tbuckley/cabot-search huggingface dataset:
Abstract 14035: Cathepsin S Activity Controls Injury-Related Vascular Repair in Mice via the TLR2-mediated p38MAPK and PI3K–Akt-pHDAC6 Signaling Pathway
Authors: Hongxian Wu, Xian Wu Cheng, Lina Hu, Aiko Inoue, Guo-Ping Shi, Masafumi Kuzuya, Toyoaki Murohara
Journal: Circulation (2016)

Objective:  Cathepsin S (CatS) participates in atherogenesis through several putative mechanisms. The ability of cathepsins to modify histone tail is likely to contribute to stem cell development. Histone deacetylases (HDAC6) is required in modulating the proliferation and migration of various types of cancer cells. Here we investigated the crosstalk between CatS and HADC6 in injury-related vascular repair in mice.   Approach and Results:  Ligation injury to the carotid artery in mice increased the CatS expression, and CatS-deficient mice showed reduced neointimal formation in injured arteries. CatS deficiency decreased the phosphorylation levels of p38MAPK, Akt and HDAC6 and toll-like receptor 2 (TLR2) expression in ligated arteries. The genetic or pharmacological inhibition of CatS also alleviated the increased phosphorylation of p38MAPK, Akt and HDAC6 induced by platelet-derived growth factor BB (PDGF-BB) in cultured vascular smooth muscle cells (VSMCs), and p38MAPK inhibition and Akt inhibition decreased the phospho-HDAC6 levels. Moreover, genetic or pharmacological CatS inhibition caused decrease in the levels of the HDAC6 activity in VSMCs in response to PDGF-BB. The HDAC6 inhibitor tubastatin A downregulated PDGF-induced VSMC proliferation and migration, whereas HDAC6 overexpression exerted the opposite effect. Tubastatin A also decreased the intimal VSMC proliferation and neointimal hyperplasia in response to injury. TLR2 silencing decreased the phosphorylation levels of p38MAPK, Akt and HDAC6 and VSMC migration and proliferation.   Conclusions:  This is the first report detailing cross-interaction between TLR-2-mediated CatS and HDAC6 during injury-related vascular repair. These data suggest that CatS-HDAC6 could be a potential therapeutic target for the control of vascular diseases that are involved in neointimal lesion formation.
Beyond Consent: Building Trusting Relationships With Diverse Populations in Precision Medicine Research
Authors: Stephanie A. Kraft, Mildred K. Cho, Katherine Gillespie, Meghan Halley, Nina Varsava, Kelly E. Ormond, Harold S. Luft, Benjamin S. Wilfond, Sandra Soo-Jin Lee
Journal: The American Journal of Bioethics (2018)

With the growth of precision medicine research on health data and biospecimens, research institutions will need to build and maintain long-term, trusting relationships with patient-participants. While trust is important for all research relationships, the longitudinal nature of precision medicine research raises particular challenges for facilitating trust when the specifics of future studies are unknown. Based on focus groups with racially and ethnically diverse patients, we describe several factors that influence patient trust and potential institutional approaches to building trustworthiness. Drawing on these findings, we suggest several considerations for research institutions seeking to cultivate long-term, trusting relationships with patients: (1) Address the role of history and experience on trust, (2) engage concerns about potential group harm, (3) address cultural values and communication barriers, and (4) integrate patient values and expectations into oversight and governance structures.
Correlation of allergen-specific T follicular helper cell counts with specific IgE levels and efficacy of allergen immunotherapy
Authors: Yin Yao, Cai-Ling Chen, Nan Wang, Zhi-Chao Wang, Jin Ma, Rong-Fei Zhu, Xiao-Yan Xu, Peng-Cheng Zhou, Di Yu, Zheng Liu
Journal: Journal of Allergy and Clinical Immunology (2018)
Pregnancy Outcomes After Exposure to Certolizumab Pegol
Authors: Megan E. B. Clowse, Angela E. Scheuerle, Christina Chambers, Anita Afzali, Alexa B. Kimball, John J. Cush, Maureen Cooney, Laura Shaughnessy, Mark Vanderkelen, Frauke Förger
Journal: Arthritis & Rheumatology (2018)

Objective Anti–tumor necrosis factor (anti‐ TNF ) medications are effective in controlling chronic inflammatory diseases, but information about their use and safety in pregnancy is limited. Consequently, anti‐ TNF agents are often discontinued early in gestation. Certolizumab pegol ( CZP ), a PEG ylated, Fc‐free anti‐ TNF agent approved for the treatment of rheumatic diseases and/or Crohn's disease, has minimal to no active placental transfer. This analysis was undertaken to evaluate pregnancy outcomes in women receiving CZP , especially those exposed during early pregnancy. Methods Prospective and retrospective data on maternal CZP exposure were extracted from the UCB Pharma safety database through March 6, 2017. Analysis was limited to prospective reports to avoid potential bias associated with retrospective submissions. The numbers of live births, miscarriages, elective abortions, stillbirths, and major congenital malformations were ascertained. Results Of 1,137 prospectively reported pregnancies with maternal exposure to CZP , 528 (including 10 twin pregnancies) had 538 known outcomes: 459 live births (85.3%), 47 miscarriages (8.7%), 27 elective abortions (5.0%), and 5 stillbirths (0.9%). There were 8 major congenital malformations (1.7%) among the 459 infants. First trimester exposure occurred in 367 (81.2%) of 452 pregnancies resulting in 459 live births. Exposure during all 3 trimesters occurred in 201 (44.5%) of 452 pregnancies. Conclusion This analysis represents the largest cohort of pregnant women exposed to an anti‐ TNF agent for management of chronic inflammatory diseases. Analysis of pregnancy outcomes does not indicate a teratogenic effect of CZP , compared to the general population, nor an increased risk of fetal death. The data are reassuring for women of childbearing age considering treatment with CZP .
Abstract 12935: Enhanced Binding of Calmodulin to RyR2 Inhibits Aberrant Ca2+ Release and Arrhythmogenesis in CPVT-Associated Mutation
Authors: Masakazu Fukuda, Takeshi Yamamoto, Takayoshi Kato, Akihiro Hino, Takeshi Suetomi, Hiroki Tateishi, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Masunori Matsuzaki, Masafumi Yano
Journal: Circulation (2012)

Calmodulin (CaM) plays a key role in modulating channel gating in ryanodine receptor (RyR2). Here, we investigated the pathogenic role of CaM in the channel disorder in CPVT, using knock-in (KI) mouse model with CPVT-associated RyR2 mutation (R2474S).   Methods and results.  Transmembrane potentials were recorded in whole cell current mode before and after pacing (1 to 5 Hz) in isolated ventricular myocytes. CaM binding was assessed by incorporation of exogenous CaM fluorescently labeled with Alexa Fluor® in saponin-permeabilised myocytes. In the presence of cAMP (1 µM) the binding affinity of CaM decreased in KI cells (Kd: 160 to 300 nM), but not in WT cells (Kd: 170 to 200 nM). Gly-Ser-His-CaM (GSH-CaM) showed higher binding affinity than CaM in cAMP-treated KI cells (70 nM), although the ability of GSH-CaM to increase CaMKII activity was similar to CaM. Neither delayed afterdepolarization (DAD) nor triggered activity (TA) were observed in WT cells even at 5 Hz pacing, whereas both DAD and TA were observed in 20% and 12% of KI cells, respectively. In response to 10 nM isoproterenol, only DAD (but not TA) was observed in 11% of WT cells, whereas in KI cells the incidence of DAD and TA further increased to 64% and 32% of cells, respectively. Addition of GSH-CaM (200 nM) decreased both DADs and TA (DAD: 20% of cells; TA: 10% of cells), whereas CaM (200 nM) did not. Addition of GSH-CaM to saponin-permeabilized KI cells decreased Ca2+ spark frequency (+6% of WT cells), which otherwise markedly increased without GSH-CaM (+50% of WT cells), whereas CaM revealed much less effect on the Ca2+ spark frequency (+23% of WT cells). Then, by incorporation of CaM or GSH-CaM to intact cells (by protein delivery kit), we assessed the in situ effect of GSH-CaM (cytosolic [CaM]=∼240 nM, cytosolic [GSH-CaM]=∼230 nM) on the frequency of spontaneous Ca2+ transient (sCaT, % of total cells). Addition of 10 nM isoproterenol to KI cells increased sCaT after transient 5 Hz pacing (37%), whereas it was much more attenuated by GSH-CaM (9%) than by CaM (26%) (p   Conclusions.  In CPVT-associated mutation of RyR2 CaM binding affinity is decreased upon PKA phosphorylation, whereas normally restored CaM binding to the mutant RyR2 inhibits aberrant Ca2+ release, DADs, and triggered activity.
Phase 3, randomized study of pembrolizumab (pembro) vs best supportive care (BSC) for second-line advanced hepatocellular carcinoma (HCC): KEYNOTE-240.
Authors: Richard S. Finn, Stephen L. Chan, Andrew X. Zhu, Jennifer J. Knox, Ann-Lii Cheng, Abby B. Siegel, Oliver Bautista, Masatoshi Kudo
Journal: Journal of Clinical Oncology (2017)

TPS4143 Background: The tyrosine kinase inhibitor sorafenib is the standard of care for first-line HCC; currently, there is no clear standard of care after disease progression on sorafenib or for patients (pts) with intolerance to sorafenib. Because most HCC is driven by inflammation, there is a strong rationale to evaluate immunotherapy in pts with this type of cancer. The randomized, double-blind, placebo-controlled phase 3 KEYNOTE-240 study (ClinicalTrials.gov, NCT02702401) was designed to compare the efficacy and safety of the anti–PD-1 antibody pembro + BSC vs placebo + BSC in pts with previously treated advanced HCC. Methods: Eligibility criteria include age ≥ 18 years, histologically or cytologically confirmed diagnosis of HCC, documented progression after stopping treatment with sorafenib or intolerance to sorafenib, disease not amenable to a curative treatmentapproach (eg, transplantation, surgery, or ablation), measurable disease confirmed by central imaging vendor review per RECIST v1.1, Child-Pugh liver score A, ECOG performance status 0-1, and predicted life expectancy &gt; 3 months. Pts will be randomly assigned 2:1 to receive pembro 200 mg IV Q3W + BSC or placebo Q3W + BSC for up to 35 cycles (~2 years) or until disease progression, unacceptable toxicity, or investigator decision. Randomization will be stratified by geographic region, presence of macrovascular invasion, and α-fetoprotein level. BSC will be provided by the investigator per local treatment practices. Response will be assessed every 6 weeks per RECIST v1.1 by central imaging vendor review. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Primary objectives are comparison of progression-free survival per RECIST v1.1 by central imaging vendor review and overall survival between treatment arms. Secondary objectives are comparison of objective response rate, duration of response, disease control rate, and time to progression per RECIST v1.1 by central imaging vendor review; and evaluation of safety and tolerability. Planned enrollment in KEYNOTE-240 is 408 pts across 26 countries. Clinical trial information: NCT02702401.
Alignment Modulates Ancestral Sequence Reconstruction Accuracy
Authors: Ricardo Assunção Vialle, Asif U Tamuri, Nick Goldman
Journal: Molecular Biology and Evolution (2018)

Accurate reconstruction of ancestral states is a critical evolutionary analysis when studying ancient proteins and comparing biochemical properties between parental or extinct species and their extant relatives. It relies on multiple sequence alignment (MSA) which may introduce biases, and it remains unknown how MSA methodological approaches impact ancestral sequence reconstruction (ASR). Here, we investigate how MSA methodology modulates ASR using a simulation study of various evolutionary scenarios. We evaluate the accuracy of ancestral protein sequence reconstruction for simulated data and compare reconstruction outcomes using different alignment methods. Our results reveal biases introduced not only by aligner algorithms and assumptions, but also tree topology and the rate of insertions and deletions. Under many conditions we find no substantial differences between the MSAs. However, increasing the difficulty for the aligners can significantly impact ASR. The MAFFT consistency aligners and PRANK variants exhibit the best performance, whereas FSA displays limited performance. We also discover a bias towards reconstructed sequences longer than the true ancestors, deriving from a preference for inferring insertions, in almost all MSA methodological approaches. In addition, we find measures of MSA quality generally correlate highly with reconstruction accuracy. Thus, we show MSA methodological differences can affect the quality of reconstructions and propose MSA methods should be selected with care to accurately determine ancestral states with confidence.
Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer
Authors: S. Siena, A. Sartore-Bianchi, S. Marsoni, H.I. Hurwitz, S.J. McCall, F. Penault-Llorca, S. Srock, A. Bardelli, L. Trusolino
Journal: Annals of Oncology (2018)

Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.
FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial
Authors: Alberto Sobrero, Sara Lonardi, Gerardo Rosati, Maria Di Bartolomeo, Monica Ronzoni, Nicoletta Pella, Mario Scartozzi, Maria Banzi, Maria Giulia Zampino, Felice Pasini, Paolo Marchetti, Maurizio Cantore, Alberto Zaniboni, Lorenza Rimassa, Libero Ciuffreda, Daris Ferrari, Vittorina Zagonel, Evaristo Maiello, Sandro Barni, Eliana Rulli, Roberto Labianca
Journal: Journal of Clinical Oncology (2018)

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.
Artistic Renaissance in Frontotemporal Dementia
Authors: Michael G. Erkkinen, Raquel Gutiérrez Zúñiga, Cristóbal Carnero Pardo, Bruce L. Miller, Zachary A. Miller
Journal: JAMA (2018)

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The combined therapeutic effects of 131iodine-labeled multifunctional copper sulfide-loaded microspheres in treating breast cancer
Authors: Qiufang Liu, Yuyi Qian, Panli Li, Sihang Zhang, Zerong Wang, Jianjun Liu, Xiaoguang Sun, Michael Fulham, Dagan Feng, Zhigang Chen, Shaoli Song, Wei Lu, Gang Huang
Journal: Acta Pharmaceutica Sinica B (2018)

Compared to conventional cancer treatment, combination therapy based on well-designed nanoscale platforms may offer an opportunity to eliminate tumors and reduce recurrence and metastasis. In this study, we prepared multifunctional microspheres loading 131I-labeled hollow copper sulfide nanoparticles and paclitaxel (131I-HCuSNPs-MS-PTX) for imaging and therapeutics of W256/B breast tumors in rats. 18F-fluordeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging detected that the expansion of the tumor volume was delayed (P<0.05) following intra-tumoral (i.t.) injection with 131I-HCuSNPs-MS-PTX plus near-infrared (NIR) irradiation. The immunohistochemical analysis further confirmed the anti-tumor effect. The single photon emission computed tomography (SPECT)/photoacoustic imaging mediated by 131I-HCuSNPs-MS-PTX demonstrated that microspheres were mainly distributed in the tumors with a relatively low distribution in other organs. Our results revealed that 131I-HCuSNPs-MS-PTX offered combined photothermal, chemo- and radio-therapies, eliminating tumors at a relatively low dose, as well as allowing SPECT/CT and photoacoustic imaging monitoring of distribution of the injected agents non-invasively. The copper sulfide-loaded microspheres, 131I-HCuSNPs-MS-PTX, can serve as a versatile theranostic agent in an orthotopic breast cancer model.
Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury
Authors: Bevan S. Main, Sonia Villapol, Stephanie S. Sloley, David J. Barton, Maia Parsadanian, Chinyere Agbaegbu, Kathryn Stefos, Mondona S. McCann, Patricia M. Washington, Olga C. Rodriguez, Mark P. Burns
Journal: Molecular Neurodegeneration (2018)

Traumatic Brain Injury (TBI) is a major cause of disability and mortality, to which there is currently no comprehensive treatment. Blood Brain Barrier (BBB) dysfunction is well documented in human TBI patients, yet the molecular mechanisms that underlie this neurovascular unit (NVU) pathology remains unclear. The apolipoprotein-E (apoE) protein has been implicated in controlling BBB integrity in an isoform dependent manner, via suppression of Cyclophilin A (CypA)–Matrix metallopeptidase-9 (MMP-9) signaling cascades, however the contribution of this pathway in TBI-induced BBB permeability is not fully investigated. We exposed C57Bl/6 mice to controlled cortical impact and assessed NVU and BBB permeability responses up to 21 days post-injury. We pharmacologically probed the role of the CypA-MMP-9 pathway in BBB permeability after TBI using Cyclosporin A (CsA, 20 mg/kg). Finally, as the apoE4 protein is known to be functionally deficient compared to the apoE3 protein, we used humanized APOE mice as a clinically relevant model to study the role of apoE on BBB injury and repair after TBI. In C57Bl/6 mice there was an inverse relationship between soluble apoE and BBB permeability, such that damaged BBB stabilizes as apoE levels increase in the days following TBI. TBI mice displayed acute pericyte loss, increased MMP-9 production and activity, and reduced tight-junction expression. Treatment with the CypA antagonist CsA in C57Bl/6 mice attenuates MMP-9 responses and enhances BBB repair after injury, demonstrating that MMP-9 plays an important role in the timing of spontaneous BBB repair after TBI. We also show that apoe mRNA is present in both astrocytes and pericytes after TBI. We report that APOE3 and APOE4 mice have similar acute BBB responses to TBI, but APOE3 mice display faster spontaneous BBB repair than APOE4 mice. Isolated microvessel analysis reveals delayed pericyte repopulation, augmented and sustained MMP-9 expression at the NVU, and impaired stabilization of Zonula Occludens-1, Occludin and Claudin-5 expression at tight junctions in APOE4 mice after TBI compared to APOE3 mice. These data confirm apoE as an important modulator of spontaneous BBB stabilization following TBI, and highlights the APOE4 allele as a risk factor for poor outcome after TBI.