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Exercise is critical for health maintenance in late life. The COVID-19 shelter in place and social distancing orders resulted in wide-scale interruptions of exercise therapies, placing older adults at risk for the consequences of decreased mobilization. The purpose of this paper is to describe rapid transition of the Gerofit facility-based group exercise program to telehealth delivery. This Gerofit-to-Home (GTH) program continued with group-based synchronous exercise classes that ranged from 1 to 24 Veterans per class and 1 to 9 classes offered per week in the different locations. Three hundred and eight of 1149 (27%) Veterans active in the Gerofit facility-based programs made the transition to the telehealth delivered classes. Participants’ physical performance testing continued remotely as scheduled with comparisons between most recent facility-based and remote testing suggesting that participants retained physical function. Detailed protocols for remote physical performance testing and sample exercise routines are described. Translation to remote delivery of exercise programs for older adults could mitigate negative health effects.

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805 ., (© 2024. The Author(s).)

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 10 6 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 ., (© 2024. The Author(s).)

T cells engineered to express HIV-specific chimeric antigen receptors (CARs) represent a promising strategy to clear HIV-infected cells, but to date have not achieved clinical benefits. A likely hurdle is the limited T cell activation and persistence when HIV antigenemia is low, particularly during antiretroviral therapy (ART). To overcome this issue, we propose to use a cytomegalovirus (CMV) vaccine to stimulate CMV-specific T cells that express CARs directed against the HIV-1 envelope protein gp120. In this study, we use a GMP-compliant platform to engineer CMV-specific T cells to express a second-generation CAR derived from the N6 broadly neutralizing antibody, one of the broadest anti-gp120 neutralizing antibodies. These CMV-HIV CAR T cells exhibit dual effector functions upon in vitro stimulation through their endogenous CMV-specific T cell receptors or the introduced CARs. Using a humanized HIV mouse model, we show that CMV vaccination during ART accelerates CMV-HIV CAR T cell expansion in the peripheral blood and that higher numbers of CMV-HIV CAR T cells were associated with a better control of HIV viral load and fewer HIV antigen p24 + cells in the bone marrow upon ART interruption. Collectively, these data support the clinical development of CMV-HIV CAR T cells in combination with a CMV vaccine in HIV-infected individuals., Competing Interests: Competing interests: A patent associated with this study covering the work has been held and submitted by City of Hope (US2016/024560) with X.W. and S.J.F. as inventors who could potentially receive licensing royalties in the future. The remaining authors declare no competing interests.

Aims: Veterans of the 1991 Gulf War reported symptoms in their spouses that mirrored veterans' symptoms following their return from the war, including problems with attention and memory. Neuropsychological functioning in these spouses has not been examined with objective tests. This study sought to determine if these spouses exhibited deficits in neuropsychological functioning., Main Methods: Spouses of a national cohort of 1991 Gulf War deployed (n = 470) and non-deployed veterans (n = 524) were examined with neuropsychological tests in 1999-2001., Key Findings: Neuropsychological tests were factor analyzed yielding five factors: verbal memory, visual memory, attention/working memory, visual organization, and motor speed. Spouses of deployed and nondeployed veterans did not differ on mean factor scores, percentage of impaired factors, or individual test scores. Spouse attention/working memory was related to their having diagnoses of PTSD or anxiety disorders, or self-reported symptoms of current anxiety. Spouse visual memory was related to a diagnosis of current depression. Spouse motor speed was related to their own status of having chronic multisymptom illness (CMI)., Significance: Spouses of Gulf War deployed and nondeployed veterans demonstrated similar neuropsychological functioning, although spouses with psychiatric diagnoses and symptoms, or CMI demonstrated neuropsychological impairments characteristic of those conditions, suggesting that monitoring spouses for these conditions and impairments may be warranted. This pattern of relative weaknesses mirrors some of the previously reported findings for Gulf War veterans, although the veterans displayed neuropsychological impairments beyond what was accounted for by these conditions., (Copyright © 2021. Published by Elsevier Inc.)

CD19-directed chimeric antigen receptor (CD19CAR) T-cell therapy has been successful in treating several B-cell lineage malignancies, including B-cell non-Hodgkin lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily as a result of concerns for potential toxicity. CD19CAR T cells administered IV are detectable in cerebrospinal fluid (CSF), suggesting that chimeric antigen receptor (CAR) T cells can migrate from the periphery into the CNS, where they can potentially mediate antilymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ongoing phase 1 clinical trial. All patients developed grade ≥ 1 cytokine release syndrome and neurotoxicity post-CAR T-cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%; 90% confidence interval, 19-92%) seemed to achieve complete remission, as indicated by resolution of enhancing brain lesions; the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrate that using CD19CAR T cells to treat PCNSL can be safe and feasible. This trial was registered at www.clinicaltrials.gov as #NCT02153580., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: We examined whether the prevalence of medical and behavioral conditions is higher in children of deployed veterans (DVs) versus non-deployed veterans (NDVs) after the 1991 Gulf War., Methods: We examined 1387 children of 737 veterans. Children ages 2-18 had physical exams and parental reports of physical history and behavior., Results: Physical health was analyzed using GEE models. Behavioral health [total, internalizing, and externalizing behavior problems (TBP, IBP, EBP)] was analyzed with mixed-effects regression models. Analyses were conducted by age group (2-3, 4-11, 12-18), and gender (ages 4-11, 12-18). Children of DVs ages 2-3 had significantly worse dentition (13.9% vs. 4.8%, P = 0.03) and more EBP {least square means (lsmeans) 54.31 vs. 47.59, P = 0.02}. Children of DVs ages 4-11 had significantly more obesity (18.8% vs. 12.7%, P = 0.02). Among children 4-11, male children of DVs had significantly more TBP (lsmeans 70.68 vs. 57.34, P = 0.003), IBP (lsmeans 63.59 vs. 56.16, P = 0.002) and EBP (lsmeans 61.60 vs. 52.93, P = 0.03), but female children did not. For children ages 12-18, male children of DVs had more EBP (lsmeans 63.73 vs. 43.51, P = 0.008), while female children of DVs had fewer EBP (lsmeans 45.50 vs. 50.48, P = 0.02). Veteran military characteristics and mental health, and children's social status and health, including obesity, predicted children's TBP for one or more age groups., Conclusions: Children of DVs experienced worse dentition, greater obesity, and more behavioral problems compared to NDV children, suggesting adverse health effects associated with parental deployment in need of further exploration., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The tolerability and efficacy of targeted therapy in older adults with cancer has not been adequately studied. Neratinib is a novel HER1, HER2, HER4 tyrosine kinase inhibitor that has recently been granted FDA approval for treatment of breast cancer. The major toxicity of neratinib is diarrhea, which affects up to 90% of patients. This phase II trial evaluates the safety and tolerability of neratinib in adults ≥60., Methods: Patients aged 60 or older with histologically proven metastatic breast cancer and HER2 amplification (defined by ASCO/CAP guideline) or HER2/HER3 activating mutation were enrolled to receive neratinib at 240 mg daily in 28-day cycles. The association between tolerability, defined as dose reduction and number of completed courses, and log 2 Cancer and Aging Research Group (CARG) toxicity risk score was assessed using a Student's t-test and linear regression, respectively. Response rate, progression free survival, and overall survival were also evaluated., Results: 25 patients were enrolled with median age of 66 (range 60-79). Seventy-six percent of patients were white, 16% Asian, and 8% African-American. Seventy-six percent were patients with hormone receptor (HR) positive metastatic breast cancer (MBC) and 24% were patients with HR negative MBC. Median number of prior lines of metastatic therapy were 3 (range 0-11). 20/25 (80%) had worst grade toxicities ≥2. A total of 9/25 (36%) had grade 3 toxicities including 5/20 (20%) diarrhea, 2/20 (8%) vomiting, and 2/20 (8%) abdominal pain. There were no grade 4 or 5 toxicities. A total of 9/25 (36%) had dose reduction, and 2/25 (8%) discontinued therapy due to toxicity. The association between dose reductions and CARG toxicity score reached borderline statistical significance suggesting a trend with participants with higher CARG toxicity risk scores being more likely to require a dose modification (p = 0.054). 1/25 (4%) had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not assessed. Median progression free survival (PFS) was 2.6 months (95% CI [2.56-5.26]), and median overall survival (OS) was 17.4 months (95% CI [10.3, NA])., Conclusions: Neratinib was safe in this population of older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer (BC). Higher CARG toxicity risk score may be associated with greater need for dose adjustments. Future studies are needed to confirm this finding., Competing Interests: Declaration of Competing Interest Dr. Yuan has contracted research sponsored by Merck, Eisai, Novartis, Puma, Genentech, and Pfizer; is a consultant for Puma, and is on the Speakers Bureau for Eisai. The other authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: Little is known about the penetration and bioactivity of systemically administered programmed cell death 1 (PD-1) antibodies in the central nervous system. Such information is critical for advancing checkpoint antibody therapies for treatment of brain tumors., Objective: To evaluate pembrolizumab concentrations and PD-1 blockade on T cells in the cerebrospinal fluid (CSF) after intravenous administration., Design, Setting, and Participants: Cerebrospinal fluid and blood samples were collected from 10 adult patients with high-grade gliomas who were participating in clinical trials of intracranially administered chimeric antigen receptor (CAR) T cells and intravenous pembrolizumab at City of Hope in Duarte, California, from 2017 through 2019. Neuropharmacokinetic and immunologic correlative studies were performed on CSF and serum samples., Interventions or Exposures: Pembrolizumab, 200 mg, was given intravenously every 3 weeks with a median of 2 cycles (range, 1-8). CAR T cells were administered intracranially every 1 to 4 weeks. Cerebrospinal fluid and blood samples were collected on the day of CAR T-cell administration and then 24 hours later for a total of 100 paired samples., Main Outcomes and Measures: Pembrolizumab concentrations were measured by enzyme-linked immunosorbent assay, PD-1 blocking on T cells by flow cytometry, and results of PD-1 blockade on CAR T-cell function by in vitro tumor rechallenge assays., Results: Of the 10 patients included in this study, the mean (SD) age was 45.7 (11.0) years, and 6 (60%) were women. Steady-state pembrolizumab concentrations in the CSF were achieved by 24 hours after initial intravenous administration, with a mean CSF:serum ratio of 0.009 (95% CI, 0.004-0.014). The CSF concentrations of pembrolizumab effectively blocked PD-1 on both endogenous T cells and intracranially administered CAR T cells in the CSF, with flow cytometric detection of surface PD-1 on the T cells decreasing from a mean (SD) of 39.3% (20.2%) before pembrolizumab to a mean (SD) of 3.8% (5.8%) 24 hours after pembrolizumab infusion. Steady-state concentrations in the CSF were maintained throughout the 21-day cycle of pembrolizumab, as was the PD-1 blocking effect, evidenced by no increase in detectable surface PD-1 on T cells in the CSF during that time period. Incubation of PD-1-expressing T cells with CSF samples from patients treated with pembrolizumab also resulted in PD-1 blockade., Conclusions and Relevance: Results of this study demonstrate steady-state concentrations of pembrolizumab in CSF after intravenous administration as well as CSF concentrations that are sufficient for blocking PD-1 on endogenous and adoptively transferred T cells. This provides mechanistic insight regarding the ability of systemically administered PD-1 blocking antibodies to modulate T-cell activity in the brain.

A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).

Health care costs in the US have grown rapidly over the past several decades. As a result, there has been increasing interest in strategies to contain health care costs, without sacrificing the quality of medical care. While many factors contribute to rising costs, one major contributor to health care expenditure is diagnostic imaging. In this article, we address the growth of diagnostic imaging, the financial and clinical adverse effects of over-utilization, and discuss a variety of strategies to encourage appropriate use of diagnostic testing., (Copyright © 2016 Alliance for Academic Internal Medicine. Published by Elsevier Inc. All rights reserved.)

Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered TCM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 × 10(6) in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8(+) TCM subsets, expressing a first-generation CD19 CAR containing only the CD3ζ endodomain (CD19R:ζ). Four of 8 patients (50%; 95% confidence interval [CI]: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4(+) and CD8(+) TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3ζ endodomains (CD19R:28ζ). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4(+)/CD8(+) TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was ≤28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy after HSCT. Trials were registered at www.clinicaltrials.gov as #NCT01318317 and #NCT01815749., (© 2016 by The American Society of Hematology.)

Purpose: The purpose of this study was to investigate the relationship between health literacy and overall medication nonadherence, unintentional nonadherence, and intentional nonadherence. Limited health literacy may be associated with worse diabetes outcomes, but the literature shows mixed results, and mechanisms remain unclear. Medication adherence is associated with diabetes outcomes and may be a mediating factor. Distinguishing between unintentional and intentional nonadherence may elucidate the relationship between health literacy and nonadherence in patients with type 2 diabetes., Methods: Cross-sectional study of 208 patients with type 2 diabetes recruited from a primary care clinic in St. Louis, Missouri. Information was obtained from written questionnaire and patient medical records. Bivariate and multivariable regression were used to examine predictors of medication nonadherence., Results: The majority of patients in the study were low income, publicly insured, and African American, with limited health literacy and a high school/GED education or less. In multivariable models, limited health literacy was significantly associated with increased unintentional nonadherence but not intentional nonadherence., Conclusions: Results suggest differences in factors affecting intentional and unintentional nonadherence. The findings also suggest interventions are needed to decrease unintentional nonadherence among patients with type 2 diabetes and limited health literacy. Efforts to address unintentional medication nonadherence among patients with type 2 diabetes with limited health literacy may improve patient health., (© 2016 The Author(s).)

We examined the prevalence of mental disorders in a primary care setting affiliated with a large academic medical center. We also examined whether there were racial differences in mental health disorders. Patients were seeking medical care in an outpatient medical clinic; mental health data were available for them via medical records (n=767). Overall, 45% of patients had a diagnosed mental health problem; the most commonly reported form of mental disorder was depression. African Americans (OR= 1.88; CI: 1.21-2.91) were more likely than Whites to have a diagnosed mental health problem. These results suggest a strong mental health treatment need among patients seeking primary care in urban settings. The evidence garnered from this study underscores the need to detect and treat mental health problems systematically within outpatient primary care clinics that serve similarly vulnerable populations.

Purpose: Inhibitors of DNA (cytosine-5)-methyltransferases (DNMT) are active antineoplastic agents. We conducted the first-in-human phase I trial of 5-fluoro-2'-deoxycytidine (FdCyd), a DNMT inhibitor stable in aqueous solution, in patients with advanced solid tumors. Objectives were to establish the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of FdCyd + tetrahydrouridine (THU)., Methods: FdCyd + THU were administered by 3 h IV infusion on days 1-5 every 3 weeks, or days 1-5 and 8-12 every 4 weeks. FdCyd was administered IV with a fixed 350 mg/m(2)/day dose of THU to inhibit deamination of FdCyd. Pharmacokinetics of FdCyd, downstream metabolites and THU were assessed by LC-MS/MS. RBC γ-globin expression was evaluated as a pharmacodynamics biomarker., Results: Patients were enrolled on the 3-week schedule at doses up to 80 mg/m(2)/day without dose-limiting toxicity (DLT) prior to transitioning to the 4-week schedule, which resulted in an MTD of 134 mg/m(2)/day; one of six patients had a first-cycle DLT (grade 3 colitis). FdCyd ≥40 mg/m(2)/day produced peak plasma concentrations >1 µM. Although there was inter-patient variability, γ-globin mRNA increased during the first two treatment cycles. One refractory breast cancer patient experienced a partial response (PR) of >90 % decrease in tumor size, lasting over a year., Conclusions: The MTD was established at 134 mg/m(2) FdCyd + 350 mg/m(2) THU days 1-5 and 8-12 every 4 weeks. Based on toxicities observed over multiple cycles, good plasma exposures, and the sustained PR observed at 67 mg/m(2)/day, the phase II dose for our ongoing multi-histology trial is 100 mg/m(2)/day FdCyd with 350 mg/m(2)/day THU.

Purpose: This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with metastatic breast cancer., Methods: Forty patients received nab-paclitaxel (100 mg/m(2) weekly for 3 weeks followed by a 1-week break) as first- or second-line chemotherapy. Blood samples were collected for analysis, and response was assessed every two cycles. Planned statistical analyses included linear regression to examine the relationship between age and pharmacokinetic variables (ln clearance [CL] and ln area under the curve [AUC]) and two-sided two-sample t tests to evaluate age differences in pharmacodynamic variables. The association between chemotherapy toxicity risk scores and pharmacokinetic and pharmacodynamic variables including grade ≥ 3 toxicity were examined post hoc., Results: Of 40 patients enrolled, 39 (98%) were evaluable (mean age: 60 years; range: 30-81 years). A partial response was achieved in 31%, and 38% had stable disease. There was a borderline positive association between age and 24-hour ln AUC (slope = 0.011; SE = 0.006; p = .055). Grade 3 toxicity was experienced by 26% (8% hematologic, 18% nonhematologic). There were no differences in age based on the presence of grade 3 toxicity (p = .75), dose reductions (p = .38), or dose omissions (p = .15). A significant association was noted between chemotherapy toxicity risk score category and presence of grade 3 toxicity (toxicity rate by risk score category: low, 5 of 30 patients; medium, 3 of 6 patients; high, 2 of 3 patients; p = .041)., Conclusion: A borderline significant relationship exists between age and 24-hour AUC, but no differences were noted for pharmacodynamic variables (grade 3 toxicity, dose reductions, or dose omissions) based on age. There is an association between toxicity risk score and grade ≥ 3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups., (©AlphaMed Press.)

Numerous stem cell-based therapies are currently under clinical investigation, including the use of neural stem cells (NSCs) as delivery vehicles to target therapeutic agents to invasive brain tumors. The ability to monitor the time course, migration, and distribution of stem cells following transplantation into patients would provide critical information for optimizing treatment regimens. No effective cell-tracking methodology has yet garnered clinical acceptance. A highly promising noninvasive method for monitoring NSCs and potentially other cell types in vivo involves preloading them with ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) to enable cell tracking using magnetic resonance imaging (MRI). We report here the preclinical studies that led to U.S. Food and Drug Administration approval for first-in-human investigational use of ferumoxytol to label NSCs prior to transplantation into brain tumor patients, followed by surveillance serial MRI. A combination of heparin, protamine sulfate, and ferumoxytol (HPF) was used to label the NSCs. HPF labeling did not affect cell viability, growth kinetics, or tumor tropism in vitro, and it enabled MRI visualization of NSC distribution within orthotopic glioma xenografts. MRI revealed dynamic in vivo NSC distribution at multiple time points following intracerebral or intravenous injection into glioma-bearing mice that correlated with histological analysis. Preclinical safety/toxicity studies of intracerebrally administered HPF-labeled NSCs in mice were also performed, and they showed no significant clinical or behavioral changes, no neuronal or systemic toxicities, and no abnormal accumulation of iron in the liver or spleen. These studies support the clinical use of ferumoxytol labeling of cells for post-transplant MRI visualization and tracking.

Medulloblastoma is a heterogeneous diffuse neoplasm that can be highly disseminated, and is the most common malignant childhood brain tumor. Although multimodal treatments have improved survival rates for patients with medulloblastoma, these tumors are associated with high morbidity and mortality. New treatment strategies are urgently needed to improve cure rates and, importantly, to spare normal brain tissue from neurotoxicity and patients from life-long cognitive and functional deficits associated with current therapies. In numerous preclinical brain tumor models, neural stem cells (NSCs) have shown great promise as delivery vehicles for therapeutic genes. Here, we have used an established, genetically modified human NSC line (HB1.F3.CD) to deliver carboxylesterase (CE) to cerebellar tumor foci and locally activate the prodrug camptothecin-11 (CPT-11) (Irinotecan) to the potent topoisomerase I inhibitor SN-38. HB1.F3.CD NSC tumor tropism, intratumoral distribution and therapeutic efficacy were investigated in clinically relevant experimental models. Magnetic resonance imaging was used for in vivo tracking of iron nanoparticle-labeled NSCs, and to assess the therapeutic efficacy of CE-expressing HB1.F3.CD cells. As compared with controls, a significant decrease in tumor growth rate was seen in mice that received both NSCs and CPT-11 as their treatment regimen. Thus, this study provides proof-of-concept for NSC-mediated CE/CPT-11 treatment of medulloblastoma, and serves as a foundation for further studies toward potential clinical application.

Purpose: This paper introduces the target equivalence range (TEQR) design, a frequentist implementation of the modified toxicity probability interval (mTPI) design, as a competitor to the standard 3+3 design (3+3). The 3+3 is the work horse design in Phase I. It is good at determining if a safe dose exits, but provides poor accuracy and precision in estimating the level of toxicity at the maximum tolerated dose (MTD). Its main competitor, the continual reassessment method (CRM) has not found a true niche in the Phase I armamentarium resulting from statistical and implementation complexities., Methods: We describe the four competing designs (3+3, mTPI, CRM, and TEQR), comparing them based on i) operating characteristics from simulated trials, and ii) ease of implementation., Results: The TEQR is better than the 3+3 when compared on; 1) number of times the dose at or nearest the target toxicity level was selected as the MTD, 2) number of patients assigned to dose levels at or nearest the MTD, 3) overall trial dose limiting toxicity rate and 4) accuracy and precision of estimates for the rate of toxicity at the MTD. Further it is reasonably comparable to the CRM and mTPI on 1-3., Conclusion: The TEQR offers trial designers a competitor to the 3+3 for ease of implementation with better operating characteristics and the added attraction of a glimpse of activity at the MTD. The R package TEQR, freely available from the comprehensive R archive network, includes functions to calculate dose escalation guidelines and operating characteristics., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Flap endonuclease 1 (FEN1) proteins, which are present in all kingdoms of life, catalyze the sequence-independent hydrolysis of the bifurcated nucleic acid intermediates formed during DNA replication and repair. How FEN1s have evolved to preferentially cleave flap structures is of great interest especially in light of studies wherein mice carrying a catalytically deficient FEN1 were predisposed to cancer. Structural studies of FEN1s from phage to human have shown that, although they share similar folds, the FEN1s of higher organisms contain a 3'-extrahelical nucleotide (3'-flap) binding pocket. When presented with 5'-flap substrates having a 3'-flap, archaeal and eukaryotic FEN1s display enhanced reaction rates and cleavage site specificity. To investigate the role of this interaction, a kinetic study of human FEN1 (hFEN1) employing well defined DNA substrates was conducted. The presence of a 3'-flap on substrates reduced Km and increased multiple- and single turnover rates of endonucleolytic hydrolysis at near physiological salt concentrations. Exonucleolytic and fork-gap-endonucleolytic reactions were also stimulated by the presence of a 3'-flap, and the absence of a 3'-flap from a 5'-flap substrate was more detrimental to hFEN1 activity than removal of the 5'-flap or introduction of a hairpin into the 5'-flap structure. hFEN1 reactions were predominantly rate-limited by product release regardless of the presence or absence of a 3'-flap. Furthermore, the identity of the stable enzyme product species was deduced from inhibition studies to be the 5'-phosphorylated product. Together the results indicate that the presence of a 3'-flap is the critical feature for efficient hFEN1 substrate recognition and catalysis.

Prior research has demonstrated that shortly after the 1991 Gulf War (Gulf War I), chronic multisymptom illness (CMI) was more common among deployed veterans than among nondeployed veterans. The aims of the current study were to determine the prevalence of CMI among deployed and nondeployed veterans 10 years after Gulf War I, compare the distribution of comorbid conditions, and identify prewar factors associated with CMI. Cross-sectional data collected from 1,061 deployed veterans and 1,128 nondeployed veterans examined between 1999 and 2001 were analyzed. CMI prevalence was 28.9% among deployed veterans and 15.8% among nondeployed veterans (odds ratio = 2.16, 95% confidence interval: 1.61, 2.90). Deployed and nondeployed veterans with CMI had similarly poorer quality-of-life measures and higher prevalences of symptom-based medical conditions, metabolic syndrome, and psychiatric disorders. Diagnoses of prewar anxiety disorders (not related to post-traumatic stress disorder) and depression were associated with CMI among both deployed and nondeployed veterans. Nicotine dependence and veteran-reported physician-diagnosed infectious mononucleosis were associated with CMI among deployed veterans, and migraine headaches and gastritis were associated with CMI among nondeployed veterans. CMI continues to be substantially more prevalent among deployed veterans than among nondeployed veterans 10 years after Gulf War I, but it manifests similarly in both groups. It is likely to be a common, persistent problem among veterans returning from the current Gulf War.

Background: United States military personnel reported various symptoms after deployment to the Persian Gulf during the 1991 Gulf War. However, the symptoms' long-term prevalence and association with deployment remain controversial., Objective: To assess and compare the prevalence of selected medical conditions in a national cohort of deployed and nondeployed Gulf War veterans who were evaluated by direct medical and teledermatologic examinations., Design: A cross-sectional prevalence study performed 10 years after the 1991 Gulf War., Setting: Veterans were examined at 1 of 16 Veterans Affairs medical centers., Participants: Deployed (n = 1061) and nondeployed (n = 1128) veterans of the 1991 Gulf War., Measurements: Primary outcome measures included fibromyalgia, the chronic fatigue syndrome, dermatologic conditions, dyspepsia, physical health-related quality of life (Short Form-36 [SF-36]), hypertension, obstructive lung disease, arthralgias, and peripheral neuropathy., Results: Of 12 conditions, only 4 conditions were more prevalent among deployed than nondeployed veterans: fibromyalgia (deployed, 2.0%; nondeployed, 1.2%; odds ratio, 2.32 [95% CI, 1.02 to 5.27]); the chronic fatigue syndrome (deployed, 1.6%; nondeployed 0.1%; odds ratio, 40.6 [CI, 10.2 to 161]); dermatologic conditions (deployed, 34.6%; nondeployed, 26.8%; odds ratio, 1.38 [CI, 1.06 to 1.80]), and dyspepsia (deployed, 9.1%; nondeployed, 6.0%; odds ratio, 1.87 [CI, 1.16 to 2.99]). The mean physical component summary score of the SF-36 for deployed and nondeployed veterans was 49.3 and 50.8, respectively., Limitations: Relatively low participation rates introduce potential participation bias, and deployment-related illnesses that resolved before the research examination could not, by design, be detected., Conclusions: Ten years after the Gulf War, the physical health of deployed and nondeployed veterans is similar. However, Gulf War deployment is associated with an increased risk for fibromyalgia, the chronic fatigue syndrome, skin conditions, dyspepsia, and a clinically insignificant decrease in the SF-36 physical component score.

Temperatures in Jupiter's atmosphere derived from Galileo Probe deceleration data increase from 109 kelvin at the 175-millibar level to 900 ± 40 kelvin at 1 nanobar, consistent with Voyager remote sensing data. Wavelike oscillations are present at all levels. Vertical wavelengths are 10 to 25 kilometers in the deep isothermal layer, which extends from 12 to 0.003 millibars. Above the 0.003-millibar level, only 90- to 270- kilometer vertical wavelengths survive, suggesting dissipation of wave energy as the probable source of upper atmosphere heating.

Choline, an essential phospholipid precursor, enters the lens by a facilitated transport system and is phosphorylated to form phosphorylcholine (P-choline). Intact lenses incubated with [3H]choline accumulate both [3H]choline and P-[3H]choline. The rate and extent of this accumulation have been used to study the effects of osmotic or oxidative cataractogenic stress, and also to test the ability of compounds to protect lenses from stress-related damage. The initial effect of oxidative stress on choline metabolism is decreased choline transport, but the mechanism by which osmotic stress affects the accumulation of [3H]choline is not understood. The effects of osmotic and oxidative stress on choline influx and metabolism were compared in rat lenses incubated in TC-199 medium. After osmotic stress by incubation with 30 mM xylose for up to 24 hr, lenses accumulated the same amount of radiolabel as controls during a 30 min pulse with [3H]choline. However, if the lenses were exposed to [3H]choline for 6 hr so that accumulation of radiolabel in the lenses was limited by the rate of P-choline synthesis, xylose treated lenses accumulated less choline than controls. Separation of the lenticular radiolabel into [3H]choline and P-[3H]choline confirmed that xylose decreased synthesis of P-choline, although adequate unphosphorylated [3H]choline was available in the lenses. A decrease in P-[3H]ethanolamine synthesis was also seen in xylose-treated lenses incubated with [3H]ethanolamine. Ethanolamine can enter lenses by a non-saturable process which is not dependent upon a transporter. Although xylose decreased P-choline synthesis in intact lenses, neither xylose nor xylitol inhibited choline kinase in lens homogenates.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone density in 13 male long distance runners (28.7 +/- 1.2 yr, 67.6 +/- 2.0 kg) and 11 male nonrunners (26.8 +/- 1.3 yr, 71.0 +/- 2.2 kg) was compared. Bone was measured at the lumbar spine and mid-tibia using dual photon absorptiometry and at the mid-radius using single photon absorptiometry. Runners (mean weekly training 92.2 +/- 6.3 km) had significantly lower (P less than 0.05) vertebral bone mineral density (1.12 +/- 0.03 g.cm-2) than nonrunners (1.24 +/- 0.04 g.cm-2). Tibial and radial bone mineral density did not differ between the groups. Daily calcium intake for runners (1,373 +/- 486 mg) and nonrunners (1,267 +/- 236 mg) exceeded the RDA. The results of this study suggest that long distance running may lead to decreased vertebral bone mineral density. The hormonal changes that occur with endurance training may contribute to this decrease.

In brief: Training on rebound exercise equipment (minitrampolines) is a popular new approach to aerobic conditioning, but its physiological benefits have been a matter of debate. This study was designed to determine if rebound aerobic dancing is an effective way to improve aerobic capacity and body composition. A group of previously sedentary college women who trained on rebound equipment three times a week for eight weeks showed a 9% increase in max but no significant change in percent body fat. A control group showed no significant changes. The improvement was similar to results produced by conventional aerobic dance programs of like intensity but moderate in comparison to other established forms of aerobic exercise.