Fred Hutchinson Cancer Research Center

About: Fred Hutchinson Cancer Research Center is a nonprofit organization based out in Cape Town, South Africa. It is known for research contribution in the topics: Population & Transplantation. The organization has 12322 authors who have published 30954 publications receiving 2288772 citations. The organization is also known as: Fred Hutch & The Hutch.

Cytomegalovirus reactivation in critically ill immunocompetent patients.

Abstract: Context Cytomegalovirus (CMV) infection is associated with adverse clinical outcomes in immunosuppressed persons, but the incidence and association of CMV reactivation with adverse outcomes in critically ill persons lacking evidence of immunosuppression have not been well defined. Objective To determine the association of CMV reactivation with intensive care unit (ICU) and hospital length of stay in critically ill immunocompetent persons. Design, setting, and participants We prospectively assessed CMV plasma DNAemia by thrice-weekly real-time polymerase chain reaction (PCR) and clinical outcomes in a cohort of 120 CMV-seropositive, immunocompetent adults admitted to 1 of 6 ICUs at 2 separate hospitals at a large US tertiary care academic medical center between 2004 and 2006. Clinical measurements were assessed by personnel blinded to CMV PCR results. Risk factors for CMV reactivation and association with hospital and ICU length of stay were assessed by multivariable logistic regression and proportional odds models. Main outcome measures Association of CMV reactivation with prolonged hospital length of stay or death. Results The primary composite end point of continued hospitalization (n = 35) or death (n = 10) by 30 days occurred in 45 (35%) of the 120 patients. Cytomegalovirus viremia at any level occurred in 33% (39/120; 95% confidence interval [CI], 24%-41%) at a median of 12 days (range, 3-57 days) and CMV viremia greater than 1000 copies/mL occurred in 20% (24/120; 95% CI, 13%-28%) at a median of 26 days (range, 9-56 days). By logistic regression, CMV infection at any level (adjusted odds ratio [OR], 4.3; 95% CI, 1.6-11.9; P = .005) and at greater than 1000 copies/mL (adjusted OR, 13.9; 95% CI, 3.2-60; P Conclusions These preliminary findings suggest that reactivation of CMV occurs frequently in critically ill immunocompetent patients and is associated with prolonged hospitalization or death. A controlled trial of CMV prophylaxis in this setting is warranted.

The SmoA1 Mouse Model Reveals That Notch Signaling Is Critical for the Growth and Survival of Sonic Hedgehog-Induced Medulloblastomas

Abstract: To develop a genetically faithful model of medulloblastoma with increased tumor incidence compared with the current best model we activated the Sonic Hedgehog (Shh) pathway by transgenically expressing a constitutively active form of Smoothened in mouse cerebellar granule neuron precursors (ND2:SmoA1 mice). This resulted in early cerebellar granule cell hyper-proliferation and a 48% incidence of medulloblastoma formation. Gene expression studies showed an increase in the known Shh targets Gli1 and Nmyc that correlated with increasing hyperplasia and tumor formation. Notch2 and the Notch target gene, HES5, were also significantly elevated in Smoothened-induced tumors showing that Shh pathway activation is sufficient to induce Notch pathway signaling. In human medulloblastomas reverse transcription-PCR for Shh and Notch targets revealed activation of both of these pathways in most tumors when compared with normal cerebellum. Notch pathway inhibition with soluble Delta ligand or gamma secretase inhibitors resulted in a marked reduction of viable cell numbers in medulloblastoma cell lines and primary tumor cultures. Treatment of mice with D283 medulloblastoma xenografts with a gamma secretase inhibitor resulted in decreased proliferation and increased apoptosis, confirming that Notch signaling contributes to human medulloblastoma proliferation and survival. Medulloblastomas in ND2:SmoA1 mice and humans have concomitant increase in Shh and Notch pathway activities, both of which contribute to tumor survival.

Recombinant Granulocyte-Macrophage Colony-Stimulating Factor after Autologous Bone Marrow Transplantation for Lymphoid Cancer

Abstract: Background. The period of neutropenia after autologous bone marrow transplantation results in substantial morbidity and mortality. The results of previous phase I-II clinical trials suggest that recombinant human granulocytemacrophage colony-stimulating factor (rhGM-CSF) may accelerate neutrophil recovery and thereby reduce complications in patients after autologous bone marrow transplantation. Methods. We conducted a randomized, double-blind, placebo-controlled trial at three institutions. The study design and treatment schedules were identical, and the results were pooled for analysis. One hundred twenty-eight patients were enrolled. Sixty-five patients received rhGM-CSF in a two-hour intravenous infusion daily for 21 days, starting within four hours of the marrow infusion, and 63 patients received placebo. Results. No toxic effects specifically ascribed to rhGM-CSF were observed. The patients given rhGM-CSF had a recovery of the neutrophil count to 500×106 per liter 7 days earlier than the patients who...

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

Abstract: per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2–positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. Conclusions Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log 10 copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)