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"Pepper, Timothy"
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UNDERSTANDING OSHA: A Look at the Agency's Complex Legal & Political Environment
OSHA has certainly had an interesting year. The agency's final ergonomics standard continues to generate controversy, and the dust has yet to fully settle over its infamous opinion letter on home offices. These controversies raise a basic question: How does OSHA make law and why does the agency do it that way? This article attempts to answer that question by showing mat OSHA operates within a complex matrix of legal, political and historical constraints.
Journal Article
Understanding OSHA: A look at the agency's complex legal & political enviornment
The OSHA Act forced OSHA down a difficult path. The agency was forced to adopt in-place standards in the beginning and is required to use notice-and-comment rulemaking to create new standards. Many critics would contend that OSHA attempts to dodge these requirements through the use of informal guidance documents - and one could cite enough examples to make that a debatable proposition. Regardless of how this debate is resolved, the fact remains that OSHA's actions are often the result of the peculiar context in which the agency operates. Safety practitioners who understand this context are better able to understand how and why OSHA makes the decisions that shape the safety profession.
Journal Article
AROMATIC CARBOXYLIC ACIDS AS LATENT FUNCTIONAL DERIVATIVES: REGIOSELECTIVE SYNTHESIS OF ANTHRACENE AND PHENANTHRENE DIKETONES
A previous study carried out in this laboratory investigated the possibility of utilizing Friedlander condensations to incorporate 1,8-naphthyridine or 1,9,10-anthyridine heterocyclic systems into polymers. This study was severely limited due to the lack of available aromatic bis-ketones. Herein is described a general, regioselective synthesis of aromatic ketones from the corresponding carboxylic acids. 3,4,5,6-Tetrahydro-1,8-(2H,7H)-anthracenedione, 3,4,7,8-tetrahydro-1,5-(2H,6H)-anthracenedione, 3,4,5,6-tetrahydro-1,8-(2H,7H)-phenanthrenedione, and 1,2,7,8-tetrahydro-4,5-(3H,6H)-phenanthrenedione were synthesized from 1,8-anthracenedicarboxylic acid, 1,5-anthracene-dicarboxylic acid, 1,8-phenanthrenedicarboxylic acid, and 4,5-phenanthrenedicarboxylic acid respectively. The key step in these sequences is the metal-ammonia reduction of the starting diacids. These reductions can be controlled to selectively reduce the outer rings and leave the middle rings aromatic. The proposed mechanism corresponds to HMO calculations.
Dissertation
Can Unmanned Aerial Systems (Drones) Be Used for the Routine Transport of Chemistry, Hematology, and Coagulation Laboratory Specimens?
Unmanned Aerial Systems (UAS or drones) could potentially be used for the routine transport of small goods such as diagnostic clinical laboratory specimens. To the best of our knowledge, there is no published study of the impact of UAS transportation on laboratory tests.
Three paired samples were obtained from each one of 56 adult volunteers in a single phlebotomy event (336 samples total): two tubes each for chemistry, hematology, and coagulation testing respectively. 168 samples were driven to the flight field and held stationary. The other 168 samples were flown in the UAS for a range of times, from 6 to 38 minutes. After the flight, 33 of the most common chemistry, hematology, and coagulation tests were performed. Statistical methods as well as performance criteria from four distinct clinical, academic, and regulatory bodies were used to evaluate the results.
Results from flown and stationary sample pairs were similar for all 33 analytes. Bias and intercepts were <10% and <13% respectively for all analytes. Bland-Altman comparisons showed a mean difference of 3.2% for Glucose and <1% for other analytes. Only bicarbonate did not meet the strictest (Royal College of Pathologists of Australasia Quality Assurance Program) performance criteria. This was due to poor precision rather than bias. There were no systematic differences between laboratory-derived (analytic) CV's and the CV's of our flown versus terrestrial sample pairs however CV's from the sample pairs tended to be slightly higher than analytic CV's. The overall concordance, based on clinical stratification (normal versus abnormal), was 97%. Length of flight had no impact on the results.
Transportation of laboratory specimens via small UASs does not affect the accuracy of routine chemistry, hematology, and coagulation tests results from selfsame samples. However it results in slightly poorer precision for some analytes.
Journal Article
Patient-specific computational models predict prognosis in B cell lymphoma by quantifying pro-proliferative and anti-apoptotic signatures from genetic sequencing data
Genetic heterogeneity and co-occurring driver mutations impact clinical outcomes in blood cancers, but predicting the emergent effect of co-occurring mutations that impact multiple complex and interacting signalling networks is challenging. Here, we used mathematical models to predict the impact of co-occurring mutations on cellular signalling and cell fates in diffuse large B cell lymphoma and multiple myeloma. Simulations predicted adverse impact on clinical prognosis when combinations of mutations induced both anti-apoptotic (AA) and pro-proliferative (PP) signalling. We integrated patient-specific mutational profiles into personalised lymphoma models, and identified patients characterised by simultaneous upregulation of anti-apoptotic and pro-proliferative (AAPP) signalling in all genomic and cell-of-origin classifications (8-25% of patients). In a discovery cohort and two validation cohorts, patients with upregulation of neither, one (AA or PP), or both (AAPP) signalling states had good, intermediate and poor prognosis respectively. Combining AAPP signalling with genetic or clinical prognostic predictors reliably stratified patients into striking prognostic categories. AAPP patients in poor prognosis genetic clusters had 7.8 months median overall survival, while patients lacking both features had 90% overall survival at 120 months in a validation cohort. Personalised computational models enable identification of novel risk-stratified patient subgroups, providing a valuable tool for future risk-adapted clinical trials.
Journal Article
A Novel In Vitro Model of the Bone Marrow Microenvironment in Acute Myeloid Leukemia Identifies CD44 and Focal Adhesion Kinase as Therapeutic Targets to Reverse Cell Adhesion-Mediated Drug Resistance
Background/Objectives: Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, the disruption of the BMME, releasing tumor cells into the peripheral circulation, has therapeutic potential. Methods: Using both primary donor AML cells and cell lines, we developed an in vitro co-culture model of the AML BMME. We used this model to identify the most effective agent(s) to block AML cell adherence and reverse adhesion-mediated treatment resistance. Results: We identified that anti-CD44 treatment significantly increased the efficacy of cytarabine. However, some AML cells remained adhered, and transcriptional analysis identified focal adhesion kinase (FAK) signaling as a contributing factor; the adhered cells showed elevated FAK phosphorylation that was reduced by the FAK inhibitor, defactinib. Importantly, we demonstrated that anti-CD44 and defactinib were highly synergistic at diminishing the adhesion of the most primitive CD34high AML cells in primary autologous co-cultures. Conclusions: Taken together, we identified anti-CD44 and defactinib as a promising therapeutic combination to release AML cells from the chemoprotective AML BMME. As anti-CD44 is already available as a recombinant humanized monoclonal antibody, the combination of this agent with defactinib could be rapidly tested in AML clinical trials.
Journal Article
Acute Gastrointestinal Infection Induces Long-Lived Microbiota-Specific T Cell Responses
The mammalian gastrointestinal tract contains a large and diverse population of commensal bacteria and is also one of the primary sites of exposure to pathogens. How the immune system perceives commensals in the context of mucosal infection is unclear. Here, we show that during a gastrointestinal infection, tolerance to commensals is lost, and microbiota-specific T cells are activated and differentiate to inflammatory effector cells. Furthermore, these T cells go on to form memory cells that are phenotypically and functionally consistent with pathogen-specific T cells. Our results suggest that during a gastrointestinal infection, the immune response to commensals parallels the immune response against pathogenic microbes and that adaptive responses against commensals are an integral component of mucosal immunity.
Journal Article
TOI-1994b: A Low-mass Eccentric Brown Dwarf Transiting A Subgiant Star
We present the discovery of TOI-1994b, a low-mass brown dwarf transiting a hot subgiant star on a moderately eccentric orbit. TOI-1994 has an effective temperature of 7700−410+720 K, V magnitude of 10.51 mag and log(g) of 3.982−0.065+0.067 . The brown dwarf has a mass of 22.1−2.5+2.6 M J, a period of 4.034 days, an eccentricity of 0.341−0.059+0.054 , and a radius of 1.220−0.071+0.082 R J. TOI-1994b is more eccentric than other transiting brown dwarfs with similar masses and periods. The population of low-mass brown dwarfs may have properties similar to planetary systems if they were formed in the same way, but the short orbital period and high eccentricity of TOI-1994b may contrast this theory. An evolved host provides a valuable opportunity to understand the influence stellar evolution has on the substellar companion’s fundamental properties. With precise age, mass, and radius, the global analysis and characterization of TOI-1994b augments the small number of transiting brown dwarfs and allows the testing of substellar evolution models.
Journal Article
Targeting the Non-Canonical NF-κB Pathway in Chronic Lymphocytic Leukemia and Multiple Myeloma
In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B- and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then assessed in terms of cytotoxicity and the expression of nuclear NF-κB subunits following monoculture and co-culture with CD40L-expressing fibroblasts, as a model of the lymphoid niche. CW15337 induced a dose-dependent increase in apoptosis, and nuclear expression of the non-canonical NF-κB subunit, p52, was correlated with sensitivity to CW15337 (p = 0.01; r2 = 0.39). Co-culture on CD40L-expressing cells induced both canonical and non-canonical subunit expression in nuclear extracts, which promoted in vitro resistance against fludarabine and ABT-199 (venetoclax) but not CW15337. Furthermore, the combination of CW15337 with fludarabine or ABT-199 showed cytotoxic synergy. Mechanistically, CW15337 caused the selective inhibition of non-canonical NF-κB subunits and the transcriptional repression of BCL2L1, BCL2A1 and MCL1 gene transcription. Taken together, these data suggest that the NIK inhibitor, CW15337, exerts its effects via suppression of the non-canonical NF-κB signaling pathway, which reverses BCL2 family-mediated resistance in the context of CD40L stimulation.
Journal Article