Search

PDF file - 113K, Odds ratios with 95% Confidence Intervals (CI) of lung cancer for circulating levels of Tryptophan, Kynurenine and Kynurenine/Tryptophan ratio by smoking status. P for trend were assessed by the base 2 logarithm of the circulating levels.

PDF file - 71K, Spearman partial correlation coefficients between biomarkers among controls of a nested case-control study in the EPIC cohort.

PDF file - 100K, Odds Ratios with 95% Confidence Intervals (CI) of Lung Cancer for circulating levels of Tryptophan, Kynurenine and Kynurenine/Tryptophan ratio by histological type. P for trend were assessed by the base 2 logarithm of the circulating levels.

Background: Imbalances in tryptophan metabolism have been linked to cancer-related immune escape and implicated in several cancers, including lung cancer.Methods: We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) that included 893 incident lung cancer cases and 1,748 matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk.Results: Tryptophan (Ptrend = 2 × 10−5) and the kynurenine/tryptophan ratio (KTR; Ptrend = 4 × 10−5) were associated with lung cancer risk overall after adjusting for established risk factors. The ORs comparing the fifth and first quintiles (OR5th vs. 1st) were 0.52 [95% confidence interval (CI), 0.37–0.74] for tryptophan and 1.74 (95% CI, 1.24–2.45) for KTR. After adjusting for plasma methionine (available from previous work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted Ptrend = 0.13) and KTR (Ptrend = 0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5th vs. 1st being 2.83 (95% CI, 1.62–4.94, Ptrend = 3 × 10−5) that was only marginally affected by adjusting for methionine.Conclusions: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. Although this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology.Impact: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk. Cancer Epidemiol Biomarkers Prev; 23(3); 461–8. ©2013 AACR.

PDF file - 98K, Odds ratios with 95% Confidence Intervals (CI) of lung cancer for circulating levels of Kynurenic acid, 3-Hydroxykynurenine, Anthralinic acid, Xanthurenic acid, 3-Hydroxyantranilic acid and Neopterine. P for trend were assessed by the base 2 logarithm of the circulating levels.

This case was an adapted version of a tax case heard in U.S. Federal District Court and the US Court of Appeals. The case involved a partnership set-up by a large US corporation with its own subsidiaries as managing partners and foreign partners as outside investors. The formation of the partnership resulted from a stated objective of finding an alternative to debt financing, but provided far more significant tax savings benefits. The case was intended for use in an undergraduate taxation class focusing on business entities or an undergraduate accounting capstone or special topics course. The case and its attendant exercises were designed as applied vehicles for exploring the dimensions of the debt vs. equity classification and the nature of economic substance doctrine. The case and exercises require little knowledge of partnership taxation, but some research of the economic substance doctrine, the concept of what constitutes a partnership, and the arguments for debt vs. equity classification are required. The case may be used as a writing assignment or for class discussion. Estimated time for completion of the assignments, including research, is about four hours. Estimated time for class discussion of answers is less than one hour.

Recent corporate scandals have increased public interest in the area of business ethics. This study examines the relationship of gender and choice of academic major to personal values and to ethical choices, and the relationship of personal values to ethical choices. Two hundred fifty three subjects read a case that presented a tax evasion dilemma. The subjects responded to a series of action statements related to the ethical dilemma and completed a personal values survey. The responses to the action statements were used to calculate a tax compliance score. Participants were also asked to make a choice as to whether the taxpayer should or should not report all of the taxable income. The results indicate that both the tax compliance score and the tax payment choice differed by gender and academic major. Furthermore, gender differences were found on five of the ten personal value constructs and academic major differences were found on four of the ten personal value constructs. With regard to the relationship of personal values to ethical choices, it was found that three of the personal value constructs were correlated with the compliance score and the tax payment decision.

Care provision and benchmarking for patients with ST-elevation myocardial infarction (STEMI) have focused on streamlining time between initial hospital presentation and opening of theinfarct-related artery. In a Boston-area regional system already characterized by expedited advanced life support (ALS) dispatch and paramedic performance of prehospital electrocardiogram (EKG), a critical pathway was designed that allows for helicopter dispatch based on ground ALS providers’ STEMI diagnosis. The pathway dictates that as soon as ALS crews make the diagnosis of STEMI from their 12-lead EKG, they will contact Boston MedFlight (BMF) and a helicopter will be immediately dispatched to the participating community hospital (Lawrence General Hospital [LGH]). Based on historical and predicted time patterns, it is expected that BMF will arrive at LGH soon after the ALS ambulance delivers the patient to the LGH emergency department (ED). The patient will then undergo BMF transport from the ED into central Boston with direct transfer into an awaiting cardiac catheterization suite (ie, bypassing the receiving hospital ED). The pathway minimizes the delay between patient arrival at LGH and BMF arrival for transport to the catheterization laboratory. It is hoped that implementation of the critical pathway will allow the region’s patients with STEMI to achieve coronary arterial patency within 90 minutes of LGH presentation. If the pathway proves effective, it can serve as a model for other regions and programs with similar clinical and logistic situations and advance the concept of “diagnosis-to-balloon” time.

Chronic Lymphocytic Leukemia (CLL) is a B-cell malignancy with aberrant activation of the B-cell receptor (BCR) pathway. Despite durable remissions with targeted therapies (e.g., ibrutinib) in CLL, it remains an incurable disease. Epigenetic modifications, including DNA methylation and dysregulation of chromatin regulators have been shown to contribute to the neoplastic phenotype and the differential biologic behavior of tumor cells, including leukemia. An additional layer of epigenetic complexity in cancer cells is the acquisition of super-enhancer regions enriched at genes with known oncogenic function including MYC and BCL2. Super-enhancers in multiple myeloma cells and other tumors have been found strongly enriched for binding of BRD4, a member of the human bromodomain and extraterminal (BET) domain family of proteins which includes BRD2, BRD3, BRD4, and the testis-specific member BRDT. BRD4 binds to acetylated lysines on histones and regulates the expression of important oncogenes (e.g., MYC and BCL2). We investigated the therapeutic benefit of BET inhibition in cell culture and in vivo disease models of leukemia/lymphoma using PLX51107, a novel BRD4 inhibitor with unique binding mode. Results: We report that BRD4 is significantly overexpressed in CLL patient-derived B-cells compared to B-cells from healthy donors on both transcript and protein level (p < .001). RNA-seq analysis of 55 CLL patients revealed expression of various BRD4 isoforms with marked abundance of BRD4-long and BRD4-short. Next we sought to investigate the anti-tumor activity of PLX51107 in multiple malignant B-cell lines and patient-derived CLL cells. PLX51107 inhibited cell growth in MEC1, OCI-Ly2 and OCI-Ly6 (p < .001) dose-dependently with IC50 of 1.0 ± 0.09, 1.2 ± 0.05, 1.8 ± 0.05 μM, respectively. Notably, PLX51107 antagonized CpG-induced increase in cell proliferation of primary CLL cells (p < .01) which was consistent with the downmodulation of MYC and MCL1 along with the accumulation of the cyclin-dependent kinase inhibitor p21 and IκBα (p < .005). Furthermore, the efficacy of PLX51107 to disrupt survival signaling from the microenvironment was investigated under co-culture conditions with two different bone marrow stroma cell lines, wherein PLX51107 treatment significantly induced cytotoxicity in B-CLL cells (p < .01) without affecting stromal cell viability. By employing microarray analysis we identified possible novel targets of BRD4 in CLL. Validation of those targets is currently ongoing. Particularly, Bruton's tyrosine kinase (BTK) and phospholipase C gamma 2 (PLCG2) were markedly decreased with PLX51107 treatment (p < .005), thereby signifying potential therapeutic effect(s) for dual targeting of BRD4 and BCR-associated kinases to achieve deeper and durable responses in relapsed/refractory B-cell malignancies. Lastly, anti-tumor effects of BRD4 inhibition were evaluated in vivo using Eμ-TCL1 and cMYC/TCL1 adoptive transfer models of leukemia and lymphoma, respectively. In the Eμ-TCL1 engraftment model of aggressive CLL, PLX51107 treatment resulted in prolonged survival (p < .001) accompanied with decreased disease burden, lymphocyte infiltration and proliferation when compared to vehicle-treated mice. Next, the cMYC/TCL1 adoptive transfer mouse model was used to evaluate BRD4 inhibition in a highly penetrant, malignant leukemia/lymphoma phenotype analogous to high grade lymphoma wherein PLX51107 prolonged survival (p < .0001), decreased peripheral lymphocyte counts and neoplastic cell infiltration and proliferation in both spleen and lymph nodes. Conclusion: Collectively our findings reveal BRD4 as a valid and novel target for epigenetic therapy directed against core transcriptional programs in malignant/proliferating B-cells and provide support for use of PLX51107 as an effective treatment in clinical trials for relapsed/refractory CLL patients and related aggressive forms of B-cell malignancies, with the ultimate goal of improving the outcome of these patients. Disclosures Byrd: Acerta Pharma BV: Research Funding.

In this study, the components of a multiple configuration small-scale horizontally curved bridge were constructed. Using these components, eight different horizontally curved bridge configurations were assembled, analyzed, and tested. In general, the results from analysis and test were sufficiently close to verify the three-dimensional method of analysis and computer program developed at Syracuse University, and the feasibility of using a small-scale multiple configuration model as a research tool to investigate internal forces and displacements in highway bridges. It was also determined that a horizontally curved bridge cannot be effectively analyzed by approximating the curved geometry with chords. If this assumption is made, the analysis will yield internal forces very close to the correct values but will underestimate the deflections of the bridge. Therefore, the stiffness relationship for horizontally curved members subjected to moment, shear, and torsion were derived and incorporated into the three-dimensional analysis and computer program.

A set of governing simultaneous partial differential equations describing the bending and membrane stress conditions in any translational shell are derived in this study. By employing a curvilinear coordinate system in the middle surface of the shell in the direction of the principal generators of the surface, the necessity of making the shallow shell assumptions is eliminated, thus the derived set of equations is equally valid for deep as well as shallow translational shells. However, the curvilinear coordinate system used is not, in general, orthogonal and the governing set of partial differential equations have variable coefficients. A finite difference solution is performed for the set of partial differential equations for a particular case - a fixed-edge hyperbolic paraboloid. The numerical solution was checked for discretization and round off error and found to be satisfactory. A small scale structural test program was instituted to verify the assumptions made in the derivation of the governing partial differential equations, and to further check the numerical solutions. Agreement between the test results and numerical solution was, in general, good and in many cases was within 10%.

A method of analysis for stress in castellated beams and beams with web openings is developed in this paper using finite difference, theory of elasticity solutions for both pure moment and pure shear loadings. An experimental program to evaluate the theory of elasticity solutions was conducted using nine full-sized test members. Three types of castellated beams fabricated from 18WF45 rolled beams are selected for comparison of stress distribution and magnitude because these three members include two different slopes of web openings and no increment plates and a member with an increment plate. In addition, the method most commonly used at present for analysis of castellated beams—the Vierendeel analysis—is compared with both the theory of elasticity solutions and the experimental data.