Clinical and immunological allergy assessment in cancer patients.

Cancer is associated with immunodeficiency, while allergies result from immune system hyperactivity mediated by cytokines and immunoglobulins. The purpose of this study was to determine the relationship between immune environment of specific cancers and allergies, emphasizing cytokines related to Th1 and Th2 responses associated with IgE. 80 adults were distributed into two groups: control (n = 20) and cancer (n = 60), distributed in three subgroups (n = 20), head and neck, stomach, and prostate cancers. This study compared Th1 (IL-2) and Th2 (IL-4) parameters, anti-inflammatory, pro-inflammatory, or regulatory profile regarding both IgE levels and reported allergies, by means of clinical manifestations and IgE, IL-1ß, IL-2, IL-4, IL-17, and TGF-ß serum concentration. Clinically allergies were observed in 50% of the control group and in 20% of the cancer group (p = 0.009). IL-2 cytokine and TGF-ß concentrations were higher in the patients with cancer as compared to the control (p < 0.005). However, there were IL-4, IL-17, and IL-1ß decreases in the patients with cancer (p < 0.05). No correlation was observed between the cytokines studied and IgE and clinically proven allergies in both investigated groups. There was an inverse association between cancer and clinical allergy manifestations. In head and neck, stomach, and prostate cancers, an immunosuppressive serum tumor environment was predominant. There was no difference in cytokines related to Th1 and Th2 parameters in relation to IgE. No correlation was found between clinically proved allergies and immunity markers related to the same allergens.

MICRO-CONTROLLED THERMAL STIMULATOR FOR DETECTING FINE FIBER CHANGES IN PATIENTS WITH DIABETES MELLITUS: A DIAGNOSTIC ACCURACY STUDY.

AIM: To evaluate sensitivity and specificity of the micro-controlled thermal stimulator (MTS) for detecting pathological changes in fine fiber of neuropathy patients with DM. METHODS: A diagnostic accuracy study including 84 patients, aged 15-75 years was conducted. A patient's foot was subjected to dermatological, musculoskeletal, vascular, and neurological evaluations. The latter was performed through the perception of a sharp touch with a toothpick (pinprick), thermal sensitivity (cold and hot temperature sensations measured using Diapason Handle and MTS, respectively), vibratory sensitivity (128 Hz Diapason Handle), 10 g Semmes-Weinstein monofilament, and a reflex test. Statistical analyses were performed using Stata® software version 13.0. The sensitivity, specificity, positive and negative predictive values, likelihood ratios, AUC, Kappa index, and accuracy of the diagnostic instruments were evaluated. RESULTS: Of the 84 volunteers, 66.7% were female, with an average age of 54 years. We observed that 17% of the total patients were positive for pain sensations in the foot, 13% for cold-temperature sensations, and 21% for hot-temperature sensations. The MTS (hot temperature) obtained 97.6% sensitivity and 90% specificity, agreeing on 87.5% (Kappa index) with the Diapason Handle (cold temperature) (AUC > 0.937; p < 0.05). CONCLUSION: MTS is an accurate, sensitive, and specific instrument for the evaluation of diabetic neuropathy as compared with the tuning fork as the standard method and, consequently, it could be of help for the early diagnosis of diabetic neuropathy.

Imunoterapia no câncer - inibidores do checkpoint imunológico / Immunotherapy and immune checkpoint inhibitors in cancer

O objetivo deste trabalho é fazer uma revisão atual do tratamento de alguns tipos de câncer com imunoterapia e inibidores do checkpoint imunológico. As fontes de dados incluíram artigos originais, revisões e publicações indexados nos bancos de dados PubMed, MEDLINE, LILACS, SciELO e publicações online nos últimos 20 anos. Os checkpoints imunológicos normalmente impedem o organismo de montar uma resposta imune contra células normais. Alguns tipos de câncer podem adquirir estes checkpoints de tal forma que estas células tumorais não são reconhecidas pelo sistema imune, e isto impede que ele seja ativado. A inibição dos checkpoints imunológicos pode melhorar a sobrevida de pacientes com malignidades avançadas. Isto inclui melanoma maligno, carcinoma renal, linfoma e câncer pulmonar de células não pequenas. Uma extraordinária quantidade de investigações pré-clínicas e clínicas estão explorando o potencial terapêutico das moléculas coestimulatórias positivas e negativas. Aqui, nós revisamos o estado atual do nosso conhecimento dos mecanismos co-estimulatórios da célula T e a inibição dos checkpoints, primariamente do CTLA-4 e do PD-1.

This paper aims to review current treatment of some types of cancer with immunotherapy and immune checkpoint inhibitors. Data sources included original articles, reviews and related texts published over the past 20 years in PubMed, MEDLINE, LILACS and SciELO databases and other online publications. Immune checkpoints normally prevent the body from developing an immune response against healthy cells. Some types of cancer may acquire these checkpoints so that the tumor cells are not recognized by the immune system, preventing it from being activated. Immune checkpoint inhibitors may improve the survival of some patients with advanced malignant tumors, including malignant melanoma, renal cell carcinoma, lymphoma and non-small cell lung cancer. An extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Herein, we review the current status of our understanding of T-cell costimulatory mechanisms and checkpoint inhibitors, primarily of CTLA-4 and PD-1.

Biomarcadores e imunobiológicos na asma / Biomarkers and immunobiological agents in asthma

A maioria dos asmáticos é bem controlada com o uso de corticosteroides inalados e beta-agonistas de ação prolongada; contudo, uma proporção de pacientes não responde a esta terapia, e mantém controle limitado da doença. Este grupo experimenta exacerbações frequentes, e requer admissão hospitalar. O desenvolvimento de novos agentes biológicos e biomarcadores da doença abre novas avenidas para o tratamento. Nós revisamos as últimas informações pertinentes aos biomarcadores e agentes biológicos, e demonstramos como os pacientes podem ser identificados e se beneficiar destes tratamentos. As fontes de dados incluíram artigos originais, revisões e publicações indexados nos bancos de dados PubMed, MEDLINE, LILACS, SciELO e publicações on-line, nos últimos 15 anos. As informações mais recentes da medicina personalizada com análise genética e biomarcadores da inflamação Th2 permitiram identificar fenótipos de asma que incluem um fenótipo T2 alto. Estudos recentes dirigidos para IgE, IL-5, IL-13, IL-17 e para os receptores de cadeias alfa de IL-4 mostraram alguma eficácia em alguns pacientes fenotipados. Para aqueles sem evidência de inflamação Th2, nenhuma terapia específica foi identificada. A disponibilidade de biomarcadores e agentes bioterapêuticos que são dirigidos para IgE, interleucinas IL-5, IL-4, IL-13 e IL-17, são uma excitante modalidade de medicina molecular. Contudo, estes agentes bioterapêuticos somente são efetivos quando dirigidos para pacientes com fenótipos de asma específicos.

Most asthmatic individuals are well managed with inhaled corticosteroids and prolonged-action beta-agonists; however, some patients are unresponsive to therapy and attain limited disease control. The latter group experiences frequent exacerbations requiring hospital admission. The development of new biological agents and disease biomarkers has provided novel avenues for treatment. We review the latest information regarding biomarkers and biological agents and demonstrate how potential patients may be identified for treatment. Data sources included original articles, reviews, and published works indexed in PubMed, MEDLINE, LILACS, SciELO, and other online databases over the past 15 years. The latest findings from personalized medicine with genetic analysis and clinical biomarkers of Th2 inflammation have allowed the identification of asthma phenotypes including a T2-high phenotype. Recent studies targeting IgE, IL-5, IL- 13, IL-17, and the IL4 receptor alpha chain have shown some efficacy in phenotyped patients. For those without evidence of Th2 inflammation, no specific therapies have been identified. The availability of biomarkers and biotherapeutic agents targeting IgE, IL-5, IL-4, IL-13, and IL-17 is an exciting advance in molecular medicine. However, those biotherapeutic agents are effective only when used in patients with specific asthma phenotypes.

Medicina de precisão na asma / Precision medicine in asthma

O objetivo deste trabalho é fazer uma revisão atual de uma medicina de precisão personalizada e dirigida para fenótipos e endótipos de asma. As fontes de dados incluíram artigos originais, revisões e publicações indexadas nos bancos de dados PubMed, MEDLINE, LILACS, SciELO e publicadas on line nos últimos 20 anos. Os resultados mostram que a asma tem sido considerada uma doença única por anos, e que estudos mais recentes cada vez mais focam na sua heterogeneidade. Esta heterogeneidade resulta em que a asma contém múltiplos fenótipos ou grupos de características consistentes. Um endótipo é um subtipo desta doença, definido por um distinto mecanismo fisiopatológico, e é associado a um biomarcador. Múltiplos modificadores da resposta imune estão sendo avaliados na asma denominada T2 alta, bloqueando as interleucinas IL-5, IL-13, imunoglobulina E e outras vias. Assim, muitas destas terapias visando a asma T2 alta têm demonstrado melhor eficácia quando certos biomarcadores estão elevados, especialmente os eosinófilos. Já o tipo de asma T2 baixo, que não apresenta biomarcadores precisos, é geralmente diagnosticada pela ausência de biomarcadores para T2 alta. Estes pacientes tendem a ter mais resistência a tratamento com esteroides e o desenvolvimento de novas terapias são muito menos apreciáveis do que as com o tipo T2 alto. As conclusões são que a disponibilidade de agentes bioterapêuticos dirigidos especificamente a IgE, IL-5 e IL-13 é uma excitante evolução da medicina molecular. Contudo, estes agentes bioterapêuticos somente são efetivos quando dirigidos a fenótipos específicos de asma.

The objective of this study was to conduct an updated review of the role of personalized phenotype-endotype driven precision medicine in asthma. Sources of data included original articles, reviews and other publications indexed in PubMed, MEDLINE, LILACS, and SciELO and published online over the last 20 years. The results showed that asthma has been considered as a single disease for years, and more recent studies have increasingly focused on its heterogeneity. This heterogeneity has promoted the concept that asthma consists of multiple phenotypes or consistent groupings of characteristics. An endotype is a subtype of a condition, defined by a distinct pathophysiological mechanism and linked to a biomarker. Several immune response modifiers have been evaluated in T2-high asthma geared at blocking interleukins IL-5, IL-13, immunoglobulin E, and other pathways. Thus, many of the T2-high asthma therapies available have shown improved effectiveness when certain biomarkers are elevated, especially eosinophils. Conversely, T2-low asthma does not currently have any readily available point-of-care biomarkers, and therefore is often diagnosed based on the absence of T2-high biomarkers. These patients tend to present greater resistance to steroids, and the development of therapies has lagged behind that observed for T2-high asthma. In conclusion, the availability of biotherapeutic agents specifically targeted at IgE, IL-5, and IL-13 is an exciting vindication of molecular medicine. However, these biotherapeutic agents are only effective when targeted at specific asthma phenotypes.

Oxidative stress and interleukin-6 secretion during the progression of type 1 diabetes.

OBJECTIVE: To evaluate inflammatory, oxidizing, and reducing responses during the progression of type 1 diabetes mellitus (T1DM) in patients without chronic complications. SUBJECTS AND METHODS: Plasma antioxidant status, reactive oxygen species (ROS), and interleukin-6 (IL-6) were measured in 42 patients with T1DM and in 24 healthy subjects. RESULTS: Significant increases were detected in the median values of ROS and IL-6 in patients with T1DM compared with healthy subjects (ROS ~ 4,836 vs. 2,036 RLU/min, respectively; P < .05: IL-6 ~ 14.2 vs. 9.7 pg/mL, respectively; P = .002). No significant between-group differences (P > 0.05) were observed in oxidizing responses or in IL-6 concentrations when diabetic patients were grouped according to time after diagnosis (0 - 10, 10 - 20 and > 20 years). Plasma antioxidant responses were similar in patients with T1DM and in healthy subjects. CONCLUSIONS: Our results demonstrate that oxidizing and inflammatory responses are increased at the onset of T1DM, but remain unchanged during disease progression. These findings suggest that functional changes involved in diabetic complications may commence in the first years after diagnosis.

Oxidative stress and interleukin-6 secretion during the progression of type 1 diabetes / Estresse oxidativo e secreção de interleucina-6 durante a progressão do diabetes tipo 1

OBJECTIVE: To evaluate inflammatory, oxidizing, and reducing responses during the progression of type 1 diabetes mellitus (T1DM) in patients without chronic complications. SUBJECTS AND METHODS: Plasma antioxidant status, reactive oxygen species (ROS), and interleukin-6 (IL-6) were measured in 42 patients with T1DM and in 24 healthy subjects. RESULTS: Significant increases were detected in the median values of ROS and IL-6 in patients with T1DM compared with healthy subjects (ROS ~ 4,836 vs. 2,036 RLU/min, respectively; P < .05: IL-6 ~ 14.2 vs. 9.7 pg/mL, respectively; P = .002). No significant between-group differences (P > 0.05) were observed in oxidizing responses or in IL-6 concentrations when diabetic patients were grouped according to time after diagnosis (0 - 10, 10 - 20 and > 20 years). Plasma antioxidant responses were similar in patients with T1DM and in healthy subjects. CONCLUSIONS: Our results demonstrate that oxidizing and inflammatory responses are increased at the onset of T1DM, but remain unchanged during disease progression. These findings suggest that functional changes involved in diabetic complications may commence in the first years after diagnosis.

OBJETIVO: Avaliar as respostas inflamatória, oxidativa e redutora na progressão do diabetes melito tipo 1 (DM1) em pacientes sem complicações crônicas. SUJEITOS E MÉTODOS: Capacidade antioxidante do plasma, espécies reativas de oxigênio (ROS) e interleucina-6 (IL-6) foram avaliadas em 42 pacientes com DM1 e 24 indivíduos saudáveis. RESULTADOS: Aumentos significativos foram detectados nas medianas de ROS e IL-6 em pacientes com DM1 comparados com indivíduos saudáveis (ROS ~ 4.836 vs. 2.036 RLU/min, respectivamente, P < 0,05: IL-6 ~ 14,2 vs. 9,7 pg/mL, respectivamente, P = 0,002). Diferenças não significativas (P > 0,05) foram observadas na resposta oxidante e IL-6 quando os diabéticos foram agrupados de acordo com o tempo após o diagnóstico (0-10, 10-20 e > 20 anos). A resposta antioxidante do plasma foi semelhante em pacientes com DM1 e em indivíduos saudáveis. CONCLUSÕES: Nossos resultados demonstram que as respostas oxidante e inflamatória estão aumentadas desde o início do DM1, mas mantêm-se inalteradas durante a progressão da doença, sugerindo que as mudanças funcionais envolvidas nas complicações diabéticas podem começar nos primeiros anos após o diagnóstico.

Pretreatment with citrulline improves gut barrier after intestinal obstruction in mice.

BACKGROUND: Citrulline has been shown to be an important marker of gut function, regulator of protein metabolism, and precursor of arginine. The authors assessed the effects of citrulline on gut barrier integrity and bacterial translocation (BT) in mice undergoing intestinal obstruction. METHODS: Mice were divided into 3 groups: sham, intestinal obstruction (IO), and citrulline (CIT). The CIT group received a diet containing 0.6% citrulline; the IO and sham groups were fed a standard chow diet. On the eighth day of treatment, all animals received a diethylenetriamine pentaacetic acid (DTPA) solution labeled with (99m)Technetium ((99m)Tc-DTPA) by gavage for the intestinal permeability study. Terminal ileum was ligated except the sham group, which only underwent laparotomy. After 4, 8, and 18 hours, blood was collected to determine radioactivity. Samples of ileum were removed 18 hours after intestinal obstruction for histological analysis. In another set of animals, BT was evaluated. Animals received 10(8) CFU/mL of (99m)Tc-Escherichia coli by gavage; 90 minutes later, they underwent ileum ligation. Intestinal fluid and serum were collected to measure sIgA and cytokines. RESULTS: The CIT group presented decreased intestinal permeability and BT when compared with the IO group (P < .05). Histopathology showed that citrulline preserved the ileum mucosa. The sIgA concentration was higher in the CIT group (P < .05). The IO group presented the highest levels of interferon-γ (P < .05). CONCLUSIONS: Pretreatment with citrulline was able to preserve barrier integrity and also modulated the immune response that might have affected BT decrease.

Correlation between ROS production and InsP3 released by granulocytes from type 1 diabetic patients in a cAMP-dependent manner.

BACKGROUND: Diabetes is associated with a pro-inflammatory status characterized by an increased production of inflammatory molecules. Reactive oxygen species (ROS) and cAMP elevating agents represent two molecular systems, normally generated during inflammation. These molecules could be responsible for the alteration of signaling pathways. In the present paper we have studied the correlation between ROS generation and inositolpolyphosphates (InsP(1), InsP(2) InsP(3) and InsP(4)) released by granulocytes from Type 1 diabetic patients (DM1) in the presence or in the absence of cyclic AMP-elevating agents. METHODS: The effect of cAMP on ROS production was quantified in a chemoluminescence assay luminol-dependent (RLU/min). InsP(1), InsP(2) InsP(3) and InsP(4) were quantified by inositol-H(3) in a Beta-counter and the results were expressed as count per minute (CPM). RESULTS: The elevation of intracellular level of cAMP inhibited both InsP(3) and ROS production in granulocytes from healthy subjects and activated in the cells from Type 1 diabetic patients. InsP(1), InsP(2) and InsP(4) did not show significant alteration in both studied cells. There was a significant correlation between InsP(3) and ROS in the presence of elevated content of cAMP. This correlation was observed in a 15 minutes reaction for healthy subjects and in 120 minutes for DM1. CONCLUSIONS: The importance of both InsP(3) release and ROS production in an inflammatory process and tissue pathophysiology in Type 1 diabetic patients is still under debate because hyperglycemia accelerates generation of oxidative stress and may play an important role in the development of complications in diabetes. Thus, our results demonstrated alteration in metabolic response in granulocytes from Type 1 diabetic patients and it may be important for the development of therapeutic processes and drugs that interfere with signaling of ROS generation and may contribute to the improvement of the severe complications of diabetes.

Participaçäo do sistema imunológico na evoluçäo da doença periodontal inflamatória crônica / Immune system and chronic inflammatory periodontal disease evolution

A proposta do presente trabalho é apresentar uma revisäo sobre a participaçäo do sistema imunológico na evoluçäo da doença periodontal inflamatória crônica. Correlaçöes entre os achados clínicos e microbiológicos com a resposta do hospedeiro na doença säo discutidas e algumas hipóteses relacionadas à sua imunopatogênese säo apresentadas

Avaliação da atividade blastogênica em células mononucleares de pacientes portadores de periodontite do adulto sob a estimulação com fitohemoaglutinina / Blastogenic activity of mononuclear cells in patients with adult periodontitis stimulated by PHA

A Doença Periodontal Inflamatória Crônica (DPIC) é uma doença de etiologia bacteriana, caracterizada por alterações no mecanismo imunorregulador. Avaliamos a atividade blastogênica de células mononucleares de pacientes portadores de Periodontite do Adulto sob a estimulação com fitohemoaglutinina. Os resultados demonstraram uma diminuição da atividade blastogênica nos pacientes comparada aos voluntários controles saudáveis (p<0.05). A relação desta imunodepressão celular com a imunopatogênese da DPIC é discutida