Cortical brain malformations: effect of clinical, neuroradiological, and modern genetic classification

BACKGROUND: Malformations of cortical development (MCDs) are a major source of handicap. Much progress in understanding the genetic causes has been made recently. The number of affected children in whom a molecularly confirmed diagnosis can be made is unclear. OBJECTIVE: To evaluate the etiology of MCDs in children and the effect of a combined radiological, clinical, and syndrome classification. DESIGN: A case series of 113 children with a radiological diagnosis of MCD from January 1, 1992, to January 1, 2006. SETTING: The Erasmus Medical Center-Sophia Children's Hospital, a secondary and tertiary referral center. PATIENTS: Patients with MCD underwent a complete radiological, clinical, and neurological assessment and testing for known genes involved in the pathogenesis of MCD as appropriate for their phenotype. RESULTS: We established an etiological diagnosis in 45 of 113 cases (40%). For 21 patients (19%), this included molecular and/or genetic confirmation (Miller-Dieker syndrome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism). In 17 (15%), a syndrome with an unknown genetic defect was diagnosed. In 7 patients (6%), we found evidence of a gestational insult. Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history with multiple affected persons (12 patients), or consanguineous parents (7 patients). CONCLUSIONS: In our cohort, combining diagnostic molecular testing with clinical, radiological, and genetic classification; syndrome identification; and family study provided a diagnosis in 40% of the cases of MCD. This contributes to the possibility of prenatal diagnosis and improved patient treatment and disease management.     

Clinical Observations from a Breast Cancer Registry in Asian Women

Background The incidence of breast cancer in Singapore, reflecting cancer trends of developed nations, is rising rapidly. It is the most common cancer in Singaporean women. Given the significant problem that breast cancer poses, this study reports the clinical-pathologic features of 1,165 women with invasive breast cancer managed at a university teaching hospital in Singapore. Methods All patients who were diagnosed, treated, and followed-up at this institution between 1990 and 2002 were analyzed. Data were obtained from the National University Hospital Breast Cancer Registry. Results Of our patients, 82% were ethnic Chinese. The median age of presentation was 49 years, and 24.5% of our patients presented with stage I disease. In addition, 51% of premenopausal and 60% of postmenopausal patients stained positive for estrogen receptor. Mastectomy was the most common surgical therapy, and about 90% of patients received adjuvant therapy. At a median follow-up of 81 months, the median 5-year survival was as follows: stage I, 97%, stage II, 78%, stage III, 52%, and stage IV, 13%. Conclusions This study supports what has been observed among breast cancer patients in this region and reflects a profile of breast cancer that differs from that seen in the West: patients present at a younger age, with more advanced stage and fewer estrogen-positive tumors. Most women in our series received systemic adjuvant therapy, and the 5-year overall survival rates are equivalent to published results from the West. The unique features of the disease in women in Singapore are important to recognize, as they may influence future prevention and management strategies for Asian women with breast cancer.     

Striatal serotonin depletion facilitates rat egocentric learning via dopamine modulation

Egocentric spatial learning has been defined as the ability to navigate in an environment using only proprioceptive information, thereby performing a motor response based on one's own movement. This form of learning has been associated with the neural memory system, including the striatum body. Cerebral serotonin depletion induces better performance, both in tasks with strong egocentric components and in egocentric navigation in the Morris' maze. Based on this, we propose that the striatal serotonergic depletion must facilitate egocentric learning. Fifteen female Sprague Dawley rats weighing 250-350 g and maintained under standard conditions were chronically implanted with infusion cannulas for bilateral application of drugs into the striatum. The animals were evaluated for egocentric navigation using the Morris' maze, under different conditions: saline solution infusion, serotonin depletion by infusion of 5,7-Dihydroxytryptamine (25 microg of free base solved in 2.5 microl of ascorbic acid 1% in saline solution), infusion of mixed dopamine D(1) and D(2) receptor antagonists (0.5 microl/min during 5 min of mixed spiperone 20 microM and SCH23390 10 microM), or serotonin depletion and dopamine blockade simultaneously. Striatal serotonin depletion facilitated egocentric learning, which was demonstrated as shorter escape latencies and the display of a defined sequence of movements for reaching the platform. The facilitation was not observed under condition of simultaneous dopamine blockade. Striatal serotonin depletion produced a dopamine-dependent facilitation of egocentric learning. A role for serotonin in the inhibition of striatal-mediated learning strategies is proposed.     

Antitumor activity, X-ray crystal structure, and DNA binding properties of thiocoraline A, a natural bisintercalating thiodepsipeptide

The marine natural product thiocoraline A displayed approximately equal cytotoxic activity at nanomolar concentrations in a panel of 12 human cancer cell lines. X-ray diffraction analyses of orthorhombic crystals of this DNA-binding drug revealed arrays of docked pairs of staple-shaped molecules in which one pendent hydroxyquinoline chromophore from each cysteine-rich molecule appears intercalated between the two chromophores of a facing molecule. This arrangement is in contrast to the proposed mode of binding to DNA that shows the two drug chromophores clamping two stacked base pairs, in agreement with the nearest-neighbor exclusion principle. Proof of DNA sequence recognition was obtained from both classical DNase I footprinting experiments and determination of the melting temperatures of several custom-designed fluorescently labeled oligonucleotides. A rationale for the DNA-binding behavior was gained when models of thiocoraline clamping a central step embedded in several octanucleotides were built and studied by means of unrestrained molecular dynamics simulations in aqueous solution.     

Raynaud's phenomenon secondary to erenumab in a patient with chronic migraine

Raynaud''s phenomenon is a rare side effect of CGRP monoclonal antibodies. These molecular treatments are a relatively new class of drugs for the prevention of migraine. It is likely that we will see this side effect more often in the future. Patients with a background of Raynaud''s phenomenon may experience worsening of their symptoms if started on these treatments.     

Visualizing the dynamics of EGFR activity and antiglioma therapies in vivo

Many altered pathways in cancer cells depend on growth factor receptors. In primary malignant gliomas, the amplification/alteration of the epidermal growth factor receptor (EGFR) has been shown to play a significant role in enhancing glioma burden. In an effort to dissect the role of EGFR expression in glioma progression in vivo and evaluate targeted therapies for gliomas, we have genetically engineered glioma cells to visualize the dynamics of EGFR and targeted therapies in real time in vivo. Using engineered lentiviral vectors bearing fusions between EGFR and its exon 2 to 7 deleted variant (EGFRvIII) with green fluorescent protein (GFP) and Renilla luciferase (Rluc), we show that there is a direct correlation between EGFR expression and glioma cell proliferation in the initial stages of glioma progression. To monitor and evaluate EGFR-targeted therapies, we have engineered (a) short hairpin RNAs (shRNA) and (b) clinically used monoclonal antibody, cetuximab. Using EGFR-GFP-Rluc/firefly luciferase (Fluc)-DsRed2 glioma model, we show that both shRNAs and cetuximab result in a considerable reduction in glioma cell proliferation in culture and glioma burden in vivo that can be monitored in real time at a cellular resolution. This study serves as a template to follow the role of growth factor receptor expression in tumor progression and to image therapeutic efficacy of targeted therapies in cancer.     

Mutational status of the epidermal growth factor receptor (EGFR) gene in thymomas and thymic carcinomas

Epithelial tumours of the thymus (thymoma, thymic carcinoma) are rare tumours of the anterior mediastinum. Current treatment options of advanced stage thymomas and thymic carcinomas include a multimodal therapy with radio- and chemotherapy as well as surgery. In recent years, new therapeutic targets such as EGFR (epidermal growth factor receptor), COX-2 and KIT have emerged as new potential therapeutic targets. So far, EGFR mutational status of different subtypes of epithelial tumours of the thymus has been analyzed only inappropriately. We have investigated 20 different subtypes of thymomas (type A, AB, and B3) and thymic carcinomas for mutations in exons 18, 19, 20, and 21 of the EGFR gene and performed immunohistochemistry for EGFR. Concerning immunohistochemistry, most of the cases (17/20) had a strong positive staining. Although sequence alterations were found in four samples, none of these alterations led to amino acid changes in the tyrosine kinase domain of EGFR comparable to those in non-small cell lung cancer. Thus EGFR-expression in thymic tumours does not rely on mutations in critical functional (activation) domains of the EGFR-gene. Experimental and therapeutic approaches have to consider this difference.     

Pediatric Cutaneous Lupus Erythematosus Treated with Pulsed Dye Laser

Pulsed dye laser (PDL) has been used in adults to treat refractory cutaneous lupus erythematosus (CLE). We report the first case of CLE in a child successfully treated with PDL.