A case series of urinary bladder rhabdomyosarcoma in seven dogs.

Background: Juvenile urinary bladder rhabdomyosarcoma (ubRMS) is a known entity; however, literature regarding its clinical behavior and endoscopic features is scarce. The aim of this study was to describe clinical and endoscopic features, and outcomes of ubRMS in dogs. Case Description: Dogs undergoing transurethral endoscopy and with a histological diagnosis of ubRMS were retrospectively collected. Seven dogs with a median age of 18 months (range 6-32 months) were included in this retrospective, multicenter, and descriptive study. Median tumor size was 58 mm (range 30-65 mm), and tumor location was bladder neck in three cases, trigone in two cases, and bladder body in two cases. Two dogs had monolateral ureteral obstruction. Two dogs presented with regional lymphadenopathy and one dog had lung lesions suggestive of metastatic disease. A grape-like mass was reported in four cases and solid in two, with variable consistency (two friables, two firms, and two not reported). Tumor treatments included surgery in three cases, surgery, and adjuvant doxorubicin in one case, and palliative therapy in three cases. The overall median survival time (ST) was 45 days. STs were shorter (range 20-45 days) for dogs treated with palliative care than for dogs treated with curative-intent treatment (range 70-120 days). Conclusion: ubRMS should be considered as a differential diagnosis in young dogs presenting with bladder masses. In this study, ubRMS confirmed its aggressive clinical behavior. Surgery and chemotherapy seem to increase STs but the prognosis remains poor.

Oral squamous cell carcinomas and oral potentially malignant disorders: A Latin American study.

OBJECTIVE: To determine the frequency of oral squamous cell carcinoma (OSCC) associated or not with oral potentially malignant disorders (OPMD), and the epidemiological profile and traditional risk factors in Latin America. METHODS: A retrospective observational study was conducted in 17 Latin American centres. There were included cases of OSCC, analysing age, gender, OSCC and their association with previous OPMD. Clinicopathological variables were retrieved. The condition of sequential-OSCC versus OSCC-de novo (OSCC-dn) was analysed concerning the aforementioned variables. Quantitative variables were analysed using Student's t-test, and qualitative variables with chi-square. RESULTS: In total, 2705 OSCC were included with a mean age of 62.8 years old. 55.8% were men. 53.75% of the patients were smokers and 38% were common drinkers. The lateral tongue border was the most affected site (24.65%). There were regional variations in OPMD, being leukoplakia the most frequent. Of the overall 2705 OSCC cases, 81.4% corresponded to OSCC-dn, while s-OSCC were 18.6%. Regarding lip vermillion SCC, 35.7% corresponded to de novo lip SCC and 64.3% were associated with previous OPMD. CONCLUSIONS: In Latin America, OSCC-dn seems to be more frequent with regional variations of some clinical and histopathological features. Further prospective studies are needed to analyse this phenomenon.

Alemtuzumab-Related Lymphocyte Subset Dynamics and Disease Activity or Autoimmune Adverse Events: Real-World Evidence.

BACKGROUND AND OBJECTIVES: alemtuzumab is a monoclonal anti-CD52 antibody acting on B and T cells in highly active multiple sclerosis (MS). We analyzed changes in lymphocyte subsets after alemtuzumab administration in relation to disease activity and autoimmune adverse events. METHODS: lymphocyte subset counts were assessed longitudinally using linear mixed models. Subset counts at baseline and during follow-up were correlated with relapse rate, adverse events, or magnetic resonance (MRI) activity. RESULTS: we recruited 150 patients followed for a median of 2.7 years (IQR: 1.9-3.7). Total lymphocytes, CD4, CD8, and CD20 significantly decreased in all patients over 2 years (p < 0.001). Previous treatment with fingolimod increased the risk of disease activity and adverse events (p = 0.029). We found a higher probability of disease reactivation in males and in patients with over three active lesions at baseline. Higher EDSS scores at baseline and longer disease duration predicted the switch to other treatments after alemtuzumab. DISCUSSION AND CONCLUSIONS: Our real-world study supports data from clinical trials in which lymphocyte subsets were not useful for predicting disease activity or autoimmune disease during treatment. The early use of an induction therapy such as alemtuzumab in patients with a lower EDSS score and short history of disease could mitigate the risk of treatment failure.

Usefulness of squash preparation cytology in the diagnosis of canine urinary bladder carcinomas.

BACKGROUND: Epithelial cells show varying degrees of cytologic atypia in dogs with nonmalignant lesions (NML) and carcinomas (ubC) of the bladder, making histopathologic examination necessary for a definitive diagnosis. OBJECTIVES: This study aimed to investigate the diagnostic performance of squash preparation cytology and identify several cytomorphologic features of ubC to assist in diagnoses. METHODS: Squash preparations were made and reviewed in dogs that underwent transurethral cystoscopy. The results were compared with histopathologic diagnoses. Two cytopathologists performed blinded assessments using a scoring system established for 11 cytologic features, including the presence of macronuclei, abnormal nucleoli, atypical mitoses, signet ring cells, multinucleated cells, nuclear molding, anisokaryosis, cytoplasmatic microvacuolization, cell arrangements, and neutrophil and lymphocyte infiltrations. Based on cytologic and histopathologic diagnoses, dogs were divided into ubC and NML groups. Associations between cytologic and histopathologic diagnoses were investigated, and agreement between the cytopathologists was calculated. Cytologic features were analyzed with multivariate logistic regression models. The performance of predictors in the final model was evaluated in terms of Sensitivity (Se), Specificity (Sp), accuracy, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio positive (LR+), and negative (LR-) values, and the diagnostic odds ratio (DOR). RESULTS: Forty-four dogs diagnosed with ubC, and 17 with NML were included in the study. Cytologic and histopathologic diagnoses were significantly associated with each cytopathologist. There was an almost perfect agreement between cytopathologists (κ = 0.88). The absence of neutrophilic infiltration, the presence of multinucleated cells, and nuclear molding were associated with ubC; using a combination of these features in parallel testing resulted in Se = 0.98, Sp = 0.65, accuracy = 0.89, PPV = 0.88, NPV = 0.92, LR + =2.77, LR- = 0.04, and DOR = 7.7. CONCLUSIONS: Squash preparation cytology could be a reliable technique to diagnose ubC in dogs. The best diagnostic combination was the absence of neutrophilic infiltration, multinucleated cells, and nuclear molding.

Oral Human Papillomavirus: a multisite infection

BACKGROUND: The Human Papillomavirus (HPV) has different strategies for persist in the cells. This characteristic has led us to consider the presence of the virus in tissues of the oral cavity that had no clinical signs of infection. The aim of this study was to detect the presence of DNA-HPV at multiple sites of the oral cavity. MATERIAL AND METHODS: A case-control study was designed: Oral Squamous Carcinoma Group (OSCG), healthy n=72 and Control Group (CG), n=72, healthy volunteers paired by sex and age with OSCG. Four samples were taken from OSCG: saliva, biopsy, brush scraping of lesion and contralateral healthy side. In CG a saliva sample and a scratch of the posterior border of tongue were collected. HPV was detected by PCR using Bioneer Accuprep genomic DNA Extraction kit, and consensus primers MY09 and MY11. Chi square test was applied. RESULTS: 432 samples were obtained from 144 individuals. DNA-HPV was detected in 30 (42%) of OSCG subjects and 3 (4%) of CG. Two or more positive samples were obtained in 67% of the OSCG, 67% in saliva and 60% in biopsy; in CG 100% of the individuals were positive in the two samples. CONCLUSIONS: HPV is frequently present in oral cavity as a multifocal infection, even without the presence of clinical lesions

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Sexually transmitted infections in oral cavity lesions: Human papillomavirus, Chlamydia trachomatis, and Herpes simplex virus.

Objective: Provide evidence of HPV, C. trachomatis, and HSV infection in the oral cavity from patients with different types of stomatological lesions. Materials and Methods: Oral swabs samples were collected from a total of 318 patients. The infectious agents were analyzed using the PCR technique. HPV genotyping and HSV type were studied using the RFLP method. Results: We studied 137 benign lesions (B), 96 potentially malignant disorders (PMD) and 85 oral squamous cell carcinomas (OSCC). The prevalence of HPV was 34%. The most frequently genotypes detected were 6 low risk and 16 high risk. The prevalence of C. trachomatis was 16% and HSV 3%. Co-infections were detected mostly in benign lesions as following: HPV-C. trachomatis in 4%, C. trachomatis- HSV in 1.8% and HPV-HSV in 0.3%. Conclusion: This report is the first contribution to the identification and genotype characterization of HPV in a scenario little studied in our area, and it also contributes to improving our understanding on sexually transmitted infectious agents and their associations with the oral cavity. Besides, we detect the presence of C. trachomatis and HSV and co-infection with HPV in the oral cavity, which they should be taken into account for diagnostic and treatment purposes.

Referência e contrarreferência no cotidiano da atenção à saúde de Divinópolis-MG, Brasil: o suporte às decisões da atenção primária / Reference and counter-reference in everyday health care in Minas Gerais,Brazil: the support to decisions of primary care / Referencia y contra-referencia en todos los días de cuidado de salud en Minas Gerais, Brasil: apoyo a las decisiones de la primaria

Objective: To understand, in the perception of professionals and managers of Primary Health Care (PHC), the reference and counter-reference system in health care and the support to decisions of APS professionals. Methods: Qualitative study, outlined by Holistic Multiple Case Study, based on Comprehensive Sociology of Everyday Life with 41 participants. Results: The support to decisions of APS professionals to direct users depends on the flow and regulation of the referenced demands; the waiting time for the user service; may be harmed by unnecessary and unreadable referrals and by the professionals’ view on the system. Conclusion: Health is a social process of collective construction, and it needs to win the welfare and curative paradigm, the excessive consumption of queries with a high rate of referrals.

Objetivo: Compreender, na percepção dos profissionais e gestores da Atenção Primária à Saúde (APS), o sistema de referência e contrarreferência na atenção à saúde e o suporte às decisões dos profissionais da APS. Métodos: Estudo qualitativo, delineado pelo Estudo de Casos Múltiplos Holísticos, fundamentado na Sociologia Compreensiva do Cotidiano com 41 participantes. Resultados: O suporte às decisões dos profissionais da APS ao encaminhar os usuários é dependente do fluxo e da regulação das demandas referenciadas; do tempo de espera do usuário para o atendimento; pode ser prejudicado pelos encaminhamentos desnecessários e ilegíveis e pela visão dos profissionais sobre o sistema. Conclusão: A Saúde é um processo social, de construção coletiva, e que precisa vencer o paradigma assistencialista e curativista, o consumo excessivo de consultas com elevado índice de encaminhamentos.

Objetivo: Comprender, en la percepción de los profesionales y directivos de Atención Primaria de Salud (APS), el sistema de referencia y contrarreferencia en la atención de salud y el apoyo a las decisiones de los profesionales de APS. Métodos: Estudio cualitativo, esbozado por Estudio de Casos Múltiples Holísticos, basado en la Sociología Comprensiva del Cotidiano con 41 participantes. Resultados: El apoyo a las decisiones de los profesionales de APS a los usuarios directos depende del flujo y la regulación de las exigencias que se hace referencia; el tiempo de espera del servicio para el usuario; pueden ser perjudicados por referencias innecesarias y ilegibles y por los puntos de vista de los profesionales en el sistema. Conclusión: La salud es un proceso social de construcción colectiva, y que necesita ganar el paradigma del bienestar y curativa, el consumo excesivo de consultas con una alta tasa de remisión.

Contos infantojuvenis: uma prática lúdica de humanização para crianças hospitalizadas / Cuentos infantiles: una práctica lúdica de humanización para niñoshospitalizados / Children's and juvenile tales: a playful practice of humanization for hospitalized children

Objetivo: compreender as reações das crianças hospitalizadas e de suas famílias ao ouvirem histórias infantis durante a execução do projeto de extensão e pesquisa: “Contos infantojuvenis: uma interface com a humanização do cuidado na hospitalização”. Método: estudo descritivo e qualitativo usando o método observacional. Participaram do estudo 12 crianças hospitalizadas e suas famílias. Os dados foram coletados por meio da observação participante e registros de campo; em seguida, foram analisados fazendo emergir três categorias. Resultados: houve a evidência de que as crianças apresentam diferentes reações ao ouvir as histórias como mudança no humor, na postura corporal e facial. Além disso, notou-se que a família da criança hospitalizada valoriza essa prática lúdica como um momento de alegria e entusiasmo. Conclusões: o estudo revela a necessidade de práticas lúdicas que humanizem o ambiente pediátrico e auxiliem a criança e sua família na hospitalização.

Objective: to understand the reactions of hospitalized children and their families as they listen to children's stories during the activities of the research and extension project: "Children’s and Juvenile Tales: an interface with the humanization of care in hospital". Method: this is a descriptive and qualitative study which used the observational method. Twelve children in hospital and their families participated in the study. Data were collected from participant observation and field record and then analyzed, giving rise to three categories. Results: there was evidence that children have different reactions while listening to the stories, such as changes in mood, body language and facial expressions. Furthermore, it was noticed that the hospitalized child’s family appreciates this playful practice as a moment of joy and enthusiasm. Conclusions: the study reveals the need for playful practices that humanize the pediatric environment and assist the child and their family in the hospitalization.

Objetivo: comprender las reacciones de los niños hospitalizados y sus familias al escuchar historias infantiles durante la ejecución del proyecto de investigación y extensión universitaria: "Cuentos infantiles: una interfaz con la humanización de la atención en la hospitalización." Método: estudio descriptivo y cualitativo utilizando elmétodo de observación. Participaron en el estudio 12 niños hospitalizados y sus familias. Los datos fueron recolectados a través de observación participante y registro de campo; luego fueron analizados, surgiendo tres categorías. Resultados: hubo evidencia de que los niños tienen diferentes reacciones a escuchar las historias como cambios en el estado de ánimo, en la postura corporal y facial. Además, se notó que la familia del niño hospitalizado valora esta práctica lúdica como un momento de alegría y entusiasmo. Conclusiones: el estudio revela la necesidad de prácticas lúdicas que humanicen el entorno pediátrico y apoyen a los niños y familias en la hospitalización.

Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology.

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.

p57(Kip2) and cancer: time for a critical appraisal.

p57(Kip2) is a cyclin-dependent kinase inhibitor belonging to the Cip/Kip family, which also includes p21(Cip1) and p27(Kip1). So far, p57(Kip2) is the least-studied Cip/Kip protein, and for a long time its relevance has been related mainly to its unique role in embryogenesis. Moreover, genetic and molecular studies on animal models and patients with Beckwith-Wiedemann syndrome have shown that alterations in CDKN1C (the p57(Kip2) encoding gene) have functional relevance in the pathogenesis of this disease. Recently, a number of investigations have identified and characterized heretofore unexpected roles for p57(Kip2). The protein appears to be critically involved in initial steps of cell and tissue differentiation, and particularly in neuronal development and erythropoiesis. Intriguingly, p27(Kip1), the Cip/Kip member that is most homologous to p57(Kip2), is primarily involved in the process of cell cycle exit. p57(Kip2) also plays a critical role in controlling cytoskeletal organization and cell migration through its interaction with LIMK-1. Furthermore, p57(Kip2) appears to modulate genome expression. Finally, accumulating evidence indicates that p57(Kip2) protein is frequently downregulated in different types of human epithelial and nonepithelial cancers as a consequence of genetic and epigenetic events. In summary, the emerging picture is that several aspects of p57(Kip2)'s functions are only poorly clarified. This review represents an appraisal of the data available on the p57(Kip2) gene and protein structure, and its role in human physiology and pathology. We particularly focus our attention on p57(Kip2) changes in cancers and pharmacological approaches for modulating p57(Kip2) levels.

Targeting p27Kip1 protein: its relevance in the therapy of human cancer.

INTRODUCTION: Cell division cycle progression is achieved by a sequential and stringently concerted activation of a family of serine-threonine kinases, namely the cyclin-dependent kinases (CDKs). p27(Kip1) is a pivotal CDK inhibitor and a tight modulator of CDK-dependent phenotypes. Thus, p27(Kip1) plays a fundamental role in key cellular processes such as proliferation, differentiation, apoptosis, substrate adhesion and motility. Intriguingly, when p27(Kip1) is localized in the nucleus, it acts as an antiproliferative protein, while, in the cytosol, p27(Kip1) promotes cytoskeleton remodeling and might positively influence metastatization. Downregulation of p27(Kip1) nuclear level or its cytosolic mislocalization are consistently correlated with poor prognosis of numerous types of human epithelial and non-epithelial cancers. AREAS COVERED: This review illustrates the basic structural features of p27(Kip1) protein, its metabolism and alterations in human malignancies, along with describing anticancer strategies based on targeting p27(Kip1). EXPERT OPINION: Given the role of p27(Kip1) in the control of cell proliferation and its decreased level observed in malignancies with poor outcome, drugs able to handle the protein levels and localization might represent an important goal for novel specific and effective anticancer strategies. Although no convincing proofs have been reported, putative negative consequences of p27(Kip1) targeting might be also conceivable.

Dermatitis Atópica: aspectos clínicos y asociación con alergenos e hipersensibilidad de contacto / Atopic dermatitis: clinical aspects and its association with allergens and contact hipersensibility

La Dermatitis Atópica (DA), es una enfermedad de la piel bien definida clínicamente, con predisposición genética y decarácter crónico-recidivante, que se asocia a menudo con otros desordenes atópicos, como rinitis y asma. Numerosos factoresdel medio ambiente: aeroalergenos, alergenos de contacto, alimentos e infecciones juegan un importante rol en laaparición y mantenimiento de los síntomas. Se estudiaron 15 niños y 41 adultos, los síntomas relevantes fueron lesionesflexurales, prurito, xerosis e infecciones dérmicas y en los niños queratosis folicular. Niños: 67% se asociaron con enfermedadrespiratoria e iniciaron los síntomas junto o después de la DA. Los aeroalergenos involucrados fueron polvo decasa, dermatophagoides mezcla, polen de gramíneas, aspergillus y alternaria. Entre los alimentos: tomate, chocolate, cítricosy huevo fueron relevantes. El 27% mostró infecciones dérmicas. Adultos: 64% tenían enfermedad respiratoria. Soloel 20% inicio los síntomas respiratorios antes de los síntomas dérmicos. El total de los pacientes testificados presentaronresultados positivos para uno o mas aeroalergenos siendo los principales: dermatophagoides mezcla, polvo de casa, alternaria,aspergillus, cladosporium, pólenes de árboles mezcla, gramíneas, ambrosia, amarantáceas, chenopodiaceas, epiteliode perro, epitelio de gato. El 35% fue positivo a alimentos y el 37% mostró infecciones dérmicas. Asociación conhipersensibilidad de contacto: el 48% de esta población presentó síntomas de Dermatitis de Contacto (DC), el 80% delos mismos refirió intolerancia al níquel. Se efectuaron parches cutáneos en 12 pacientes adultos, resultando positivos en9 de ellos, lo cual representa que un 22% de la población adulta presenta hipersensibilidad de contacto.

Atopic dermatitis is a clinically well defined, chronic - intermitant, genetically predisposed skin disease, it is regularlyassociated with other allergic disorders such as asthma and rhinitis. Many environmental factors, aeroallergens, contactallergens, foods and infections are playing an important role in triggering and sustaining the disease. 15 children and41 adults were studied. Classics symptoms as: flexural dermatitis, itching, dry skin, and follicle queratoses were relevant,In children: 67% associated with respiratory disease, and started their respiratory symptoms together or right after theonset of atopic dermatitis. Aeroallergens involved were: house dust mite, Dermatophagoides mix, Aspergillus spp, grasspollen, and Alternaria. In addition these patients had sensitivity to foods allergens such as tomato, cocoa, citric fruits,and egg. 27% also showed skin infections. In adults: 64% had respiratory disease. Only 20% presents respiratory diseaseprevious to atopic dermatitis. All patients had positive to at least one of the aeroallergens tested. The most importantallergens were:Dermatophagoides mix, house dust mite, Alternaria, Aspergillus spp, Cladosporium, tree pollen, grasspollen, ragweed, amaranthus spp, chenopodium, dog dander and cat dander. 35% of the patients had positive prick teststo food allergens, and 37% of them also showed skin infections. Association with contact hipersensibility: 48% of thestudy population had symptoms of contact dermatitis, Patch Test was performed in 12 adults patients, only 9 patientsof them had positive test, which represent 22 % of the adult population with contact hipersensibility.

Histone deacetylase inhibitors upregulate p57Kip2 level by enhancing its expression through Sp1 transcription factor.

Histone deacetylase inhibitors (HDACIs) represent a new class of targeted anticancer agents. Here, we evaluate the effects of butyrate (BuA) and other HDACIs on p57(Kip2), a cyclin-dependent kinase inhibitor (cki). We observed that inhibitors of class I/II histone deacetylases (HDACs), but not of class III HDACs, induce a remarkable accumulation of p57(Kip2) in several cells. The cki upregulation is associated with an increased gene expression that was not prevented by cycloheximide, indicating that HDACIs affect directly p57(Kip2) transcription. The characterization of p57(Kip2) promoter indicates that the first 165 bp are mostly involved in the BuA effects. Chromatin immunoprecipitation studies demonstrated that the BuA treatment causes the recruitment of Sp1 transcription factor. The Sp1 importance was confirmed by the reduction of BuA effects by mithramycin A (an Sp1 antagonist) and, most stringently, by Sp1 downregulation due to Sp1 siRNA. Moreover, both the treatments reduce the p57(Kip2) transcription in untreated cells, suggesting that Sp1 is required for the constitutive cki expression. Studies employing plasmids containing parts of the 165 bp of p57(Kip2) promoter indicate that the promoter region between -87 and -113 bp, which includes two putative Sp1 consensus sequences, plays a critical role in the response to HDACIs. Since this p57(Kip2) promoter region also embraces the consensus sequence for the transcriptional repressor chicken ovalbumin upstream promoter transcription factor-interacting protein 2 (CTIP2), we evaluated whether this factor is involved into the BuA effect. When CTIP2 was downregulated by a specific siRNA, we observed the enhancement of BuA activity on p57(Kip2) expression suggesting that CTIP2 might also be involved in HDACIs effects.

Retinoic acid induces p27Kip1 nuclear accumulation by modulating its phosphorylation.

All-trans-retinoic acid (ATRA), the most biologically active metabolite of vitamin A, controls cell proliferation, apoptosis, and differentiation depending on the cellular context. These activities point to ATRA as a candidate for cancer therapy. A pivotal effect of the molecule is the modulation of p27Kip1, a cyclin-dependent kinase (CDK) inhibitor (CDKI). Here, we investigate the mechanisms by which ATRA regulates p27Kip1 level in LAN-5, a neuroblastoma cell line. When added to the cells, ATRA causes a rapid nuclear increase of p27Kip1, which clearly precedes growth arrest. The early buildup is not due to impairment of the CDKI degradation, in contrast to previous observations. Particularly, we did not detect the down-regulation of Skp2 and Cks1, two proteins involved in the nuclear ubiquitin-dependent p27Kip1 removal. Moreover, the morphogen does not impair the CDKI nuclear export and does not cause CDK2 relocalization. The characterization of CDKI isoforms by two-dimensional PAGE/immunoblotting showed that ATRA induces an early nuclear up-regulation of monophosphorylated p27Kip1. Immunologic studies established that this isoform corresponds to p27Kip1 phosphorylated on S10. The buildup of phospho(S10)p27Kip1 precedes the CDKI accumulation and increases its half-life. Finally, ATRA-treated nuclear LAN-5 extracts showed an enhanced capability of phosphorylating p27Kip1 on S10, thus explaining the nuclear up-regulation of the isoform. In conclusion, our data suggest a novel mechanism of ATRA antiproliferative activity, in which the morphogen rapidly up-regulates a nuclear kinase activity that phosphorylates p27Kip1 on S10. In turn, this event causes the stabilization of p27Kip1 and its accumulation in the nuclear compartment.

Sialometaplasia Necrotizante: Presentación de cinco casos clínicos / Necrotizing sialometaplasia: Report of five cases

La sialometaplasia necrotizante (SN) es una afección inflamatoria, autoresolutiva, que afecta a las glándulas salivales, más frecuentemente a las menores. Si bien su etiopatogenia permanece aún desconocida, diversos autores sugieren que una agresión fisico-química o biológica sobre los vasos sanguíneos produciría isquemia, la cual conduciría al infarto de la glándula y su posterior necrosis. Su aspecto clínico e histológico tiene apariencias de malignidad. Clínicamente puede presentarse como una úlcera de bordes irregulares, ligeramente elevados y lecho necrótico, mientras que histopatológicamente se caracteriza por presentar metaplasia escamosa de conductos y acinos e hiperplasia pseudoepiteliomatosa del epitelio mucoso, características éstas que pueden inducir a un diagnóstico incorrecto de neoplasia maligna anexial. Es fundamental realizar un correcto diagnóstico a los efectos de evitar tratamientos quirúrgicos mutilantes, debido a que se trata de una patología autoresolutiva. En el presente trabajo se describen cinco casos de (SN) en pacientes de sexo femenino, ubicados en glándulas salivales menores del paladar (AU)

Necrotizing sialometaplasia (NS) is a self-limiting inflammatory disease, that involves salivary glands, more frequently the minor ones. Although its etiopathogenesis remains still unknown some authors suggest that a physicochemical or biological injury on the blood vessels may produce ischemic changes, leading to infarction of the gland and its further necrosis. Its clinical and histologic feature resemble malignancy. Clinically it may appear like an ulcer with slightly elevated irregular borders and necrotic base. Histologic features are squamous metaplasia of ducts and acini and a pseudoepitheliomatous hyperplasia of the overlying mucosa. These characteristics may induce to an inapropiated diagnosis of malignant neoplasia. A correct diagnosis to avoid mutilant surgical treatments is essential, considering that it is a self-limiting disease. In this report we describe five cases of NS in females, located in minor glands of the palate (AU)

Necrotizing sialometaplasia: report of five cases.

Necrotizing sialometaplasia (NS) is a self-limiting inflammatory disease, that involves salivary glands, more frequently the minor ones. Although its etiopathogenesis remains still unknown some authors suggest that a physico-chemical or biological injury on the blood vessels may produce ischemic changes, leading to infarction of the gland and its further necrosis. Its clinical and histologic feature resemble malignancy. Clinically it may appear like an ulcer with slightly elevated irregular borders and necrotic base. Histologic features are squamous metaplasia of ducts and acini and a pseudoepitheliomatous hyperplasia of the overlying mucosa. These characteristics may induce to an inapropiated diagnosis of malignant neoplasia. A correct diagnosis to avoid mutilant surgical treatments is essential, considering that it is a self-limiting disease. In this report we describe five cases of NS in females, located in minor glands of the palate.

[Expression of leukocytic adhesion molecules in a patient with common variable immunodeficiency]. / Expresión de las moléculas de adhesión leucocitaria en un paciente con inmunodeficiencia variable común.

BACKGROUND: Common variable immunodeficiency is one of the main antibodies' deficiency syndromes. OBJECTIVE: To present the immunological study of a 29-year-old patient with common variable immunodeficiency who assisted to a check-up after being four years without treatment with gammaglobuline. MATERIAL AND METHODS: We studied a sample of peripheral blood and saliva of a patient with common variable immunodeficiency and that of a healthy patient (control). Assessment of immunoglobulin G, immunoglobulin A and immunoglobuin M was performed by a simple radial immunodiffusion test, and immunoglobulin E by immunoassay. Immunophenotypic study of leukocytic subpopulations was done by citometry by using the following panel of monoclonal antibodies: CD3 (Leu-4), CD4 (Leu-3a), CD8 (Leu-2a), CD19 (Leu-12), CD14 (Leu-M3), CD11a (LFA-I), CD49d (VLA-4), CD54 (ICAM-1), CD31 (PECAM). RESULTS: It was found a significant reduction in most of the serum and secretory immunoglobulins, levels of unusual expression of integrines CD11a and CD31 in lymphocytes T related to the low percentage of activated lymphocytes T/memory.

Caspase 3 and 8 deficiency in human neuroblastoma.

An altered apoptotic response represents a pivotal feature of cancer and is involved in cancerogenesis and resistance to chemotherapy. So far, however, only a few studies have been devoted to survey caspase content in malignant cell lines and primary tumor specimens. In this report, we investigated the expression of two pivotal caspases, 3 and 8, in 63 neuroblastoma specimens by three complementary techniques (i.e., reverse transcriptase polymerase chain reaction, immunoblotting, and immunohistochemistry). We confirmed the frequent absence of caspase 8 expression. Moreover and most important, we demonstrated, for the first time to our knowledge, that a significant percentage of neuroblastomas lack caspase 3 mRNA and protein. Both caspase alterations do not show any correlation with tumor stage and MYCN status. Immunohistochemistry showed a large number of caspase-negative cell islets also present in positive samples. Our findings suggest that the absence of caspases might play an important role in neuroblastoma development and resistance to apoptosis-based treatments.

Spectrum of FANCA mutations in Italian Fanconi anemia patients: identification of six novel alleles and phenotypic characterization of the S858R variant.

Fanconi anemia (FA) is an autosomal recessive disorder characterized by genomic instability, bone marrow failure, congenital malformations, and cancer predisposition. FA is a genetically heterogeneous disease with at least seven genes so far identified. The role of FA proteins is unknown although they interact in a common functional pathway. Here, we report six novel FANCA sequence changes and review all the mutations identified in Italy. Except for two missense substitutions, all are expected to cause a premature termination of the FANCA protein at various sites throughout the molecule. The premature terminations are due to nonsense and splice site mutations, as well as small insertions and deletions, and large genomic rearrangements. The expected truncated proteins were not detectable on Western blot analyses. The FANCA-S858R variant is instead expressed at lower level than that seen in normal cell lines and is associated with a non-ubiquinated FANCD2 protein, strongly suggesting that the amino acid substitution is a disease-causing mutation. The spectrum of FA mutations is widely in agreement with the heterogeneous ethnic origin of the Italian population.

Retinoic acid inhibits the growth of bone marrow mesenchymal stem cells and induces p27Kip1 and p16INK4A up-regulation.

The importance of bone marrow mesenchymal stem cells in hemopoiesis has been definitely demonstrated. Thus, their impairment might cause profound alteration on production and maturation of blood cells. In the present paper, we investigated, for the first time, the effect of retinoic acid, an important antileukemic molecule, on the proliferation of primary cultures of human bone marrow mesenchymal stem cells. We demonstrated that retinoic acid, at a pharmacological concentration, hampers strongly the growth of the cells, without inducing osteoblastic differentiation. The analysis of cell division cycle machinery showed that the antiproliferative effect is associated with (i) the up-regulation of two cyclin-dependent kinase inhibitors, namely p27Kip1 and p16INK4A, and (ii) the down-regulation of cyclin-dependent kinase 2 activity and pRB phosphorylation. The reported findings represent novel insights into the antileukemic effects of the drug and contribute in clarifying the molecular mechanism of its pharmacological activity.