Ethnic variation in the HER-2 codon 655 genetic polymorphism previously associated with breast cancer

HER-2, a protooncogene located on chromosome 17q21, encodes a transmembrane glycoprotein (p185) with tyrosine kinase activity. Alterations of the HER-2 gene have been implicated in the carcinogenesis and prognosis of breast cancer and other solid tumors. It is also a cancer-therapeutic target for antibody-based therapy against the HER-2 protein. A single-nucleotide polymorphism (SNP) at codon 655, resulting in a G-to-A transition (Ile655Val) in the transmembrane domain-coding region of this gene has been associated with an increased risk of breast cancer, particularly among younger women. To understand the importance of this finding throughout the world, we evaluated this polymorphism in Ghanaian, Kenyan, Sudanese, Caucasian, African–American, Saudi, and Filipino subjects using a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of the Val allele, which is associated with increased breast cancer risk, was highly variable between populations (0%–24%). Continental African populations had a lower frequency of the Val allele than did Saudi, Chinese, Filipino, Caucasian, and African–American subjects. The data suggest that this SNP has variable frequency in different ethnic groups. The findings in this study correspond with the lower incidence and lower risk of breast cancer in African women compared with Caucasian and African–American women. Received: December 13, 2001 / Accepted: January 16, 2002     

Aneurysmal subarachnoid hemorrhage during pregnancy: a comprehensive and systematic review of the literature

Neurosurgical Review - Aneurysmal subarachnoid hemorrhage (aSAH) is an emergent condition requiring rapid intervention and prolonged monitoring. There are few recommendations regarding the...     

Genetic diversity of OXA-51-like genes among multidrug-resistant Acinetobacter baumannii in Riyadh,Saudi Arabia

We explore the genetic diversity of class D oxacillinases, including OXA-23, -24 (-40), -58 and, particularly, the intrinsic OXA-51-like genes, among multidrug-resistant (MDR) Acinetobacter baumannii strains from inpatients at a tertiary care hospital in Riyadh, Saudi Arabia. Sequence-based typing (SBT) of the OXA-51-like gene was carried out on 253 isolates. Selected isolates (n?=?66) were subjected to multilocus sequence typing (MLST). The polymerase chain reaction (PCR) typing results showed that all isolates (n?=?253) contained the OXA-51-like and OXA-23 genes. However, the OXA-58 gene was detected in five isolates. Further, none of the isolates had the OXA-40 (identical to the OXA-24) gene. SBT revealed a high OXA-51-like genotypic diversity and showed that all isolates were clustered into four main groups: OXA-66 (62.3 %), followed by OXA-69 (19.1 %), OXA-132 (7.6 %) and other OXA-51-like genes (10.3 %), including OXA-79, -82, -92, -131 and -197. MLST revealed four main sequence types (STs), 2, 19, 20 and 25, among the isolates, in addition to six isolates with newly designated ST194–ST197 singletons. Further, a high prevalence (81.4 %) of OXA-66 and OXA-69-like genes in A. baumannii was identified. More studies are essential in order to explore the molecular mechanisms that confer carbapenem-resistant phenotypes for A. baumannii isolates and to investigate the genetic diversity of other OXA-D genes.     

Molecular diagnostic tools for the detection of nodal micrometastases in prostate cancer patients undergoing radical prostatectomy with extended pelvic lymph node dissection: a prospective study

Background: Routine pathological examination can miss micro-metastatic tumor foci in the lymph nodes (LN) of patients with prostate cancer (PCa) that undergo radical prostatectomy and pelvic lymph node dissection (PLND). The aim of the present prospective study was to evaluate the impact of micrometastases assessed by serial section (SS), immunohistochemistry (IHC), and Real-time Polymerase Chain Reaction (RT-PCR) in patients undergoing radical prostatectomy with extended PLND. Materials and methods: 32 consecutive patients who underwent radical prostatectomy with extended PLND (obturator, internal/external and distal 2cm common iliac lymph-nodes (LN)) for intermediate (clinical T1c-T2 and PSA:10-20 ng/mL and clinical Gleason Score = 7) or high (clinical stage T3 or PSA>20 or clinical Gleason Score = 8-10) PCa were enrolled. The nodes were processed by the one uropathologist, both according to the routine pathological examination (analysis of the central section for 4 mm nodes or every 2 mm for LN>4 mm), which served as comparative method, both according to SS, IHC with antibodies against PSA and broad-spectrum Cytokeratins (BSCK), and quantitative RT-PCR targeting PSA, PSMA (PS Membrane Antigen), and Glucuronidase-S-Beta (GUSB) mRNA, that are over-expressed in prostatic cancer cells. Results: A total of 628 LN were analyzed, with a mean number of LN removed of 19.6 (SD = 7.2). Applying the routine pathological examination, 10 (31.2%) patients and 23 (3.9%) LN resulted positive for nodal involvement, with mean positive LN of 2.2 (SD = 1.4). After applying the SS and the molecular method of analysis (IHC and RT-PCR), micrometastases were found in 7 LN (SS showed micrometastases in 3 of them, IHC in 6 of them and RT-PCR in 7 of them); a total of 3 (9.3%) node-negative patients showed micrometastases at routine pathological examination (in 2 patients with RT-PCR and in 1 with IHC). Conclusions: The significance of micrometastases in PCa and the potential therapeutic role of PLND is not yet clarified, but the molecular analysis of the LN can detect a significant percentage of patients who harbor micro-metastatic PCa missed at routine pathological examination, and can enhance the accuracy of lymphadenectomy as a staging method.     

Mutations in TAX1BP3 Cause Dilated Cardiomyopathy with Septo‐Optic Dysplasia

We describe a Bedouin family with a novel autosomal recessive syndrome characterized by dilated cardiomyopathy and septo‐optic dysplasia. Genetic analysis revealed a homozygous missense mutation in TAX1BP3, which encodes a small PDZ domain containing protein implicated in regulation of the Wnt/β‐catenin signaling pathway, as the causative mutation. The mutation affects a conserved residue located at the core of TAX1BP3 binding pocket and is predicted to impair the nature of a crucial hydrophobic patch, thereby interrupting the structure and stability of the protein, and its ability to interact with other proteins. TAX1BP3 is highly expressed in heart and brain and consistent with the clinical findings observed in our patients; a knockdown of TAX1BP3 causes elongation defects, enlarged pericard, and enlarged head structures in zebrafish embryos. Thus, we describe a new genetic disorder that expands the monogenic cardiomyopathy disease spectrum and suggests that TAX1BP3 is essential for heart and brain development.