Niss O, Quinn CT, Lane A, Daily J, Khoury PR, Bakeer N, Kimball TR, Towbin JA, Malik P, Taylor MD. Cardiomyopathy with Restrictive Physiology in Sickle Cell Disease. JACC Cardiovasc Imaging. 2016 Mar; 9(3):243-52.
Different cardiac morphologic features and mortality risk factors identified in sickle cell disease, have not been a unifying pathophysiology to explain these findings or link the adverse factors to cardiac phenotype. This study identifies a unique cardiomyopathy with features of restrictive physiology and anemia-related hyperdynamic physiology in patients with sickle cell disease. The cardiomyopathy of sickle cell disease is the likely pathophysiology that links cardiac phenotype to the adverse risk factors of sickle cell disease.
Adams GN, Rosenfeldt L, Frederick M, Miller W, Waltz D, Kombrinck K, McElhinney KE, Flick MJ, Monia BP, Revenko AS, Palumbo JS. Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen. Cancer Res. 2015 Oct 1;75(19):4235-43.
This paper documented, for the first time, that the central hemostatic protease, thrombin, plays an unexpected and multifaceted role in colon cancer progression, driving not only metastasis, but also tumor proliferation and local invasion. We also showed that at least two downstream thrombin targets, stromal cell-associated protease activated receptor-1 and fibrinogen, are significant determinants of tumor growth, suggests thrombin coupled to tumor growth in this setting through multiple distinct mechanisms. These studies also represented the first cancer context where fibrinogen was unambiguously demonstrated to promote tumor growth. Taken together with previous studies from our laboratory showing that the thrombin/fibrinogen axis is a major determinant of intestinal tumorigenesis, these studies suggest that hemostatic system components play a broad role in colon cancer progression, driving very early steps important in tumor formation, as well as later steps critical for tumor growth and dissemination. An important implication of these studies is that therapies targeting thrombin generation and/or downstream thrombin functions, including therapies with little or no bleeding risk, could represent a novel and effective way to prevent colon cancer and/or an adjuvant treatment for this important malignancy.
Konstantinidis DG, Giger KM, Risinger M, Pushkaran S, Zhou P, Dexheimer P, Yerneni S, Andreassen P, Klingmüller U, Palis J, Zheng Y, Kalfa TA. Cytokinesis failure in RhoA-deficient mouse erythroblasts involves actomyosin and midbody dysregulation and triggers p53 activation. Blood. 2015 Sep 17;126(12):1473-82.
Erythropoiesis is a remarkably industrious process producing two million reticulocytes per second in a healthy adult. To maintain a normal hemoglobin level and avoid anemia, the mechanisms of cell proliferation and cell division have to be fully optimized. To understand this process better, we developed a mouse model with erythroid-specific deletion of RhoA, which is a member of the Rho GTPase family of proteins that act as molecular switches, turning on or off a wide variety of biological processes. This model was embryonic lethal and caused severe dyserythropoietic anemia by mouse mid-gestation. Cytokinesis failure caused by RhoA deficiency resulted in p53 activation and p21-transcriptional upregulation with associated cell-cycle arrest, increased DNA damage, and cell death. Our findings demonstrated the role of RhoA as a critical regulator for efficient erythroblast cytokinesis and proliferation and the p53 pathway as a powerful quality control mechanism in erythropoiesis.
Ndeezi G, Kiyaga C, Hernandez AG, Munube D, Howard TA, Ssewanyana I, Nsungwa J, Kiguli S, Ndugwa CM, Ware RE, Aceng JR. Burden of sickle cell trait and disease in the Uganda Sickle Surveillance Study (US3): a cross-sectional study. Lancet Glob Health. 2016 Mar;4(3):e195-200.
In collaboration with Makerere University and the Uganda Ministry of Health, we created a specialized Sickle Cell Laboratory and trained local personnel to conduct a large prospective surveillance study of sickle cell trait and disease across the Republic of Uganda. Researchers analyzed dried blood spots collected for the Early Infant Diagnosis HIV testing program by hemoglobin electrophoresis at the Uganda Central Public Health Laboratory, mapping results by region and district to provide a geospatial display of the sickle cell burden. The study tested almost 100,000 samples with an overall prevalence of 13.3% sickle cell trait and 0.7% sickle cell disease. Substantial variation note included ~20% trait primarily in the East Central and mid-Northern regions. Sickle cell disease was less common in children older than 12 months, or who were HIV positive, which is consistent with comorbidity and early mortality. Based on these results, targeting hemoglobinopathy screening in the highest burden districts has commenced.