Browsing by Subject "Serine Endopeptidases"
Now showing 1 - 6 of 6
Results Per Page
Sort Options
Item Open Access Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy.(Clinical cardiology, 2012-01) Kohli, Payal; Desai, Nihar R; Giugliano, Robert P; Kim, Jae B; Somaratne, Ransi; Huang, Fannie; Knusel, Beat; McDonald, Shannon; Abrahamsen, Timothy; Wasserman, Scott M; Scott, Robert; Sabatine, Marc SLowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 60-80 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein's role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-C-lowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-Thrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia.Item Open Access Is SARS-CoV-2 Infection a Risk Factor for Early Pregnancy Loss? ACE2 and TMPRSS2 Coexpression and Persistent Replicative Infection in Primitive Trophoblast.(The Journal of infectious diseases, 2021-12) Zhou, Jie; Choi, Sehee; Liu, Heidi; Zhang, Jialin; Tian, Yuchen; Edlow, Andrea G; Ezashi, Toshihiko; Roberts, R Michael; Ma, Wenjun; Schust, Danny JBackground
SARS-CoV-2 infection in term placenta is rare. However, growing evidence suggests that susceptibility of the human placenta to infection may vary by gestational age and pathogen. For several viral infections, susceptibility appears to be greatest during early gestation. Peri-implantation placental infections that result in pre-clinical pregnancy loss would typically go undetected. Little is known about the effects of SARS-CoV-2 on the peri-implantation human placenta since this time in pregnancy can only be modeled in vitro.Methods
We used a human embryonic stem cell (hESC)-derived model of peri-implantation placental development to assess patterns of ACE2 and TMPRSS2 transcription and protein expression in primitive trophoblast. We then infected the same trophoblast cell model with a clinical isolate of SARS-CoV-2 and documented infection dynamics.Results
ACE2 and TMPRSS2 were transcribed and translated in hESC-derived trophoblast, with preferential expression in syncytialized cells. These same cells supported replicative and persistent infection by SARS-CoV-2, while non-syncytialized trophoblast cells in the same cultures did not.Conclusions
Co-expression of ACE2 and TMPRSS2 in hESC-derived trophoblast and the robust and replicative infection limited to syncytiotrophoblast equivalents support the hypothesis that increased viral susceptibility may be a defining characteristic of primitive trophoblast.Item Open Access Placental Expression of ACE2 and TMPRSS2 in Maternal Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Are Placental Defenses Mediated by Fetal Sex?(The Journal of infectious diseases, 2021-12) Shook, Lydia L; Bordt, Evan A; Meinsohn, Marie-Charlotte; Pepin, David; De Guzman, Rose M; Brigida, Sara; Yockey, Laura J; James, Kaitlyn E; Sullivan, Mackenzie W; Bebell, Lisa M; Roberts, Drucilla J; Kaimal, Anjali J; Li, Jonathan Z; Schust, Danny; Gray, Kathryn J; Edlow, Andrea GBackground
Expression of angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), host molecules required for viral entry, may underlie sex differences in vulnerability to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated whether placental ACE2 and TMPRSS2 expression vary by fetal sex in the presence of maternal SARS-CoV-2 infection.Methods
Placental ACE2 and TMPRSS2 expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-PCR) and by Western blot in 68 pregnant women (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. The impact of fetal sex and maternal SARS-CoV-2 exposure on ACE2 and TMPRSS2 was analyzed by 2-way analysis of variance (ANOVA).Results
Maternal SARS-CoV-2 infection impacted placental TMPRSS2 expression in a sexually dimorphic fashion (2-way ANOVA interaction, P = .002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on ACE2. TMPRSS2 expression was significantly correlated with ACE2 expression in males (Spearman ρ = 0.54, P = .02) but not females (ρ = 0.23, P = .34) exposed to maternal SARS-CoV-2.Conclusions
Sex differences in placental TMPRSS2 but not ACE2 were observed in the setting of maternal SARS-CoV-2 infection, which may have implications for offspring vulnerability to placental infection.Item Open Access Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.(Nature medicine, 2021-03) Muus, Christoph; Luecken, Malte D; Eraslan, Gökcen; Sikkema, Lisa; Waghray, Avinash; Heimberg, Graham; Kobayashi, Yoshihiko; Vaishnav, Eeshit Dhaval; Subramanian, Ayshwarya; Smillie, Christopher; Jagadeesh, Karthik A; Duong, Elizabeth Thu; Fiskin, Evgenij; Torlai Triglia, Elena; Ansari, Meshal; Cai, Peiwen; Lin, Brian; Buchanan, Justin; Chen, Sijia; Shu, Jian; Haber, Adam L; Chung, Hattie; Montoro, Daniel T; Adams, Taylor; Aliee, Hananeh; Allon, Samuel J; Andrusivova, Zaneta; Angelidis, Ilias; Ashenberg, Orr; Bassler, Kevin; Bécavin, Christophe; Benhar, Inbal; Bergenstråhle, Joseph; Bergenstråhle, Ludvig; Bolt, Liam; Braun, Emelie; Bui, Linh T; Callori, Steven; Chaffin, Mark; Chichelnitskiy, Evgeny; Chiou, Joshua; Conlon, Thomas M; Cuoco, Michael S; Cuomo, Anna SE; Deprez, Marie; Duclos, Grant; Fine, Denise; Fischer, David S; Ghazanfar, Shila; Gillich, Astrid; Giotti, Bruno; Gould, Joshua; Guo, Minzhe; Gutierrez, Austin J; Habermann, Arun C; Harvey, Tyler; He, Peng; Hou, Xiaomeng; Hu, Lijuan; Hu, Yan; Jaiswal, Alok; Ji, Lu; Jiang, Peiyong; Kapellos, Theodoros S; Kuo, Christin S; Larsson, Ludvig; Leney-Greene, Michael A; Lim, Kyungtae; Litviňuková, Monika; Ludwig, Leif S; Lukassen, Soeren; Luo, Wendy; Maatz, Henrike; Madissoon, Elo; Mamanova, Lira; Manakongtreecheep, Kasidet; Leroy, Sylvie; Mayr, Christoph H; Mbano, Ian M; McAdams, Alexi M; Nabhan, Ahmad N; Nyquist, Sarah K; Penland, Lolita; Poirion, Olivier B; Poli, Sergio; Qi, CanCan; Queen, Rachel; Reichart, Daniel; Rosas, Ivan; Schupp, Jonas C; Shea, Conor V; Shi, Xingyi; Sinha, Rahul; Sit, Rene V; Slowikowski, Kamil; Slyper, Michal; Smith, Neal P; Sountoulidis, Alex; Strunz, Maximilian; Sullivan, Travis B; Sun, Dawei; Talavera-López, Carlos; Tan, Peng; Tantivit, Jessica; Travaglini, Kyle J; Tucker, Nathan R; Vernon, Katherine A; Wadsworth, Marc H; Waldman, Julia; Wang, Xiuting; Xu, Ke; Yan, Wenjun; Zhao, William; Ziegler, Carly GK; NHLBI LungMap Consortium; Human Cell Atlas Lung Biological NetworkAngiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.Item Open Access Therapy and clinical trials.(Curr Opin Lipidol, 2013-06) Sodhi, Nishtha; Krasuski, Richard AItem Open Access Thousands of human mobile element fragments undergo strong purifying selection near developmental genes.(Proceedings of the National Academy of Sciences of the United States of America, 2007-05) Lowe, Craig B; Bejerano, Gill; Haussler, DavidAt least 5% of the human genome predating the mammalian radiation is thought to have evolved under purifying selection, yet protein-coding and related untranslated exons occupy at most 2% of the genome. Thus, the majority of conserved and, by extension, functional sequence in the human genome seems to be nonexonic. Recent work has highlighted a handful of cases where mobile element insertions have resulted in the introduction of novel conserved nonexonic elements. Here, we present a genome-wide survey of 10,402 constrained nonexonic elements in the human genome that have all been deposited by characterized mobile elements. These repeat instances have been under strong purifying selection since at least the boreoeutherian ancestor (100 Mya). They are most often located in gene deserts and show a strong preference for residing closest to genes involved in development and transcription regulation. In particular, constrained nonexonic elements with clear repetitive origins are located near genes involved in cell adhesion, including all characterized cellular members of the reelin-signaling pathway. Overall, we find that mobile elements have contributed at least 5.5% of all constrained nonexonic elements unique to mammals, suggesting that mobile elements may have played a larger role than previously recognized in shaping and specializing the landscape of gene regulation during mammalian evolution.