Batf stabilizes Th17 cell development via impaired Stat5 recruitment of Ets1-Runx1 complexes.

Although the activator protein-1 (AP-1) factor Batf is required for Th17 cell development, its mechanisms of action to underpin the Th17 program are incompletely understood. Here, we find that Batf ensures Th17 cell identity in part by restricting alternative gene programs through its actions to restrain IL-2 expression and IL-2-induced Stat5 activation. This, in turn, limits Stat5-dependent recruitment of Ets1-Runx1 factors to Th1- and Treg-cell-specific gene loci. Thus, in addition to pioneering regulatory elements in Th17-specific loci, Batf acts indirectly to inhibit the assembly of a Stat5-Ets1-Runx1 complex that enhances the transcription of Th1- and Treg-cell-specific genes. These findings unveil an important role for Stat5-Ets1-Runx1 interactions in transcriptional networks that define alternate T cell fates and indicate that Batf plays an indispensable role in both inducing and maintaining the Th17 program through its actions to regulate the competing actions of Stat5-assembled enhanceosomes that promote Th1- and Treg-cell developmental programs.

Recruitment and Data Collection Challenges of Research Focused on Older Adults and Family Caregivers from Asian American Communities: A Case Study Series.

OBJECTIVES: The purpose of this case study series was to present recruitment and data collection strategies used for Asian American ethnic groups by documenting challenges experienced by researchers in the field of aging. SUMMARY: We compiled four case studies investigating Asian American older adults and/or family caregivers (i.e., Vietnamese, South Asians, Chinese, and Koreans). Each case study employed unique research methods to overcome experienced challenges associated with recruitment and data collection. DISCUSSION: Three constructs were organized for effective recruitment and data collection strategies of this racial group and included (1) forming a bilingual and bicultural research team (research-centered); (2) establishing reciprocal partnerships between researchers and community partners (community-centered); and (3) understanding the historical and cultural backgrounds of targeted ethnic groups (participant-centered). Approaches taken to address the range of challenges and limitations identified in this case study series may also help increase the representation of Asian-American older adults and family caregivers in research. CLINICAL IMPLICATIONS: Successfully including racial and ethnic minority groups in research, especially Asian Americans, may reduce existing racial disparities in mental and physical health. Any barriers and facilitators affecting the research regarding Asian American ethnic groups should continue to be discussed.

Monitoring of biodistribution and persistence of conditionally replicative adenovirus in a murine model of ovarian cancer using capsid-incorporated mCherry and expression of human somatostatin receptor subtype 2 gene.

A significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR) subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection. Analysis of 64Cu-CB-TE2A-Y3-TATE biodistribution in mice revealed reduced uptake in tumors injected with the imaging CRAd relative to the replication-incompetent, Ad-expressing SSTR2 but significantly greater uptake compared to the negative CRAd control. Optical imaging demonstrated relative correlation of fluorescent signal with virus replication as determined by viral genome quantification in tumors. Positron emission tomography/computed tomography studies demonstrated that we can visualize radioactive uptake in tumors injected with imaging CRAd and the trend for greater uptake by standardized uptake value analysis compared to control CRAd. In the aggregate, the plasticity of our dual imaging approach should provide the technical basis for monitoring CRAd biodistribution and persistence in preclinical studies while offering potential utility for a range of clinical applications.

A culturally and linguistically tailored Community-Engaged Dementia Education Program (CEDEP) for the Houston Vietnamese American community.

Data from the Vietnamese Aging and Care Survey (VACS) showed the high prevalence of disability, depressive symptoms, and cognitive impairment in older Vietnamese immigrants and refugees. We proposed a Community-Engaged Dementia Education Program to examine the Houston Vietnamese American community's literacy on dementia and develop a one-pager educational material. This is a cross-sectional, qualitative study (interviews and focus groups) using the Cultural Exchange Model as a conceptual framework. We interviewed fourteen Vietnamese key informants and assessed the community's knowledge of dementia based on Edwards' 9-stage Community Readiness Model. The community's low literacy on dementia (Stages 2-3: Denial/resistance to vague awareness) was revealed. Approaches to introducing dementia conversations to the community and what to include in the one-pager were discussed. Based on the key informants' insight, we developed a dementia one-pager tailored to the community by using lay language with a representative image of the target population, indicating warning signs of dementia, and encouraging them to see their doctors for cognitive check-ups. The plan for the next steps includes utilizing the local ethnic media, collaborating with the existing pillars of the Cultural Exchange model, leveraging the university students' learning opportunities, and disseminating the culturally and linguistically tailored one-pager.

Multiple Chronic Conditions and Disability among Vietnamese Older Adults: Results from the Vietnamese Aging and Care Survey (VACS).

Using data from Vietnamese-origin older immigrants/refugees in the Houston, Texas area, we assessed their overall health, chronic conditions, disability, depressive symptoms, and cognitive impairment, and examined the association between their chronic conditions and disability by comorbidity clusters. The mean age of the sample was 76 years old. The majority were married in fair/poor health with several chronic conditions and disabilities and lived with families in low-income households. Hypertension and arthritis were the most common health conditions, but cognitive impairment had the most significant impact on their disability. They experienced similar health conditions to other older Americans but had higher rates of depressive symptoms and cognitive impairment possibly due to cultural factors that may have delayed mental health treatment. Culturally and linguistically tailored services created by policymakers, healthcare professionals, and local social service agencies are recommended for the well-being of immigrants/refugees who migrated to the U.S. for a better life.

FANCM c5791C>T stopgain mutation (rs144567652) is a familial colorectal cancer risk factor.

PURPOSE: While familial aggregation of colorectal cancer (CRC) is recognized, the majority of the germline predisposition factors remain unidentified, and many high-risk CRC pedigrees remain unexplained by known risk variants. Fanconi Anemia genes have been recognized to be associated with cancer risk. Notably, FANCM (OMIM 609644) variants have been reported to confer risk for CRC and breast cancer. METHODS: Exome sequencing of CRC-affected cousins in a set of 47 independent extended high-risk CRC pedigrees identified a candidate set of rare, shared variants. Variants were tested for association with risk in 744 Utah CRC cases and 1525 controls, and for segregation with CRC in affected relatives. RESULTS: A FANCM stopgain variant was observed in two CRC-affected cousin pairs, each from an independent Utah high-risk pedigree, and yielded a nonsignificant, but elevated OR = 2.05 in a set of Utah cases and controls. Segregation of the variant to other related CRC-affected cases was observed in the two extended pedigrees. CONCLUSION: A rare stopgain variant in FANCM (rs144567652) that is recognized as a breast cancer predisposition variant, and that has previously been proposed, but not confirmed, as a CRC predisposition variant, is validated here as a risk factor for familial CRC.

Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma.

Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a well-established model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, alpha-SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described water-soluble HPMA copolymer-TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumor-microenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma.

Native and synthetic scaffolds for limbal epithelial stem cell transplantation.

Limbal stem cell deficiency (LSCD) is a complex blinding disease of the cornea, which cannot be treated with conventional corneal transplants. Instead, a stem cell (SC) graft is required to replenish the limbal epithelial stem cell (LESC) reservoir, which is ultimately responsible for regenerating the corneal epithelium. Current therapies utilize limbal tissue biopsies that harbor LESCs as well as tissue culture expanded cells. Typically, this tissue is placed on a scaffold that supports the formation of corneal epithelial cell sheets, which are then transferred to diseased eyes. A wide range of biological and synthetic materials have been identified as carrier substrates for LESC, some of which have been used in the clinic, including amniotic membrane, fibrin, and silicon hydrogel contact lenses, each with their own advantages and limitations. This review will provide a brief background of LSCD, focusing on bio-scaffolds that have been utilized in limbal stem cell transplantation (LSCT) and materials that are being developed as potentially novel therapeutics for patients with this disease. STATEMENT OF SIGNIFICANCE: The outcome of patients with corneal blindness that receive stem cell grafts to restore eye health and correct vision varies considerably and may be due to the different biological and synthetic scaffolds used to deliver these cells to the ocular surface. This review will highlight the positive attributes and limitations of the myriad of carriers developed for clinical use as well as those that are being trialled in pre-clinical models. The overall focus is on developing a standardized therapy for patients, however due to the multiple causes of corneal blindness, a personal regenerative medicine approach may be the best option.

64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: in silico through in vivo studies.

Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3-TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues.

Ionizing radiation exposure among kidney transplant recipients due to medical imaging during the pretransplant evaluation.

BACKGROUND AND OBJECTIVES: Kidney transplant recipients are at increased risk for malignancies. One recognized risk for malignancy is ionizing radiation. The purpose of this study was to determine, among kidney transplant recipients, the medical imaging procedures that contribute to radiation exposure and their cumulative radiation exposure, as a result of their pretransplant evaluation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Medical records of patients who received a first, kidney-alone transplant during 2008 at a single transplant center were examined. This study identified medical imaging procedures that were performed as prerequisites for deceased donor wait-listing or receipt of live donor kidney transplants and to maintain active status on the wait list. Frequencies of medical imaging procedures and cumulative effective doses of radiation were calculated. RESULTS: Among the 172 kidney transplant recipients, 905 procedures were performed. Seventy patients (40.7%) were exposed to low dose (0-20 mSv), 51 (29.7%) were exposed to moderate dose (>20-50 mSv), 28 (16.3%) were exposed to high dose (>50-100 mSv), and 23 (13.4%) were exposed to very high dose (>100 mSv) cumulative effective radiation. Nuclear stress tests accounted for 82.9% of the total radiation exposure. In multivariate analysis, older age, diabetes, and black race were associated with exposure to >20 mSv radiation during the pretransplant evaluation. CONCLUSIONS: Kidney transplant recipients are exposed to large amounts of ionizing radiation from medical imaging during the pretransplant evaluation. The effects of radiation upon malignancy risk and strategies to reduce this radiation exposure warrant further investigation.

Non-stem cell origin for oligodendroglioma.

Malignant astrocytic brain tumors are among the most lethal cancers. Quiescent and therapy-resistant neural stem cell (NSC)-like cells in astrocytomas are likely to contribute to poor outcome. Malignant oligodendroglial brain tumors, in contrast, are therapy sensitive. Using magnetic resonance imaging (MRI) and detailed developmental analyses, we demonstrated that murine oligodendroglioma cells show characteristics of oligodendrocyte progenitor cells (OPCs) and are therapy sensitive, and that OPC rather than NSC markers enriched for tumor formation. MRI of human oligodendroglioma also suggested a white matter (WM) origin, with markers for OPCs rather than NSCs similarly enriching for tumor formation. Our results suggest that oligodendroglioma cells show hallmarks of OPCs, and that a progenitor rather than a NSC origin underlies improved prognosis in patients with this tumor.