Early stage breast cancer

Breast cancer is the most common malignancy seen in women. Due to the increasing awareness for this disease and the increasing use of screening mammography, more patients are now diagnosed with early stage disease. Over the past few years, the indications for adjuvant treatment have expanded considerably, and more women are now candidates for chemotherapy, hormonal therapy, or both. The role of various prognostic factors and their implications on the design of a multidisciplinary therapeutic approach is discussed in this review. Current recommendations regarding the extent of the surgery, the role of radiation, and its integration to the adjuvant treatment are discussed. Guidelines on adjuvant chemotherapy and adjuvant hormonal therapy are also being presented.     

Poly-L-lysine-based molecular conjugate vectors: a high efficiency gene transfer system for human progenitor and leukemia cells

BACKGROUND: Targeted, specific receptor mediated gene transfer is a major goal of gene therapy research to accomplish gene transfer exclusively to the desired cell population. METHODS: First, the use of natural receptor for stem cell factor and transferrin receptor-targeted gene transfer using poly-L-lysine-based molecular conjugate vectors was evaluated in a panel of hematopoietic progenitor cell lines. Second, the ability of poly-L-lysine to enhance adenovirus mediated gene transfer efficiency was examined in different cell lines by using recombinant adenovirus-poly-L-lysine molecular conjugate conglomerates (recMCVEGFP). RESULTS: Despite effective ligand internalization receptor, gene expression amplification in receptor positive cell lines was not uniformly observed. Therefore, using a poly-L-lysine-based, receptor-targeted vector, neither transferrin nor natural receptor for stem cell factor mediated gene transfer can be considered a universally applicable procedure that exclusively depends on the presence of receptors on the cell surface; rather, it is a cell specific phenomenon. In our model, poly-L-lysine is the major contributor for gene transfer to hematopoietic progenitor cells, mediating the initial vector-cell binding. Human progenitor cell lines are poorly transduceable with recombinant adenovirus vectors. This new poly-L-lysine-modified, adenovirus-based vector could overcome virus tropism restrictions and consistently achieve very high transduction efficiency (>90%) in cells otherwise refractory to adenovirus gene transfer. CONCLUSIONS: Polylysine-based adenovirus vectors may have promise for situations in which high-efficiency gene transfer with transient high level transgene expression in hematopoietic cells is needed, such as leukemia vaccine protocols or for purging strategies in leukemia cell contaminated stem cell preparations.     

语言刺激的功能性MR成像在自闭症诊断中的潜在应用价值

目的对自闭症病人给予被动性语言刺激,评价采用功能性磁共振(MR)成像作为判断病人有无语言缺陷的客观指标的可行性。材料与方法本研究为前瞻性研究,研究方     

Development of a gene therapy based bone marrow purging system for leukemias

Although viable gene therapy based methods have been reported for the selective removal or purging of contaminating epithelial derived cancer cells from stem cell grafts, similar strategies for the purging of leukemia cells have been significantly less efficient. Hematopoietic cells are difficult targets for transduction with currently available vectors. Polylysine based molecular conjugate vectors (MCV) were previously found to effectively transduce both normal and malignant hematopoietic cells. A panel of human leukemia cell lines as well as CD34+ selected primary human hematopoietic progenitor cells (HPC) were tested for differential gene expression utilizing different promoters. Reporter gene expression under the control of RSV and SV40 promoters showed a 6-log fold increase in leukemia cells when compared to primary HPC. Using a polylysine based recombinant molecular conglomerate vector (recMCV) encoding the HSV-tk suicide gene under control of RSV, we demonstrated effective and specific cell killing in all leukemia cell lines as well as in primary human leukemia cells derived from chemotherapy refractory patients, while HPC survived under the same conditions at approximately 20% viability. These proof of principle experiments demonstrate that gene therapy technology could be utilized to successfully purge leukemia cells from HPC.     

Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense

Bacterial pneumonia is an increasing complication of HIV infection and inversely correlates with the CD4(+) lymphocyte count. Interleukin (IL)-17 is a cytokine produced principally by CD4(+) T cells, which induces granulopoiesis via granulocyte colony-stimulating factor (G-CSF) production and induces CXC chemokines. We hypothesized that IL-17 receptor (IL-17R) signaling is critical for G-CSF and CXC chemokine production and lung host defenses. To test this, we used a model of Klebsiella pneumoniae lung infection in mice genetically deficient in IL-17R or in mice overexpressing a soluble IL-17R. IL-17R-deficient mice were exquisitely sensitive to intranasal K. pneumoniae with 100% mortality after 48 h compared with only 40% mortality in controls. IL-17R knockout (KO) mice displayed a significant delay in neutrophil recruitment into the alveolar space, and had greater dissemination of K. pneumoniae compared with control mice. This defect was associated with a significant reduction in steady-state levels of G-CSF and macrophage inflammatory protein (MIP)-2 mRNA and protein in the lung in response to the K. pneumoniae challenge in IL-17R KO mice. Thus, IL-17R signaling is critical for optimal production of G-CSF and MIP-2 and local control of pulmonary K. pneumoniae infection. These data support impaired IL-17R signaling as a potential mechanism by which deficiency of CD4 lymphocytes predisposes to bacterial pneumonia.     

Treatment of mesothelioma with gene-modified PA1STK cells and ganciclovir: a phase I study

Mesothelioma is an incurable cancer of the pleura with a life expectancy of less than 1 year. On the basis of in vivo efficacy seen with the herpes simplex virus type 1 thymidine kinase (HSVtk) suicide gene-modified PA1STK cell line and ganciclovir (GCV) in a murine model of mesothelioma, a first in humans, clinical trial was designed for this therapeutic concept. The study was a phase I clinical trial using direct infusion of escalating doses of HSVtk suicide gene-modified PA1STK cells directly into tumor-associated pleural effusions followed by 7 days of intravenous GCV infusion. Therapeutic levels of GCV in both serum and pleura were achieved within 1?h, and GCV trough levels remained above the therapeutic threshold for the duration of GCV treatment. The treatment was well tolerated without any Grade 3 or 4 toxicity observed. Significant inductions of both Th1 and Th2 cytokines up to 20-fold over baseline were observed. No significant differences were seen between serum and pleura cytokine profiles, with the exception of interleukin-10, which was consistently elevated in the pleura specimens. No objective radiographic responses were observed. The data indicate significant immunological responses and validate the principal anti-tumor mechanisms observed in preclinical models of mesothelioma in a human clinical trial.     

Dose-dependent systemic and regional hemodynamic effects of calcitonin gene-related peptide

The dose-response effects of infused calcitonin gene-related peptide (CGRP), a potent vasodilator, on systemic and regional hemodynamics in the conscious rat remain incompletely defined. The radioactive microsphere technique provided these determinations before and after the intravenous administration of vehicle or 22, 65, 220, and 2200 pmol of CGRP. Neither vehicle nor 22 pmol of CGRP significantly changed any systemic or regional hemodynamic parameter. Starting at the 65-pmol dose, CGRP significantly decreased mean blood pressure and total peripheral resistance, while increasing heart rate without changing cardiac output. CGRP produced selective regional vasodilatory effects, with the coronary circulation being unusually sensitive. In contrast, CGRP caused significant increases in blood flow to the mesenteric and cutaneous circulations only at the two highest doses. CGRP increased plasma norepinephrine, epinephrine, and renin activity significantly at only the 2200-pmol dose. In conclusion, CGRP decreases blood pressure by peripheral vasodilation, with a threshold dose occurring between 22 and 65 pmol. In addition, the coronary circulation appears to be particularly sensitive to the vasodilatory properties of CGRP.