Molecular analysis of a human PAX6 homeobox mutant

Pax6 controls eye, pancreas and brain morphogenesis. In humans, heterozygous PAX6 mutations cause aniridia and various other congenital eye abnormalities. Most frequent PAX6 missense mutations are located in the paired domain (PD), while very few missense mutations have been identified in the homeodomain (HD). In the present report, we describe a molecular analysis of the human PAX6 R242T missense mutation, which is located in the second helix of the HD. It was identified in a male child with partial aniridia in the left eye, presenting as a pseudo-coloboma. Gel-retardation assays revealed that the mutant HD binds DNA as well as the wild-type HD. In addition, the mutation does not modify the DNA-binding properties of the PD. Cell transfection assays indicated that the steady-state levels of the full length mutant protein are higher than those of the wild-type one. In cotransfection assays a PAX6 responsive promoter is activated to a higher extent by the mutant protein than by the wild-type protein. In vitro limited proteolysis assays indicated that the presence of the mutation reduces the sensitivity to trypsin digestion. Thus, we suggest that the R242T human phenotype could be due to abnormal increase of PAX6 protein, in keeping with the reported sensitivity of the eye phenotype to increased PAX6 dosage.     

Nevus sebaceus of Jadassohn

The nevus sebaceus of Jadassohn (SNJ) is a hamartomatous disorder of the skin and its adnexa pertaining to the group of "organoid nevi,' most frequently involving the face and scalp. During adulthood, patients with SNJ have a 10% to 20% risk of the development of cutaneous or adnexal neoplasia, so that prophylactic excision before puberty is recommended by most authors, and tissue expansion is considered to be the best method of reconstruction. It has been largely demonstrated in literature that most of the lesions that have been interpreted as basal cell carcinoma (BCC) are actually examples of primitive follicular induction or trichoblastomas, not authentic BCCs. A literature review on histopathologic findings associated with SNJ and a retrospective chart review of two cases occurring in young females are presented. In one case, the lesion was treated by intraoperative expander-assisted reduction and scalp graft (Case 1); in the other one, a primary closure with adjacent tissue was performed (Case 2). No signs of malignant degeneration or residual pathology have been found. For treatment of the biggest lesions, when preoperative tissue expansion cannot be performed, intraoperative one, transfer of a scalp graft has been shown to be a good reconstructive method. For the smallest lesions, a primary closure with adjacent tissue is sufficient.     

Unusual foreign body in the nasal cavity

Foreign objects frequently have been reported in the nasal structures, often these foreign bodies are occasionally inhaled by children or they are often inserted in nasal cavities after various accidents. Frequently, the presence of foreign bodies in the nose represents an emergency, particularly for pediatric patients where the incidence is high. The report in this article described an unusual nasal foreign body in an adult discovered incidentally during a cranial radiography. This report is an unusual case of facial asymmetry caused by a foreign nasal body in adult, which is destitute of complications, connected to long-term presence of the intranasal button. The finding was accidental; moreover the patient was an adult and did not present a clear symptomatology. Through careful clinical and fibroscopy exam, valuating also the site of the foreign body, it is necessary an intranasal surgery treatment. The results of the treatment is connected to a combined use of different branches of learning with the aim of obtaining positive results from both a clinical and legal point of view.     

Dose-dense CHOP plus rituximab (R-CHOP14) for the treatment of elderly patients with high-risk diffuse large B cell lymphoma: a pilot study

BACKGROUND: Aggressive non-Hodgkin's lymphomas (NHL) require intensive therapies which seemed impracticable in elderly patients. Dose reduction and therapy attenuation reduced treatment-related toxicity, but also decreased therapeutic efficacy. In elderly patients too, the achievement of complete remission is the most important prognostic factor affecting outcome. Therefore, we have treated elderly patients with a dose-intensified protocol. Aim of the study was to verify the feasibility of this scheme in a subset of patients with high-risk aggressive lymphomas. METHODS: Between June 2002 and June 2004, 26 patients over the age of 60 years with a diagnosis of aggressive NHL and an intermediate-high or high International Prognostic Index were treated with biweekly CHOP plus rituximab with the support of granulocyte colony-stimulating factors (G-CSF). RESULTS: Seventeen patients (65%) regularly kept the interval between cycles. Haematological and extrahaematological toxicities were moderate in all the patients. Twenty (77%) patients achieved complete remissions, 6 (23%) partial remissions with an overall response rate of 100%. After a median follow-up of 23 months, the overall survival was 79%; after a median follow-up of 17 months, the disease-free survival was 70%. CONCLUSION: These results confirm that a dose-dense CHOP programme can be administered safely and effectively in a subset of elderly patients with high-risk aggressive NHL. The addition of rituximab could increase the response rate without adding toxicity.     

Looking for celiac disease: diagnostic accuracy of two rapid commercial assays

BACKGROUND: Early diagnosis and treatment with gluten-free diet reduces mortality and the prevalence of associated disorders in celiac disease (CD). A simple "in the office" test of anti-transglutaminase antibodies might be of great help in first-line screening for CD. AIMS: We evaluated the sensitivity and specificity of two commercial kits based, respectively, on rapid detection of IgA-IgG anti-human-transglutaminase antibodies (anti-h-tTG) in serum and IgA anti-h-tTG antibody in one drop of whole blood. These assays were compared to a well-established enzyme-linked immunosorbent assay technique. METHODS: Serum samples were analyzed from 114 biopsy-confirmed celiacs, 120 healthy controls, 20 first-degree relatives of celiacs, and 75 diseased controls. The whole blood samples were analyzed from 51 biopsy-confirmed celiacs and 100 controls. RESULTS: The serum-based test was positive in all 114 celiacs (sensitivity 100%). Among the controls there were seven healthy blood donors, one first-degree relative, and three diseased controls who tested positive (specificity 94.9%). The blood drop-based assay testing IgA antibodies was positive in 46 of 51 (sensitivity 90.2%), and since three of the five patients testing negative had total IgA deficiency, the sensitivity value can be increased to 95.8%. All 100 controls tested negative (specificity 100%). CONCLUSIONS: The commercial kits described here produce high values of sensitivity and specificity, offering the general practitioner who suspects a possible case of CD the real possibility to look for anti-h-tTG antibodies in his own medical office during a standard visit at a satisfyingly low cost.     

Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer

Chemotherapy has produced unsatisfactory results in pancreas cancer and novel approaches, including treatment tailoring by pharmacogenetic analysis and new molecular-targeted drugs, are required. The scarcity of effective therapies may reflect the lack of knowledge about the influence of tumor-related molecular abnormalities on responsiveness to drugs. Advances in the understanding of pancreas cancer biology have been made over the past decade, including the discovery of critical mutations in oncogenes (i.e., K-Ras) as well as the loss of tumor suppressor genes, such as TP53 and p16(INK4). Other studies showed the dysregulation of the expression of proteins involved in the control of cell cycle, proliferation, apoptosis, and invasiveness, such as Bcl-2, Akt, mdm2, and epidermal growth factor receptor. These characteristics might contribute to the aggressive behavior of pancreatic cancer and influence response to treatment. Indeed, the inactivation of p53 may explain the relative resistance to 5-fluorouracil, whereas Bcl-2 overexpression is associated with reduced sensitivity to gemcitabine. However, the future challenge of pancreas cancer chemotherapy relies on the identification of molecular markers that help in the selection of drugs best suited to the individual patient. Recent pharmacogenetic studies focused on genes encoding proteins directly involved in drug activity, showing the role of thymidylate synthase and human equilibrative nucleoside transporter-1 as prognostic factor in 5-fluorouracil- and gemcitabine-treated patients, respectively. Finally, inhibitors of signal transduction and angiogenesis are under extensive investigation, and several prospective trials have been devoted to this area. Pharmacogenetics is likely to play a central role in the personalization of treatment, to stratify patients based on their likelihood of response to both standard agents (i.e., gemcitabine/nucleoside transporters) and targeted treatments (i.e., epidermal growth factor receptor gene mutations and/or amplification and tyrosine kinase inhibitors), Thus, molecular analysis should be implemented in the optimal management of the patient affected by pancreatic adenocarcinoma.