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Brent Wood

Publications and source records attributed to Brent Wood.

10 recordsLinked to original sources
PubMed2026

Multimodal analysis of CD38 in T-cell Acute Lymphoblastic Leukemia Identifies Combinatorial Therapeutic Strategies.

Outcomes for pediatric patients with refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) are poor, underscoring the need for improved therapeutic strategies. CD38, a type II transmembrane glycoprotein, is a promising target in T-ALL, with clinical trials evaluating CD38-targeting immunotherapies in frontline and relapsed settings. However, the biological role of CD38 in T-ALL has not been systematically defined. We interrogated CD38 biology through multimodal profiling of pediatric T-ALL samples. Bulk RNA sequencing of 1,335 primary tumors revealed that CD38 expression varies across genomic and immunophenotypic subtypes in T-ALL. Flow cytometry of 150 primary samples and CITE-sequencing of 40 cases demonstrated broad surface expression of CD38. A transcription factor CRISPR-screen identified RUNX1, RUNX3, and TP53 as candidate positive regulators of CD38. Metabolomic profiling of cell lines further revealed disruption of the polyamine pathway following CD38 perturbation. Supporting this finding, co-targeting CD38 with difluoromethylornithine (DFMO), a polyamine metabolism disruptor, improved survival in preclinical models. Across transcriptomic datasets, including primary tumors, cell lines, and patient-derived xenograft models, IL32 expression consistently decreased following CD38 loss or negativity, supporting an association between CD38 and inflammatory signaling pathways. Additionally, CD38 and LCK expression were positively correlated across majority of genomic subtypes, implicating SRC kinase signaling. Consistent with this, daratumumab in cell lines increased LCK phosphorylation, and combination therapy with dasatinib improved survival compared to monotherapy. Collectively, these findings define previously unrecognized interactions between CD38 and targetable pathways and genes in T-ALL and identify rational combinatorial strategies to enhance CD38-directed therapies and reduce relapse risk.

Journal Article↗
PubMed2006

Moderate-intensity exercise reduces the incidence of colds among postmenopausal women.

PURPOSE: Our aim was to assess the effect of a moderate-intensity, year-long exercise program on the risk of colds and other upper respiratory tract infections in postmenopausal women. SUBJECTS: A total of 115 overweight and obese, sedentary, postmenopausal women in the Seattle area participated. METHODS: Participants were randomly assigned to the moderate-intensity exercise group or the control group. The intervention consisted of 45 minutes of moderate-intensity exercise 5 days per week for 12 months. Control participants attended once-weekly, 45-minute stretching sessions. Questionnaires asking about upper respiratory tract infections in the previous 3 months were administered quarterly during the course of the year-long trial. Poisson regression was used to estimate the effect of exercise on colds and other upper respiratory tract infections. RESULTS: Over 12 months, the risk of colds decreased in exercisers relative to stretchers (P = .02): In the final 3 months of the study, the risk of colds in stretchers was more than threefold that of exercisers (P = .03). Risk of upper respiratory tract infections overall did not differ (P = .16), yet may have been biased by differential proportions of influenza vaccinations in the intervention and control groups. CONCLUSIONS: This study suggests that 1 year of moderate-intensity exercise training can reduce the incidence of colds among postmenopausal women. These findings are of public health relevance and add a new facet to the growing literature on the health benefits of moderate exercise.

Aged↗
PubMed2006

Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women.

Folic acid (FA) supplements and food fortification are used to prevent neural tube defects and to lower plasma homocysteine. Through exposure to food fortification and vitamin supplement use, large populations in the United States and elsewhere have an unprecedented high FA intake. We evaluated dietary and supplemental intakes of folate and FA in relation to an index of immune function, natural killer cell (NK) cytotoxicity, among 105 healthy, postmenopausal women. Among women with a diet low in folate (<233 microg/d), those who used FA-containing supplements had significantly greater NK cytotoxicity (P = 0.01). However, those who consumed a folate-rich diet and in addition used FA supplements > 400 microg/d had reduced NK cytotoxicity compared with those consuming a low-folate diet and no supplements (P = 0.02). Prompted by this observation, we assessed the presence of unmetabolized FA in plasma as a biochemical marker of excess FA. Unmetabolized folic acid was detected in 78% of plasma samples from fasting participants. We found an inverse relation between the presence of unmetabolized FA in plasma and NK cytotoxicity. NK cytotoxicity was approximately 23% lower among women with detectable folic acid (P = 0.04). This inverse relation was stronger among women >or= 60 y old and more pronounced with increasing unmetabolized FA concentrations (P-trend = 0.002). Because of the increased intake of FA in many countries, our findings highlight the need for further studies on the effect of long-term high FA intake on immune function and health.

Diet↗
PubMed2006

9-color and 10-color flow cytometry in the clinical laboratory.

CONTEXT: The development of commercial flow cytometers capable of detecting more than 10 simultaneous fluorescent signals presents opportunities for improved diagnosis and monitoring of patients with leukemia and lymphoma. OBJECTIVE: To describe instrument and reagent characteristics necessary for successful 9-color and 10-color flow cytometry in a clinical setting. DESIGN: Systematic review of issues related to instrument settings, reagent performance, and general principles of panel construction. RESULTS: Nine-color and 10-color flow cytometry offers the possibility for increased accuracy in population identification, the ability to obtain detailed information from paucicellular specimens, improved laboratory efficiency, and the means to consistently detect abnormal populations at low levels. Careful attention to details of instrument and reagent performance allows for the development of panels suitable for screening of samples for leukemia and lymphoma in a clinical setting. CONCLUSIONS: The characteristics of this technique are particularly well suited to the analysis of leukemia and lymphoma and have the potential to revolutionize and standardize this type of analysis in the clinical laboratory.

Cell Separation↗
PubMed2005

Analysis of T-cell receptor gene rearrangement for predicting clinical outcome in patients with cutaneous T-cell lymphoma: a comparison of Southern blot and polymerase chain reaction methods.

OBJECTIVE: To extend previous observations regarding the prognostic value of analyzing lymph node DNA from patients with cutaneous T-cell lymphoma for the presence of a monoclonal T-cell population by Southern blot vs polymerase chain reaction (PCR) methods. DESIGN: Inception cohort study from 1982 to 1998. Recruitment of new patients ended in 1994. SETTING: A tertiary care referral center in Seattle, Wash. Patients Fifty-five uniformly staged patients with the diagnosis of cutaneous T-cell lymphoma who underwent a lymph node biopsy, 21 with clinically abnormal nodes and 34 with normal nodes. Interventions Lymph nodes were evaluated for T-cell receptor (TCR) gamma-chain gene rearrangement by 2 PCR methods: capillary electrophoresis and denaturing gradient gel electrophoresis. The same lymph nodes were evaluated by Southern blot analysis for TCR beta-chain gene rearrangement and examined histopathologically on the basis of the National Cancer Institute lymph node classification system. Patients were observed clinically for a mean of 9.5 years. MAIN OUTCOME MEASURES: Skin stage, clinical lymph node examination, lymph node histologic examination, Southern blot analysis, and PCR analyses were evaluated as potential prognostic predictors by univariate and multivariate analyses. The statistical association of TCR analysis and clinical outcome was determined among all patients. Hazard ratios (HRs) by Cox proportional hazards regression analysis were used to estimate the risk of a poor clinical outcome. Cumulative survival rates were analyzed by the Kaplan-Meier method. RESULTS: A skin stage of T3 (tumors) or T4 (erythroderma) was the most powerful predictor of a poor clinical outcome (HR, 31.3 vs T1; P<.001). Patients with detectable TCR gamma-chain gene rearrangement in lymph node DNA by PCR also were more likely to have a poor outcome (HR, 5.1; P<.001), but it was a less powerful predictor than skin stage. Even when the skin stage, presence or absence of lymphadenopathy, and histologic lymph node score were known for the patient, Southern blot analysis still added to prediction of a poor outcome (HR, 9.3; P = .007), whereas PCR provided no statistically significant additional information on outcome. CONCLUSIONS: Detection of a monoclonal T-cell population by PCR in lymph nodes of patients with cutaneous T-cell lymphoma does not enhance prediction of clinical outcome and probability of survival beyond what can be determined from clinical examination and histologic lymph node scores. Skin stage and the presence or absence of lymphadenopathy remain the most important determinants of clinical outcome.

Aged↗
PubMed2005

Augmented mobilization and collection of CD34+ hematopoietic cells from normal human volunteers stimulated with granulocyte-colony-stimulating factor by single-dose administration of AMD3100, a CXCR4 antagonist.

BACKGROUND: AMD3100, a selective antagonist of CXCR4, rapidly mobilizes CD34+ hematopoietic progenitor cells (HPCs) from marrow to peripheral blood with minimal side effects. STUDY DESIGN AND METHODS: To further investigate potential clinical utility of AMD3100 for CD34+ cell mobilization and collection, a Phase I study in normal volunteers was performed examining single-dose administration of AMD3100 alone and in combination with a standard 5-day granulocyte-colony-stimulating factor (G-CSF) regimen. RESULTS: AMD3100 (160 microg/kg x 1 on Day 5) significantly increased both G-CSF-stimulated (10 microg/kg/day) mobilization of CD34+ cells (3.8-fold) and leukapheresis yield of CD34+ cells. Moreover, collection of CD34+ cells was comparable between individuals mobilized by a single-dose regimen of AMD3100 (240 microg/kg) and individuals mobilized with a 5-day regimen of G-CSF. AMD3100-mobilized leukapheresis products contained significantly greater numbers of T and B cells compared to G-CSF-stimulated leukapheresis products. CONCLUSION: These findings indicate that AMD3100 can be used alone or as an adjunct to G-CSF to mobilize cells for HPC transplantation.

Anti-HIV Agents↗
PubMed2004

Frequent intentional weight loss is associated with lower natural killer cell cytotoxicity in postmenopausal women: possible long-term immune effects.

OBJECTIVE: Weight-loss attempts are likely to become more frequent as the prevalence of obesity rises. Repeated cycles of loss and gain are a common consequence of failed weight-loss attempts. The question of whether this pattern has negative health effects is unresolved. The objective of this research was to investigate associations between weight-loss history and current measures of immune function. DESIGN: The study design was a cross-sectional study. SUBJECTS: One hundred fourteen healthy, overweight, sedentary, postmenopausal women were recruited for an exercise intervention study and were currently weight stable. METHODS: History of intentional weight loss was assessed by questionnaire. Flow cytometry was used to measure natural killer cell (NK) cytotoxicity at four effector-to-target (E:T) ratios and for enumerating and phenotyping lymphocytes. Multiple linear regression analysis was used to investigate associations between weight loss within the past 20 years and current immune function. RESULTS: Women who reported ever intentionally losing >or=10 pounds had lower measured NK cytotoxicity than those who did not (24.7%+/-12.1% vs 31.1%+/-14.7%, respectively, at E:T 25:1; P=.01). Increasing frequency of previous intentional weight loss was associated with lower NK cytotoxicity (P=.003, trend). As an independent predictor, longer duration of recent weight stability was associated with higher NK cytotoxicity (21.6%+/-11.9%, 24.4%+/-11.0%, and 31.9%+/-14.4% for 2 to 5 years of weight stability, respectively; P=.0002, trend). The frequency of weight loss episodes was also associated with differences in the number and proportion of NK cells. CONCLUSIONS: This study provides evidence that frequent intentional weight loss may have long-term effects on immune function.

Aged↗
PubMed2003

Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist.

Stromal cell-derived factor 1 (SDF1/CXCL12) and its cognate receptor, CXCR4, play key regulatory roles in CD34+ cell trafficking. We investigated whether AMD3100, a selective CXCR4 antagonist, could mobilize hematopoietic progenitor cells from marrow to peripheral blood in healthy human volunteers. Initially, 10 persons each received a single dose of AMD3100 (80 microsubcutaneously), which induced rapid, generalized leukocytosis associated with an increase in peripheral blood CD34+ cells, representing pluripotent hematopoietic progenitors by in vitro colony-forming unit assays, from 3.8 +/- 0.5/microL to 20.7 +/- 3.5/microL at 6 hours. Subsequent dose-response studies showed a maximum increase in circulating CD34+ cells from 2.6 +/- 0.3/microL to 40.4 +/- 3.4/microL at 9 hours after 240 micro/kg AMD3100. Serial administration of AMD3100 (80 microg/kg/d for 3 days) resulted in consistent, reversible increases in peripheral blood CD34+ cells. AMD3100 was well tolerated and caused only mild, transient toxicity. These findings suggest potential clinical application of AMD3100 for CD34+ cell mobilization and collection for hematopoietic stem cell transplantation.

Adult↗
PubMed2002

Multicenter clinical experience with flow cytometric method for fetomaternal hemorrhage detection.

BACKGROUND: Enumeration of fetal red blood cells (RBCs) is important in the management of fetomaternal hemorrhage (FMH), particularly in situations of Rh incompatibility. METHODS: We evaluated results from three institutions using the flow cytometric method (FCM) to detect fetal RBCs based on the anti-hemoglobin F (HbF) monoclonal antibody method. RESULTS: During 1997-2001, 69 of 1248 patients (5.5%) had measurable fetal erythrocytes (RBCs) in maternal blood. Only 21 patients (1.7%) had more than 30 mL of fetal blood detected in maternal blood. Of the 11 patients with large FMH and clinical follow-up, 7 had fetal demise (64%). In positive samples, significant differences were found in the fluorescence intensity (FI) of anti-HbF antibody staining between HbF-negative erythrocytes (HbF-) and adult HbF containing erythrocytes (F cells; 4 +/- 0 versus 57 +/- 9 linear mean channels [LMC]; P < 0.001) and between HbF-cells and fetal RBCs (4 +/- 0 versus 433 +/- 136 LMC; P < 0.001). In addition, significant differences were observed in forward light scatter intensity between HbF-cells and fetal RBCs (298 +/- 15 versus 355 +/- 68 LMC, P = 0.03). The transportability of the test is also addressed by comparing results from two other laboratories. The experience of our three laboratories, as well as the results from the recently reinitiated College of American Pathologists survey, which compares FCM and manual methods, clearly documents the superiority of the FCM test over the manual Kleihauer-Betke (KB) test. CONCLUSIONS: The FCM is a simpler, more objective, and more precise alternative to the KB method in clinical testing. The high mortality rate associated with large FMH and therapeutic implications of these results should give laboratories motivation to abandon the KB method with more robust FCM to detect FMH.

Adult↗