Antitumor activity of AZD0754, a dnTGFßRII-armored, STEAP2-targeted CAR-T cell therapy, in prostate cancer.

Prostate cancer is generally considered an immunologically "cold" tumor type that is insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent antitumor immune response to "heat up" the tumor microenvironment. However, many antigens expressed on prostate tumor cells are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a suboptimal therapeutic index. Our studies revealed that six-transmembrane epithelial antigen of prostate-2 (STEAP2) was a prevalent prostate cancer antigen that displayed high, homogeneous cell surface expression across all stages of disease with limited distal normal tissue expression, making it ideal for therapeutic targeting. A multifaceted lead generation approach enabled development of an armored STEAP2 chimeric antigen receptor T cell (CAR-T) therapeutic candidate, AZD0754. This CAR-T product was armored with a dominant-negative TGF-ß type II receptor, bolstering its activity in the TGF-ß-rich immunosuppressive environment of prostate cancer. AZD0754 demonstrated potent and specific cytotoxicity against antigen-expressing cells in vitro despite TGF-ß-rich conditions. Further, AZD0754 enforced robust, dose-dependent in vivo efficacy in STEAP2-expressing cancer cell line-derived and patient-derived xenograft mouse models, and exhibited encouraging preclinical safety. Together, these data underscore the therapeutic tractability of STEAP2 in prostate cancer as well as build confidence in the specificity, potency, and tolerability of this potentially first-in-class CAR-T therapy.

Preclinical evaluation of a COVID-19 vaccine candidate based on a recombinant RBD fusion heterodimer of SARS-CoV-2.

Current COVID-19 vaccines have been associated with a decline in infection rates, prevention of severe disease, and a decrease in mortality rates. However, SARS-CoV-2 variants are continuously evolving, and development of new accessible COVID-19 vaccines is essential to mitigate the pandemic. Here, we present data on preclinical studies in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine (PHH-1V) consisting of an RBD fusion heterodimer comprising the B.1.351 and B.1.1.7 SARS-CoV-2 variants formulated in SQBA adjuvant, an oil-in-water emulsion. A prime-boost immunisation with PHH-1V in BALB/c and K18-hACE2 mice induced a CD4+ and CD8+ T cell response and RBD-binding antibodies with neutralizing activity against several variants, and also showed a good tolerability profile. Significantly, RBD fusion heterodimer vaccination conferred 100% efficacy, preventing mortality in SARS-CoV-2 infected K18-hACE2 mice, but also reducing Beta, Delta and Omicron infection in lower respiratory airways. These findings demonstrate the feasibility of this recombinant vaccine strategy.

Impact of Betamethasone Pretreatment on Engrafment of Cord Blood-Derived Hematopoietic Stem Cells.

Hematopoietic stem cell (HSC) transplantation is crucial to cure hematologic malignancies. Umbilical cord blood (UCB) is a source of stem cells, but 90% of UCB units are discarded due to low cellularity. Improving the engraftment capacities of CD34+ stem cells would allow the use of UCB that were so far rejected. Betamethasone induces long-term transcriptomic and epigenomic changes in immune cells through glucocorticoid receptor. We hypothesize that discarded UCB could be used owing to improvements induced by betamethasone. Isolated CD34+ HSC from UCB were exposed to the synthetic glucocorticoids betamethasone and fluticasone for 20 h, and cell phenotype was determined before transplantation. NSG mice were sub-lethally irradiated (1 Gy or 2 Gy) 6 h before intravenously transferring 2-5 × 105 CD34+ HSC. The peripheral blood engraftment levels and the leukocyte subsets were followed up for 20 weeks using flow cytometry. At end point, the engraftment and leukocyte subsets were determined in the spleen and bone marrow. We demonstrated that betamethasone has surprising effects in recovering immune system homeostasis. Betamethasone and fluticasone increase CXCR4 and decrease HLA class II and CD54 expression in CD34+ HSCs. Both glucocorticoids-exposed cells showed a similar engraftment in 2 Gy-irradiated NSG mice. Interestingly, betamethasone-exposed cells showed enhanced engraftment in 1 Gy-irradiated NSG mice, with a trend to increase regulatory T cell percentage when compared to control. Betamethasone induces alterations in CD34+ HSCs and improve the engraftment, leading to a faster immune system recovery, which will contribute to engrafted cells survival.

A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).

A Randomized Trial of Lipid Metabolism Modulation with Fenofibrate for Acute Coronavirus Disease 2019.

Background Abnormal cellular lipid metabolism appears to underlie SARS-CoV-2 cytotoxicity and may involve inhibition of peroxisome proliferator activated receptor alpha (PPARα). Fenofibrate, a PPAR-α activator, modulates cellular lipid metabolism. Fenofibric acid has also been shown to affect the dimerization of angiotensin-converting enzyme 2, the cellular receptor for SARS-CoV-2. Fenofibrate and fenofibric acid have been shown to inhibit SARS-CoV-2 replication in cell culture systems in vitro . Methods We randomly assigned 701 participants with COVID-19 within 14 days of symptom onset to 145 mg of fenofibrate (nanocrystal formulation with dose adjustment for renal function or dose-equivalent preparations of micronized fenofibrate or fenofibric acid) vs. placebo for 10 days, in a double-blinded fashion. The primary endpoint was a ranked severity score in which participants were ranked across hierarchical tiers incorporating time to death, duration of mechanical ventilation, oxygenation parameters, subsequent hospitalizations and symptom severity and duration. ClinicalTrials.gov registration: NCT04517396. Findings: Mean age of participants was 49 ± 16 years, 330 (47%) were female, mean BMI was 28 ± 6 kg/m 2 , and 102 (15%) had diabetes mellitus. A total of 41 deaths occurred. Compared with placebo, fenofibrate administration had no effect on the primary endpoint. The median (interquartile range [IQR]) rank in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in various secondary and exploratory endpoints, including all-cause death, across randomization arms. These results were highly consistent across pre-specified sensitivity and subgroup analyses. Conclusion Among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes.

Factores de riesgo asociado al bajo peso al nacer. Municipio Guisa. Enero- diciembre 2019 / Risk factors associated with the low birth weight. Guise municipality. January - December 2019 / Fatores de risco associados ao baixo peso ao nascer. Municipio Guisa. Enero- diciembre 2019

RESUMEN Introducción: la reducción del bajo peso al nacer constituye una prioridad en el país por ser determinante para disminuir la mortalidad infantil. Objetivo: determinar los principales factores de riesgo asociados al bajo peso al nacer Guisa, Granma. Métodos: se realizó un estudio descriptivo de corte transversal, incluyó a 37 gestantes que aportaron los nacimientos con bajo peso en el periodo de estudio. Se analizaron las variables edad materna, evaluación nutricional al inicio del embarazo, edad gestacional al momento del parto, tipo de bajo peso, antecedentes personales y enfermedades asociadas al embarazo. Resultados: se produjeron 511 nacimientos, 37 mostraron un peso inferior a 2500 g. El mayor número de nacimientos ocurrió en edades fértiles de la vida, predominando la evaluación nutricional normopeso al inicio del embarazo. La edad gestacional entre 37-42 semanas fueron las que más aportaron bajo peso, no ocurrieron nacimientos en gestantes con menos de 32 semanas. Predominaron los crecimientos intrauterinos restringidos. Entre los antecedentes patológicos resalta, la hipertensión arterial, seguida por el asma bronquial, la anemia ligera. Conclusiones: el bajo peso al nacer es un problema de salud en el municipio Guisa y por consiguiente su influencia negativa sobre la calidad de vida de los infantes. Las edades extremas no resultaron factores de incidencia en el bajo peso al nacer al igual que el estado nutricional. Las principales causales son el crecimiento intrauterino restringido y el parto pretérmino. La identificación precoz de los factores de riesgo y la adopción de medidas efectivas permitirá disminuir la incidencia de estas causas.

ABSTRACT Introduction: reducing low birth weight is a priority in the country as it is decisive for reducing infant mortality. Objective: to determine the main risk factors associated with low birth weight Guisa, Granma. Methods: a descriptive cross-sectional study was carried out, it included 37 pregnant women who provided births with low birth weight in the study period. The variables maternal age, nutritional evaluation at the beginning of pregnancy, gestational age at delivery, type of low weight, personal history and diseases associated with pregnancy were analyzed. Results: there were 511 births, 37 showed a weight less than 2500 g. The highest number of births occurred in fertile ages of life, predominating the normal weight nutritional assessment at the beginning of pregnancy. Gestational ages between 37-42 weeks were the ones that contributed the most to low weight, there were no births in pregnant women with less than 32 weeks. Restricted intrauterine growths predominated. Among the pathological antecedents, arterial hypertension stands out, followed by bronchial asthma, mild anemia. Conclusions: low birth weight is a health problem in the Guisa municipality and therefore its negative influence on the quality of life of infants. Extreme ages were not factors of incidence in low birth weight as well as nutritional status. The main causes are restricted intrauterine growth and preterm delivery. The early identification of risk factors and the adoption of effective measures will reduce the incidence of these causes.

RESUMO Introdução: a redução do baixo peso ao nascer é uma prioridade no país, pois é decisiva para a redução da mortalidade infantil. Objetivo: determinar os principais fatores de risco associados ao baixo peso ao nascer Guisa, Granma. Métodos: foi realizado um estudo transversal descritivo, com 37 gestantes que realizaram partos com baixo peso ao nascer no período do estudo. Foram analisadas as variáveis ​​idade materna, avaliação nutricional no início da gestação, idade gestacional no parto, tipo de baixo peso, antecedentes pessoais e doenças associadas à gravidez. Resultados: ocorreram 511 nascimentos, 37 apresentavam peso inferior a 2.500 g. O maior número de nascimentos ocorreu em idades férteis de vida, predominando a avaliação nutricional de peso normal no início da gestação. As idades gestacionais entre 37-42 semanas foram as que mais contribuíram para o baixo peso, não ocorrendo partos em gestantes com menos de 32 semanas. Predominaram crescimentos intrauterinos restritos. Dentre os antecedentes patológicos, destaca-se a hipertensão arterial, seguida da asma brônquica, anemia leve. Conclusões: o baixo peso ao nascer é um problema de saúde no município de Guisa e, portanto, influencia negativamente na qualidade de vida dos lactentes. As idades extremas não foram fatores de incidência no baixo peso ao nascer, bem como no estado nutricional. As principais causas são o crescimento intrauterino restrito e o parto prematuro. A identificação precoce dos fatores de risco e a adoção de medidas eficazes irão reduzir a incidência dessas causas.

Factores de riesgo asociado al bajo peso al nacer. Municipio Guisa. Enero–diciembre 2019 / Risk factors associated with the low birth weight. Guise municipality. January December 2019

Introducción: la reducción del bajo peso al nacer constituye una prioridad en el país por ser determinante para disminuir la mortalidad infantil. Objetivo: determinar los principales factores de riesgo asociados al bajo peso al nacer Guisa, Granma. Métodos: se realizó un estudio descriptivo de corte transversal, incluyó a 37 gestantes que aportaron los nacimientos con bajo peso en el periodo de estudio. Se analizaron las variables edad materna, evaluación nutricional al inicio del embarazo, edad gestacional al momento del parto, tipo de bajo peso, antecedentes personales y enfermedades asociadas al embarazo. Resultados: se produjeron 511 nacimientos, 37 mostraron un peso inferior a 2500 g. El mayor número de nacimientos ocurrió en edades fértiles de la vida, predominando la evaluación nutricional normopeso al inicio del embarazo. La edad gestacional entre 37-42 semanas fueron las que más aportaron bajo peso, no ocurrieron nacimientos en gestantes con menos de 32 semanas. Predominaron los crecimientos intrauterinos restringidos. Entre los antecedentes patológicos resalta, la hipertensión arterial, seguida por el asma bronquial, la anemia ligera. Conclusiones: el bajo peso al nacer es un problema de salud en el municipio Guisa y por consiguiente su influencia negativa sobre la calidad de vida de los infantes. Las edades extremas no resultaron factores de incidencia en el bajo peso al nacer al igual que el estado nutricional. Las principales causales son el crecimiento intrauterino restringido y el parto pretérmino. La identificación precoz de los factores de riesgo y la adopción de medidas efectivas permitirá disminuir la incidencia de estas causas(AU)

Introduction: reducing low birth weight is a priority in the country as it is decisive for reducing infant mortality. Objective: to determine the main risk factors associated with low birth weight Guisa, Granma. Methods: a descriptive cross-sectional study was carried out, it included 37 pregnant women who provided births with low birth weight in the study period. The variables maternal age, nutritional evaluation at the beginning of pregnancy, gestational age at delivery, type of low weight, personal history and diseases associated with pregnancy were analyzed. Results: there were 511 births, 37 showed a weight less than 2500 g. The highest number of births occurred in fertile ages of life, predominating the normal weight nutritional assessment at the beginning of pregnancy. Gestational ages between 37-42 weeks were the ones that contributed the most to low weight, there were no births in pregnant women with less than 32 weeks. Restricted intrauterine growths predominated. Among the pathological antecedents, arterial hypertension stands out, followed by bronchial asthma, mild anemia. Conclusions: low birth weight is a health problem in the Guisa municipality and therefore its negative influence on the quality of life of infants. Extreme ages were not factors of incidence in low birth weight as well as nutritional status. The main causes are restricted intrauterine growth and preterm delivery. The early identification of risk factors and the adoption of effective measures will reduce the incidence of these causes(EU)

Respuesta del primer nivel de atención de salud del Perú a la pandemia COVID-19 / Peruvian primary care response to the COVID-19 pandemic

RESUMEN Desde el primer caso reportado por el nuevo coronavirus en el Perú se han implementado distintas estrategias para mejorar los servicios de salud, con gran énfasis en la respuesta hospitalaria. En el presente artículo, hacemos un recuento de las acciones orientadas al primer nivel de atención de salud que el gobierno peruano intenta implementar. Proponemos medidas clave a cumplir como implementación de clínicas de sintomáticos en el primer nivel de atención de salud, cuidados sanitarios en domicilio, inserción de médicos de familia y uso intensivo de consultas telefónicas y otra TICs que al adoptarse e implementarse a la realidad peruana, lograrían una respuesta más efectiva ante la pandemia por COVID-19.

ABSTRACT Since the first case reported by the new coronavirus in Peru, different strategies have been implemented to improve health services, with great emphasis on the hospital response. In this article, we review the actions that Peruvian government tried to implement in Primary Care. We propose key measures such as the implementation of fever clinics in primary care, home health care, insertion of family doctors and intensive use of telephone consultations and other ICTs, their adoption and implementation in the Peruvian reality, would achieve a more effective response towards the COVID-19 pandemic.

Prenatal Betamethasone interferes with immune system development and alters target cells in autoimmune diabetes.

Non-genetic factors are crucial in the pathogenesis of type 1 diabetes (T1D), a disease caused by autoimmunity against insulin-producing ß-cells. Exposure to medications in the prenatal period may influence the immune system maturation, thus altering self-tolerance. Prenatal administration of betamethasone -a synthetic glucocorticoid given to women at risk of preterm delivery- may affect the development of T1D. It has been previously demonstrated that prenatal betamethasone administration protects offspring from T1D development in nonobese diabetic (NOD) mice. The direct effect of betamethasone on the immature and mature immune system of NOD mice and on target ß-cells is analysed in this paper. In vitro, betamethasone decreased lymphocyte viability and induced maturation-resistant dendritic cells, which in turn impaired γδ T cell proliferation and decreased IL-17 production. Prenatal betamethasone exposure caused thymus hypotrophy in newborn mice as well as alterations in immune cells subsets. Furthermore, betamethasone decreased ß-cell growth, reduced C-peptide secretion and altered the expression of genes related to autoimmunity, metabolism and islet mass in T1D target tissue. These results support the protection against T1D in the betamethasone-treated offspring and demonstrate that this drug alters the developing immune system and ß-cells. Understanding how betamethasone generates self-tolerance could have potential clinical relevance in T1D.

Expansión de la medicina familiar en América Latina: desafíos y líneas de acción / Expansion of family medicine in Latin America: challenges and lines of action / Expansão da medicina familiar na América Latina: desafios e linhas de ação

Este documento tiene por objetivos resumir los desafíos actuales de la medicina familiar en América Latina y proponer posibles líneas de acción para consolidar su desarrollo. En los últimos 40 años, los sistemas de salud de la Región de las Américas han encarado reformas cuyos resultados fueron negativos en términos de equidad, y la atención primaria de la salud, lejos de ser aquella estrategia destinada a reducirla, se restringió a una política focal y selectiva. En este contexto, las propuestas técnicas de expansión de las plazas de formación en medicina familiar y su inserción en las carreras de Medicina, han carecido de coherencia y de una dirección política clara, por lo que su falta de eficacia puede leerse como un síntoma de estas reformas incompletas. Al respecto, la Confederación Iberoamericana de Medicina Familiar realizó recomendaciones sobre el compromiso político de los gobiernos para asegurar la estructura y el financiamiento necesarios, consolidar el modelo de medicina familiar como mecanismo de instrumentación de la atención primaria de la salud, la jerarquización de los programas de formación, las condiciones laborales de los médicos de familia y la certificación profesional, entre otras. Estas recomendaciones técnicas, sin acción política coherente y oportuna, no serán más exitosas que los intentos previos.(AU)

This article summarizes the current challenges of family medicine in Latin America and proposes possible lines of action to consolidate its development. In the last 40 years, the health systems of the Region of the Americas have faced reforms whose results were negative in terms of equity, and primary health care, far from being a strategy designed to reduce it, was restricted to a selective and focal policy. In this context, the technical proposals for expansion of training positions in family medicine and their insertion in medical careers have lacked consistency and a clear political direction, and thus their lack of effectiveness can be considered a symptom of these incomplete reforms. In this regard, the Ibero-American Confederation of Family Medicine made recommendations on the political commitment of governments to ensure the necessary structure and funding, consolidate the model of family medicine as a mechanism for the implementation of primary health care, the hierarchy of programs of training, the working conditions of family doctors and professional certification, among others. These technical recommendations, without a consistent and timely political action, will not be more successful than previous attempts.(AU)

Este documento tem como objetivo resumir os desafios atuais da medicina familiar na América Latina e propor possíveis linhas de ação para consolidar seu desenvolvimento. Nos últimos 40 anos, os sistemas de saúde da Região das Américas encararam reformas cujos resultados foram negativos em termos de igualdade, e a atenção primária à saúde, longe de sê-la aquela estratégia destinada a reducir-la, restringiu-se a uma política focal e seletiva. Neste contexto, as propostas técnicas de expansão das praças de formação em medicina familiar e sua inserção nas carreiras de Medicina, não dispuseram de coerência e de uma direção política clara, razão pela qual sua falta de eficácia se pode ler como um sintoma destas reformas incompletas. Neste sentido, a Confederação Ibero-americana de Medicina Familiar realizou recomendações sobre o compromisso político dos governos a fim de assegurar a estrutura e o financiamento necessários, consolidar o modelo de medicina familiar como mecanismo de instrumentação da atenção primária à saúde, a hierarquização dos programas de formação, as condições laborais dos médicos de família e a certificação profissional, entre outras. Estas recomendações técnicas, sem ação política coerente e oportuna, não serão mais exitosos que as tentativas prévias.(AU)

Expansión de la medicina familiar en América Latina: desafíos y líneas de acción

[RESUMEN]. Este documento tiene por objetivos resumir los desafíos actuales de la medicina familiar en América Latina y proponer posibles líneas de acción para consolidar su desarrollo. En los últimos 40 años, los sistemas de salud de la Región de las Américas han encarado reformas cuyos resultados fueron negativos en términos de equidad, y la atención primaria de la salud, lejos de ser aquella estrategia destinada a reducirla, se restringió a una política focal y selectiva. En este contexto, las propuestas técnicas de expansión de las plazas de formación en medicina familiar y su inserción en las carreras de Medicina, han carecido de coherencia y de una dirección política clara, por lo que su falta de eficacia puede leerse como un síntoma de estas reformas incompletas. Al respecto, la Confederación Iberoamericana de Medicina Familiar realizó recomendaciones sobre el compromiso político de los gobiernos para asegurar la estructura y el financiamiento necesarios, consolidar el modelo de medicina familiar como mecanismo de instrumentación de la atención primaria de la salud, la jerarquización de los programas de formación, las condiciones laborales de los médicos de familia y la certificación profesional, entre otras. Estas recomendaciones técnicas, sin acción política coherente y oportuna, no serán más exitosas que los intentos previos.

[ABSTRACT]. This article summarizes the current challenges of family medicine in Latin America and proposes possible lines of action to consolidate its development. In the last 40 years, the health systems of the Region of the Americas have faced reforms whose results were negative in terms of equity, and primary health care, far from being a strategy designed to reduce it, was restricted to a selective and focal policy. In this context, the technical proposals for expansion of training positions in family medicine and their insertion in medical careers have lacked consistency and a clear political direction, and thus their lack of effectiveness can be considered a symptom of these incomplete reforms. In this regard, the Ibero-American Confederation of Family Medicine made recommendations on the political commitment of governments to ensure the necessary structure and funding, consolidate the model of family medicine as a mechanism for the implementation of primary health care, the hierarchy of programs of training, the working conditions of family doctors and professional certification, among others. These technical recommendations, without a consistent and timely political action, will not be more successful than previous attempts.

[RESUMO]. Este documento tem como objetivo resumir os desafios atuais da medicina familiar na América Latina e propor possíveis linhas de ação para consolidar seu desenvolvimento. Nos últimos 40 anos, os sistemas de saúde da Região das Américas encararam reformas cujos resultados foram negativos em termos de igualdade, e a atenção primária à saúde, longe de sê-la aquela estratégia destinada a reducir-la, restringiu-se a uma política focal e seletiva. Neste contexto, as propostas técnicas de expansão das praças de formação em medicina familiar e sua inserção nas carreiras de Medicina, não dispuseram de coerência e de uma direção política clara, razão pela qual sua falta de eficácia se pode ler como um sintoma destas reformas incompletas. Neste sentido, a Confederação Ibero-americana de Medicina Familiar realizou recomendações sobre o compromisso político dos governos a fim de assegurar a estrutura e o financiamento necessários, consolidar o modelo de medicina familiar como mecanismo de instrumentação da atenção primária à saúde, a hierarquização dos programas de formação, as condições laborais dos médicos de família e a certificação profissional, entre outras. Estas recomendações técnicas, sem ação política coerente e oportuna, não serão mais exitosos que as tentativas prévias.

Periodontitis may modulate long-non coding RNA expression.

Periodontitis is a chronic inflammatory disease that compromises the integrity of the periodontium. Despite extensive research involving periodontitis, the detailed mechanisms underlying periodontal inflammation remain unclear. However, new important expression regulators have been emerging, such as non-coding RNAs, which are important determinants in the molecular control of the inflammatory process. Taking into consideration the vital role of non-coding RNAs, we determined for the first time the expression profiles of different long non-coding RNAs (lncRNAs) that are implicated in inflammation. In this study, we take periodontal samples of healthy subjects, patients with gingivitis and with periodontitis. In both disease groups, the lncRNA OIP5-AS1 expression levels were lower than levels in healthy subjects (P < 0.05). This study reveals new insights into the relative levels of OIP5-AS1 lncRNA in healthy, gingivitis and periodontal tissue, which may have important applications as a potential biomarker with protagonist activity in the development and manifestation of destructive periodontitis.

Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer.

Despite recent advances in treatment, breast cancer remains the second-most common cause of cancer death among American women. A greater understanding of the molecular characteristics of breast tumors could ultimately lead to improved tumor-targeted treatment options, particularly for subsets of breast cancer patients with unmet needs. Using an unbiased genomics approach to uncover membrane-localized tumor-associated antigens (TAAs), we have identified glial cell line derived neurotrophic factor (GDNF) family receptor α 1 (GFRA1) as a breast cancer TAA. Immunohistochemistry (IHC) revealed that GFRA1 displays a limited normal tissue expression profile coupled with overexpression in specific breast cancer subsets. The cell surface localization as determined by fluorescence-activated cell sorting (FACS) and the rapid internalization kinetics of GFRA1 makes it an ideal target for therapeutic exploitation as an antibody-drug conjugate (ADC). Here, we describe the development of a pyrrolobenzodiazepine (PBD)-armed, GFRA1-targeted ADC that demonstrates cytotoxicity in GFRA1-positive cell lines and patient-derived xenograft (PDX) models. The safety profile of the rat cross-reactive GFRA1-PBD was assessed in a rat toxicology study to find transient cellularity reductions in the bone marrow and peripheral blood, consistent with known off-target effects of PBD ADC's. These studies reveal no evidence of on-target toxicity and support further evaluation of GFRA1-PBD in GFRA1-positive tumors.

[Expansion of family medicine in Latin America: challenges and lines of actionExpansão da medicina familiar na América Latina: desafios e linhas de ação]. / Expansión de la medicina familiar en América Latina: desafíos y líneas de acción.

This article summarizes the current challenges of family medicine in Latin America and proposes possible lines of action to consolidate its development. In the last 40 years, the health systems of the Region of the Americas have faced reforms whose results were negative in terms of equity, and primary health care, far from being a strategy designed to reduce it, was restricted to a selective and focal policy. In this context, the technical proposals for expansion of training positions in family medicine and their insertion in medical careers have lacked consistency and a clear political direction, and thus their lack of effectiveness can be considered a symptom of these incomplete reforms. In this regard, the Ibero-American Confederation of Family Medicine made recommendations on the political commitment of governments to ensure the necessary structure and funding, consolidate the model of family medicine as a mechanism for the implementation of primary health care, the hierarchy of programs of training, the working conditions of family doctors and professional certification, among others. These technical recommendations, without a consistent and timely political action, will not be more successful than previous attempts.

Este documento tem como objetivo resumir os desafios atuais da medicina familiar na América Latina e propor possíveis linhas de ação para consolidar seu desenvolvimento. Nos últimos 40 anos, os sistemas de saúde da Região das Américas encararam reformas cujos resultados foram negativos em termos de igualdade, e a atenção primária à saúde, longe de sê-la aquela estratégia destinada a reducir-la, restringiu-se a uma política focal e seletiva. Neste contexto, as propostas técnicas de expansão das praças de formação em medicina familiar e sua inserção nas carreiras de Medicina, não dispuseram de coerência e de uma direção política clara, razão pela qual sua falta de eficácia se pode ler como um sintoma destas reformas incompletas. Neste sentido, a Confederação Ibero-americana de Medicina Familiar realizou recomendações sobre o compromisso político dos governos a fim de assegurar a estrutura e o financiamento necessários, consolidar o modelo de medicina familiar como mecanismo de instrumentação da atenção primária à saúde, a hierarquização dos programas de formação, as condições laborais dos médicos de família e a certificação profissional, entre outras. Estas recomendações técnicas, sem ação política coerente e oportuna, não serão mais exitosos que as tentativas prévias.

Expansión de la medicina familiar en América Latina: desafíos y líneas de acción / Expansion of family medicine in Latin America: challenges and lines of action / Expansão da medicina familiar na América Latina: desafios e linhas de ação

RESUMEN Este documento tiene por objetivos resumir los desafíos actuales de la medicina familiar en América Latina y proponer posibles líneas de acción para consolidar su desarrollo. En los últimos 40 años, los sistemas de salud de la Región de las Américas han encarado reformas cuyos resultados fueron negativos en términos de equidad, y la atención primaria de la salud, lejos de ser aquella estrategia destinada a reducirla, se restringió a una política focal y selectiva. En este contexto, las propuestas técnicas de expansión de las plazas de formación en medicina familiar y su inserción en las carreras de Medicina, han carecido de coherencia y de una dirección política clara, por lo que su falta de eficacia puede leerse como un síntoma de estas reformas incompletas. Al respecto, la Confederación Iberoamericana de Medicina Familiar realizó recomendaciones sobre el compromiso político de los gobiernos para asegurar la estructura y el financiamiento necesarios, consolidar el modelo de medicina familiar como mecanismo de instrumentación de la atención primaria de la salud, la jerarquización de los programas de formación, las condiciones laborales de los médicos de familia y la certificación profesional, entre otras. Estas recomendaciones técnicas, sin acción política coherente y oportuna, no serán más exitosas que los intentos previos.

ABSTRACT This article summarizes the current challenges of family medicine in Latin America and proposes possible lines of action to consolidate its development. In the last 40 years, the health systems of the Region of the Americas have faced reforms whose results were negative in terms of equity, and primary health care, far from being a strategy designed to reduce it, was restricted to a selective and focal policy. In this context, the technical proposals for expansion of training positions in family medicine and their insertion in medical careers have lacked consistency and a clear political direction, and thus their lack of effectiveness can be considered a symptom of these incomplete reforms. In this regard, the Ibero-American Confederation of Family Medicine made recommendations on the political commitment of governments to ensure the necessary structure and funding, consolidate the model of family medicine as a mechanism for the implementation of primary health care, the hierarchy of programs of training, the working conditions of family doctors and professional certification, among others. These technical recommendations, without a consistent and timely political action, will not be more successful than previous attempts.

RESUMO Este documento tem como objetivo resumir os desafios atuais da medicina familiar na América Latina e propor possíveis linhas de ação para consolidar seu desenvolvimento. Nos últimos 40 anos, os sistemas de saúde da Região das Américas encararam reformas cujos resultados foram negativos em termos de igualdade, e a atenção primária à saúde, longe de sê-la aquela estratégia destinada a reducir-la, restringiu-se a uma política focal e seletiva. Neste contexto, as propostas técnicas de expansão das praças de formação em medicina familiar e sua inserção nas carreiras de Medicina, não dispuseram de coerência e de uma direção política clara, razão pela qual sua falta de eficácia se pode ler como um sintoma destas reformas incompletas. Neste sentido, a Confederação Ibero-americana de Medicina Familiar realizou recomendações sobre o compromisso político dos governos a fim de assegurar a estrutura e o financiamento necessários, consolidar o modelo de medicina familiar como mecanismo de instrumentação da atenção primária à saúde, a hierarquização dos programas de formação, as condições laborais dos médicos de família e a certificação profissional, entre outras. Estas recomendações técnicas, sem ação política coerente e oportuna, não serão mais exitosos que as tentativas prévias.

A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of PTEN Status on Tumor Response.

HER3/ERBB3 is a kinase-deficient member of the EGFR family receptor tyrosine kinases (RTK) that is broadly expressed and activated in human cancers. HER3 is a compelling cancer target due to its important role in activation of the oncogenic PI3K/AKT pathway. It has also been demonstrated to confer tumor resistance to a variety of cancer therapies, especially targeted drugs against EGFR and HER2. HER3 can be activated by its ligand (heregulin/HRG), which induces HER3 heterodimerization with EGFR, HER2, or other RTKs. Alternatively, HER3 can be activated in a ligand-independent manner through heterodimerization with HER2 in HER2-amplified cells. We developed a fully human mAb against HER3 (KTN3379) that efficiently suppressed HER3 activity in both ligand-dependent and independent settings. Correspondingly, KTN3379 inhibited tumor growth in divergent tumor models driven by either ligand-dependent or independent mechanisms in vitro and in vivo Most intriguingly, while investigating the mechanistic underpinnings of tumor response to KTN3379, we discovered an interesting dichotomy in that PTEN loss, a frequently occurring oncogenic lesion in a broad range of cancer types, substantially blunted the tumor response in HER2-amplified cancer, but not in the ligand-driven cancer. To our knowledge, this represents the first study ascertaining the impact of PTEN loss on the antitumor efficacy of a HER3 mAb. KTN3379 is currently undergoing a phase Ib clinical trial in patients with advanced solid tumors. Our current study may help us optimize patient selection schemes for KTN3379 to maximize its clinical benefits. Mol Cancer Ther; 15(4); 689-701. ©2016 AACR.

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors.

Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for IL6 in promoting tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Notably, in tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2(+) tumor cells by targeting the CD44(+)CD24(-) cancer stem cell population. Collectively, our findings extend the evidence of important pleiotropic roles of IL6 in tumorigenesis and drug resistance, and offer a preclinical proof of concept for the use of IL6 antibodies in combination regimens to heighten therapeutic responses and overcome drug resistance.

Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis.

BACKGROUND: Decreased intestinal perfusion may contribute to the development of necrotizing enterocolitis (NEC). Vascular endothelial growth factor (VEGF) is an angiogenic protein necessary for the development and maintenance of capillary networks. Whether VEGF is dysregulated in NEC remains unknown. OBJECTIVES: The objective of this study was to determine whether intestinal VEGF expression is altered in a neonatal mouse model of NEC and in human NEC patients. METHODS: We first assessed changes of intestinal VEGF mRNA and protein in a neonatal mouse NEC model before significant injury occurs. We then examined whether exposure to formula feeding, bacterial inoculation, cold stress and/or intermittent hypoxia affected intestinal VEGF expression. Last, we visualized VEGF protein in intestinal tissues of murine and human NEC and control cases by immunohistochemistry. RESULTS: Intestinal VEGF protein and mRNA were significantly decreased in pups exposed to the NEC protocol compared to controls. Hypoxia, cold stress and commensal bacteria, when administered together, significantly downregulated intestinal VEGF expression, while they had no significant effect when given alone. VEGF was localized to a few single intestinal epithelial cells and some cells of the lamina propria and myenteric plexus. VEGF staining was decreased in murine and human NEC intestines when compared to control tissues. CONCLUSION: Intestinal VEGF protein is reduced in human and experimental NEC. Decreased VEGF production might contribute to NEC pathogenesis.

Multivalent scaffold proteins as superagonists of TRAIL receptor 2-induced apoptosis.

Activation of TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) can induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in normal cells. The natural ligand and agonistic antibodies show antitumor activity in preclinical models of cancer, and this had led to significant excitement in the clinical potential of these agents. Unfortunately, this optimism has been tempered by trial data that, thus far, are not showing clear signs of efficacy in cancer patients. The reasons for discrepant preclinical and clinical observations are not understood, but one possibility is that the current TRAILR2 agonists lack sufficient potency to achieve a meaningful response in patients. Toward addressing that possibility, we have developed multivalent forms of a new binding scaffold (Tn3) that are superagonists of TRAILR2 and can induce apoptosis in tumor cell lines at subpicomolar concentrations. The monomer Tn3 unit was a fibronectin type III domain engineered for high-affinity TRAILR2 binding. Multivalent presentation of this basic unit induced cell death in TRAILR2-expressing cell lines. Optimization of binding affinity, molecular format, and valency contributed to cumulative enhancements of agonistic activity. An optimized multivalent agonist consisting of 8 tandem Tn3 repeats was highly potent in triggering cell death in TRAIL-sensitive cell lines and was 1 to 2 orders of magnitude more potent than TRAIL. Enhanced potency was also observed in vivo in a tumor xenograft setting. The TRAILR2 superagonists described here have the potential for superior clinical activity in settings insensitive to the current therapeutic agonists that target this pathway.

EphB4 promotes or suppresses Ras/MEK/ERK pathway in a context-dependent manner: Implications for EphB4 as a cancer target.

EphB4 is a member of the Eph receptor tyrosine kinase family shown to act in neuronal guidance and mediate venal/arterial separation. In contrast to these more established roles, EphB4's function in cancer is much less clear. Here we illustrate both tumor promoting as well as suppressing roles of EphB4, by showing that its activation resulted in inhibition of the Ras/ERK pathway in endothelial cells but activation of the same pathway in MCF-7 breast cancer cells. This was true if EphB4 was stimulated with EphrinB2, its natural ligand, or an agonistic monoclonal antibody for EphB4. Correspondingly, EphB4 activation stimulated MCF7 growth while inhibiting HUVEC cell proliferation. The reason for these dramatic differences is due to functional coupling of EphB4 to different downstream effectors. Reduction of p120 RasGAP in HUVEC cells attenuated the inhibitory effect of EphB4 activation on the ERK pathway, whereas knockdown of PP2A in MCF7 cells attenuated EphB4 activation of the ERK pathway. This represents the first time a functional coupling between Eph receptor and PP2A has been demonstrated leading to activation of an oncogenic pathway. Our study illustrates the caveats and potential challenges of targeting EphB4 for cancer therapy due to the conflicting effects on cancer cell and endothelial cell compartments.