Characterization of a large group of individuals with huntington disease and their relatives enrolled in the COHORT study

Background

Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition.

Methods

We conducted a cohort study in the United States, Canada, and Australia of members of families affected by HD. We collected demographic and clinical data, conducted the Unified Huntington''s Disease Rating Scale and Mini-Mental State Examination, and determined Huntingtin trinucleotide CAG repeat length. We report primarily on cross-sectional baseline data from this recently completed prospective, longitudinal, observational study.

Results

As of December 31, 2009, 2,318 individuals enrolled; of these, 1,985 (85.6%) were classified into six analysis groups. Three groups had expanded CAG alleles (36 repeats or more): individuals with clinically diagnosed HD [n = 930], and clinically unaffected first-degree relatives who had previously pursued [n = 248] or not pursued [n = 112] predictive DNA testing. Three groups lacked expanded alleles: first-degree relatives who had previously pursued [n = 41] or not pursued [n = 224] genetic testing, and spouses and caregivers [n = 430]. Baseline mean performance differed across groups in all motor, behavioral, cognitive, and functional measures (p<0.001). Clinically unaffected individuals with expanded alleles weighed less (76.0 vs. 79.6 kg; p = 0.01) and had lower cognitive scores (28.5 vs. 29.1 on the Mini Mental State Examination; p = 0.008) than individuals without expanded alleles. The frequency of “high normal” repeat lengths (27 to 35) was 2.5% and repeat lengths associated with reduced penetrance (36 to 39) was 2.7%.

Conclusion

Baseline analysis of COHORT study participants revealed differences that emerge prior to clinical diagnosis. Longitudinal investigation of this cohort will further characterize the natural history of HD and genetic and biological modifiers.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00313495","term_id":"NCT00313495"}}NCT00313495     

Relationship between tumor DNA methylation status and patient characteristics in African-American and European-American women with breast cancer

Aberrant DNA methylation is critical for development and progression of breast cancer. We investigated the association of CpG island methylation in candidate genes and clinicopathological features in 65 African-American (AA) and European-American (EA) breast cancer patients. Quantitative methylation analysis was carried out on bisulfite modified genomic DNA and sequencing (pyrosequencing) for promoter CpG islands of p16, ESR1, RASSF1A, RARβ2, CDH13, HIN1, SFRP1 genes and the LINE1 repetitive element using matched paired non-cancerous and breast tumor specimen (32 AA and 33 EA women). Five of the genes, all known tumor suppressor genes (RASSF1A, RARβ2, CDH13, HIN1 and SFRP1), were found to be frequently hypermethylated in breast tumor tissues but not in the adjacent non-cancerous tissues. Significant differences in the CDH13 methylation status were observed by comparing DNA methylation between AA and EA patients, with more obvious CDH13 methylation differences between the two patient groups in the ER- disease and among young patients (age<50). In addition, we observed associations between CDH13, SFRP1, and RASSF1A methylation and breast cancer subtypes and between SFRP1 methylation and patient's age. Furthermore, tumors that received neoadjuvant therapy tended to have reduced RASSF1A methylation when compared with chemotherapy na?ve tumors. Finally, Kaplan Meier survival analysis showed a significant association between methylation at 3 loci (RASSF1A, RARβ2 and CDH13) and reduced overall disease survival. In conclusion, the DNA methylation status of breast tumors was found to be significantly associated with clinicopathological features and race/ethnicity of the patients.     

Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit

Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month) Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice) and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF treatment against AD.     

Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting neurotoxic effect of chemotherapy, is the most common reason for early cessation of cancer treatment. This can result in an increased risk of recurrence and decreased survival rate. Inflammatory cascade activation, proinflammatory cytokine upregulation, and neuro-immune communication pathways play essential roles in the initiation and progression of CIPN. Most notably, TNF-α, IL-1β, IL-6, and CCL2 are involved in neuropathic pain. Further elucidation of the role of these cytokines could lead to their development and use as biomarkers for predicting the onset of painful peripheral neuropathy and early axonal damage. In this review, we provide evidence for the involvement of cytokines in CIPN, the possible underlying mechanisms, and their use as potential therapeutic targets and biomarkers to prevent and improve the painful peripheral neuropathy related to chemotherapeutic agents.     

An integrated method for reproducible and accurate image-guided stereotactic cranial irradiation of brain tumors using the small animal radiation research platform

Preclinical studies of cranial radiation therapy (RT) using animal brain tumor models have been hampered by technical limitations in the delivery of clinically relevant RT. We established a bioimageable mouse model of glioblastoma multiforme (GBM) and an image-guided radiation delivery system that facilitated precise tumor localization and treatment and which closely resembled clinical RT. Our novel radiation system makes use of magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) to define tumor volumes, computed tomographic (CT) imaging for accurate treatment planning, a novel mouse immobilization system, and precise treatments delivered with the Small Animal Radiation Research Platform. We demonstrated that, in vivo, BLI correlated well with MRI for defining tumor volumes. Our novel restraint system enhanced setup reproducibility and precision, was atraumatic, and minimized artifacts on CT imaging used for treatment planning. We confirmed precise radiation delivery through immunofluorescent analysis of the phosphorylation of histone H2AX in irradiated brains and brain tumors. Assays with an intravenous near-infrared fluorescent probe confirmed that radiation of orthografts increased disruption of the tumor blood-brain barrier (BBB). This integrated model system, which facilitated delivery of precise, reproducible, stereotactic cranial RT in mice and confirmed RT's resultant histologic and BBB changes, may aid future brain tumor research.     

4,4-Disubstituted cyclohexylamine based CCR5 chemokine receptor antagonists as anti-HIV-1 agents

A series of 4,4-disubstituted cyclohexylamine based CCR5 antagonists has been designed and synthesized. Their antiviral structure–activity relationship has been extensively explored.     

Financing of U.S. Biomedical Research and New Drug Approvals across Therapeutic Areas

Background

We estimated U.S. biomedical research funding across therapeutic areas, determined the association with disease burden, and evaluated new drug approvals that resulted from this investment.

Methodology/Principal Findings

We calculated funding from 1995 to 2005 and totaled Food and Drug Administration approvals in eight therapeutic areas (cardiovascular, endocrine, gastrointestinal, genitourinary, HIV/AIDS, infectious disease excluding HIV, oncology, and respiratory) primarily using public data. We then calculated correlations between funding, published estimates of disease burden, and drug approvals.Financial support for biomedical research from 1995 to 2005 increased across all therapeutic areas between 43% and 369%. Industry was the principal funder of all areas except HIV/AIDS, infectious disease, and oncology, which were chiefly sponsored by the National Institutes of Health (NIH). Total (ρ = 0.70; P = .03) and industry funding (ρ = 0.69; P = .04) were correlated with projected disease burden in high income countries while NIH support (ρ = 0.80; P = .01) was correlated with projected disease burden globally. From 1995 to 2005 the number of new approvals was flat or declined across therapeutic areas, and over an 8-year lag period, neither total nor industry funding was correlated with future approvals.

Conclusions/Significance

Across therapeutic areas, biomedical research funding increased substantially, appears aligned with disease burden in high income countries, but is not linked to new drug approvals. The translational gap between funding and new therapies is affecting all of medicine, and remedies must include changes beyond additional financial investment.     

A content analysis of dissemination and implementation science resource initiatives: what types of resources do they offer to advance the field?

Background

The recent growth in organized efforts to advance dissemination and implementation (D & I) science suggests a rapidly expanding community focused on the adoption and sustainment of evidence-based practices (EBPs). Although promising for the D & I of EBPs, the proliferation of initiatives is difficult for any one individual to navigate and summarize. Such proliferation may also result in redundant efforts or missed opportunities for participation and advancement. A review of existing D & I science resource initiatives and their unique merits would be a significant step for the field. The present study aimed to describe the global landscape of these organized efforts to advance D & I science.

Methods

We conducted a content analysis between October 2015 and March 2016 to examine resources and characteristics of D & I science resource initiatives using public, web-based information. Included resource initiatives must have engaged in multiple efforts to advance D & I science beyond conferences, offered D & I science resources, and provided content in English. The sampling method included an Internet search using D & I terms and inquiry among internationally representative D & I science experts. Using a coding scheme based on a priori and grounded approaches, two authors consensus coded website information including interactive and non-interactive resources and information regarding accessibility (membership, cost, competitive application, and location).

Results

The vast majority (83%) of resource initiatives offered at least one of seven interactive resources (consultation/technical assistance, mentorship, workshops, workgroups, networking, conferences, and social media) and one of six non-interactive resources (resource library, news and updates from the field, archived talks or slides, links pages, grant writing resources, and funding opportunities). Non-interactive resources were most common, with some appearing frequently across resource initiatives (e.g., news and updates from the field).

Conclusion

Findings generated by this study offer insight into what types of D & I science resources exist and what new resources may have the greatest potential to make a unique and needed contribution to the field. Additional interactive resources may benefit the field, particularly mentorship opportunities and resources that can be accessed virtually. Moving forward, it may be useful to consider strategic attention to the core tenets of D & I science put forth by Glasgow and colleagues to most efficiently and effectively advance the field.

     

Identification and structure-activity studies of novel ultrashort-acting benzodiazepine receptor agonists

The synthesis and evaluation of novel ultrashort-acting benzodiazepine (USA BZD) agonists is described. A BZD scaffold was modified by incorporation of amino acids and derivatives. The propionate side chain of glutamic acid tethers an enzymatically labile functionality where the metabolite carboxylic acid displays markedly reduced BZD receptor affinity. The USA BZDs were characterized by full agonism profiles. Copyright2000 Elsevier Science Ltd.