In 2007, higher maternal vitamin D intake during pregnancy was shown to be associated with a lower risk of wheezing illnesses by age 3 and 5 years.2 Two subsequent studies examining 25-hydroxyvitamin ...D (25OHD) in cord blood found lower levels of cord blood 25(OH)D to be related to allergic sensitization3 and wheeze,4 but not asthma.3,4 Of 10 observational studies, half of which assessed vitamin D status by estimating dietary intake using questionnaires and half of which measured 25(OH)D in maternal serum or cord blood, 5 found a significantly reduced risk of asthma or atopy among children of mothers with higher vitamin D status during pregnancy, 3 found increased asthma or atopy risk in this same population, and the remaining 2 studies found no relationship.5 In current analyses, we used an objective measure of vitamin D status--the concentration of plasma 25(OH)D in umbilical cord blood--in 2 US birth cohorts with widely divergent populations to examine the relationship of vitamin D status at birth with various atopic and asthma-related outcomes in children after 5 to 6 years of follow-up. Because 25(OH)D concentrations can be highly variable, it is possible that cord blood concentrations, while reflecting vitamin D status at the end of pregnancy, may not fully reflect vitamin D exposure of the infant during critical time windows in pregnancy and development.
Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU ...(genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify etiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7 and 9) in the prediction of CU (age 13), for youth low vs high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth-age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth-age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.
The potential efficacy and clinical feasibility of gene therapy for prostate cancer were tested. Efficacy was tested using the Dunning rat prostate carcinoma model. Rats with anaplastic, hormone ...refractory prostate cancer treated with irradiated prostate cancer cells genetically engineered to secrete human granulocyte-macrophage colony-stimulating factor (GM-CSF) showed longer disease-free survival compared to either untreated control rats or rats receiving prostate cancer cell vaccine mixed with soluble human GM-CSF. A gene modified prostate cancer cell vaccine thus provided effective therapy for anaplastic, hormone refractory prostate cancer in this animal model. An evaluation of the clinical feasibility of gene therapy for human prostate cancer based on these findings was then undertaken. Prostate cancer cells from patients with stage T2 prostate cancer undergoing radical prostatectomy were first transduced with MFG-lacZ, a retroviral vector carrying the beta-galactosidase reporter gene. Efficient gene transfer was achieved in each of 16 consecutive cases (median transduction efficiency 35%, range 12 to 65%). Cotransduction with a drug-selectable gene was not required to achieve high yield of genetically modified cells. Histopathology confirmed malignant origin of these cells and immunofluorescence analysis of cytokeratin 18 expression confirmed prostatic luminal-epithelial phenotype in each case tested. Cell yields (2.5 x 10(8) cells per gram of prostate cancer) were sufficient for potential entry into clinical trials. Autologous human prostate cancer vaccine cells were then transduced with MFG-GM-CSF, and significant human GM-CSF secretion was achieved in each of 10 consecutive cases. Sequential transductions increased GM-CSF secretion in each of 3 cases tested, demonstrating that increased gene dose can be used to escalate desired gene expression in individual patients. These studies show a preclinical basis for proceeding with clinical trials of gene therapy for human prostate cancer.
How Much Does the Asthma Outcome Definition Matter? Visness, Cynthia M., PhD; Calatroni, Agustin, MA, MS; Jaffee, Katy F., MS ...
Journal of allergy and clinical immunology,
02/2017, Letnik:
139, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Methods We use data from the Urban Environment and Childhood Asthma (URECA) to explore how the prevalence of asthma at age 7 years varies using 4 different definitions, encompassing combinations of ...parent-reported physician diagnosis, lung function measures, airway hyperresponsiveness, wheezing symptoms, medication use, and health care utilization.
Women in poor urban neighborhoods have high rates of stress and allergic diseases, but whether stress or stress correlates such as depression promote inflammatory and type 2 cytokine responses is ...unknown.
To examine associations among external stressors, perceived stress, depression, and peripheral blood mononuclear cell cytokine responses of mothers enrolled in the Urban Environment and Childhood Asthma Study and test the hypothesis that stress would be positively associated with type 2 and selected proinflammatory (tumor necrosis factor-α and interleukin-8) responses.
Questionnaire data from mothers living in 4 inner cities included information about external stress, stress perception, and depression. The external stress domains (interpersonal problems, housing, and neighborhood stress) were combined into a Composite Stressor score. Peripheral blood mononuclear cells were stimulated ex vivo and cytokine responses to innate, adaptive, and polyclonal immune stimuli were compared with stress and depression scores for 469 of the 606 study participants.
There were no significant positive associations between Composite Stressor scores, perceived stress, or depression scores and proinflammatory or type 2 cytokine responses, and these findings were not modified by allergy or asthma status. There were some modest associations with individual stressors and cytokine responses, but no consistent relations were noted. Depression was associated with decreased responses to some stimuli, particularly dust mite.
Composite measurements of stressors, perceived stress, or depression were not positively related to proinflammatory or type 2 cytokine responses in these young urban women. These data do not support the hypothesis that these factors promote cytokine responses associated with allergy.
ClinicalTrials.gov, identifier NCT00114881.
Military risk factors for Alzheimer's disease Weiner, Michael W; Friedl, Karl E; Pacifico, Anthony ...
Alzheimer's & dementia,
July 2013, Letnik:
9, Številka:
4
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Abstract Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are signature injuries of the wars in Iraq and Afghanistan and have been linked to an increased risk of Alzheimer's ...disease (AD) and other dementias. A meeting hosted by the Alzheimer's Association and the Veterans' Health Research Institute (NCIRE) in May 2012 brought together experts from the U.S. military and academic medical centers around the world to discuss current evidence and hypotheses regarding the pathophysiological mechanisms linking TBI, PTSD, and AD. Studies underway in civilian and military populations were highlighted, along with new research initiatives such as a study to extend the Alzheimer's Disease Neuroimaging Initiative (ADNI) to a population of veterans exposed to TBI and PTSD. Greater collaboration and data sharing among diverse research groups is needed to advance an understanding and appropriate interventions in this continuum of military injuries and neurodegenerative disease in the aging veteran.
Experimental studies using murine tumor models have demonstrated that potent systemic immunity can be generated using tumor vaccines engineered by gene transfer to secrete certain cytokines. The ...underlying physiological principle behind these strategies involves the sustained release of high doses of cytokine at the site of the tumor. In some cases, this paracrine approach appears to enhance tumor antigen presentation and avoids systemic cytokine toxicity. The widespread clinical use of autologous cytokine gene transduced tumor vaccines may be limited by the technical difficulty and labor intensity of individualized gene transfer. We have therefore explored an alternate approach to generating sustained release of cytokines local to the tumor cells. High doses of granulocyte-macrophage colony-stimulating factor encapsulated in cell-sized gelatin-chondroitin sulfate microspheres were mixed with irradiated tumor cells prior to s.c. injection. This vaccination scheme resulted in systemic anti-tumor immune responses comparable to granulocyte-macrophage colony-stimulating factor gene transduced tumor vaccines.
Background Both EUS and ERCP sampling techniques may provide tissue diagnoses in suspected malignant biliary obstruction. However, there are scant data comparing these 2 methods. Objective To compare ...EUS-guided FNA (EUS-FNA) and ERCP tissue sampling for the diagnosis of malignant biliary obstruction. Design Prospective, comparative, single-blind study. Setting Tertiary center. Patients Fifty-one patients undergoing same-session EUS and ERCP for the evaluation of malignant biliary obstruction over a 1-year period. Interventions EUS-FNA and ERCP tissue sampling with biliary brush cytology and intraductal forceps biopsies. Main Outcome Measurements Diagnostic sensitivity and accuracy of each sampling method compared with final diagnoses. Results EUS-FNA was more sensitive and accurate than ERCP tissue sampling ( P < .0001) in 51 patients with pancreatic cancers (n = 34), bile duct cancers (n = 14), and benign biliary strictures (n = 3). The overall sensitivity and accuracy were 94% and 94% for EUS-FNA, and 50% and 53% for ERCP sampling, respectively. EUS-FNA was superior to ERCP tissue sampling for pancreatic masses (sensitivity, 100% vs 38%; P < .0001) and seemed comparable for biliary masses (79% sensitivity for both) and indeterminate strictures (sensitivity, 80% vs 67%). Limitations Single-center study. Conclusion EUS-FNA is superior to ERCP tissue sampling in evaluating suspected malignant biliary obstruction, particularly for pancreatic masses. EUS-FNA appears similar to ERCP sampling for biliary tumors and indeterminate strictures. Given the superior performance characteristics of EUS-FNA and the higher incidence of pancreatic cancer compared with cholangiocarcinoma, EUS-FNA should be performed before ERCP in all patients with suspected malignant biliary obstruction. (Clinical trial registration number: NCT01356030 .)
Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated ...protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required.
In this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity.
High TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established.
TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.
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