What Can Business Leaders Learn from Medical Misdiagnoses?

Mistakes of diagnoses are often topics in medical schools, hospitals and medical practices. These errors can range from the minor and inexpensive to the harmful and costly. According to Johns Hopkins University researchers, devastating errors can lead to permanent damage or death for as many as 160,000 patients yearly. Diagnostic errors, however, may be becoming more preventable as many health-care providers are turning to a number of innovative strategies that are addressing the complicated web of errors, biases, and oversights. Included in innovative changes in medicine are the methods of managing patients’ records through electronic means. These modernizations are often touted as part of an overall plan to provide better health care delivery which in turn will lead to more efficient and effective health outcomes. But with any automation, there are potential downsides, such as information overload. In comparison, business analytics has become a very popular and growing field of operational research with application to many areas of business. Just as in medicine, it is the mission of “big data” to provide targeted and precise information to enhance the probability of making more effective and efficient decisions. Medicine and business have many overlapping concerns around the collection, analysis, and distribution of data. Bringing these professionals together, albeit they work in different contexts, has the possibility for advancing interdisciplinary insights around major decision-making issues that are paramount to both groups. Additionally, many medical professionals are in an ongoing effort to cut down on errors of misdiagnoses through the improvements in communication. Common biases have been identified that can exacerbate physicians making an incorrect diagnosis. For example, last year Dalhousie University in Halifax, Nova Scotia established a Critical Thinking Program that aims to help identify and analyze critical thinking biases. Physician Pat Crosberry, a researcher on the role of cognitive error in diagnosis, developed a list of 50 different types of biases that lead to diagnostic error. Businesses are often involved in strategic diagnostic research and misdiagnoses in this context are always a concern too. An interdisciplinary discussion of these issues will be discussed by panelists

Is Stormwater Treated? A Survey of Awareness and Behaviors That May Impact Nonpoint Source Education

2010 S.C. Water Resources Conference - Science and Policy Challenges for a Sustainable Futur

Self-Calibrated Warping for Mass Spectra Alignment

With recent advances in mass spectrometry (MS) technologies, it is now possible to study protein profiles over a wide range of molecular weights in small biological specimens. However, MS spectra are usually not aligned or synchronized between samples. To ensure the consistency of the subsequent analysis, spectrum alignment is necessary to align the spectra such that the same biological entity would show up at the same m/z value for different samples. Although a variety of alignment algorithms have been proposed in the past, most of them are developed based on chromatographic data and do not address some of the unique characteristics of the serum or other body fluid MS data. In this work, we propose a self-calibrated warping (SCW) algorithm to address some of the challenges associated with serum MS data alignment. In addition, we compare the proposed algorithm with five existing representative alignment methods using a clinical surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) data set

Overexpression of cytochrome P450 1A1 and its novel spliced variant in ovarian cancer cells: alternative subcellular enzyme compartmentation may contribute to carcinogenesis

Epithelial ovarian cancer derived from the human ovarian surface epithelium (HOSE) is the leading cause of death from gynecologic malignancies among American women. Metabolic activation of endogenous and exogenous chemicals by cytochrome P450 (CYP) class I enzymes has been implicated in its etiology. In this study, we showed overexpression of CYP1A1 mRNA, but not CYP1B1 transcripts, in ovarian cancer cell lines when compared with primary cultures or immortalized HOSE cell lines. Importantly, we identified a novel, enzymatically active, spliced variant of CYP1A1 (CYP1A1v) formed by excision of an 84-bp cryptic intron in exon 2. CYP1A1v is overexpressed in ovarian cancer cell lines and exhibits a unique subcellular distribution restricted to the nucleus and mitochondria, contrary to the endoplasmic reticulum localization of the wild-type enzyme. In concordance, total CYP1A1 activity, as measured by the ethoxyresorufin O-deethylase assay, was detected in mitochondrial, nuclear, and microsomal fractions of ovarian cancer cells but was notably absent in all subcellular fractions of HOSE cells. Immunocytochemistry studies in 30 clinical specimens revealed overexpression of CYP1A1 in various types of ovarian cancers compared with benign epithelia and frequent localization of the enzyme to cancer cell nuclei. Forced expression of CYP1A1wt or CYP1A1v in HOSE cells resulted in nuclear localization of the enzyme and acquisition of anchorage-independent growth, which was further exacerbated following exposure to benzo(a)pyrene or 17beta-estradiol. Collectively, these data provided the first evidence that CYP1A1 overexpression and alternative splicing could contribute to ovarian cancer initiation and progression

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions

Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosome-cell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression

Branched fatty acids in dairy and beef products markedly enhance alpha-methylacyl-CoA racemase expression in prostate cancer cells in vitro

An enzyme previously identified as alpha-methylacyl-CoA racemase (AMACR) is overexpressed in high-grade prostatic intraepithelial neoplasia and in a majority (60-100%) of prostate cancers (CaPs) as compared with normal and benign hyperplastic lesions of the prostate, where it is minimally expressed. This enzyme is required for the beta-oxidation of branched-chain fatty acids, which include phytanic acid and its alpha-oxidation product, pristanic acid. Interestingly, there is an established correlation between CaP risk and the consumption of dairy and beef products, which also contain marked quantities of these two phytols. In this context, it has also been reported that sex steroids influence lipogenesis through the induction of fatty acid synthase in CaP-derived cell lines and CaP tissues. These findings indicate a potential role for AMACR and the possible influence of sex steroids in both the early development and subsequent progression of CaP. Despite the recent interest in AMACR as a histological marker for CaP, little is known about the regulation of this enzyme and its role in CaP development. To identify potential AMACR-regulating factors, we treated LNCaP cells (an androgen-responsive CaP-derived cell line) and NPrEC cells (a normal prostate basal epithelial cell line) with increasing concentrations of pristanic acid, phytanic acid, 5alpha-dihydrotestosterone, and 17beta-estradiol. Neither the biologically potent androgen 5alpha-dihydrotestosterone nor 17beta-estradiol had any apparent effect on AMACR expression at the protein or transcriptional levels in either cell line. Conversely, pristanic acid and, to a much lesser extent, phytanic acid markedly increased AMACR protein levels selectively in the LNCaP cell line, but not the NPrEC cell line. However, no change was measured at the transcriptional level in either cell line. AMACR is therefore significantly increased at the protein level in CaP cells, through what appears to be the stabilizing effect of the same fatty acids that are present at appreciable concentrations in beef and dairy products, which have been associated with CaP risk. Our findings therefore provide a link between the consumption of dietary fatty acids and the enhanced expression of AMACR, an enzyme that may play an important role in genesis and progression of CaP

Effects of Heterozygous Deletion of Autism-related gene Cullin-3 in mice

Autism Spectrum Disorder (ASD) is a developmental disorder in which children display repetitive behavior, restricted range of interests, and atypical social interaction and communication. CUL3, coding for a Cullin family scaffold protein mediating assembly of ubiquitin ligase complexes through BTB domain substrate-recruiting adaptors, has been identified as a high-risk gene for autism. Although complete knockout of Cul3 results in embryonic lethality, Cul3 heterozygous mice have reduced CUL3 protein, demonstrate comparable body weight, and display minimal behavioral differences including decreased spatial object recognition memory. In measures of reciprocal social interaction, Cul3 heterozygous mice behaved similarly to their wild-type littermates. In area CA1 of hippocampus, reduction of Cul3 significantly increased mEPSC frequency but not amplitude nor baseline evoked synaptic transmission or paired-pulse ratio. Sholl and spine analysis data suggest there is a small yet significant difference in CA1 pyramidal neuron dendritic branching and stubby spine density. Unbiased proteomic analysis of Cul3 heterozygous brain tissue revealed dysregulation of various cytoskeletal organization proteins, among others. Overall, our results suggest that Cul3 heterozygous deletion impairs spatial object recognition memory, alters cytoskeletal organization proteins, but does not cause major hippocampal neuronal morphology, functional, or behavioral abnormalities in adult global Cul3 heterozygous mice

Proteomic analysis of the \u3cem\u3eS. cerevisiae\u3c/em\u3e response to the anticancer ruthenium complex KP1019

Like platinum-based chemotherapeutics, the anticancer ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(iii)], or KP1019, damages DNA, induces apoptosis, and causes tumor regression in animal models. Unlike platinum-based drugs, KP1019 showed no dose-limiting toxicity in a phase I clinical trial. Despite these advances, the mechanism(s) and target(s) of KP1019 remain unclear. For example, the drug may damage DNA directly or by causing oxidative stress. Likewise, KP1019 binds cytosolic proteins, suggesting DNA is not the sole target. Here we use the budding yeast Saccharomyces cerevisiae as a model in a proteomic study of the cellular response to KP1019. Mapping protein level changes onto metabolic pathways revealed patterns consistent with elevated synthesis and/or cycling of the antioxidant glutathione, suggesting KP1019 induces oxidative stress. This result was supported by increased fluorescence of the redox-sensitive dye DCFH-DA and increased KP1019 sensitivity of yeast lacking Yap1, a master regulator of the oxidative stress response. In addition to oxidative and DNA stress, bioinformatic analysis revealed drug-dependent increases in proteins involved ribosome biogenesis, translation, and protein (re)folding. Consistent with proteotoxic effects, KP1019 increased expression of a heat-shock element (HSE) lacZ reporter. KP1019 pre-treatment also sensitized yeast to oxaliplatin, paralleling prior research showing that cancer cell lines with elevated levels of translation machinery are hypersensitive to oxaliplatin. Combined, these data suggest that one of KP1019’s many targets may be protein metabolism, which opens up intriguing possibilities for combination therapy

Presence of Putative Repeat-in-Toxin Gene tosA in Escherichia coli Predicts Successful Colonization of the Urinary Tract

Uropathogenic Escherichia coli (UPEC) strains, which cause the majority of uncomplicated urinary tract infections (UTIs), carry a unique assortment of virulence or fitness genes. However, no single defining set of virulence or fitness genes has been found in all strains of UPEC, making the differentiation between UPEC and fecal commensal strains of E. coli difficult without the use of animal models of infection or phylogenetic grouping. In the present study, we consider three broad categories of virulence factors simultaneously to better define a combination of virulence factors that predicts success in the urinary tract. A total of 314 strains of E. coli, representing isolates from fecal samples, asymptomatic bacteriuria, complicated UTIs, and uncomplicated bladder and kidney infections, were assessed by multiplex PCR for the presence of 15 virulence or fitness genes encoding adhesins, toxins, and iron acquisition systems. The results confirm previous reports of gene prevalence among isolates from different clinical settings and identify several new patterns of gene associations. One gene, tosA, a putative repeat-in-toxin (RTX) homolog, is present in 11% of fecal strains but 25% of urinary isolates. Whereas tosA-positive strains carry an unusually high number (11.2) of the 15 virulence or fitness genes, tosA-negative strains have an average of only 5.4 virulence or fitness genes. The presence of tosA was predictive of successful colonization of a murine model of infection, even among fecal isolates, and can be used as a marker of pathogenic strains of UPEC within a distinct subset of the B2 lineage