Sialyl Tn-Expressing Bladder Cancer Cells Induce a Tolerogenic Phenotype in Innate and Adaptive Immune Cells

Despite the wide acceptance that glycans are centrally implicated in immunity, exactly how they contribute to the tilt immune response remains poorly defined. In this study, we sought to evaluate the impact of the malignant phenotype-associated glycan, sialyl-Tn (STn) in the function of the key orchestrators of the immune response, the dendritic cells (DCs). In high grade bladder cancer tissue, the STn antigen is significantly overexpressed and correlated with the increased expression of ST6GALNAC1 sialyltransferase. Bladder cancer tissue presenting elevated expression of ST6GALNAC1 showed a correlation with increased expression of CD1a, a marker for bladder immature DCs and showed concomitant low levels of Th1-inducing cytokines IL-12 and TNF-α. In vitro, human DCs co-incubated with STn+ bladder cancer cells, had an immature phenotype (MHC-IIlow, CD80low and CD86low) and were unresponsive to further maturation stimuli. When contacting with STn+ cancer cells, DCs expressed significantly less IL-12 and TNF-α. Consistent with a tolerogenic DC profile, T cells that were primed by DCs pulsed with antigens derived from STn+ cancer cells were not activated and showed a FoxP3high IFN-γlow phenotype. Blockade of STn antigens and of STn+ glycoprotein, CD44 and MUC1, in STn+ cancer cells was able to lower the induction of tolerance and DCs become more mature. Overall, our data suggest that STn-expressing cancer cells impair DC maturation and endow DCs with a tolerogenic function, limiting their capacity to trigger protective anti-tumour T cell responses. STn antigens and, in particular, STn+ glycoproteins are potential targets for circumventing tumour-induced tolerogenic mechanisms.

Biological and Physiological Markers of Tactile Sensorial Processing in Healthy Newborns

The main objective of this review is to provide a descriptive analysis of the biological and physiological markers of tactile sensorial processing in healthy, full-term newborns. Research articles were selected according to the following study design criteria: (a) tactile stimulation for touch sense as an independent variable; (b) having at least one biological or physiological variable as a dependent variable; and (c) the group of participants were characterized as full-term and healthy newborns; a mixed group of full-term newborns and preterm newborns; or premature newborns with appropriate-weight-for-gestational age and without clinical differences or considered to have a normal, healthy somatosensory system. Studies were then grouped according to the dependent variable type, and only those that met the aforementioned three major criteria were described. Cortisol level, growth measures, and urinary catecholamine, serotonin, and melatonin levels were reported as biological-marker candidates for tactile sensorial processing. Heart rate, body temperature, skin-conductance activity, and vagal reactivity were described as neurovegetative-marker candidates. Somatosensory evoked potentials, somatosensory evoked magnetic fields, and functional neuroimaging data also were included.

Anti-Tumor Necrosis Factor Alpha-Induced Drug Eruptions: One Patient, More Than a Pattern

Background: Tumor necrosis factor alpha (TNFα) antagonists are effective in treating several immune-inflammatory diseases, including psoriasis and inflammatory bowel disease. The paradoxical and unpredictable induction of psoriasis and psoriasiform skin lesions is a recognized adverse event, although of unclear aetiology. However, histological analysis of these eruptions remains insufficient, yet suggesting that some might constitute a new pattern of adverse drug reaction, rather than true psoriasis. Case report: The authors report the case of a 43-year-old woman with severe recalcitrant Crohn disease who started treatment with infliximab. There was also a personal history of mild plaque psoriasis without clinical expression for the past eight years. She developed a heterogeneous cutaneous eruption of psoriasiform morphology with pustules and crusts after the third infliximab infusion. The histopathological diagnosis was of a Sweet-like dermatosis. The patient was successfully treated with cyclosporine in association with both topical corticosteroid and vitamin D3 analogue. Three weeks after switching to adalimumab a new psoriasiform eruption was observed, histologically compatible with a psoriasiform drug eruption. Despite this, and considering the beneficial effect on the inflammatory bowel disease, it was decided to maintain treatment with adalimumab and to treat through with topicals, with progressive control of skin disease. Discussion: Not much is known about the pathogenesis of psoriasiform eruptions induced by biological therapies, but genetic predisposition and Koebner phenomenon may contribute to it. Histopathology can add new facets to the comprehension of psoriasiform reactions. In fact, histopathologic patterns of such skin lesions appear to be varied, in a clear asymmetry with clinical findings. Conclusion: The sequential identification in the same patient of two clinical and histopathologic patterns of drug reaction to TNFα antagonists is rare. Additionally, to the authors’ knowledge, there is only one other description in literature of a TNFα antagonist-induced Sweet-like dermatosis, emphasizing the singularity of this case report.

Automatic Small Bowel Tumor Diagnosis by Using Multi-Scale Wavelet-Based Analysis in Wireless Capsule Endoscopy Images

BACKGROUND: Wireless capsule endoscopy has been introduced as an innovative, non-invasive diagnostic technique for evaluation of the gastrointestinal tract, reaching places where conventional endoscopy is unable to. However, the output of this technique is an 8 hours video, whose analysis by the expert physician is very time consuming. Thus, a computer assisted diagnosis tool to help the physicians to evaluate CE exams faster and more accurately is an important technical challenge and an excellent economical opportunity. METHOD: The set of features proposed in this paper to code textural information is based on statistical modeling of second order textural measures extracted from co-occurrence matrices. To cope with both joint and marginal non-Gaussianity of second order textural measures, higher order moments are used. These statistical moments are taken from the two-dimensional color-scale feature space, where two different scales are considered. Second and higher order moments of textural measures are computed from the co-occurrence matrices computed from images synthesized by the inverse wavelet transform of the wavelet transform containing only the selected scales for the three color channels. The dimensionality of the data is reduced by using Principal Component Analysis. RESULTS: The proposed textural features are then used as the input of a classifier based on artificial neural networks. Classification performances of 93.1% specificity and 93.9% sensitivity are achieved on real data. These promising results open the path towards a deeper study regarding the applicability of this algorithm in computer aided diagnosis systems to assist physicians in their clinical practice.

Evaluation of Bone Remodeling in Hemodialysis Patients: Serum Biochemistry, Circulating Cytokines and Bone Histomorphometry

BACKGROUND: To optimize the noninvasive evaluation of bone remodeling, we evaluated, besides routine serum markers, serum levels of several cytokines involved in bone turnover. METHODS: A transiliac bone biopsy was performed in 47 hemodialysis patients. Serum levels of intact parathyroid hormone (iPTH; 1-84), total alkaline phosphatases (tAP), calcium, phosphate and aluminum (Al) were measured. Circulating levels of interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1Ra) and soluble IL-6 receptor (sIL-6r) were determined using ELISA. Circulating IL-1beta, IL-6, IL-8, IL-10, IL-12p70 and tumor necrosis factor-alpha (TNF-alpha) were simultaneously quantified by flow cytometric immunoassay. RESULTS: Patients with low/normal bone formation rate (L/N-BFR) had significantly lower serum iPTH (p<0.001) and tAP (p<0.008) and significantly higher Al (p<0.025) than patients with high BFR. Serum calcium and phosphorus, however, did not differ (p=NS). An iPTH >300 pg/mL in association with tAP >120 U/L showed low sensitivity (58.8%) and low negative predictive value (44.0%) for the diagnosis of high BFR disease. An iPTH <300 pg/mL in association with normal or low tAP, <120 U/L, was associated with low sensitivity (66.7%) but high specificity (97.1%) for the diagnosis of L/N-BFR. Serum IL-1, IL-6, IL-12p70 and TNF-alpha were positively correlated with BFR, serum IL1-Ra and IL-10 with bone area, and by multiple regression analysis, tAP and IL-6 were independently predictive of BFR. CONCLUSIONS: Significant associations were found between several circulating cytokines and bone histomorphometry in dialysis patients. The usefulness of these determinations in the noninvasive evaluation of bone remodeling needs to be confirmed in larger dialysis populations.

Borderline CD30+ Cutaneous Lymphoproliferative Disorder: Report of a Case with Expression of Cytotoxic Markers and Response to Clarithromycin

CD30+ cutaneous lymphoproliferative disorders (CLPDs) are usually characterized by a benign clinical course. The prognostic value of cytotoxic markers in these lymphomas has not been evaluated in large series. We describe a case of borderline CD30+ CLPD with cytotoxic phenotype, presenting in a 22-year-old male patient as an ulcer on the forearm. He reported having had similar ulcers on the buttock and thigh that spontaneously regressed over the course of 1 year. The lesion resolved with a single course of clarithromycin; a subsequent lesion, too, responded to clarithromycin, and no recurrences or systemic involvement have been documented in the 9-month follow-up. A conservative approach in the management of CD30+ CLPD is recommended. We believe that the anti-inflammatory and apoptotic effects of clarithromycin on T cells may have hastened the remission process.

Tumor Fibroso Localizado da Pleura: Análise de 11 Novos Casos

Pretende-se neste trabalho fazer uma revisão retrospectiva duma patologia, rara na sua incidência(5% de todos os tumores pleurais) e singular nas suas características, analisando na nossa casuística as formas de apresentação, terapêutica cirúrgica e resultados obtidos. Os tumores solitários da pleura são formações neoplásicas raras, cujo comportamento biológico não é obrigatoriamente correlacionável com características imuno-histoquímicas, pois os considerados benignos apresentam um sensível índice de recidiva e metastização, independentemente do volume que apresentam. A cirurgia é o único tratamento disponível e a excisão cirúrgica completa é decisiva para a cura. De Agosto de 1995 a Janeiro de 2003, na casuística do Serviço de Cirurgia Cardiotorácica do Hospital de Santa Marta, foram analisados todos os doentes com o diagnóstico de tumor fibroso localizado da pleura (TFLP). Neste contexto, identificaram-se 11 doentes com idade média de 57,54 anos, dos quais 6 do sexo feminino, em que foi colocado o diagnóstico de tumor fibroso localizado da pleura; 6 dos tumores foram classificados como malignos e 5 como benignos. Nesta série, todos os doentes foram submetidos a intervenção cirúrgica, com técnicas variadas, sem mortalidade intra-operatória ou morbilidade intra-hospitalar significativas, apesar da dificuldade da cirurgia nos tumores mais volumosos (um dos tumores pesava 2,5 kg). O follow up decorreu entre os 4 e os 84 meses (média – 39,4 meses). Um doente faleceu 13 meses após a intervenção, por embolia pulmonar maciça, depois de várias crises de tromboembolismo pulmonar (sem relação determinável com a cirurgia ou a patologia base), apesar da anticoagulação iniciada e controlada na Consulta do Hospital.

Blood Donation in the Hospital de S. José. A 11-Year Retrospective Analysis of Deferrals and Exclusions

Background: Approximately 5% of the population donates blood each year in developed countries. Recruiting and maintaining a pool of altruistic and healthy blood donors is a challenging task. Blood donation as a dynamic process must naturally co-exist with the arguably essential deferrals. Aims: To analyse a 11-year cohort of donors and blood donations in order to determine the profile of the average donor and the typical donation. Characterize the donor’s population in terms of gender, age, number of donations, most common causes for deferral and exclusion and the possible relationships between them. Establish the tendency flow of donations per year. Methods: Analysis of 95861 blood donations from 31550 donors collected between 2000 and 2010 (11 years) in the Immunohemotherapy Department of the ‘‘Centro Hospitalar Lisboa Central - Hospital de Sa˜o Jose´’’ (Lisboa, Portugal). Prior to blood donation, donors were required to fill out a form of informed consent, a questionnaire of 21 ‘‘yes or no’’ questions and were submitted to a clinical assessment and physical examination including: measurement of weight, blood pressure, pulse and capillary hemoglobin levels. Post-donation, the collected blood was tested for ALT elevation and blood-borne viral agents (HBV, HCV, HIV 1 and 2 and HTLV 1 and 2) and other infections (Treponema pallidum). Blood donors and donations were registered in a database and statistically studied in terms of: gender and age distribution, number of donations, most common causes for deferral and exclusion. The frequency of blood donations throughout the period of observation was analyzed and statistically significant relationships between the collected variables were investigated. Results: From the population of 31550 donors 61% were male and a mean age of 41.5 years (± 12.5 years) was found. From the total of 95682 blood donations collected 78% were successful while the most common causes for deferral were: donation incompatible hemoglobin levels (5% of the blood donations and 22% of deferrals), ALT elevation (3% and 14%), positive blood screening test for Treponema pallidum (1% and 6%), medication (1% and 4%), positive serological blood markers for HBV (1% and 4%), endoscopy in the previous 12 months (1% and 3%), arterial hypertension (1% and 3%), infectious conditions (1% and 3%), influenza or influenza-like symptoms (1% and 2%) and positive serological blood markers for HCV (1% and 2%). Summary/Conclusions: Several factors may have contributed to a limited number of new regular donors in the population, namely: ageing population, the alienation of the individual from the community induced by modern lifestyles and job precariousness. It is of the utmost importance to refine our blood donation campaigns according to the existing population of donors. The optimization of the blood donation potential of a population of donors must be achieved through the development of reliable and consistent screening methods. In order to appeal to new donors it is important to promote blood donations considering the profile of the regular and healthy blood donor of the existing population.

The HIF1A Functional Genetic Polymorphism at Locus +1772 Associates with Progression to Metastatic Prostate Cancer and Refractoriness to Hormonal Castration

The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.