GRP94 (gp96) and GRP94 N-Terminal Geldanamycin Binding Domain Elicit Tissue Nonrestricted Tumor Suppression

In chemical carcinogenesis models, GRP94 (gp96) elicits tumor-specific protective immunity. The tumor specificity of this response is thought to reflect immune responses to GRP94-bound peptide antigens, the cohort of which uniquely identifies the GRP94 tissue of origin. In this study, we examined the apparent tissue restriction of GRP94-elicited protective immunity in a 4T1 mammary carcinoma model. We report that the vaccination of BALB/c mice with irradiated fibroblasts expressing a secretory form of GRP94 markedly suppressed 4T1 tumor growth and metastasis. In addition, vaccination with irradiated cells secreting the GRP94 NH2-terminal geldanamycin-binding domain (NTD), a region lacking canonical peptide-binding motifs, yielded a similar suppression of tumor growth and metastatic progression. Conditioned media from cultures of GRP94 or GRP94 NTD-secreting fibroblasts elicited the up-regulation of major histocompatibility complex class II and CD86 in dendritic cell cultures, consistent with a natural adjuvant function for GRP94 and the GRP94 NTD. Based on these findings, we propose that GRP94-elicited tumor suppression can occur independent of the GRP94 tissue of origin and suggest a primary role for GRP4 natural adjuvant function in antitumor immune responses

Body Composition Measurements from Birth through 5 Years: Challenges, Gaps, and Existing & Emerging Technologies—A National Institutes of Health workshop

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156150/2/obr13033_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156150/1/obr13033.pd

Binocular Goggle Augmented Imaging and Navigation System provides real-time fluorescence image guidance for tumor resection and sentinel lymph node mapping

The inability to identify microscopic tumors and assess surgical margins in real-time during oncologic surgery leads to incomplete tumor removal, increases the chances of tumor recurrence, and necessitates costly repeat surgery. To overcome these challenges, we have developed a wearable goggle augmented imaging and navigation system (GAINS) that can provide accurate intraoperative visualization of tumors and sentinel lymph nodes in real-time without disrupting normal surgical workflow. GAINS projects both near-infrared fluorescence from tumors and the natural color images of tissue onto a head-mounted display without latency. Aided by tumor-targeted contrast agents, the system detected tumors in subcutaneous and metastatic mouse models with high accuracy (sensitivity = 100%, specificity = 98% ± 5% standard deviation). Human pilot studies in breast cancer and melanoma patients using a near-infrared dye show that the GAINS detected sentinel lymph nodes with 100% sensitivity. Clinical use of the GAINS to guide tumor resection and sentinel lymph node mapping promises to improve surgical outcomes, reduce rates of repeat surgery, and improve the accuracy of cancer staging

Plasma‐derived biomarkers of Alzheimer\u27s disease and neuropsychiatric symptoms: A community‐based study

INTRODUCTION: We examined associations between plasma-derived biomarkers of Alzheimer\u27s disease (AD) and neuropsychiatric symptoms (NPS) in community-dwelling older adults. METHODS: Cross-sectional study involving 1005 persons ≥50 years of age (mean 74 years, 564 male, 118 cognitively impaired), who completed plasma-derived biomarker (amyloid beta 42 [Aβ42]/Aβ40, phosphorylated tau 181 [p-tau181], p-tau217, total tau [t-tau], neurofilament light [NfL]), and NPS assessment. RESULTS: P-tau181 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.41–3.00, p < 0.001), p-tau217 (OR 1.70, 95% CI 1.10–2.61, p = 0.016), and t-tau (OR 1.44, 95% CI 1.08–1.92, p = 0.012) were associated with appetite change. We also found that p-tau181 and p-tau217 were associated with increased symptoms of agitation (OR 1.93, 95% CI 1.20–3.11, p = 0.007 and OR 2.04, 95% CI 1.21–3.42, p = 0.007, respectively), and disinhibition (OR 2.39, 95% CI 1.45–3.93, p = 0.001 and OR 2.30, 95% CI 1.33–3.98, p = 0.003, respectively). Aβ42/Aβ40 and NfL were not associated with NPS. CONCLUSION: Higher plasma-derived p-tau181 and p-tau217 levels are associated with increased symptoms of appetite change, agitation, and disinhibition. These findings may support the validity of plasma tau biomarkers for predicting behavioral symptoms that often accompany cognitive impairment. HIGHLIGHTS - We studied 1005 community-dwelling persons aged ≥ 50 years - Higher plasma tau levels are associated with increased neuropsychiatric symptoms - Aβ42/Aβ40 and NfL are not associated with neuropsychiatric symptoms - Clinicians should treat neuropsychiatric symptoms in persons with high plasma-derived ta

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC

Interactions between Neuropsychiatric Symptoms and Alzheimer’s Disease Neuroimaging Biomarkers in Predicting Longitudinal Cognitive Decline

OBJECTIVE: To examine interactions between Neuropsychiatric symptoms (NPS) with Pittsburgh Compound B (PiB) and fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting cognitive trajectories. METHODS: We conducted a longitudinal study in the setting of the population-based Mayo Clinic Study of Aging in Olmsted County, MN, involving 1581 cognitively unimpaired (CU) persons aged ≥50 years (median age 71.83 years, 54.0% males, 27.5% APOE ɛ4 carriers). NPS at baseline were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Brain glucose hypometabolism was defined as a SUVR ≤ 1.47 (measured by FDG-PET) in regions typically affected in Alzheimer\u27s disease. Abnormal cortical amyloid deposition was measured using PiB-PET (SUVR ≥ 1.48). Neuropsychological testing was done approximately every 15 months, and we calculated global and domain-specific (memory, language, attention, and visuospatial skills) cognitive z-scores. We ran linear mixed-effect models to examine the associations and interactions between NPS at baseline and z-scored PiB- and FDG-PET SUVRs in predicting cognitive z-scores adjusted for age, sex, education, and previous cognitive testing. RESULTS: Individuals at the average PiB and without NPS at baseline declined over time on cognitive z-scores. Those with increased PiB at baseline declined faster (two-way interaction), and those with increased PiB and NPS declined even faster (three-way interaction). We observed interactions between time, increased PiB and anxiety or irritability indicating accelerated decline on global z-scores, and between time, increased PiB and several NPS (e.g., agitation) showing faster domain-specific decline, especially on the attention domain. CONCLUSIONS: NPS and increased brain amyloid deposition synergistically interact in accelerating global and domain-specific cognitive decline among CU persons at baseline

A systematic review of correlates of sedentary behaviour in adults aged 18–65 years: a socio-ecological approach

Background: Recent research shows that sedentary behaviour is associated with adverse cardio-metabolic consequences even among those considered sufficiently physically active. In order to successfully develop interventions to address this unhealthy behaviour, factors that influence sedentariness need to be identified and fully understood. The aim of this review is to identify individual, social, environmental, and policy-related determinants or correlates of sedentary behaviours among adults aged 18-65 years. Methods: PubMed, Embase, CINAHL, PsycINFO and Web of Science were searched for articles published between January 2000 and September 2015. The search strategy was based on four key elements and their synonyms: (a) sedentary behaviour (b) correlates (c) types of sedentary behaviours (d) types of correlates. Articles were included if information relating to sedentary behaviour in adults (18-65 years) was reported. Studies on samples selected by disease were excluded. The full protocol is available from PROSPERO (PROSPERO 2014:CRD42014009823). Results: 74 original studies were identified out of 4041: 71 observational, two qualitative and one experimental study. Sedentary behaviour was primarily measured as self-reported screen leisure time and total sitting time. In 15 studies, objectively measured total sedentary time was reported: accelerometry (n = 14) and heart rate (n = 1). Individual level factors such as age, physical activity levels, body mass index, socio-economic status and mood were all significantly correlated with sedentariness. A trend towards increased amounts of leisure screen time was identified in those married or cohabiting while having children resulted in less total sitting time. Several environmental correlates were identified including proximity of green space, neighbourhood walkability and safety and weather. Conclusions: Results provide further evidence relating to several already recognised individual level factors and preliminary evidence relating to social and environmental factors that should be further investigated. Most studies relied upon cross-sectional design limiting causal inference and the heterogeneity of the sedentary measures prevented direct comparison of findings. Future research necessitates longitudinal study designs, exploration of policy-related factors, further exploration of environmental factors, analysis of inter-relationships between identified factors and better classification of sedentary behaviour domains

The clonal evolution of metastatic colorectal cancer

Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine

Longitudinal Clinical, Neuropsychological, and Neuroimaging Characterization of a Kindred with a 12-Octapeptide Repeat Insertion in PRNP: The Next Generation

Background: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. Method: Clinical, neuropsychological, and neuroimaging characterization of a kindred. Results: Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment. Conclusions and relevance: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection