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Summary: Diabetic mastopathy (MD) was described for the first time in 1984 by Soler and Khardori, in insulin-dependent patients with type I diabetes, representing 1% of benign mastopathy. The clinical-imaging presentation raises carcinomas or benign lesions such as fibroadenomas as the main differential diagnoses, for which excisional biopsy is the treatment of choice. The communication of this case aims to highlight the importance of the differential diagnosis of this low incidence breast disease entity whose etiology is systemic. This is a 45-year-old patient, native from Córdoba capital, taxi driver, with a toxic history of smoking and alcoholism; Personal pathological history of type I diabetes treated with NPH insulin and good glycemic controls. She consulted due to the presentation of a right breast phlogotic erythematous tumor of 40 days of evolution. She had undergone antibiotic treatment for two weeks, without obtaining a response. A mammogram was performed in the right breast, finding a radiopaque area with diffuse lobulated edges that caused retraction of the nipple and frank skin thickening, with a proliferative appearance (BIRADS classification V). An incisional biopsy and drainage are performed, indicating hospitalization and combined antibiotic treatment (clindamycin + gentamicin). It evolves favorably and subsequently a pathological anatomy report is received. In the macroscopy, four irregularly shaped tissue fragments of approximately 2x1 cm are observed, which present a whitish color and firm consistency in the cut. Histopathology reports slices processed with standard techniques and stained with H-E exhibiting in the breast tissue dense stroma, prominent hyaline bundles of collagen, blood vessels with thickened hyaline walls, which produce lumen stenosis. There is an important mononuclear inflammatory infiltrate, neutrophil polymorphonuclear leukocytes and histiocytes, ducts with epithelial cells reactive to the inflammatory process, and areas of necrosis and skin with polymorphonuclear leukocytes in transepithelial migration. This findings described are linked to diabetic mastopathy / acute nonspecific mastitis. The clinical case, highlights the fact that when we are faced with a clinical-imaging lesion suggestive of malignancy, it is essential to always consider the clinical context, because despite its low prevalence, DM is an entity to consider, especially in patients with a history of type diabetes I.Resumen:  La mastopatía diabética (MD) fue descripta por primera vez en 1984 por Soler y Khardori, en pacientes insulinodependientes con diabetes tipo I, representando el 1% de la mastopatía benigna. La presentación clínico-imagenológica plantea como principales diagnósticos diferenciales a carcinomas o lesiones benignas tales como los fibroadenomas, por lo cual la biopsia escisional es el tratamiento de elección. La comunicación del presente caso pretende destacar la importancia del diagnóstico diferencial de esta entidad patológica mamaria de baja incidencia cuya etiología es sistémica. Se trata de una paciente de 45 años de edad, oriunda de Córdoba capital, taxista,  con antecedentes tóxicos de tabaquismo y etilismo; antecedentes personales patológicos diabetes tipo I tratada con insulina NPH y buenos controles glucémicos. Consulta por guardia central por presentar en mama derecha, tumoración eritematosa flogótica de 40 días de evolución. Había realizado tratamiento antibiótico con amoxicilina-ácido clavulánico durante dos semanas, sin obtener respuesta. Se realiza mamografía encontrándose en mama derecha, área radiopaca de bordes difusos lobulados que provoca retracción del pezón y franco engrosamiento cutáneo, de aspecto proliferativo (clasificación BIRADS V). Se realiza biopsia incisional, drenaje, indicandose internación y tratamiento antibiótico combinado (clindamicina+gentamicina). Evoluciona favorablemente y posteriormente se recibe informe de anatomía patológica. En la macroscopia se observan cuatro fragmentos de tejido de forma irregular de aproximadamente 2x1 cm, los cuales presentan al corte colorido blanquecino y consistencia firme. La histopatología informa cortes procesados con técnicas habituales y coloreados con H&E,  que exhiben en el tejido mamario estroma denso, haces hialinos prominentes de colágeno, vasos sanguíneos de paredes hialinas engrosadas, las cuales producen estenosis de la luz. Se observa importante infiltrado inflamatorio mononuclear, leucocitos polimorfonucleares neutrófilos e histiocitos, conductos con células epiteliales reactivas al proceso inflamatorio y áreas de necrosis. Piel con leucocitos polimorfonucleares en migración transepitelial. Los hallazgos descriptos son vinculables a Mastopatía diabética/mastitis aguda inespecífica. El caso clínico expuesto, destaca que ante una lesión clínico-imagenológica sugestiva de malignidad, resulta fundamental considerar siempre el contexto clínico ya que a pesar de su baja prevalencia, la MD es una entidad a considerar, sobre todo en pacientes con antecedentes de diabetes tipo I.

Tumor BRCA Test for Patients with Epithelial Ovarian Cancer: The Role of Molecular Pathology in the Era of PARP Inhibitor Therapy

The PARP inhibitor olaparib has been approved in the maintenance setting of platinum-sensitive epithelial ovarian cancer patients with germline or somatic BRCA1/2 mutation. Therefore, the availability of a tumor BRCA test has become a clinical need. We report the results of the clinical implementation of a tumor BRCA test within the frame of an institutional workflow for the management of patients with nonmucinous and nonborderline epithelial ovarian cancer. In total, 223 patients with epithelial ovarian cancer were prospectively analyzed. BRCA1/2 status was evaluated on formalin-fixed, paraffin-embedded tumor specimens using next-generation sequencing technology. The tumor BRCA test had a success rate of 99.1% (221 of 223 successfully analyzed cases) and a median turnaround time of 17 calendar days. Among the 221 cases, BRCA1 or BRCA2 pathogenic/likely pathogenic mutations were found in 62 (28.1%) cases and variants of uncertain significance in 25 (11.3%) cases. The concordance rate between tumor BRCA test results and germline BRCA1/2 status was 87%, with five cases harboring pathogenic/likely pathogenic somatic-only mutations. The next-generation, sequencing-based tumor BRCA test showed a high success rate and a turnaround time compatible with clinical purposes. The tumor BRCA test could be implemented in a molecular diagnostic setting and it may guide the clinical management of patients with epithelial ovarian cancer

T Cell Therapy for Nasopharyngeal Carcinoma

Among the novel biologic therapeutics that will increase our ability to cure human cancer in the years to come, T cell therapy is one of the most promising approaches. However, with the possible exception of tumor-infiltrating lymphocytes therapy for melanoma, clinical trials of adoptive T-cell therapy for solid tumors have so far provided only clear proofs-of-principle to build on with further development. Epstein-Barr virus (EBV)-associated malignancies offer a unique model to develop T cell-based immune therapies, targeting viral antigens expressed on tumor cells. In the last two decades, EBV-specific cytotoxic T-lymphocytes (CTL) have been successfully employed for the prophylaxis and treatment of EBV-related lymphoproliferative disorders in immunocompromised hosts. More recently, this therapeutic approach has been applied to the setting of EBV-related solid tumors, such as nasopharyngeal carcinoma. The results are encouraging, although further improvements to the clinical protocols are clearly necessary to increase anti-tumor activity. Promising implementations are underway, including harnessing the therapeutic potential of CTLs specific for subdominant EBV latent cycle epitopes, and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells

Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies.

Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric disorders, including schizophrenia and attention-deficit/hyperactivity disorder. Consistently, SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. We analysed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and electroencephalogram (EEG) abnormalities. The functional effects of rs363050 single-nucleotide polymorphism (SNP) on the gene transcriptional activity, by means of the luciferase reporter gene, were evaluated. To investigate the functional consequences that SNAP-25 reduction may have in children, the behaviour and EEG of SNAP-25(+/-) adolescent mice (SNAP-25(+/+)) were studied. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25(+/-) hippocampi was also observed by means of western blotting. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice. VLP treatment could result in novel therapeutic strategies

A Functional Variant in ERAP1 Predisposes to Multiple Sclerosis

The ERAP1 gene encodes an aminopeptidase involved in antigen processing. A functional polymorphism in the gene (rs30187, Arg528Lys) associates with susceptibility to ankylosying spondylitis (AS), whereas a SNP in the interacting ERAP2 gene increases susceptibility to another inflammatory autoimmune disorder, Crohn's disease (CD). We analysed rs30187 in 572 Italian patients with CD and in 517 subjects suffering from multiple sclerosis (MS); for each cohort, an independent sex- and age-matched control group was genotyped. The frequency of the 528Arg allele was significantly higher in both disease cohorts compared to the respective control population (for CD, OR = 1.20 95%CI: 1.01–1.43, p = 0.036; for RRMS, OR = 1.26; 95%CI: 1.04–1.51, p = 0.01). Meta-analysis with the Wellcome Trust Cases Control Consortium GWAS data confirmed the association with MS (pmeta = 0.005), but not with CD. In AS, the rs30187 variant has a predisposing effect only in an HLA-B27 allelic background. It remains to be evaluated whether interaction between ERAP1 and distinct HLA class I alleles also affects the predisposition to MS, and explains the failure to provide definitive evidence for a role of rs30187 in CD. Results herein support the emerging concept that a subset of master-regulatory genes underlay the pathogenesis of autoimmunity

Expression of a Constitutively Active Calcineurin Encoded by an Intron-Retaining mRNA in Follicular Keratinocytes

Hair growth is a highly regulated cyclical process. Immunosuppressive immunophilin ligands such as cyclosporin A (CsA) and FK506 are known as potent hair growth modulatory agents in rodents and humans that induce active hair growth and inhibit hair follicle regression. The immunosuppressive effectiveness of these drugs has been generally attributed to inhibition of T cell activation through well-characterized pathways. Specifically, CsA and FK506 bind to intracellular proteins, principally cyclophilin A and FKBP12, respectively, and thereby inhibit the phosphatase calcineurin (Cn). The calcineurin (Cn)/NFAT pathway has an important, but poorly understood, role in the regulation of hair follicle development. Here we show that a novel-splicing variant of calcineurin Aß CnAß-FK, which is encoded by an intron-retaining mRNA and is deficient in the autoinhibitory domain, is predominantly expressed in mature follicular keratinocytes but not in the proliferating keratinocytes of rodents. CnAß-FK was weakly sensitive to Ca2+ and dephosphorylated NFATc2 under low Ca2+ levels in keratinocytes. Inhibition of Cn/NFAT induced hair growth in nude mice. Cyclin G2 was identified as a novel target of the Cn/NFATc2 pathway and its expression in follicular keratinocytes was reduced by inhibition of Cn/NFAT. Overexpression of cyclin G2 arrested the cell cycle in follicular keratinocytes in vitro and the Cn inhibitor, cyclosporin A, inhibited nuclear localization of NFATc2, resulting in decreased cyclin G2 expression in follicular keratinocytes of rats in vivo. We therefore suggest that the calcineurin/NFAT pathway has a unique regulatory role in hair follicle development

Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

Proteolytic cleavage of the Na(+)/Ca(2+) exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca(2+) dynamics, calpain activation and cell viability, in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. Selective overactivation of AMPA receptors caused the reversal of the NCX, which accounted for approximately 30% of the rise in intracellular free calcium concentration ([Ca(2+)](i)). The NCX reverse-mode inhibitor, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943), partially inhibited the initial increase in [Ca(2+)](i), and prevented a delayed increase in [Ca(2+)](i). In parallel, overactivation of AMPA receptors strongly activated calpains and led to the proteolysis of NCX3. KB-R7943 prevented calpain activation, cleavage of NCX3 and was neuroprotective. Silencing of NCX3 reduced Ca(2+) uptake, calpain activation and was neuroprotective. Our data show for the first time that NCX reversal is an early event following AMPA receptor stimulation and is linked to the activation of calpains. Since calpain activation subsequently inactivates NCX, causing a secondary Ca(2+) entry, NCX may be viewed as a new suicide substrate operating in a Ca(2+)-dependent loop that triggers cell death and as a target for neuroprotectio

Genetic Epidemiology of Glioblastoma Multiforme: Confirmatory and New Findings from Analyses of Human Leukocyte Antigen Alleles and Motifs

Human leukocyte antigen (HLA) class I genes mediate cytotoxic T-lymphocyte responses and natural killer cell function. In a previous study, several HLA-B and HLA-C alleles and haplotypes were positively or negatively associated with the occurrence and prognosis of glioblastoma multiforme (GBM).As an extension of the Upper Midwest Health Study, we have performed HLA genotyping for 149 GBM patients and 149 healthy control subjects from a non-metropolitan population consisting almost exclusively of European Americans. Conditional logistic regression models did not reproduce the association of HLA-B*07 or the B*07-Cw*07 haplotype with GBM. Nonetheless, HLA-A*32, which has previously been shown to predispose GBM patients to a favorable prognosis, was negatively associated with occurrence of GBM (odds ratio=0.41, p=0.04 by univariate analysis). Other alleles (A*29, A*30, A*31 and A*33) within the A19 serology group to which A*32 belongs showed inconsistent trends. Sequencing-based HLA-A genotyping established that A*3201 was the single A*32 allele underlying the observed association. Additional evaluation of HLA-A promoter and exon 1 sequences did not detect any unexpected single nucleotide polymorphisms that could suggest differential allelic expression. Further analyses restricted to female GBM cases and controls revealed a second association with a specific HLA-B sequence motif corresponding to Bw4-80Ile (odds ratio=2.71, p=0.02).HLA-A allelic product encoded by A*3201 is likely to be functionally important to GBM. The novel, sex-specific association will require further confirmation in other representative study populations