The Role of WRAP53 in Cell Homeostasis and Carcinogenesis Onset.

The WD repeat containing antisense to TP53 (WRAP53) gene codifies an antisense transcript for tumor protein p53 (TP53), stabilization (WRAP53α), and a functional protein (WRAP53ß, WDR79, or TCAB1). The WRAP53ß protein functions as a scaffolding protein that is important for telomerase localization, telomere assembly, Cajal body integrity, and DNA double-strand break repair. WRAP53ß is one of many proteins known for containing WD40 domains, which are responsible for mediating a variety of cell interactions. Currently, WRAP53 overexpression is considered a biomarker for a diverse subset of cancer types, and in this study, we describe what is known about WRAP53ß's multiple interactions in cell protein trafficking, Cajal body formation, and DNA double-strand break repair and its current perspectives as a biomarker for cancer.

Kinase Inhibition in Multiple Myeloma: Current Scenario and Clinical Perspectives.

Multiple myeloma (MM) is a blood cell neoplasm characterized by excessive production of malignant monoclonal plasma cells (activated B lymphocytes) by the bone marrow, which end up synthesizing antibodies or antibody fragments, called M proteins, in excess. The accumulation of this production, both cells themselves and of the immunoglobulins, causes a series of problems for the patient, of a systemic and local nature, such as blood hyperviscosity, renal failure, anemia, bone lesions, and infections due to compromised immunity. MM is the third most common hematological neoplasm, constituting 1% of all cancer cases, and is a disease that is difficult to treat, still being considered an incurable disease. The treatments currently available cannot cure the patient, but only extend their lifespan, and the main and most effective alternative is autologous hematopoietic stem cell transplantation, but not every patient is eligible, often due to age and pre-existing comorbidities. In this context, the search for new therapies that can bring better results to patients is of utmost importance. Protein tyrosine kinases (PTKs) are involved in several biological processes, such as cell growth regulation and proliferation, thus, mutations that affect their functionality can have a great impact on crucial molecular pathways in the cells, leading to tumorigenesis. In the past couple of decades, the use of small-molecule inhibitors, which include tyrosine kinase inhibitors (TKIs), has been a hallmark in the treatment of hematological malignancies, and MM patients may also benefit from TKI-based treatment strategies. In this review, we seek to understand the applicability of TKIs used in MM clinical trials in the last 10 years.

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives.

Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.

Targeting aurora kinases as a potential prognostic and therapeutical biomarkers in pediatric acute lymphoblastic leukaemia.

Aurora kinases (AURKA and AURKB) are mitotic kinases with an important role in the regulation of several mitotic events, and in hematological malignancies, AURKA and AURKB hyperexpression are found in patients with cytogenetic abnormalities presenting a unfavorable prognosis. The aim of this study was evaluated the mRNA expression profile of pediatric Acute Lymphoblastic Leukaemia (ALL) patients and the efficacy of two AURKA and AURKB designed inhibitors (GW809897X and GW806742X) in a leukemia cell line as a potential novel therapy for ALL patients. Cellular experiments demonstrated that both inhibitors induced cell death with caspase activation and cell cycle arrest, however only the GW806742X inhibitor decreased with more efficacy AURKA and AURKB expression in K-562 leukemia cells. In ALL patients both AURKA and AURKB showed a significant overexpression, when compared to health controls. Moreover, AURKB expression level was significant higher than AURKA in patients, and predicted a poorer prognosis with significantly lower survival rates. No differences were found in AURKA and AURKB expression between gene fusions, immunophenotypic groups, white blood cells count, gender or age. In summary, the results in this study indicates that the AURKA and AURKB overexpression are important findings in pediatric ALL, and designed inhibitor, GW806742X tested in vitro were able to effectively inhibit the gene expression of both aurora kinases and induce apoptosis in K-562 cells, however our data clearly shown that AURKB proves to be a singular finding and potential prognostic biomarker that may be used as a promising therapeutic target to those patients.

Pleuropulmonary blastoma type II: a case report

Pleuropulmonary blastoma (PPB) is a rare embrionary mesenchymal neoplasm but is recognized as the most common pulmonary malignancy of childhood. It may present metastasis to the brain and also be indicative of other neoplasms in affected individuals or in their relatives. Being such a rare disease, it is considered a difficult diagnosis to be made. A 3-year-old female presented with fever and respiratory distress. At first, she had been treated for pneumonia with antibiotics for 14 days in another hospital with no response. Computed tomography (CT) scan showed a right lung/mediastinal mass. The patient was referred to our institution and a new CT-scan evidenced a complex mass of irregular borders, cystic areas and solid projections, along with a right pneumotorax. The mass was biopsied and hematoxylin-and-eosin (HE) stained histological sections showed a neoplasm composed of small and round cells with hyperchromatic nuclei and scant cytoplasm. The immunohistochemical profile demonstrated positivity for desmin, myogenin and Myo-D1, suggesting the diagnosis of rhabdomyosarcoma. After two weeks of hospitalization, the patient was clinically stable and initiated the first chemotherapy cycle. Surgical resection of the mass was performed and the HE slides demonstrated a neoplasm composed of anaplastic and condrossarcomatous cells with extensive necrosis. The correlation of clinical data, radiological and morphological features were conclusive of a PPB type II. The recognition and diagnosis of this entity is of great importance due to its clinical and prognostic particularities.

Estudo de crianças com constipação intestinal em ambulatório de gastroenterologia / Estudy of children with constipation intestinal assisted in ambulatory of gastroenterology

Análise clínico-epidemiológica de crianças com Constipação Intestinal (CI). Método: estudo transversal de prevalência das crianças com CI atendidas no Ambulatório de Gastroenterologia Pediátrica da Fundação Santa Casa de Misericórdia do Pará (FSCMPA), entre agosto de 2006 a março de 2008. Resultados: houve predomínio de CI nos pacientes do sexo feminino; em 53,7% dos pacientes, os sintomas iniciaram nos primeiros 2 anos de vida e 65,9% tinham mais de 4 anos à primeira consulta especializada; 90,2% tinham fezes com calibre aumentado; 63,4% tinham fezes endurecidas e 56,1% tinham escape fecal; distensão abdominal foi encontrado em 82,9% dos pacientes e dor abdominal em 24,4%; 73,2% receberam tratamento prévio à consulta especializada e a Constipação Funcional (CF) correspondeu a 90,2% das causas de CI. Conclusão: as características clínicas e epidemiológicas das crianças pesquisadas aproximaram-se das encontradas na literatura, com predomínio da CF.

To analyze the clinical Epidemiologic profile on patients with Constipation Intestinal(CI).Methods: cross-sectional study of the children with CI assisted in the ambulatory of Pediatric Gastroenterology of the Santa Casa de Misericórdia do Pará Foundation (FSCMPA), between August 2006 and March of 2008. Results: there was a most prevalence of CI in femalepatients. In 53,7% of patients, the symptoms started before two year old age and 65,9 % of patients had 4 years old up in the first visit to the ambulatory; About 90, 2% of patients had large diameter stools; 63.4% had hard stools and 56.1% had fecal incontinence; abdominal distension was found in 82.9% of patients and abdominal pain in 24.4%; 73.2% of patients received treatment prior to specialized visit and Functional Constipation (CF) accounted in 90.2% of the causes of CI. Conclusion: the study showed similar results to those observed at other studies, with predominance of the CF.