Rabies Prophylaxis for Pregnant Women

Rabies Prophylaxis for Wome

Redirecting abiraterone metabolism to fine tune prostate cancer anti-androgen therapy

Abiraterone blocks androgen synthesis and prolongs survival in castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to D4A, which has even greater anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone3. Here, we show that D4A is converted to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted, while D4A concentrations rise, effectively blocking production of a tumor-promoting metabolite and permitting D4A accumulation. Furthermore, dutasteride does not deplete three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacologic 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Analysis of clathrin vesicle transport from the <italic>trans</italic> Golgi network to the late endosome.

Vesicle transport from the trans-Golgi network (TGN) to the late endosome/prevacuolar compartment (PVC) represents a conserved, clathrin-dependent sorting event that separates lysosomal from secretory cargo molecules and is also required for localization of integral membrane proteins to the TGN. The principal aim of this thesis has been the development of a cell-free assay that authentically reconstitutes the transport of membrane proteins from the TGN to the late endosome/PVC. The cell-free reaction exhibits features consistent with authentic membrane fusion reactions including dependence on time, temperature, ATP, and cytosol. Molecular analysis indicates that factors required for formation of clathrin-coated vesicles at the TGN (the Chc1p clathrin heavy chain, the Vps1p dynamin homolog, the Gga clathrin adaptor) and for vesicle fusion at the PVC (the Pep12p t-SNARE, the Vps21p rab protein, the Vps45p SM (Sec1/Munc18) protein) are required for cell-free transport. We used the TGN-PVC transport assay to determine the roles of clathrin adaptors Gga and AP-1 in TGN-PVC transport. We find that the Gga1/2 proteins, and not AP-1, function in the direct transport of two TGN transmembrane proteins, Kex2p and Vps10p, from the TGN to the PVC. To characterize the role of the yeast Gga proteins in TGN to PVC transport, we employ directed yeast two-hybrid and in vitro binding experiments to identify interactions between the sequences in the C-tails of TGN cargo molecules and Gga1/2p. Together, these experiments demonstrate that sequences in the cytosolic tails of Kex2p and Vps10p bind to the VHS domain of the Gga1/2p adaptor. Details of these experiments as well as further studies directed toward identifying the binding regions that mediate these interactions are described. Finally, we show that truncated forms of Gga proteins are able to form homo- and hetero-dimers and that sequence elements in the Gga hinge domain function to block both cargo binding and dimer formation. All together, these results establish the first cell-free assay reconstitution of TGN to late endosome/PVC transport in any system and describe new insights into the process of molecular recruitment of cargo proteins into Gga-containing clathrin coated vesicles at the TGN.Ph.D.Biological SciencesCellular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126995/2/3304908.pd

Potential systematic uncertainties in IGRT when FBCT reference images are used for pancreatic tumors

The purpose of this study was to quantify the systematic uncertainties resulting from using free breathing computed tomography (FBCT) as a reference image for image-guided radiation therapy (IGRT) for patients with pancreatic tumors, and to quantify the associated dosimetric impact that resulted from using FBCT as refer-ence for IGRT. Fifteen patients with implanted fiducial markers were selected for this study. For each patient, a FBCT and an average intensity projection computed tomography (AIP) created from four-dimensional computed tomography (4D CT) were acquired at the simulation. The treatment plan was created based on the FBCT. Seventy-five weekly kilovoltage (kV) cone-beam computed tomography (CBCT) images (five for each patient) were selected for this study. Bony align-ment without rotation correction was performed 1) between the FBCT and CBCT, 2) between the AIP and CBCT, and 3) between the AIP and FBCT. The contours of the fiducials from the FBCT and AIP were transferred to the corresponding CBCT and were compared. Among the 75 CBCTs, 20 that had&gt; 3 mm differences in centers of mass (COMs) in any directions between the FBCT and AIP were chose

RNA expression and risk of venous thromboembolism in lung cancer

Abstract Background The propensity to develop venous thromboembolism (VTE) on the basis of individual tumor biological features remains unknown. Objectives We conducted a whole transcriptome RNA sequencing strategy, focusing on a single cancer type (lung cancer), to identify biomarkers of cancer‐associated VTE. Methods Twelve propensity‐matched patients, 6 each with or without VTE, were identified from a prospective institutional review board–approved registry at the Cleveland Clinic with available tissue from surgical excision of a primary lung mass between 2010 and 2015. Patients were propensity matched based on age, sex, race, history of prior cancer, date of cancer diagnosis, stage, histology, number of lines of chemotherapy, and length of follow‐up. RNA sequencing was performed on tumor tissue, and gene set enrichment analysis (GSEA) was performed on differentially expressed genes. Results We identified 1037 genes with differential expression. In patients with VTE, 869 genes were overexpressed and 168 were underexpressed compared to patients without VTE. Of these, 276 overexpressed and 35 underexpressed were significantly different (Q < 0.05). GSEA revealed upregulation of genes in complement, inflammation, and KRAS signaling pathways in tumors from patients with VTE. Conclusions These differentially expressed genes and associated pathways provide biologic insights into cancer‐associated VTE and may provide insignts to develop new risk stratification schemes, prevention, or treatment strategies

Targeting the Epidermal Growth Factor Receptor in EGFR-Mutated Lung Cancer: Current and Emerging Therapies

Epidermal growth factor receptor-targeting tyrosine kinase inhibitors (EGFR TKIs) are the standard of care for patients with EGFR-mutated metastatic lung cancer. While EGFR TKIs have initially high response rates, inherent and acquired resistance constitute a major challenge to the longitudinal treatment. Ongoing work is aimed at understanding the molecular basis of these resistance mechanisms, with exciting new studies evaluating novel agents and combination therapies to improve control of tumors with all forms of EGFR mutation. In this review, we first provide a discussion of EGFR-mutated lung cancer and the efficacy of available EGFR TKIs in the clinical setting against both common and rare EGFR mutations. Second, we discuss common resistance mechanisms that lead to therapy failure during treatment with EGFR TKIs. Third, we review novel approaches aimed at improving outcomes and overcoming resistance to EGFR TKIs. Finally, we highlight recent breakthroughs in the use of EGFR TKIs in non-metastatic EGFR-mutated lung cancer