The Correlation between Zip Codes and Health

This research proposal focuses on public health and economics. It focuses on how the zip code you reside in affects your health. Studies have shown that the correlation between zip codes and health may be stronger than the correlation between genetic codes and health. Many of the reasons zip codes affect your health are economic. This research aims to address the economic reasons and explore the disparities in life expectancy between areas with higher socioeconomic levels and lower socioeconomic levels. In places like Chicago there are life expectancies with up to 30 years in between them (Ducharme and Wolfson, 2019). Socioeconomic variables such as medical, education levels, and demographic will be utilized. This project will test the significance of zip codes and health within different communities specifically focusing on Los Angeles County and its zip codes

N-terminal pro–brain natriuretic peptide and exercise capacity in chronic heart failure: Data from the Heart Failure and a Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study

To examine the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) and exercise capacity in a large contemporary cohort of patients with chronic heart failure

Physical examination for lumbar radiculopathy due to disc herniation in patients with low-back pain

Background: Low-back pain with leg pain (sciatica) may be caused by a herniated intervertebral disc exerting pressure on the nerve root. Most patients will respond to conservative treatment, but in carefully selected patients, surgical discectomy may provide faster relief of symptoms. Primary care clinicians use patient history and physical examination to evaluate the likelihood of disc herniation and select patients for further imaging and possible surgery. Objectives: (1) To assess the performance of tests performed during physical examination (alone or in combination) to identify radiculopathy due to lower lumbar disc herniation in patients with low-back pain and sciatica; (2) To assess the influence of sources of heterogeneity on diagnostic performance. Search strategy: We searched electronic databases for primary studies: PubMed (includes MEDLINE), EMBASE, and CINAHL, and (systematic) reviews: PubMed and Medion (all from earliest until 30 April 2008), and checked references of retrieved articles. Selection criteria: We considered studies if they compared the results of tests performed during physical examination on patients with back pain with those of diagnostic imaging (MRI, CT, myelography) or findings at surgery. Data collection and analysis: Two review authors assessed the quality of each publication with the QUADAS tool, and extracted details on patient and study design characteristics, index tests and reference standard, and the diagnostic two-by-two table. We presented information on sensitivities and specificities with 95% confidence intervals (95% CI) for all aspects of physical examination. Pooled estimates of sensitivity and specificity were computed for subsets of studies showing sufficient clinical and statistical homogeneity. Main results: We included 16 cohort studies (median N = 126, range 71 to 2504) and three case control studies (38 to100 cases). Only one study was carried out in a primary care population. When used in isolation, diagnostic performance of most physical tests (scoliosis, paresis or muscle weakness, muscle wasting, impaired reflexes, sensory deficits) was poor. Some tests (forward flexion, hyper-extension test, and slump test) performed slightly better, but the number of studies was small. In the one primary care study, most tests showed higher specificity and lower sensitivity compared to other settings. Most studies assessed the Straight Leg Raising (SLR) test. In surgical populations, characterized by a high prevalence of disc herniation (58% to 98%), the SLR showed high sensitivity (pooled estimate 0.92, 95% CI: 0.87 to 0.95) with widely varying specificity (0.10 to 1.00, pooled estimate 0.28, 95% CI: 0.18 to 0.40). Results of studies using imaging showed more heterogeneity and poorer sensitivity. The crossed SLR showed high specificity (pooled estimate 0.90, 95% CI: 0.85 to 0.94) with consistently low sensitivity (pooled estimate 0.28, 95% CI: 0.22 to 0.35). (aut. ref.

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Gap Junctional Intercellular Communication in Bone

Gap junctional intercellular communication has been demonstrated in bone cells and may contribute to the mechanism by which osteoblasts integrate and amplify extracellular signals, both chemical (hormonal) and biophysical (electrical and mechanical). Connexin 43 (Cx43) is the predominant gap junction protein expressed by bone cells. Experiments with osteoblastic cells in which Cx43 expression was diminished by antisense transfection demonstrate that cell-to-cell coupling in osteoblastic ROS 17/2.8 cells is via gap junctions composed of Cx43. Cellular networks of these coupling deficient clones are dramatically less responsive to parathyroid hormone (PTH) suggesting that coupling contributes to hormonal responsiveness. Furthermore, PTH per se can upregulate cell-to-cell communication in these networks. Membrane deformation-induced Ca2+ signals propagate from the deformed cell to neighboring undeformed cells. This phenomenon is blocked by octanol, a gap junction uncoupler. Physiologically relevant electric fields, i.e., induced by mechanical load, stimulate alkaline phosphatase activity in ROS 17/2.8 cells, but this response is greatly reduced in coupling deficient Cx43 antisense transfectants. Furthermore, electric fields per se regulate Cx43 expression in osteoblastic cells. Gap junctional intercellular communication appears critical for the regulation of osteoblastic behavior and thus bone metabolism by extracellular signals