The incidence and mortality rates of cervical cancer are declining in the United States; however, worldwide, cervical cancer is still one of the leading causes of death in women, second only to ...breast cancer. This disparity is at least partially explained by the absence of or comparatively ineffective screening programs in the developing world. Recent advances in expression genomics have enabled the use of DNA microarray to profile gene expression of various cancers. These expression profiles may be suitable for molecular classification and prediction of disease outcome and treatment response. We envision that expression genomics applied in cervical cancer may provide a more rational approach to the classification and treatment of the disease.
In this report, we examined the expression profiles of cervical cancer compared with normal cervical tissues in DNA microarrays that contained approximately 11,000 features that correspond to either human transcripts with known function or anonymous expressed sequence tags.
Our results showed that normal cervical tissues were completely segregated from the cancer samples using about 40 genes whose expressions were significantly different between these specimens. In addition, clinical stage IB and stage IIB tumors could also be classified based on their signature expression patterns. Most importantly, some of the tumor samples were further stratified into two major groups based on their response to radiotherapy, and we were able to predict the response of these patients to radiotherapy from their expression profiles.
Gene expression profiling by DNA microarray may be used for further molecular classification of disease stages and prediction of treatment response in cervical cancer.
Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active ...inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.
The epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases have been implicated in the development, progression, and severity of several human cancers and are attractive targets for ...therapeutic intervention. SU11925 was developed as a small molecule inhibitor of the tyrosine kinase activity of both EGFR and HER-2. In cellular assays, SU11925 exhibited similar potency against EGFR and HER-2, inhibiting EGF-stimulated EGFR autophosphorylation in A431 (human epidermoid carcinoma) cells with an IC(50) of 30 nM and HER-2 phosphorylation in SK-OV-3TP5 (human ovarian carcinoma) cells with an IC(50) of 38 nM. In contrast to its similar activity against the two targets in cellular assays, approximately 10-fold higher plasma concentrations of SU11925 were required to inhibit HER-2 phosphorylation in HER-2-overexpressing tumors compared with EGFR phosphorylation in EGFR-overexpressing tumors in vivo. Consistent with the proposed mechanism of action of this inhibitor, SU11925 inhibited the s.c. growth of EGFR- and HER-2-dependent tumors in athymic mice at doses that produced substantial inhibition of target receptor phosphorylation in vivo. An unexpected finding from these studies was that higher plasma concentrations of SU11925 were required to inhibit EGFR phosphorylation in vivo in tumors that also express high levels of HER-2 than in tumors that express EGFR alone. This observation, which suggests that it is more difficult to inhibit EGFR phosphorylation in vivo in cells that express high levels of HER-2, was confirmed with ZD1839 (Iressa), a selective EGFR inhibitor that also targets the tyrosine kinase catalytic site. The potential clinical implications of this observation are discussed.
Apolipoprotein (apo) B is essential for the assembly and secretion of triglyceride-rich lipoproteins made by the liver. As the sole protein component in LDL, apoB is an important determinant of ...atherosclerosis susceptibility and a potential pharmaceutical target. Single-chain antibodies (sFvs) are the smallest fragment of an IgG molecule capable of maintaining the antigen binding specificity of the parental antibody. In the present study, we describe the cloning and construction of two intracellular antibodies (intrabodies) to human apoB. We targeted these intrabodies to the endoplasmic reticulum for the purpose of retaining nascent apoB within the ER, thereby preventing its secretion. Expression of the 1D1 intrabody in the apoB-secreting human hepatoma cell line HepG2 resulted in marked reduction of apoB secretion. This study demonstrates the utility of an intrabody to specifically block the secretion of a protein determinant of plasma LDL as a therapeutic strategy for the treatment of hyperlipidemia.
The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a ...transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.
The current practice of evaluating heterotopic heart xenografts by palpation allows only detection of severe graft dysfunction, which indicates terminal graft failure. Therefore, we evaluated whether ...echocardiography is a better method of detecting early graft dysfunction as a marker of rejection in abdominal pig heart xenografts in cynomolgus monkeys.
Six cynomolgus monkeys received heterotopic heart transplants from pig donors transgenic for human decay-accelerating factor (hDAF). Induction therapy consisted of either cyclophosphamide or rabbit anti-thymocyte globulin. Maintenance therapy consisted of cyclosporine or tacrolimus, steroids, and sodium mycophenolate or mycophenolate mofetil, GAS914 (alphaGal oligosaccharide containing glycoconjugate), and for some animals TP10 (soluble complement receptor type 1). Echocardiography was performed immediately after transplantation and 3 times a week after surgery. We scored contractility and measured left ventricular wall thickness. Impaired contractility or increased wall thickness were considered graft dysfunction and were treated with pulse steroids. Palpation score was recorded daily. We also obtained myocardial biopsy specimens.
Palpation score remained at 4 out of 4 in all animals until 2 to 5 days before final graft failure, whereas echocardiography detected several episodes of impaired graft function, either decreased left ventricular contractility or increased left ventricular wall thickness before graft failure. Treatment with pulse steroids improved graft function only during early episodes of graft impairment. Final graft failure was steroid resistant and caused by severe vascular rejection.
Echocardiography is a better method of assessing graft dysfunction than is palpation. Therefore, echocardiography may detect early rejection episodes of heterotopic heart xenografts in non-human primates.
Here we report the production of transgenic pigs that express enhanced green fluorescent protein (eGFP). Porcine oocytes were matured in vitro in a serum-free, chemically defined maturation medium, ...subsequently infected with a replication deficient pseudotyped retrovirus, fertilized and cultured in vitro before being transferred to a recipient female. Two litters were born from these embryo transfers; one pig from each litter was identified as transgenic and both expressed eGFP. From a tool in basic research to direct applications in production agriculture, domestic livestock capable of expressing foreign genes have many scientific applications.
"Skills are key to a better job and a better life. Yet acquiring them is often most difficult for the people who need them most: those trapped in low-paid jobs with hard working conditions. ...Innovative experiments throughout OECD member countries show that barriers to skills acquisition can be overcome. A wide range of actors from government, business and civil society have joined efforts and embarked on initiatives that indeed fill the gap between labour market policy and vocational training, and workers' weaknesses and employers' evolving needs. There are rich lessons to be learned from the experiences of Belgium (Flanders), Canada, Denmark, the United Kingdom and the United States, which are investigated in this book." Die Untersuchung enthält quantitative Daten. Forschungsmethode: empirisch; Querschnitt; Fallstudie. (author's abstract, IAB-Doku). Contents: Sylvain Giguere: Chapter 1. An Introduction to Skills Upgrading: Why a Shift in Policy is Needed (23-32); Corinne Nativel: Chapter 2. From Welfare-to-Work to Welfare-in-Work: Concepts and Policies (33-84); Mette Norholm: Chapter 3. Education and Training for the Low-Skilled in Denmark: Linking Public Policy to Workplace Needs and Practice (85-128); Penny Tamkin, Jim Hillage, Viona Gerova: Chapter 4. The Regional Implementation of the Employer Training Pilots in the United Kingdom (129-173); Randall W. Eberts: Chapter 5. Sectoral Initiatives to Train Low-Qualified Incumbent Workers in the United States: Two Case Studies (175-221); Ides Nicaise, Roel Verlinden, Frank Pirard: Chapter 6. Skills Upgrading for Low-Qualified Workers in Flanders (223-259); Richard Brisbois, Ron Saunders: Chapter 7. Skills Upgrading Initiatives in Canada: Evidence from Alberta and the Northwest Territories (261-310).
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