pediatric index cases (n = 6) and their relatives (n = 44) were conducted followed by multilocus sequence typing (MLST). Results: TPA was detected in swab samples in 16 cases and 12 were characterized by MLST. Nichols lineage was identified in two of five families and SS14-lineage in three of five. In four families, MLST profiles linked index cases to relatives. Conclusion: This is the first report of TPA characterization in children infected by NSAT.

Syphilis is a disease caused by the bacterium Treponema pallidum subsp. pallidum (TPA). Although it is considered a sexually transmitted disease, syphilis can also be transmitted by nonsexual close contact with active lesions. There are clinical reports of this route of transmissions in children; however, there are no molecular characterizations of TPA in this population. A multidisciplinary study (epidemiological, clinical, social and molecular) was performed in six children from five families with clinical diagnosis of nonsexually transmitted syphilis. As a result, 18 infected persons were detected. In 16 individuals the presence of the bacterium genetic material was confirmed by molecular biology techniques, and in 12, its strain was analyzed. When we compared the data, we observed that in four families, the child's strain coincided with the one found in close contact, while in one family, this could not be determined. To our knowledge, this is the first report of TPA characterization in children, which underscore the importance of including molecular biology techniques in complex clinical scenarios such as these.

KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape.

Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NKTROG+) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a 'don't kill me' signal to NK cells upon engagement with their TROG+ siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.

[Improved cognitive performance and post-injury plasticity during intensive outpatient treatment for substance use disorder. A case report]. / Mejoramiento del rendimiento cognitivo y plasticidad post lesional durante el tratamiento ambulatorio intensivo por trastorno por uso de sustancias. Reporte de caso.

There are different degrees of cognitive functional decline and modifiable risk factors related to their evolution. Mild cognitive impairment is a state of cognitive function between that seen in normal aging and dementia and is related to an increased risk of developing dementia. Among its potentially modifiable risk factors, substance use disorders have been described. In particular, techniques with predictive value have been developed to identify this impairment during neuropsychological assessment. We present a clinical case of a young patient with mild cognitive deficit and multiple drug abuse who after 24 months of an intensive outpatient treatment showed improvement in cognitive screening scores and neuroimaging. Together with other modifiable lifestyle factors, early cognitive screening in patients with substance use disorder could be a tool to detect other dimensions affected and contribute with specific therapies that promote post-injury plasticity and overall patient improvement.

Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.

Multidimensional evaluation of a 12-month intensive outpatient program for the treatment of substance use disorder. Experience in Argentina / Evaluación multidimensional de un programa de tratamiento ambulatorio intensivo de 12 meses para el trastorno por uso de sustancias. Experiencia en Argentina.

OBJECTIVE: The purpose of this study was to asess the efficacy of an intensive outpatient treatment (IOT) for substance use disorder (SUD) using a multidimensional approach. METHODS: All the patients consecutively admitted to a private institution between May 2019 and May 2020 were invited to participate in the study. The program consisted in a 12-month set of psychosocial, medical and recreative interventions requiring an attendance of at least 9 hours per week. Efficacy was evaluated at admission and every three months by the Addiction Severity Index (ASI). Quality of life was evaluated at admission and at the end of the treatment by the WHOQOL-Bref questionnaire. A comparison of parameters obtained at admission between the group that completed and the one that abandonned the treatment was also performed to detect potential predictors of early dropout. Six months after the end of the treatment, the participants were contacted in order to repeat an evaluation through the ASI and the WHOQOL-Bref scales. RESULTS: 41 participants (73% male, age 42.8 ± 16 years) were included. 14 participants dropped out at a median time of 88 days. Among those who completed the treatment improvements were observed in different clinical dimensions: in alcohol and drug consumption (3 months), in medical problems (6 months), in family/social relationships (9 months), in psychological scores (12 months) and in the four dimensions of WHOQOL-Bref. No changes were observed in legal problems and in the employment status. Only legal problems and family/social relationships at admission were significantly different among patients who completed versus those who dropped-out. Six months after discharge, no differences in WHOQOL-Bref scores were observed in the 15 participants who could be located and accepted the assessment. A little but statistically significant worsening was observed in the psychological problems dimension of the ASI in post-discharge follow-up. The rest of the ASI dimensions remained unchanged 6 months after concluding the treatment. CONCLUSION: This is one of the few studies performed in a latinamerican setting assessing the efficacy of a long-term IOT for SUD. It confirms previous works from developed countries, showing the potential benefits of IOTs implementation in our region.

OBJETIVO: Evaluar la eficacia de un tratamiento ambulatorio intensivo (TAI) para el trastorno por uso de sustancias (TUS) utilizando un enfoque multidimensional. Métodos: Se incluyeron todos los pacientes admitidos consecutivamente en una institución privada entre mayo de 2019 y mayo de 2020. El programa duró 12 meses y consistió en un conjunto de intervenciones médicas, psicosociales y recreativas, con una intensidad ≥ 9 horas/semana. La eficacia fue evaluada comparando los puntajes en el Índice de Severidad de Adicción (ASI) a lo largo del programa y en el cuestionario WHOQOL-Bref al inicio y al finalizar. En 15 pacientes se realizó una nueva medición seis meses después de concluido el tratamiento. MÉTODOS: Se incluyeron todos los pacientes admitidos consecutivamente en una institución privada entre mayo de 2019 y mayo de 2020. El programa duró 12 meses y consistió en un conjunto de intervenciones médicas, psicosociales y recreativas, con una intensidad ≥ 9 horas/semana. La eficacia fue evaluada comparando los puntajes en el Índice de Severidad de Adicción (ASI) a lo largo del programa y en el cuestionario WHOQOL-Bref al inicio y al finalizar. En 15 pacientes se realizó una nueva medición seis meses después de concluido el tratamiento. RESULTADOS: Se incluyeron 41 participantes (73% hombres, edad 42,8 ± 16 años). 14 participantes abandonaron (media 88 días). En los participantes que completaron el tratamiento, se observaron mejoras en los índices de alcohol y drogas (a los 3 meses), en problemas médicos (a los 6 meses), en las relaciones sociales y familiares (a los 9 meses) y en problemas psicológicos (a los 12 meses) así como  en las cuatro dimensiones del WHOQOL-Bref. Estas mejoras persistieron en la evaluación 6 meses post-alta cuando sólo un empeoramiento leve en la dimensión de problemas psicológicos del ASI fue objetivado. Conclusión: Este es uno de los pocos estudios realizados en un ámbito latinoamericano que evalúa la eficacia de un TAI para el TUS. Confirma trabajos previos de países desarrollados, mostrando los beneficios potenciales de la implementación de TAIs en nuestra región. CONCLUSIÓN: Este es uno de los pocos estudios realizados en un ámbito latinoamericano que evalúa la eficacia de un TAI para el TUS. Confirma trabajos previos de países desarrollados, mostrando los beneficios potenciales de la implementación de TAIs en nuestra región.

Harnessing Macrophages through the Blockage of CD47: Implications for Acute Myeloid Leukemia.

CD47 is a surface membrane protein expressed by all normal tissues. It is the so-called "don't eat me signal" because it protects the cells against phagocytosis. The CD47 interacts with the signal regulatory protein alpha (SIRPα) on the surface of macrophages, leading to downstream inhibitory signaling that dampens phagocytic capacity. Since macrophages exert immune surveillance against cancers, cancer cells overexpress CD47 to defend themselves against phagocytosis. Acute myeloid leukemia (AML) is a cancer of hematopoietic stem/progenitor cells (HSPC), and similar to other types of cancers, leukemic blasts show enhanced levels of CD47. In patients with AML, CD47 has been associated with a higher disease burden and poor overall survival. Blockage of CD47-SIRPα signaling leads to improved phagocytosis of AML cells and better overall survival in xenograft models. However, the introduction of a pro-phagocytic signal is needed to induce greater phagocytic capacity. These pro-phagocytic signals can be either Fc receptor stimulants (such as monoclonal antibodies) or natural pro-phagocytic molecules (such as calreticulin). Based on these pre-clinical findings, various clinical trials investigating the blockade of CD47-SIRPα interaction have been designed as monotherapy and in combination with other anti-leukemic agents. In this review, we will discuss CD47 biology, highlight its implications for AML pathophysiology, and explore the potential clinical translation of disrupting CD47-SIRPα to treat patients with AML.

Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy.

Adoptive cell therapy with virus-specific T cells has been used successfully to treat life-threatening viral infections, supporting application of this approach to coronavirus disease 2019 (COVID-19). We expand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observe that the choice of cytokines modulates the expansion, phenotype, and hierarchy of antigenic recognition by SARS-CoV-2 T cells. Culture with interleukin (IL)-2/4/7, but not under other cytokine-driven conditions, results in more than 1,000-fold expansion in SARS-CoV-2 T cells with a retained phenotype, function, and hierarchy of antigenic recognition compared with baseline (pre-expansion) samples. Expanded cytotoxic T lymphocytes (CTLs) are directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T cells cannot be expanded efficiently from the peripheral blood of non-exposed controls. Because corticosteroids are used for management of severe COVID-19, we propose an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.

Acquired Syphilis by Nonsexual Contact in Childhood.

BACKGROUND: Children may acquire syphilis by nonsexual contact as a consequence of close and repetitive contact with mucosal or skin lesions of people with active syphilis. METHODS: Prospective cohort study of pediatric patients with acquired syphilis by nonsexual contact. Demographics, clinical findings, posttreatment serology development and general laboratory data were collected. Sexual transmission was ruled out after a careful medical and psychosocial evaluation of the patient and his/her family. RESULTS: Twenty-four patients were included in the study. Mean age at diagnosis was 4.2 years old. All of them came from overcrowded households with poor hygiene conditions. The most frequent reason for consultations was secondary syphilis skin lesions (79.2%). The psychosocial evaluation of children and their families did not reveal signs of sexual abuse in any of the cases. Seventy-eight families and their cohabitants were evaluated, 23 (29.5%) resulted positive for rapid plasma reagin and treponemal test of hemagglutination; 60.9% of the cases were asymptomatic. The symptomatic relatives showed lesions of secondary syphilis. A sustained fall on nontreponemal antibodies titer (rapid plasma reagin) was observed after treatment, becoming negative in 6/24 (25%) cases within 12 months posttreatment. DISCUSSION: Following evaluation, it was considered that sexual abuse was unlikely. However, if examination and psychosocial evaluation do not support it, other ways of transmission must be considered. Overcrowded and poor household conditions boost the risks for nonsexual treponema transmission. An infected member of the family or a caretaker are a particular risk to an infant due to common practices such as using saliva to moisten the rubber nipples of the milk bottles or trying the food temperature using the lips before feeding the infants.

CAR-NK cells: the next wave of cellular therapy for cancer.

T cells engineered to express chimeric antigen receptors (CARs) have revolutionised the field of cellular therapy for cancer. Despite its success, this strategy has some recognised limitations and toxicities. Hence, there is growing interest in developing novel cellular therapies based on non-αß T-cell immune effector cells, including NK cells that offer clear advantages in cancer immunotherapy. As a result, NK cells are being explored as an alternative platform for CAR engineering and are becoming recognised as important players in the next generation of cellular therapies targeting cancer. In this review, we highlight preclinical and clinical studies of CAR-NK cells derived from different sources and discuss strategies under investigation to enhance the antitumor activity of these engineered innate immune cells.

Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD.

Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders.

Congenital syphilis in Argentina: Experience in a pediatric hospital.

In spite of being preventable, Congenital syphilis (CS) is still an important, and growing health problem worldwide. Fetal infection can be particularly aggressive, but newborns can be asymptomatic at birth and, if left untreated, develop systemic compromise afterwards with poor prognosis. We analyzed 61 CS diagnosis cases between 1987-2019 presenting at the Buenos Aires Children' Hospital. The distribution of cases showed a bimodal curve, with a peak in 1992-1993 and in 2014-2017. Median age at diagnosis was 2 months (IQ 1-6 months). The main clinical findings were: bone alterations (59%); hepatosplenomegaly (54.1%); anemia (62.8%); skin lesions (42.6%) and renal compromise (33.3%). Cerebrospinal fluid (CSF) was abnormal in 5 patients, normal in 45 and was not available for 11 patients. Remarkably, spinal lumbar puncture did not modify therapeutic decisions in any case. Between mothers, only 46% have been tested for syphilis during pregnancy and 60.5% patients had non-treponemal titers equal to or less than fourfold the maternal titer. Intravenous penicillin G was prescribed for all except one patient, who received ceftriaxone with good therapeutic response. During follow-up, 1.6% infants died, 6.5% had persistent kidney disorders and 1.6% showed bone sequelae damage. RPR titers decreased after treatment, reaching negative seroconversion in 43% subjects at a median of 26.4 months. Low adherence to follow up was observed due to inherent vulnerable and low-income population characteristics in our cohort. Our results highlight a rising tendency in cases referred for CS in our population with high morbidity related to delayed diagnosis. A good therapeutic response was observed. CS requires a greater effort from the health system to adequately screen for this disease during pregnancy, and to detect cases earlier, to provide an adequate diagnosis and treatment.