Receptor tyrosine kinases as therapeutic targets in cancer.

Extract: Tyrosine kinases are a large and diverse family of proteins found only in Metazoans. The ERBB receptor tyrosine kinases (RTK), the main focus of this article, belong to the sub-group encompassing the cell surface proteins. All receptor tyrosine kinases have an extracellular domain that binds peptide ligands, span the membrane once, and have an intracellular portion with protein tyrosine kinase activity.

The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2 and PDGF-AA on the chronicity of venous leg ulcers.

Introduction: Alteration in the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinase-2 (MMP-2), tissue inhibitors of matrix metalloproteinases (TIMP-2) and platelet derived growth factor (PDGF-AA) may contribute to poor healing in venous leg ulcers.

Aim: The aim of this study is to determine the expression of EMMPRIN, MMP-2, TIMP-2 and PDGF-AA in the ulcer exudates and perivascular tissue of healing and non-healing chronic venous ulcers.

Patients, Materials And Methods: Forty patients with chronic venous ulcers were included in this study, with a mean age of 60 years.

Recombinant factor VIIa in the treatment of intractable bleeding in vascular surgery.

Intractable bleeding unresponsive to conventional haemostatic measures is an uncommon but potentially life threatening surgical complication. Several studies have suggested that recombinant factor VIIa (rVIIa), a genetically engineered substitute for endogenous factor VIIa may have therapeutic application in patients with uncontrollable haemorrhage not previously diagnosed with coagulopathy. We report our experience of rVIIa use in eight such vascular surgery patients who developed life-threatening non-surgical haemorrhage either intra-operative or post-operatively.

Through and through defects of the lower face.

This article considers the particular demands of reconstruction of this complex region of the head and neck in terms of its functional and aesthetic requirements. It presents a classification system that may assist in the selection of the appropriate reconstruction. Finally, the authors discuss some of the more common techniques and flaps that should be considered when planning microsurgical management, and they review the outcomes they have seen in terms of speech, diet tolerance, oral continence, and survival.

The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade.

Purpose: Receptor tyrosine kinases of the ErbB family play important roles in the control of tumor growth. Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, enhances vascular permeability, and plays an important role in tumor vascularization. We evaluated the effects of selective VEGF receptor (VEGFR; PTK787/ZK222584) and ErbB (PKI166 and ZD1839) inhibitors on tumor growth and angiogenesis and asked whether additional therapeutic benefit was conferred by combination treatment.

The influence of subintimal angioplasty on level of amputation and limb salvage rates in lower limb critical ischaemia: a 15-year experience.

Objectives: The aim of this study is to assess the influence of subintimal angioplasty (SIA) on lower limb amputation rate and level in critically ischaemic limbs.

Methods: Between January 1989 and March 2004, 1268 patients were admitted for treatment of lower limb critical ischaemia. Eight hundred and twenty-nine patients underwent revascularisation (bypass 671 and angioplasty 158), while 439 patients had primary amputations.

Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli.

Integrin-extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. To study the role of beta1 integrin in the mammary gland, Itgbeta1(flox/flox) mice were crossed with WAPiCre transgenic mice, which led to specific ablation of beta1 integrin in luminal alveolar epithelial cells. In the beta1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell-basement membrane associations.

ERBB receptors and cancer: the complexity of targeted inhibitors.

ERBB receptor tyrosine kinases have important roles in human cancer. In particular, the expression or activation of epidermal growth factor receptor and ERBB2 are altered in many epithelial tumours, and clinical studies indicate that they have important roles in tumour aetiology and progression. Accordingly, these receptors have been intensely studied to understand their importance in cancer biology and as therapeutic targets, and many ERBB inhibitors are now used in the clinic.

ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events.

The epidermal growth factor receptor family member ERBB4 is required for mammary gland development and lactation. ERBB4 activities in the breast are mediated through the signal transducer and activator of transcription (STAT) family member STAT5A, and ERBB4 directly activates STAT5A, in part, through phosphorylation of STAT5A at the regulatory Tyr-694. Here we show that STAT5A regulation by ERBB4 is also mediated through STAT5A serine phosphorylation.

Multistate outbreak of Listeria monocytogenes infection linked to delicatessen turkey meat.

Background: Despite a decreasing incidence of listeriosis in the United States, molecular subtyping has increased the number of recognized outbreaks. In September 2000, the New York City Department of Health identified a cluster of infections caused by Listeria monocytogenes isolates with identical molecular subtypes by pulsed-field gel electrophoresis (PFGE) and ribotyping.

Methods: To determine the magnitude of the outbreak and identify risk factors for infection, we notified state health departments and conducted a case-control study.

Endovascular repair of early rupture of Dacron aortic graft--two case reports.

Complications after open aortic surgery pose a challenge both to the vascular surgeon and the patient because of aging population, widespread use of cardiac revascularization, and improved survival after aortic surgery. The perioperative mortality rate for redo elective aortic surgery ranges from 5% to 29% and increases to 70-100% in emergency situation. Endovascular treatment of the postaortic open surgery (PAOS) patient has fewer complications and a lower mortality rate in comparison with redo open surgical repair.

Sexually Transmitted Diseases in Travelers.

International travelers engaging in casual sex are at risk for acquiring sexually transmitted diseases (STDs), including HIV. The frequency of international travel emphasizes the need for a travel sexual activity history to be included in the clinical assessment of any returned traveler. When formulating a differential diagnosis, the STD prevalence rates at the travel destination and the risk profile of the traveler and the sexual partner need to be considered.

Cooperation between fibroblast growth factor receptor-4 and ErbB2 in regulation of cyclin D1 translation.

Alterations in ErbB2 or fibroblast growth factor receptor-4 (FGFR-4) expression and activity occur in a significant fraction of breast cancers. Because signaling molecules and pathways cooperate to drive cancer progression, simultaneous targeting of multiple pathways is an appealing therapeutic strategy. With this in mind, we examined breast tumor cells for their sensitivity to the ErbB2 and FGFR inhibitors, PKI166 and PD173074, respectively.

Subintimal angioplasty as a primary modality in the management of critical limb ischemia: comparison to bypass grafting for aortoiliac and femoropopliteal occlusive disease.

Purpose: To compare the 30-day morbidity, mortality, length of hospital stay, and patency rates in patients with critically ischemic limbs treated with subintimal angioplasty (SA) versus standard bypass surgery.

Method: Between October 2001 and August 2003, 137 patients (74 women; mean age 70 years, range 43-92) with critical limb ischemia underwent subintimal angioplasty (n=88) or bypass surgery (n=49) for superficial femoral artery (SFA) or aortoiliac lesions. All patients had lesions classified as C or D according to the TransAtlantic Inter-Society Consensus.

TEL/ETV6 is a signal transducer and activator of transcription 3 (Stat3)-induced repressor of Stat3 activity.

The signal transducer and activator of transcription 3 (Stat3) transcription factor is required for the antiproliferative effects induced by cytokines, such as the interleukin-6 type. In order to investigate the role of Stat3 in inhibition of cell proliferation, we have used an inducible Stat3 construct in A375 melanoma cells. We found that activation of Stat3 to moderate levels was sufficient to repress A375 proliferation, by slowing cell transit through the cell cycle.

Posterior interosseous nerve compression secondary to a parosteal lipoma: Case report and literature review.

An unusual case of limited radial nerve palsy secondary to a parosteal lipoma is presented, along with a thorough review of the literature. Palsy of the posterior interosseous nerve secondary to compression by a lipoma is a rare occurrence. Most cases tend to occur in the fifth to eighth decades of life.

Memo mediates ErbB2-driven cell motility.

Clinical studies have revealed that cancer patients whose tumours have increased ErbB2 expression tend to have more aggressive, metastatic disease, which is associated with parameters predicting a poor outcome. The molecular basis underlying ErbB2-dependent cell motility and metastases formation, however, still remains poorly understood. In this study, we show that activation of a set of signalling molecules, including MAPK, phosphatidylinositol-3-OH kinase (PI(3)K) and Src, is required for Neu/ErbB2-dependent lamellipodia formation and for motility of breast carcinoma cells.

Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins.

Overexpression of fibroblast growth factor receptor (FGFR) tyrosine kinases has been found in many human breast cancers and has been associated with poor patient prognosis. In order to understand the mechanism by which FGFR mediates breast cancer cell proliferation, we used a low molecular weight compound, PD173074, that selectively inhibits FGFR tyrosine kinase activity and autophosphorylation. This potential anticancer agent caused a G1 growth arrest of MDA-MB-415, MDA-MB-453 and SUM 52 breast cancer cells.

A new therapeutic antibody masks ErbB2 to its partners.

In cancer cells, the ErbB2 receptor tyrosine kinase can be activated in two ways: by overexpression or by ligand-mediated stimulation of another ErbB receptor. The ErbB2-targeting antibody trastuzumab (Herceptin) is used for treatment of metastatic breast cancer patients whose tumors overexpress ErbB2. A new structural study in this issue of Cancer Cell reveals how targeting ErbB2 with another antibody, pertuzumab (Omnitarg), prevents ligand-induced dimerization of ErbB2 with the other ErbB receptors.

Survival of ruptured abdominal aortic aneurysms in the west of Ireland: do prognostic indicators of outcome exist?

Ruptured abdominal aortic aneurysm (RAAA) is a demanding vascular surgical problem and the cause of significant morbidity and mortality. The aim of this study was to identify prognostic factors that influence outcome. Over 6 years, 42 ruptured abdominal aortic aneurysms were operated on with a mean diameter of 7.

ErbB receptors: directing key signaling networks throughout life.

The epidermal growth factor (EGF)-related peptides bind the ErbB receptors, inducing the formation of different homo- and heterodimers. Receptor dimerization promotes activation of the intrinsic kinase, leading to phosphorylation of specific tyrosines located in the ErbB's cytoplasmic region. These phosphorylated residues serve as docking sites for a variety of signaling molecules whose recruitment stimulates intracellular signaling cascades, which ultimately control diverse genetic programs.

Innovative surveillance methods for rapid detection of disease outbreaks and bioterrorism: results of an interagency workshop on health indicator surveillance.

A system designed to rapidly identify an infectious disease outbreak or bioterrorism attack and provide important demographic and geographic information is lacking in most health departments nationwide. The Department of Defense Global Emerging Infections System sponsored a meeting and workshop in May 2000 in which participants discussed prototype systems and developed recommendations for new surveillance systems. The authors provide a summary of the group's findings, including expectations and recommendations for new surveillance systems.

The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation.

ErbB2 is a receptor tyrosine kinase whose activity in normal cells depends on dimerization with another ligand-binding ErbB receptor. In contrast, amplification of c-erbB2 in tumors results in dramatic overexpression and constitutive activation of the receptor. Breast cancer cells overexpressing ErbB2 depend on its activity for proliferation, because treatment of these cells with ErbB2-specific antagonistic antibodies or kinase inhibitors blocks tumor cells in the G1 phase of the cell cycle.