Ghassan J. Samara

Human Genome Project

The Human Genome Project is an international effort to clone and sequence the entire human genome. This audacious undertaking, estimated to cost 200 million dollars per year and require 15 years to complete, promises to be one of the most revolutionary and captivating scientific endeavors ever conceived by mankind. By knowing the sequence of the estimated 3 billion base pairs of the haploid human genome and its more than 30,000 genes, many questions will be answered. Moreover, our ability to intervene at the genetic level will be possible. This review outlines the scientific goals and methods of this project and discusses some of its ethical, legal, and social ramifications.

Putative tumor-suppressor gene on chromosome 11 is important in sporadic endocrine tumor formation

Endocrine tumors arising sporadically or as a manifestation of the multiple endocrine neoplasia type I syndrome (MEN I) have been shown to have mutations on chromosome 11. These mutations can be detected at the molecular level by loss of heterozygosity (LOH) for DNA markers from chromosome 11. This study represents one of the largest collections of sporadic endocrine tumors in which LOH was systematically assessed on chromosome 11 for the loci flanking the proposed MEN I region. DNA was isolated from 39 endocrine tumors and probed with 7 DNA probes spanning the region of chromosome 11q13 from the loci PYGM to INT-2. Eleven tumors demonstrated LOH at any two loci in this region. The remaining 28 tumors showed no LOH or were noninformative at these loci. Thus, nearly 30% of these tumors showed LOH in the region (from PYGM to INT-2) that is thought to contain the MEN I gene(s). Previous studies of sporadic endocrine tumors have suggested that these tumors may arise via the same mechanism as tumors of the MEN I syndrome. Namely, these sporadic tumors are thought to result from mutations leading to genetic loss on the long arm of chromosome 11, thereby inactivating a possible tumor-suppressor gene (or genes). These findings strongly support the hypothesis that sporadic pancreatic endocrine tumors share a similar etiology of tumorigenesis with tumors of the MEN I syndrome, which principally involves deletion of a tumor-suppressor element (or elements).

Molecular biology and therapy of disease

Molecular biology will have a profound impact upon the treatment of disease. Molecular techniques provide protein products for treatment of more diseases each year. The understanding of pathophysiology at the molecular level allows for improved drug design. Antisense technology can selectively control gene expression. Gene therapy is potentially the most important aspect of molecular biology. Physical and viral transduction mechanisms are being developed toward this end. Gene replacement, creation of antisense oligonucleotides, and prodrug strategies are being developed. Currently, gene replacement and prodrug therapy are feasible in at least a few cases, but further study will yield additional applications.

Methicillin-resistant Staphylococcus aureus bacteraemia associated with Lemierre's syndrome: case report and literature review

BACKGROUND Community-acquired methicillin-resistant Staphylococcus aureus is a growing health concern. Lemierres syndrome is a septic jugular thrombophlebitis that primarily affects young adults. This paper aimed to identify a possible sub-group of Lemierres syndrome cases associated with community-acquired methicillin-resistant Staphylococcus aureus. METHOD This paper reports the case of a 16-year-old male who was admitted for increasing fever, tachycardia, tachypnoea and neck pain. The patient was diagnosed with methicillin-resistant Staphylococcus aureus bacteraemia associated with Lemierres syndrome. A literature review was subsequently conducted. RESULTS Following intravenous antibiotic treatment and the sterilisation of blood cultures, the patient improved. The literature review indicated a rise in the past 2 years of Lemierres syndrome associated with methicillin-resistant Staphylococcus aureus among patients less than 18 years of age. CONCLUSION Community-acquired methicillin-resistant Staphylococcus aureus bacteraemia can lead to pulmonary sequelae. When it is associated with pharyngitis, nasopharyngitis or parapharyngeal lymphadenitis, the affected patient may be predisposed to Lemierres syndrome. As bacterial carriage is predominantly nasal, pharyngitis may not be present. Methicillin-resistant Staphylococcus aureus should be included as an offending bacterium where there is suspicion of Lemierres syndrome. It is unclear whether anticoagulation alters the course of the bacterium, and surgery is probably contraindicated.

Robot-assisted sialolithotomy with sialendoscopy for the management of large submandibular gland stones

The objectives of this study were to describe robot‐assisted sialolithotomy with sialendoscopy (RASS) for the management of large palpable hilar submandibular gland (SMG) stones and analyze procedural success and lingual nerve damage following RASS in comparison to the combined transoral sialendoscopic approach.

MT1-MMP Activation of TGF-β Signaling Enables Intercellular Activation of an Epithelial-mesenchymal Transition Program in Cancer

Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) is associated with cancer invasion and metastasis leading to poor patient prognosis. MT1-MMP mediates cancer cell invasion via degradation of basement membrane and extracellular matrix, and induction of cell migration. However, MT1-MMP expression in the cancer stroma can drive invasion of carcinoma cells in vivo, suggesting MT1-MMP may also promote cancer invasiveness via paracrinemediated mechanisms. A major step in cancer cell metastasis is thought to be an epithelial-mesenchymal transition (EMT), in which carcinoma cells evolve from a stationary epithelial phenotype to a more motile mesenchymal phenotype. We demonstrate here that EMT is triggered by MT1-MMP-mediated activation of TGF-. signaling, involving induction of CUTL1 and subsequently, of Wnt5a. Mesenchymal-like cancer cells expressing endogenous MT1-MMP reverted to an epithelial phenotype when MT1-MMP, SMAD4, CUTL1, or Wnt5a expression or TGF-. activity was inhibited. Wnt5a knockdown in MT1- MMP expressing LNCaP cells caused decreased cell migration and cell growth in soft agar. While MT1-MMP expression did not affect total TGF-. level, MT1-MMP catalytic activity increased the availability of active TGF-., enabling MT1-MMP-expressing cells to activate the EMT in nearby cells. MT1-MMP-expressing cells induced co-cultured non-MT1-MMP-expressing cells to undergo EMT by a TGF-.-dependent process. These results highlight a pathway by which tumor invasiveness may be expanded via MT1-MMP-mediated activation of TGF-. signaling, enabling autocrine and paracrine-mediated induction of EMT.

The Effects of the Plasminogen Pathway on Scar Tissue Formation

Objectives/Hypothesis The authors sought to determine the role of the plasminogen pathway in wound healing. They hypothesized that decreased fibrin degradation may lead to increased collagen deposition. Presuming that the degree of histopathological abnormality correlates with the aesthetic appearance of the scar, we conducted a study that attempted to determine the histopathological appearance of scar tissue in mice with and without impaired function of the plasminogen pathway.

Molecular mechanisms of tumor formation

DNA is the fundamental guide for the cells processes. The alterations in DNA that can lead to abnormal or absent proteins and the role of chromosomal alterations in changing the function of the DNA are reviewed. The role of viruses in derailing a cells normal functions, the major mechanisms of oncogene action, and tumor suppressor genes are also discussed.

Molecular biology: An overview

An overview of molecular biology is presented for the practicing surgeon. Definitions of the constructs and activity of DNA, RNA, and protein synthesis are defined. These principles are illustrated in their use in recombinant DNA technologies. A glossary is provided for the terms utilized.

Mutational analysis of thePTEN gene in head and neck squamous cell carcinoma

Loss of heterozygosity (LOH) at chromosome band 10q23 occurs frequently in a wide variety of human tumors. A recently identified candidate tumor suppressor gene, PTEN located on 10q23, is mutated in multiple advanced cancers. To explore whether PTEN is associated with human squamous cell carcinoma of the head and neck (SCCHN), DNAs from both normal muscle and tumor tissue in 19 SCCHN were used for detecting LOH at chromosome 10q23 and mutational analysis of PTEN by direct polymerase chain reaction (PCR)‐DNA sequencing. LOH at 10q23 was identified in 6/15 SCCHN. Mutation of PTEN was identified in 3/19 SCCHN. Of these 3 patients, 2 had stage IV disease; the third patient, with recurrent, metastatic and stage III disease, showed a 36 bp germline heterozygous deletion within intron 7. Furthermore, a missense mutation at codon 501 (TCT → TTT: Ser → Phe) in exon 8 was also found in tumor from the same patient. Our results suggest that PTEN may play a role in the genesis of some SCCHNs. Int. J. Cancer 77:684–688, 1998.