A chromosomal region 7p11.2 transcript map: its development and application to the study of EGFR amplicons in glioblastoma

Cumulative information available about the organization of amplified chromosomal regions in human tumors suggests that the amplification repeat units, or amplicons, can be of a simple or complex nature. For the former, amplified regions generally retain their native chromosomal configuration and involve a single amplification target sequence. For complex amplicons, amplified DNAs usually undergo substantial reorganization relative to the normal chromosomal regions from which they evolve, and the regions subject to amplification may contain multiple target sequences. Previous efforts to characterize the 7p11.2 epidermal growth factor receptor ) amplicon in glioblastoma have relied primarily on the use of markers positioned by linkage analysis and/or radiation hybrid mapping, both of which are known to have the potential for being inaccurate when attempting to order loci over relatively short (<1 Mb) chromosomal regions. Due to the limited resolution of genetic maps that have been established through the use of these approaches, we have constructed a 2-Mb bacterial and P1-derived artificial chromosome (BAC-PAC) contig for the EGFR region and have applied markers positioned on its associated physical map to the analysis of 7p11.2 amplifications in a series of glioblastomas. Our data indicate that EGFR is the sole amplification target within the mapped region, although there are several additional 7p11.2 genes that can be coamplified and overexpressed with EGFR. Furthermore, these results are consistent with EGFR amplicons retaining the same organization as the native chromosome 7p11.2 region from which they are derived.     

Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects.

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 22q11 deletions. We previously showed that bacterial artificial chromosome (BAC) transgenic mice overexpressing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had reduced viability, cardiovascular malformations and thymus gland hypoplasia. Since these are hallmark features of VCFS/DGS, we analyzed the mice for additional anomalies. We found that the mice have important defects in the middle and inner ear that are directly relevant to the disorder. The most striking defect was the presence of chronic otitis media, a common finding in VCFS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner ear malformations, analogous to Mondini dysplasia in humans reported to occur in VCFS/DGS patients. We propose that overexpression of one or more of the transgenes is responsible for the etiology of the ear defects in the mice. Based upon its pattern of expression in the ear and functional studies of the gene, TbX1 likely plays a central role. Haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients.     

Functional genomics identifies ABCC3 as a mediator of taxane resistance in HER2-amplified breast cancer

Breast cancer is a heterogeneous disease with distinct molecular subtypes characterized by differential response to targeted and chemotherapeutic agents. Enhanced understanding of the genetic alterations characteristic of different subtypes is needed to pave the way for more personalized administration of therapeutic agents. We have taken a functional genomics approach using a well-characterized panel of breast cancer cell lines to identify putative biomarkers of resistance to antimitotic agents such as paclitaxel and monomethyl-auristatin-E (MMAE). In vitro studies revealed a striking difference in sensitivity to these agents between cell lines from different subtypes, with basal-like cell lines being significantly more sensitive to both agents than luminal or HER2-amplified cell lines. Genome-wide association studies using copy number data from Affymetrix single nucleotide polymorphism arrays identified amplification of the chromosome 17q21 region as being highly associated with resistance to both paclitaxel and MMAE. An unbiased approach consisting of RNA interference and high content analysis was used to show that amplification and concomitant overexpression of the gene encoding the ABCC3 drug transporter is responsible for conferring in vitro resistance to paclitaxel and MMAE. We also show that amplification of ABCC3 is present in primary breast tumors and that it occurs predominantly in HER2-amplified and luminal tumors, and we report on development of a specific fluorescence in situ hybridization assay that may have utility as a predictive biomarker of taxane resistance in breast cancer.     

Fine needle aspiration of an intrathyroidal parathyroid carcinoma mimicking a primary thyroid anaplastic carcinoma: A case report with review of the literature

Intrathyroidal parathyroid carcinoma is an uncommon malignancy. A 46‐year‐old male presented with a left neck mass. Computed tomography (CT) scan revealed a hypodense mass in the left thyroid lobe along with evidence of metastatic lymphadenopathy. Aspiration of the left thyroid nodule was performed, and a diagnosis of malignancy was rendered, favoring a primary anaplastic carcinoma. Based on the cytologic diagnosis, the patient underwent a total thyroidectomy. Before the surgery, intact parathyroid hormone (PTH) and calcium level (PTH = 78 pg/mL; Calcium = 10.6 mg/dL) were found to be minimally elevated. On gross examination, a 3.2 cm mass within the left inferior thyroid lobe was seen. Histopathologic examination and ancillary studies supported the diagnosis of a parathyroid carcinoma. We, hereby present, an exceedingly rare presentation of an intrathyroidal parathyroid carcinoma with only minimal elevation of PTH and calcium, mimicking a primary anaplastic thyroid carcinoma on cytologic examination.     

4D flow MRI left atrial kinetic energy in hypertrophic cardiomyopathy is associated with mitral regurgitation and left ventricular outflow tract obstruction

To noninvasively assess left atrial (LA) kinetic energy (KE) in hypertrophic cardiomyopathy (HCM) patients using 4D flow MRI and evaluate coupling associations with mitral regurgitation (MR) and left ventricular outflow tract (LVOT) obstruction. Twenty-nine retrospectively identified patients with HCM underwent 4D flow MRI. MRI-estimated peak LVOT pressure gradient (?P_MRI) was used to classify patients into non-obstructive and obstructive HCM. Time-resolved volumetric LA kinetic energy (KE_LA) was computed throughout systole. Average systolic (KE_LA-avg) and peak systolic (KE_LA-peak) KE_LA were compared between non-obstructive and obstructive HCM groups, and associations to MR severity and LVOT ?P_MRI were tested.The study included 15 patients with non-obstructive HCM (58.6 [45.9, 65.2] years, 7 females) and 14 patients with obstructive HCM (51.9 [47.6, 62.6] years, 6 females). Obstructive HCM patients demonstrated significantly elevated instantaneous KE_LA over all systolic time-points compared to non-obstructive HCM (P?<?0.05). Obstructive HCM patients also demonstrated higher KE_LA-avg (14.8 [10.6, 20.4] J/m³ vs. 33.4 [23.9, 61.3] J/m³, P?<?0.001) and KE_LA-peak (22.1 [15.9, 28.7] J/m³ vs. 57.2 [44.5, 121.4] J/m³, P?<?0.001) than non-obstructive HCM. MR severity was significantly correlated with KE_LA-avg (rho?=?0.81, P?<?0.001) and KE_LA-peak (rho?=?0.79, P?<?0.001). LVOT ?P_MRI was strongly correlated with KE_LA metrics in obstructive HCM (KE_LA-avg: rho?=?0.86, P?<?0.001; KE_LA-peak: rho?=?0.85, P?<?0.001).In HCM patients, left atrial kinetic energy, by 4D flow MRI, is associated with MR severity and the degree of LVOT obstruction.

     

Prevalence of coeliac disease in healthy blood donors: a study from north India

BackgroundBlood donor screening can help predict prevalence of coeliac disease in population.MethodsBetween December 2010 and June 2011, healthy blood donors were screened using anti-tissue glutaminase antibodies. Those positive underwent duodenoscopy. Their age, gender, body mass index and haemoglobin and histological changes were recorded.ResultsOf the 1610 blood donors screened, 1581 (98.2%) were males. The mean age of donors was 31.51 ± 9.66 years and the mean body mass index was 22.12 ± 4.24 kg/m². Nine (0.56%) men were seropositive. Endoscopic features included reduced fold height (9), scalloping (8), grooving (7) and mosaic mucosal pattern (3). Eight had Marsh IIIa changes whilst one had IIIb change. The prevalence of coeliac disease was 1:179 (0.56%, 95% confidence interval 1/366–1/91, 0.27–1.1%). None of the 9 patients had any symptoms. Their mean haemoglobin and body-mass index was similar to rest of the cohort.ConclusionThe prevalence of coeliac disease amongst apparently healthy blood donors was 1:179 (0.56%).