The Diagnostic Capacity of Physical Examinations in Diagnosing Musculoskeletal Disorders of the Lower Limbs in Children with Down Syndrome.

Background and Objectives: although musculoskeletal alterations are common in patients with Down syndrome (DS), studies investigating this association are scarce, and proposals for diagnostic standardization are limited. We aimed to evaluate the prevalence of musculoskeletal disorders in the lower limbs in a sample of children and adolescents with DS and to investigate the diagnostic capacity of orthopedic clinical examinations performed by orthopedists and pediatricians to diagnose these alterations. Materials and Methods: Twenty-two patients aged between three and ten years with DS were included. Patients and guardians answered a simple questionnaire regarding orthopedic complaints and underwent a systematic orthopedic physical examination, performed twice: once by an orthopedist and again by a pediatrician. Patients underwent a series of radiographs to diagnose anisomelia, hip dysplasia, epiphysiolysis, flatfoot valgus, mechanical axis varus, and mechanical axis valgus. The radiological diagnosis was considered the gold standard, and the diagnostic capacity of the physical examination performed by each physician was determined. Results: The median age was 6.50 years. Only four patients (18.2%) presented with orthopedic complaints. All patients were diagnosed with at least one musculoskeletal disorder. The only musculoskeletal disorder with a good diagnostic capacity was flatfoot valgus. Limited sensitivity values were found for hip dysplasia, mechanical axis varus, and mechanical axis valgus. The agreement between the orthopedic physical examinations performed by the two examiners was weak, poor, or indeterminate for most of the analyzed items. Conclusions: There was a high prevalence of orthopedic alterations in children with DS who did not present with musculoskeletal complaints. The diagnostic capacity of the physical examination was limited. Therefore, all children with DS should undergo a radiological evaluation of the musculoskeletal system and subsequent specialized orthopedic evaluation. Level of Evidence: Level II (Diagnostic Studies).

Prevalence and genetic characterization of Dientamoeba fragilis in asymptomatic children attending daycare centers.

In order to provide additional data on the prevalence and genetic diversity of Dientamoeba fragilis in human populations, we conducted a study in children from low-income communities in Sao Paulo State, Brazil. Fecal samples from daycare center attendees up to 6 years old (n=156) and staff members (n=18) were submitted to PCR and sequencing of D. fragilis as well as to microscopic examination for the presence of other intestinal parasites. All children assessed were asymptomatic and 10.3% (16/156) were positive for D. fragilis. No worker was found to be positive. An association between Dientamoeba and coinfection with other intestinal parasites was observed. Concerning the genetic diversity, 14 and only two isolates were genotype 1 and genotype 2, respectively. Our findings outline interesting aspects: (1) asymptomatic children as carriers of Dientamoeba in communities in which environmental conditions ensure parasite transmission and, (2) association between Dientamoeba infection in young children and coinfection with other enteric parasites, reinforcing its transmission via the fecal-oral route.

Avaliação do estado nutricional e da dieta de crianças e adolescentes com síndrome de down / Evaluación del estado nutricional y de la dieta de niños y adolescentes con síndrome de down / Evaluation of nutritional status and diet of children and adolescents with down syndrome

RESUMO Introdução: As crianças com síndrome de Down (SD) podem apresentar maior incidência de neofobia e de seletividade alimentar, sobrepeso e obesidade. A alimentação saudável e equilibrada é de suma importância para o crescimento adequado dessas crianças. Objetivo: Avaliar a adequação dos componentes da dieta e o estado nutricional de crianças e adolescentes com síndrome de Down em seguimento no ambulatório de pediatria genética do Hospital das Clínicas de Botucatu. Método: Estudo clínico descritivo transversal, com coleta de dados clínicos e avaliação nutricional, realizadopor meio de dados antropométricos e recordatório alimentar para avaliação da dieta. Análise estatística dos testes de Qui-quadrado e de Tukey. Resultados: Foram incluídos 35 crianças e dois adolescentes. Os diagnósticos nutricionais foram 2,7% de magreza, 81,1% de eutrofia, 8,1% de obesidade e 8,1% em risco ou sobrepeso. Houve excesso de ingestão de lipídeos naqueles com sobrepeso e obesidade, e a dieta deficiente em fibras foi prevalente a partir do primeiro ano de vida, bem como excesso de calorias e adequação de ferro e zinco. Entre os dois adolescentes, predominou a dieta com déficits em macro e micronutrientes, exceto em vitamina C e colesterol. Conclusões: A dieta com excesso de calorias, carboidratos e lipídios, como tambémcom déficit de fibras, aponta uma alimentação pouco balanceada entre crianças e adolescentes com SD, principalmente após o primeiro ano de vida, apesar do seu adequado estado nutricional.

RESUMEN Introducción: los niños consíndrome de Down (SD) pueden presentar mayor incidencia de neofobia yde selectividad alimentaria, sobrepeso y obesidad. La alimentación saludabley equilibradaes de gran importancia para el crecimiento adecuado de estos niños. Objetivo: la adecuación de los componentes de la dieta yel estado nutricional de niños y adolescentes con síndrome de Downasistidosen la clínica médica depediatría genética delHospital das Clínicas de Botucatu. Método: estudio clínico descriptivo transversal, con recolección de datos clínicos yevaluación nutricional, realizado medianteindicadores antropométricos y recordatorio alimentario para la evaluación de la dieta. Análisis estadísticode laspruebas de ji-cuadrado y de Tukey. Resultados: fueron incluidos 35niños ydos adolescentes. Los diagnósticos nutricionales fueron 2,7% de delgadez, 81,1% de eutrofia, 8,1% de obesidady8,1% en riesgo o sobrepeso. Hubo exceso de ingestión delípidosenaquellos con sobrepeso y obesidad, yla dieta deficiente en fibrasfueprevalentea partir del primer año de vida, así como exceso de calorías y adecuación de hierro y zinc. Entre los dos adolescentes, predominóla dieta con déficits en macro y micronutrientes, excepto en vitamina C y colesterol. Conclusiones: la dieta con exceso de calorías, carbohidratosylípidos, como tambiéncondéficit de fibras, señala una alimentación poco balanceada entre niños y adolescentes con SD, principalmente trasel primer año de vida, apesar de su adecuado estado nutricional.

ABSTRACT Introduction: Children with Down syndrome (DS) may have a prevalence of neophobia and food selectivity, overweight, and obesity. A healthy and balanced diet is of utmost importance for the proper growth of these children. Objective: To evaluate the adequacy of diet components and the nutritional status of children and adolescents with Down syndrome followed up at the outpatient care of genetic pediatrics, Hospital das Clínicas de Botucatu. Method: A cross-sectional descriptive clinical study, with a collection of clinical data and nutritional assessment, using anthropometric data and dietary records to evaluate the diet. Statistical analysis of the Chi-square and Tukey tests were performed. Results: A total of 35 children and two adolescents were included. Nutritional diagnoses were 2.7% lean, 81.1% eutrophic, 8.1% obese, and 8.1% at risk or overweight. There was an excess of lipid intake in overweight and obese children, and a fiber-deficient diet was prevalent since the first year of age, as well as extra calories and adequate iron and zinc intake. Among the two adolescents, a diet with deficits in macro and micronutrients, except for vitamin C and cholesterol, stood out. Conclusions: A diet with an excess of calories, carbohydrates, and lipids, as well as a fiber-deficient diet, indicates an unbalanced diet among children and adolescents with DS, especially after one year of age, despite their adequate nutritional status.

Periodontal disease: Repercussions in pregnant woman and newborn health-A cohort study.

OBJECTIVE: To investigate the repercussion of periodontal disease (PD) in the pregnant woman health and the complications during pregnancy and delivery, as well as negative outcomes for the newborn (as infections, prematurity, low birth weight and fetal growth restriction). METHOD: Retrospective cohort study, based on medical records of 142 pregnant women assisted at a prenatal service of usual risk between 2012-2014, with a dental evaluation for PD. Maternal variables, along with labor and newborn variables, were analyzed. The newborns were stratified into two groups: offspring of mothers with PD (subdivided into Severe Periodontal Disease-SPD) and offspring of mothers without PD. Each outcome was adjusted by a multiple logistic regression model, with significance for p-value <0.05, considering all potential confounding factors. RESULTS: Among women diagnosed with SPD, the odds ratio for vulvovaginitis was 3.45 times greater (OR = 3.45, p-value = 0.050) and 5.59 times higher for premature rupture of membranes (OR = 5.59; p-value = 0.017). For neonates, the chance of fetal growth restriction was 11.53 times higher for pregnant women with SPD (OR = 11.53, p = 0.041). CONCLUSION: The periodontal disease increased the chance of neonatal and maternal negative outcomes, being the fetal growth restriction, vulvovaginitis and premature rupture of the membrane (PROM) the main results driven by the presence of Severe Periodontal Disease.

Environmental stress is the major cause of transcriptomic and proteomic changes in GM and non-GM plants.

The approval of genetically modified (GM) crops is preceded by years of intensive research to demonstrate safety to humans and environment. We recently showed that in vitro culture stress is the major factor influencing proteomic differences of GM vs. non-GM plants. This made us question the number of generations needed to erase such "memory". We also wondered about the relevance of alterations promoted by transgenesis as compared to environment-induced ones. Here we followed three rice lines (1-control, 1-transgenic and 1-negative segregant) throughout eight generations after transgenesis combining proteomics and transcriptomics, and further analyzed their response to salinity stress on the F6 generation. Our results show that: (a) differences promoted during genetic modification are mainly short-term physiological changes, attenuating throughout generations, and (b) environmental stress may cause far more proteomic/transcriptomic alterations than transgenesis. Based on our data, we question what is really relevant in risk assessment design for GM food crops.

Biologic Activity of Autologous, Granulocyte-Macrophage Colony-Stimulating Factor Secreting Alveolar Soft-Part Sarcoma and Clear Cell Sarcoma Vaccines.

PURPOSE: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviral-mediated gene transfer to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). EXPERIMENTAL DESIGN: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. RESULTS: Vaccines were successfully manufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1-2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell-mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)-positive CD8(+) T cells in association with PD ligand-1 (PD-L1)-expressing sarcoma cells. No tumor regressions were observed. CONCLUSIONS: Vaccination with irradiated, GM-CSF-secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1-negative regulatory pathway might intensify immune-mediated tumor destruction.

In vitro culture may be the major contributing factor for transgenic versus nontransgenic proteomic plant differences.

Identification of differences between genetically modified plants and their original counterparts plays a central role in risk assessment strategy. Our main goal was to better understand the relevance of transgene presence, genetic, and epigenetic changes induced by transgene insertion, and in vitro culture in putative unintended differences between a transgenic and its comparator. Thus, we have used multiplex fluorescence 2DE coupled with MS to characterize the proteome of three different rice lines (Oryza sativa L. ssp. japonica cv. Nipponbare): a control conventional line (C), an Agrobacterium-transformed transgenic line (Ta) and a negative segregant (NSb). We observed that Ta and NSb appeared identical (with only one spot differentially abundant--fold difference ≥ 1.5), contrasting with the control (49 spots with fold difference ≥ 1.5, in both Ta and NSb vs. control). Given that in vitro culture was the only event in common between Ta and NSb, we hypothesize that in vitro culture stress was the most relevant condition contributing for the observed proteomic differences. MS protein identification support our hypothesis, indicating that Ta and NSb lines adjusted their metabolic pathways and altered the abundance of several stress related proteins in order to cope with in vitro culture.

Adequacy of antenatal care and its relationship with low birth weight in Botucatu, São Paulo, Brazil: a case-control study.

BACKGROUND: Birth weight reflects gestational conditions and development during the fetal period. Low birth weight (LBW) may be associated with antenatal care (ANC) adequacy and quality. The purpose of this study was to analyze ANC adequacy and its relationship with LBW in the Unified Health System in Brazil. METHODS: A case-control study was conducted in Botucatu, São Paulo, Brazil, 2004 to 2008. Data were collected from secondary sources (the Live Birth Certificate), and primary sources (the official medical records of pregnant women). The study population consisted of two groups, each with 860 newborns. The case group comprised newborns weighing less than 2,500 grams, while the control group comprised live newborns weighing greater than or equal to 2,500 grams. Adequacy of ANC was evaluated according to three measurements: 1. Adequacy of the number of ANC visits adjusted to gestational age; 2. Modified Kessner Index; and 3. Adequacy of ANC laboratory studies and exams summary measure according to parameters defined by the Ministry of Health in the Program for Prenatal and Birth Care Humanization. RESULTS: Analyses revealed that LBW was associated with the number of ANC visits adjusted to gestational age (OR = 1.78, 95% CI 1.32-2.34) and the ANC laboratory studies and exams summary measure (OR = 4.13, 95% CI 1.36-12.51). According to the modified Kessner Index, 64.4% of antenatal visits in the LBW group were adequate, with no differences between groups. CONCLUSIONS: Our data corroborate the association between inadequate number of ANC visits, laboratory studies and exams, and increased risk of LBW newborns. No association was found between the modified Kessner Index as a measure of adequacy of ANC and LBW. This finding reveals the low indices of coverage for basic actions already well regulated in the Health System in Brazil. Despite the association found in the study, we cannot conclude that LBW would be prevented only by an adequate ANC, as LBW is associated with factors of complex and multifactorial etiology. The results could be used to plan monitoring measures and evaluate programs of health care assistance during pregnancy, at delivery and to newborns, focusing on reduced LBW rates.

Maize IgE binding proteins: each plant a different profile?

BACKGROUND: Allergies are nearly always triggered by protein molecules and the majority of individuals with documented immunologic reactions to foods exhibit IgE hypersensitivity reactions. In this study we aimed to understand if natural differences, at proteomic level, between maize populations, may induce different IgE binding proteins profiles among maize-allergic individuals. We also intended to deepen our knowledge on maize IgE binding proteins. RESULTS: In order to accomplish this goal we have used proteomic tools (SDS-PAGE and 2-D gel electrophoresis followed by western blot) and tested plasma IgE reactivity from four maize-allergic individuals against four different protein fractions (albumins, globulins, glutelins and prolamins) of three different maize cultivars. We have observed that maize cultivars have different proteomes that result in different IgE binding proteins profiles when tested against plasma from maize-allergic individuals. We could identify 19 different maize IgE binding proteins, 11 of which were unknown to date. Moreover, we found that most (89.5%) of the 19 identified potential maize allergens could be related to plant stress. CONCLUSIONS: These results lead us to conclude that, within each species, plant allergenic potential varies with genotype. Moreover, considering the stress-related IgE binding proteins identified, we hypothesise that the environment, particularly stress conditions, may alter IgE binding protein profiles of plant components.

Coping with abiotic stress: proteome changes for crop improvement.

Plant breeders need new and more precise tools to accelerate breeding programs that address the increasing needs for food, feed, energy and raw materials, while facing a changing environment in which high salinity and drought have major impacts on crop losses worldwide. This review covers the achievements and bottlenecks in the identification and validation of proteins with relevance in abiotic stress tolerance, also mentioning the unexpected consequences of the stress in allergen expression. While addressing the key pathways regulating abiotic stress plant adaptation, comprehensive data is presented on the proteins confirmed as relevant to confer tolerance. Promising candidates still to be confirmed are also highlighted, as well as the specific protein families and protein modifications for which detection and characterization is still a challenge. This article is part of a Special Issue entitled: Translational Plant Proteomics.

Evaluation of pre-natal care from the perspective of different models in primary care.

OBJECTIVES: to evaluate the quality of the pre-natal care delivered in primary care, comparing the traditional model and the Family Health Strategy. METHOD: a service evaluation study, grounded in the public health policies. The data was obtained from interviews with managers, observation in the health centers, and analysis of patient records of pregnant women, selected at random. Differences in the indicators for structure and process were evaluated using the Chi-squared test, adopting p<0.05 as the critical value, calculation of the odds ratio, and confidence intervals of 95%. RESULTS: Similar structures were evidenced in both models of care. Synthesis indicators for the process created in the present study, and those indicated by the public policies, indicated that the situation is more favorable in Family Health Centers. Regarding the set of activities called for in pre-natal care, the performance was flawed in both models, although it was slightly better in the Family Health Centers. CONCLUSION: the results indicate the need for actions to improve pre-natal care in the two models of primary care evaluated in the municipality.

Evaluation of pre-natal care from the perspective of different models in primary care / Avaliação da atenção pré-natal na perspectiva dos diferentes modelos na atenção primária / Evaluación de atención prenatal bajo la perspectiva de los diferentes modelos en la atención primaria

OBJECTIVES: to evaluate the quality of the pre-natal care delivered in primary care, comparing the traditional model and the Family Health Strategy. METHOD: a service evaluation study, grounded in the public health policies. The data was obtained from interviews with managers, observation in the health centers, and analysis of patient records of pregnant women, selected at random. Differences in the indicators for structure and process were evaluated using the Chi-squared test, adopting p<0.05 as the critical value, calculation of the odds ratio, and confidence intervals of 95%. RESULTS: Similar structures were evidenced in both models of care. Synthesis indicators for the process created in the present study, and those indicated by the public policies, indicated that the situation is more favorable in Family Health Centers. Regarding the set of activities called for in pre-natal care, the performance was flawed in both models, although it was slightly better in the Family Health Centers. CONCLUSION: the results indicate the need for actions to improve pre-natal care in the two models of primary care evaluated in the municipality. .

OBJETIVOS: avaliar a qualidade do cuidado pré-natal desenvolvido na atenção primária, comparando os modelos tradicional e Estratégia Saúde da Família. MÉTODO: estudo de avaliação de serviço, pautado nas políticas públicas de saúde. Os dados foram obtidos por meio de entrevista com gerentes, observação nas unidades de saúde e análise de prontuários de gestantes, selecionados aleatoriamente. Diferenças nos indicadores de estrutura e processo foram avaliadas pelo teste qui-quadrado, adotando-se p<0,05 como nível crítico, cálculo dos odds ratio e intervalos de confiança de 95%. RESULTADOS: foram evidenciadas estruturas semelhantes em ambos os modelos de atenção. Indicadores-síntese de processo, criados neste estudo, e os indicados pelas políticas públicas apontaram situação mais favorável nas Unidades de Saúde da Família. Para o conjunto de atividades preconizadas para o pré-natal, o desempenho foi deficiente em ambos os modelos, embora pouco melhor nas Unidades de Saúde da Família. CONCLUSÃO: os resultados indicam a necessidade de ações para melhoria da atenção pré-natal nos dois modelos de atenção básica no município avaliado. .

OBJETIVOS: Evaluar la calidad del cuidado prenatal desarrollado en la atención primaria, comparando los modelos tradicional y Estrategia Salud de la Familia. MÉTODO: estudio de evaluación de servicio, pautado en las políticas públicas de salud. Los datos fueron recolectados por entrevista con gerentes, observación en las unidades de salud y análisis de archivos de gestantes elegidos aleatoriamente. Diferencias en los indicadores de estructura y proceso fueron evaluadas mediante el test ji cuadrado, adoptándose p<0,05 como nivel crítico, cálculo de los odds ratio e intervalos de confianza del 95%. RESULTADOS: Fueron evidenciadas estructuras semejantes en ambos modelos de atención. Indicadores síntesis de proceso creados en este estudio y aquellos indicados por las políticas públicas mostraron situación más favorable en las Unidades de Salud de la Familia. Para el conjunto de actividades recomendadas para el prenatal, el desempeño fue deficiente en ambos modelos, aunque poco mejor en las Unidades de Salud de la Familia. CONCLUSIÓN: los resultados indican la necesidad de acciones para mejorar la atención prenatal en los dos modelos de atención básica en el municipio evaluado. .

Characterization of maize allergens - MON810 vs. its non-transgenic counterpart.

One of the main concerns about genetically modified foods and their potential impacts on human health is that the introduction of a new/ altered gene may putatively alter the expression of others, namely endogenous allergens. We intended to evaluate, and to compare, using quantitative real time RT-PCR technique, the expression of 5 already known maize allergens (Zea m14, Zea m25, Zea m27kD, 50kD Zein and trypsin inhibitor) in MON 810 vs. its non-transgenic counterpart, throughout seed development (10, 16 and 23days after pollination). We have shown that none of the tested allergen genes presented differential expression, with statistic significance, along all tested seed development stages, in MON810 vs. its conventional counterpart. We have also used bidimensional gel electrophoresis followed by Western blotting with plasma from two maize allergic subjects to characterize their immunologic responses against MON 810 vs. its non-transgenic control. Immunoreactive spots were characterized by MS. We have identified fourteen new IgE-binding proteins present in both transgenic and non-transgenic maize.

Risk factors for low birth weight in Botucatu city, SP state, Brazil: a study conducted in the public health system from 2004 to 2008.

BACKGROUND: Low birth weight (LBW), defined as birth weight less than 2500 g, has a complex etiology and may be a result of premature interruption of pregnancy or intrauterine growth restriction. The objective of this study was to provide information on determinants of LBW and contribute to the understanding of the problem in Brazil. METHODS: A case-control study was conducted in Botucatu city, SP state, Brazil. The study population consisted of 2 groups with 860 newborns in each group as follows: low weight newborns (LWNB) and a control group (weight ≥ 2500 g). Secondary data from 2004 to 2008 were collected using the Live Birth Certificate (LBC) and records from medical charts of pregnant women in Basic Health Units (BHU) and in the Public University Hospital (UH). Variables were as follows: maternal socio-demographic characteristics, pregnancy and birth conditions including quality of prenatal care according to 3 criteria. They were based on parameters established by the Ministry of Health (MH), one of them, the modified Kessner Index. The multivariable analysis by logistic regression was used to evaluate the association between variables and LBW. RESULTS: According to the analysis, the factors associated with LBW were as follows: prematurity (OR = 56.98, 95% CI 29.52-109.95), twin pregnancy (OR = 20.00, 95% CI 6.25-100.00), maternal smoking (OR = 2.12, 95% CI 1.33-3.45), maternal malnourishment (OR = 2.30, 95% CI 1.08-5.00), maternal obesity (OR = 2.30, 95% IC 1.18-4.48), weight gain during pregnancy less than 5 kg (OR = 2.63, 95% CI 1.35-5.00) and weight gain during pregnancy more than 15 kg (OR = 2.26, 95% CI 1.16-4.41). Adequacy of prenatal care visits adjusted to gestational age was less frequent in the LBW group than in the control group (68.7% vs. 80.5%, x2 p < 0.001). According to the modified Kessner Index, 64.4% of prenatal visits in the LWNB group were adequate. CONCLUSION: LWNB are a quite heterogeneous group of infants concerning their determinants and prevention actions against LBW and the follow-up of these infants have also been very complex. Therefore, improvement in the quality of care provided should be given priority through concrete actions for prevention of LBW.

Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.

CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8(+) T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8(+) T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes--such as BATF--that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.

Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction.

The identification of cancer antigens that contribute to transformation and are linked with immune-mediated tumor destruction is an important goal for immunotherapy. Toward this end, we screened a murine renal cell carcinoma cDNA expression library with sera from mice vaccinated with irradiated tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF). Multiple nonmutated, overexpressed proteins that function in tumor cell migration, protein/nucleic acid homeostasis, metabolism, and stress responses were detected. Among these, the most frequently recognized clone was protein disulfide isomerase (PDI). High titer antibodies to human PDI were similarly induced in an acute myeloid leukemia patient who achieved a complete response after vaccination with irradiated, autologous GM-CSF-secreting tumor cells in the setting of nonmyeloablative allogeneic bone marrow transplantation. Moreover, ERp5, a closely related disulfide isomerase involved in major histocompatibility complex (MHC) class I chain-related protein A (MICA) shedding, also evoked potent humoral reactions in diverse solid and hematologic malignancy patients who responded to GM-CSF-secreting tumor cell vaccines or antibody blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Together, these findings reveal the unexpected immunogenicity of PDIs and raise the possibility that these gene products might serve as targets for therapeutic monoclonal antibodies.

Capitalizing on the immunogenicity of dying tumor cells.

Cancer cell death occurs continually during tumor development and progression, whereas the selective killing of surviving cancer cells remains the primary objective of antineoplastic treatments. Recent insights into the immunologic consequences of cancer cell death have begun to elucidate the ways in which host antitumor immunity is shaped during cancer pathogenesis and then modulated by therapeutic intervention. Dying tumor cells evoke a range of host responses, dependent in part upon the mode of cell death, which may either impede or foster additional immune-mediated cancer destruction. Within the tumor microenvironment, the capture of apoptotic tumor cells by macrophages and dendritic cells may trigger tolerance networks that contribute to immune suppression, whereas the uptake of necrotic cancer cells may engender inflammatory pathways that fuel antitumor cytotoxicity. Milk fat globule epidermal growth factor 8, a phosphatidylserine-binding protein, and MHC class I chain-related protein A, an NKG2D ligand, play key roles in these competing outcomes. A deeper understanding of the mechanisms underlying the immunogenicity of dying cells informs the crafting of strategies that exploit endogenous or treatment-induced cancer cell death as the basis for stimulating sustained host antitumor cytotoxic reactions.