Pharmacogenetics and proteomics of anticancer drugs in non-Hodgkin's lymphoma

The variability of tumor responses to chemotherapeutic agents is a topic of major interest in current cancer research. Advances in the knowledge of dysregulation of key molecular pathways in cancer cells have enabled techniques to be developed that can profile tumor cells for their genetic background, allowing selection of anticancer agents on an individual basis. The next generation of anticancer treatments might therefore be tailored according to the molecular alterations identified in tumor cells of individual patients. However, before these alterations can be exploited from a therapeutic point of view, it is necessary to understand how such alterations influence the cellular pathways that control sensitivity to chemotherapeutic agents. Pharmacogenetics and pharmacoproteomics, novel disciplines that investigate the relationship between gene and protein expression in tumor cells and the response to anticancer agents, will be instrumental in developing optimal chemotherapeutic regimens for patients with non-Hodgkin's lymphoma.     

Virus-specific DNA sequences in mouse and rat cells transformed by the Harvey and Moloney murine sarcoma viruses detected by in situ hybridization.

The [³H]DNA product of the murine sarcoma-leukemia virus (MSV(MLV)) and viral 60–70 S [³H]RNA was annealed with cytological preparations of mouse and rat cells transformed by the Harvey and Moloney strains of MSV. With viral [³H]DNA as cytological probe, these in situ hybridization measurements detected from 25 to 30 autoradiographic grains per interphase nucleus of transformed cells and 1 to 3 grains per nucleus of uninfected rat and mouse cells. With viral 60–70 S [³H]RNA of lower specific radioactivity as cytological probe, 12 grains per transformed cell nucleus were detected. These findings indicate that transformation of cells with MSV(MLV) produces a several-fold increase in the content of some virus-specific DNA sequences. Virus-specific sequences in transformed mouse cells were localized in the chromocenters of interphase nuclei.     

Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma.

PURPOSE: To investigate the use of a nonmyeloablative fludarabine-based immunosuppressive regimen to allow engraftment of HLA-sibling donors' mobilized stem cells and induction of a graft-versus-lymphoma effect for patients with advanced resistant Hodgkin's disease and non-Hodgkin's lymphoma. PATIENTS AND METHODS: Fifteen patients with Hodgkin's disease (n = 10) and non-Hodgkin's lymphoma (n = 5) were studied. All patients received cyclophosphamide and granulocyte colony-stimulating factor to mobilize autologous hematopoietic stem cells (HSCs). Subsequently, they received high-dose therapy with carmustine, etoposide, cytarabine, and melphalan and reinfusion of HSCs. At a median of 61 days after engraftment, patients were given fludarabine 30 mg/m(2) with cyclophosphamide 300 mg/m(2) daily for 3 days. Donor-mobilized HSC collections were prepared for fresh infusion and were not T-cell depleted. Methotrexate and cyclosporine were used to prevent graft rejection and as graft-versus-host disease (GVHD) prophylaxis. RESULTS: Combined treatment was well tolerated. After mini-allografting, hematologic recovery was prompt. Thirteen patients had 100% donor cell engraftment. Eleven patients achieved complete remission (CR) after the combined procedure. Nine patients, who were in partial remission after autografting, achieved CR after mini-allografting. Seven patients developed >/= grade 2 acute GVHD (aGVHD) and two developed extensive chronic GVHD (cGVHD). Three patients who received the highest number of donor lymphocyte infusions (DLIs) developed grade 3 GVHD (two patients) and extensive cGVHD (one patient). Ten patients are currently alive, and five are in continuous CR. Seven patients received DLI, with five CRs. Five patients died: one of progressive disease, two of progressive disease combined with aGVHD or cGVHD, one of extensive cGVHD, and one of infection. CONCLUSION: Fludarabine/cyclophosphamide was well tolerated and allowed consistent engraftment in lymphoma allografted patients. Response rates were high in this group of refractory and heavily pretreated patients. This dual procedure seems to be most promising in patients with end-stage malignant lymphomas.     

Neighborhood Context and Black Heterosexual Men’s Sexual HIV Risk Behaviors

The effects of neighborhood context on sexual risk behavior are understudied, particularly for Black heterosexual men who do not inject drugs or report heavy drug use. Evidence of a generalized HIV epidemic (>1 %) among Black heterosexuals in low-income urban U.S. communities underscores the importance of examining the effects of neighborhood context on Black heterosexual men’s sexual risk, however. We used structural equation modeling to test the pathways between neighborhood context (neighborhood disorder, personal violence, neighborhood threats), depression, substance use, and sexual risk behavior. Participants were 526 self-identified Black heterosexual men, ages 18–45, recruited via randomized venue-based probability sampling in Philadelphia, PA. Analyses of model fit statistics from Mplus indicated statistically significant direct pathways between neighborhood context, depression, substance use, and sexual risk behavior. The total indirect effect of neighborhood context on sexual risk behavior through substance use was also significant. The study’s results highlight a need for more research on neighborhood context and sexual HIV risk, and for multilevel interventions to address the effects of negative neighborhood context on Black heterosexual men’s sexual HIV risk.     

Helium (argon) plasma coagulation in neurosurgery. morphology of tissue damage and reparation.

Plasma coagulation, used in some neurosurgical operative settings, is currently under experimental investigation for the precise assessment of the kind and extent of tissue damage. We established a standardised trial to investigate the effects of helium (argon) plasma coagulation - H(A)PC - on rat brain tissue. The tissue reactions were observed with common methods of morphology including immunohistology and electron microscopy. A time dependent profile of the tissue reactions was performed from day 1 after operation up to 6 weeks. The tissue reaction consisted of clearly demarcated concentric zones. The depth of the lesion was about 1 mm maximally, at the beginning. Reparative forces acted at variance both in the different layers and at the edges versus the center of the damage. A manifold but reproducible picture emerges in the various compartments allowing the study of different aspects of organisation and/or elimination of tissue components. This study has demonstrated that a defined circumscribed and reproducible small lesion can be performed with H(A)PC. As in other areas of surgery, this technique has proven to be minimally traumatic. Clinical application of this technique in neurosurgery is therefore promising. In addition, H(A)PC lesions are obviously best suited for morphological studies of early and late reparative reactions in cells and tissues.