Browsing by Subject "Translocation"

Now showing 1 - 3 of 3
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    Effect of t (11;14) Abnormality on Outcomes of Patients With Newly Diagnosed Multiple Myeloma in the Connect MM Registry
    (Elsevier, 2022) Gasparetto, Cristina; Jagannath, Sundar; Rifkin, Robert M.; Durie, Brian G. M.; Narang, Mohit; Terebelo, Howard R.; Toomey, Kathleen; Hardin, James W.; Wagner, Lynne; Ailawadhi, Sikander; Omel, James L.; Srinivasan, Shankar; Dhalla, Mazaher; Catamero, Donna; Kitali, Amani; Agarwal, Amit; Abonour, Rafat; Connect MM Registry Investigators; Medicine, School of Medicine
    Background: The t (11;14) (q13;32) translocation [t (11;14)] is present in ∼20% of patients with newly diagnosed multiple myeloma (NDMM), but studies examining its prognostic ability have yielded divergent results, and data are lacking on outcomes from first-line therapy. Patients and methods: Data from the Connect MM Registry, a large US, multicenter, prospective observational cohort study of patients with NDMM were used to examine the effect of t (11;14) status on first-line therapy outcomes in the Overall population (n = 1574) and race groups (African American [AA] vs. non-African American [NAA]). Results: Baseline characteristics were generally similar between patients with (n = 378) and without (n = 1196) t (11;14). Prevalence of t (11;14) was similar by race (AA, 27%; NAA, 24%). In the overall population, regardless of first-line therapy, t (11;14) status did not affect progression-free survival (hazard ratio, 1.02; P = 0.7675) or overall survival (hazard ratio, 0.99; P = .9417). AA patients with t (11;14) had higher likelihood of death (Nominal Cox regression P = .0298) vs. patients without t (11;14). Conclusions: Acknowledging observational study and inferential limitations, this exploratory analysis of a predominantly community-based population suggests that t (11;14) is a neutral prognostic factor in the general MM population but may be a negative factor for overall survival in AA patients.
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    Roles of the Site 2 Protease Eep in Staphylococcus aureus
    (American Society for Microbiology, 2020-07-09) Cheng, Danhong; Lv, Huiying; Yao, Yong; Cheng, Sen; Huang, Qian; Wang, Hua; Liu, Xiaoyun; Bae, Taeok; Li, Min; Liu, Qian; Microbiology and Immunology, School of Medicine
    In Enterococcus faecalis, the site 2 protease Eep generates sex pheromones, including cAM373. Intriguingly, in Staphylococcus aureus, a peptide similar to cAM373, named cAM373_SA, is produced from the camS gene. Here, we report that the staphylococcal Eep homolog is not only responsible for the production of cAM373_SA but also critical for staphylococcal virulence. As with other Eep proteins, the staphylococcal Eep protein has four transmembrane (TM) domains, with the predicted zinc metalloprotease active site (HEXXH) in the first TM domain. eep deletion reduced the cAM373_SA activity in the culture supernatant to the level of the camS deletion mutant. It also markedly decreased the cAM373 peptide peak in a high-performance liquid chromatography (HPLC) analysis. Proteomics analysis showed that Eep affects the production and/or the release of diverse proteins, including the signal peptidase subunit SpsB and the surface proteins SpA, SasG, and FnbA. eep deletion decreased the adherence of S. aureus to host epithelial cells; however, the adherence of the eep mutant was increased by overexpression of the surface proteins SpA, SasG, and FnbA. eep deletion reduced staphylococcal resistance to killing by human neutrophils as well as survival in a murine model of blood infection. The overexpression of the surface protein SpA in the eep mutant increased bacterial survival in the liver. Our study illustrates that in S. aureus, Eep not only generates cAM373_SA but also contributes to the survival of the bacterial pathogen in the host.IMPORTANCE The emergence of multidrug-resistant Staphylococcus aureus makes the treatment of staphylococcal infections much more difficult. S. aureus can acquire a drug resistance gene from other bacteria, such as Enterococcus faecalis Intriguingly, S. aureus produces a sex pheromone for the E. faecalis plasmid pAM373, raising the possibility that S. aureus actively promotes plasmid conjugation from E. faecalis In this study, we found that the staphylococcal Eep protein is responsible for sex pheromone processing and contributes to the survival of the bacteria in the host. These results will enhance future research on the drug resistance acquisition of S. aureus and can lead to the development of novel antivirulence drugs.
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    The Secreted Acid Phosphatase Domain-Containing GRA44 from Toxoplasma gondii Is Required for c-Myc Induction in Infected Cells.
    (American Society for Microbiology, 2020-02-19) Blakely, William J.; Holmes, Michael J.; Arrizabalaga, Gustavo; Pharmacology and Toxicology, School of Medicine
    During host cell invasion, the eukaryotic pathogen Toxoplasma gondii forms a parasitophorous vacuole to safely reside within the cell, while it is partitioned from host cell defense mechanisms. From within this safe niche, parasites sabotage multiple host cell systems, including gene expression, apoptosis, and intracellular immune recognition, by secreting a large arsenal of effector proteins. Many parasite proteins studied for active host cell manipulative interactions have been kinases. The translocation of effectors from the parasitophorous vacuole into the host cell is mediated by a putative translocon complex, which includes the proteins MYR1, MYR2, and MYR3. Whether other proteins are involved in the structure or regulation of this putative translocon is not known. We have discovered that the secreted protein GRA44, which contains a putative acid phosphatase domain, interacts with members of this complex and is required for host cell effects downstream of effector secretion. We have determined that GRA44 is processed in a region with homology to sequences targeted by protozoan proteases of the secretory pathway and that both major cleavage fragments are secreted into the parasitophorous vacuole. Immunoprecipitation experiments showed that GRA44 interacts with a large number of secreted proteins, including MYR1. Importantly, conditional knockdown of GRA44 resulted in a lack of host cell c-Myc upregulation, which mimics the phenotype seen when members of the translocon complex are genetically disrupted. Thus, the putative acid phosphatase GRA44 is crucial for host cell alterations during Toxoplasma infection and is associated with the translocon complex which Toxoplasma relies upon for success as an intracellular pathogen.IMPORTANCE Approximately one-third of humans are infected with the parasite Toxoplasma gondii Toxoplasma infections can lead to severe disease in those with a compromised or suppressed immune system. Additionally, infections during pregnancy present a significant health risk to the developing fetus. Drugs that target this parasite are limited, have significant side effects, and do not target all disease stages. Thus, a thorough understanding of how the parasite propagates within a host is critical in the discovery of novel therapeutic targets. Toxoplasma replication requires that it enter the cells of the infected organism. In order to survive the environment inside a cell, Toxoplasma secretes a large repertoire of proteins, which hijack a number of important cellular functions. How these Toxoplasma proteins move from the parasite into the host cell is not well understood. Our work shows that the putative phosphatase GRA44 is part of a protein complex responsible for this process.