tbuckley/cabot-search huggingface dataset:
Pharmacogenetic pathway analysis to identify factors for survival in metastatic renal cell cancer patients treated with sunitinib.
Authors: K. Eechoute, A. A. van der Veldt, H. Gelderblom, J. A. Gietema, H. Guchelaar, N. Van Erp, E. Boven, J. B. Haanen, R. Mathijssen, J. A. Wessels
Journal: Journal of Clinical Oncology (2010)

4521 Background: The objective of this study was to identify genetic polymorphisms involved in the pharmacokinetics and pharmacodynamics of sunitinib that are associated with progression-free survival (PFS) and/or overall survival (OS) in patients with metastatic renal cell cancer (mRCC). Methods: A multicenter pharmacogenetic association study was performed in 136 clear-cell mRCC patients treated with sunitinib. A total of 31 polymorphisms in 12 candidate genes, together with 12 clinical characteristics were tested univariately in a Kaplan-Meier survival analysis for association with PFS as primary and OS as secondary outcome. Candidate variables with P-value ≤ .1 were then analyzed in a multivariate Cox regression model. Results: Multivariate analysis showed that both PFS and OS were significantly prolonged when a copy of TCG in the ABCB1 haplotype (3435C/T, 1236C/T, 2677G/T) was present (HR=0.53 and 0.54, p=.025 and .042, respectively). Also for the ABCG2 34 G/A polymorphism, a trend towards a prolonged PFS (HR=0.44, p=.087) and OS (HR=0.39, p=.052) was seen when the A-allele was present. The combined effect of these mutations in both efflux transporters showed an even more significant difference (HR=0.48; p=.006 for PFS and HR=0.45, p=.004 for OS). In case of NR1I3, patients with the CAT haplotype (5719C/T, 7738A/C, 7837T/G) had a decreased PFS (HR=1.59, p=.015). Next to the genetic variants, the only clinical characteristics significantly associated with survival were the Motzer Criteria with PFS (HR=2.20; p<.001) and OS (HR=2.41; p=.001). Conclusions: This exploratory study shows that polymorphisms in genes encoding the drug transporters ABCB1 and ABCG2 are associated with PFS and OS in mRCC patients treated with sunitinib. These findings advocate further elucidation of these genetic determinants in relation to drug exposure and survival. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer
Telomere Length Identifies Two Distinct Populations with Different Outcome among VH-Unmutated CLL Patients.
Authors: Irene Ricca, Alberto Rocci, Daniela Drandi, Mara Compagno, Roberto Francese, Paola Omedè, Loredana Santo, Michela Rosace, Federica De Marco, Monica Astolfi, Chiara Lobetti Bodoni, Maria Dell’Aquila, Sonia Vallet, Luciana Bergui, Andrea Gallamini, Carlo Marinone, Mario Boccadoro, Corrado Tarella, Marco Ladetto
Journal: Blood (2005)
Higher Weight Adjusted Doses of TNK are Associated with Improved Non-Culprit, Global and Post PTCA Flow in Addition to Improved Culprit Flow
Authors: CM Gibson, MJ Rizzo, KA Ryan, MB Kelley, SJ Marble, RP Giugliano, CH McCabe, CP Cannon, Frans Van de Werf, E Braunwald
Journal: Circulation (1998)
Sodium Excretion, Cardiovascular Disease, and Chronic Kidney Disease
Authors: Mehmet Hursitoglu
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Lower Mortality RAtes with TNK-tPA in Late-Treated Patients: REsults from the ASSENT-2 Study
Authors: Peter Sinnaeve, J Adgey, PE Aylward, A Binbrek, R Diaz, S Husted, A Oto, R Seabra-Gomes, L Soares-Piegas, Frans Van de Werf
Journal: Circulation (2001)
Preclinical Combination Of The Oral Investigational Agents ACY-1215, a Selective HDAC6 Inhibitor, and Ixazomib, a Proteasome Inhibitor, Demonstrates Combination Benefit In Multiple Myeloma Cell Lines and Xenograft Models
Authors: Allison J Berger, Bret Bannerman, Steven N Quayle, Jie Yu, Khristofer Garcia, Jeffrey Ciavarri, David Tamang, Min Yang, Simon S Jones
Journal: Blood (2013)
Prospective randomized study of coronary artery bypass surgery in stable angina pectoris: a progress report on survival.
Journal: Circulation (1982)

This progress report on the prospective randomized study of the effect of coronary bypass surgery on prognosis presents the results of a minimum follow-up of 4 years. Seven hundred sixty-eight patients were recruited; all were men younger than age 65 years who had mild-to-moderate angina pectoris, at least two-vessel disease, and good left ventricular function. Of these, 373 were randomized to medical treatment and 395 to surgical treatment. Although 83 "medical" patients subsequently underwent surgery and 27 "surgical" patients did not undergo surgery, these patients were not excluded from the analysis, and the group randomized to coronary bypass surgery was compared with the group randomized to medical treatment. The surgical treatment group showed significantly better survival than the medical treatment group in the total patient population (p less than 0.001), particularly among patients with three-vessel disease (p less than 0.001). Although the 24% higher survival among surgical patients with left main coronary artery disease failed to reach statistical significance, the trend is probably meaningful. No significant difference in survival between medical and surgical treatment groups was noted in patients with two-vessel disease.
Impact of CNS metastases on treatment and survival in patients receiving trastuzumab for metastatic breast cancer (MBC).
Authors: R. Griffiths, K. Lindquist, D. Lalla, J. F. Doan, M. G. Brammer, M. Danese
Journal: Journal of Clinical Oncology (2010)

1064 Background: Trastuzumab (T) is an important part of therapy for patients diagnosed with MBC who are HER2-positive. Approximately one third of these patients develop CNS metastases. The impact of CNS metastases on T use and survival in elderly patients has not been described. Methods: We used SEER-Medicare data to examine associations between diagnosis of CNS metastases, treatment, and survival, in a cohort of women who first received T following diagnosis of MBC. Medicare claims were used to identify T, chemotherapy, and diagnosis of CNS and other types of metastases. Patients were included if their first Medicare claim for T was between January 1, 2000 and December 31, 2006. Patients were excluded if they were diagnosed with CNS metastases prior to beginning T. They were followed from the start of T until death or the end of their claims. Multivariate analyses were performed to identify the associations between diagnosis of CNS metastases and (A) permanent discontinuation of T, and (B) all-cause mortality. Permanent discontinuation was defined as two or more months in a row prior to death or censoring with no claim for T. Results: 651 patients met the eligibility criteria. The mean age was 76 years, 422 (65%) were diagnosed with stage 0-III disease and had a distant recurrence, while the remainder were diagnosed with de novo stage IV disease. The mean duration of follow-up was 37 months, and 133 (20%) were diagnosed with CNS metastases during this interval. In multivariate analysis, diagnosis of CNS metastases (HR 2.11; p <0.001), age ≥ 80 (HR 1.65; p=0.004), and hospitalization (HR 1.89; p <0.001) all were associated with higher rates of discontinuing T. In multivariate survival analysis, diagnosis of CNS metastases (HR 3.60; p <0.001), discontinuing T (HR 3.35; p <0.001), discontinuing or not having had other chemotherapy (HR 2.48; p <0.001), and de novo stage IV disease (HR 1.32; p =0.03) were associated with higher mortality rates. Diagnosis of other metastases did not affect mortality. Conclusions: Although causality cannot be determined, there appears to be an association between diagnosis of CNS metastases and discontinuation of T, and also between discontinuation of therapy, including T, and survival. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech
T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells
Authors: Ilaria Marigo, Serena Zilio, Giacomo Desantis, Bernhard Mlecnik, Andrielly H.R. Agnellini, Stefano Ugel, Maria Stella Sasso, Joseph E. Qualls, Franz Kratochvill, Paola Zanovello, Barbara Molon, Carola H. Ries, Valeria Runza, Sabine Hoves, Amélie M. Bilocq, Gabriela Bindea, Emilia M.C. Mazza, Silvio Bicciato, Jérôme Galon, Peter J. Murray, Vincenzo Bronte
Journal: Cancer Cell (2016)
Delays in Start of Intensification Therapy Are Common for Adults with Acute Lymphoblastic Leukemia, and Are Associated with Decreased Survival in Patients Who Undergo Allogeneic Stem Cell Transplant (SCT)
Authors: Anita J. Kumar, Phyllis A. Gimotty, Joel Gelfand, Georgina Buck, Jacob M. Rowe, Anthony H Goldstone, Adele Fielding, David I Marks, Mark Litzow, Elisabeth Paietta, Hillard M. Lazarus, Martin S. Tallman, Selina M. Luger, Alison W. Loren
Journal: Blood (2014)
Ph III randomized studies of the oral pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer (BC) after aromatase inhibitor (AI; BELLE-2) or AI and mTOR inhibitor (BELLE-3) treatment.
Authors: Hiroji Iwata, José Baselga, Mario Campone, Carlos L. Arteaga, Javier Cortes, Walter Jonat, Michelino De Laurentiis, Eva Ciruelos, Wolfgang Janni, Thomas Bachelot, Per Eystein Lonning, Cynthia Ma, Ruth O'Regan, Emmanuelle Di Tomaso, Bharani Bharani-Dharan, Vincent Duval, Helen Lau, Caroline Germa, Patrick Urban, Angelo Di Leo
Journal: Journal of Clinical Oncology (2013)

TPS650^ Background: The PI3K/Akt/mTOR pathway is commonly dysregulated in BC and linked to resistance to endocrine therapy, including AIs. Buparlisib is an oral inhibitor of class I PI3K isoforms (α, β, γ, δ), showing near complete tumor regression in an in vivo model of ER+ BC in combination with fulvestrant. Preliminary clinical activity in BC pts has been observed with buparlisib as a single agent and in combination with letrozole (Mayer et al. ASCO 2012). Methods: BELLE-2 (NCT01610284) and BELLE-3 (NCT01633060) are 2 Ph III randomized, double-blind, placebo-controlled trials of oral buparlisib (100 mg/d) in combination with fulvestrant (500 mg) given on D1 and 15 of Cycle 1 and D1 of each 28-day cycle thereafter in postmenopausal women with HR+/HER2– locally advanced/metastatic BC. Additional eligibility criteria: disease progression on/after AI treatment for BELLE-2; prior treatment with AI and progression on mTOR inhibitor in combination with endocrine therapy (as last therapy prior to study entry) for BELLE-3; ≤1 previous line of chemotherapy for advanced disease; available archival tumor tissue for PI3K-related biomarker analysis. Randomization to either arm (1:1 for BELLE-2 and 2:1 for BELLE-3) is stratified according to PI3K pathway activation status (activated vs non-activated vs unknown) and visceral disease status (present vsabsent). Study treatment is given until disease progression or discontinuation for any reason. Co-primary endpoints in both trials: PFS in full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints: overall survival (OS) in full and PI3K pathway-activated populations; other secondary endpoints: PFS and OS in PI3K non-activated/unknown population, overall response rate, clinical benefit rate, safety (CTCAE 4.03), PK, and patient-reported outcomes (EORTC QLQ-C30 and QLQ-BR23). Estimated enrollment is 842 pts for BELLE-2 and 615 for BELLE-3. As of January 2013, 96 pts were randomized to BELLE-2 and 1 pt to BELLE-3. Recruitment is ongoing globally. Clinical trial information: NCT01610284 and NCT01633060.
Single-centre experience with third-line chemotherapy with irinotecan plus 5-fluorouracil and leucovorin (FOLFIRI) in metastatic gastric cancer patients
Authors: G. Pasquini, L. Fornaro, E. Vasile, M. Lencioni, I. Petrini, C. Caparello, C. Vivaldi, G. Musettini, A. Falcone
Journal: Annals of Oncology (2015)
Reply to 'Age-related variations in the use of axillary staging may explain the increased risk of axillary lymph node involvement in older women with breast cancer' by Adri Voogd et al
Authors: Hans Wildiers, Ben Van Calster, T Vandorpe, A.S Dieudonne, Ann Smeets, Rose Christiaens, P Neven
Journal: Journal of Clinical Oncology (2009)
IRF8 Transcription Factor Controls Survival and Function of Terminally Differentiated Conventional and Plasmacytoid Dendritic Cells, Respectively
Authors: Dorine Sichien, Charlotte L. Scott, Liesbet Martens, Matthias Vanderkerken, Sofie Van Gassen, Maud Plantinga, Thorsten Joeris, Sofie De Prijck, Leen Vanhoutte, Manon Vanheerswynghels, Gert Van Isterdael, Wendy Toussaint, Filipe Branco Madeira, Karl Vergote, William W. Agace, Björn E. Clausen, Hamida Hammad, Marc Dalod, Yvan Saeys, Bart N. Lambrecht, Martin Guilliams
Journal: Immunity (2016)
Gli1+ Pericyte Loss Induces Capillary Rarefaction and Proximal Tubular Injury
Authors: Rafael Kramann, Janewit Wongboonsin, Monica Chang-Panesso, Flavia G. Machado, Benjamin D. Humphreys
Journal: Journal of the American Society of Nephrology (2016)

Peritubular capillary rarefaction is hypothesized to contribute to the increased risk of future CKD after AKI. Here, we directly tested the role of Gli1 + kidney pericytes in the maintenance of peritubular capillary health, and the consequences of pericyte loss during injury. Using bigenic Gli1-CreER t2 ; R26tdTomato reporter mice, we observed increased distance between Gli1 + pericytes and endothelial cells after AKI (mean±SEM: 3.3±0.1 µ m before injury versus 12.5±0.2 µ m after injury; P &lt;0.001). Using a genetic ablation model, we asked whether pericyte loss alone is sufficient for capillary destabilization. Ten days after pericyte ablation, we observed endothelial cell damage by electron microscopy. Furthermore, pericyte loss led to significantly reduced capillary number at later time points (mean±SEM capillaries/high-power field: 67.6±4.7 in control versus 44.1±4.8 at 56 days; P &lt;0.05) and increased cross-sectional area (mean±SEM: 21.9±0.4 µ m 2 in control versus 24.1±0.6 µ m 2 at 10 days; P &lt;0.01 and 24.6±0.6 µ m 2 at 56 days; P &lt;0.001). Pericyte ablation also led to hypoxic focal and subclinical tubular injury, reflected by transient expression of Kim1 and vimentin in scattered proximal tubule segments. This analysis provides direct evidence that AKI causes pericyte detachment from capillaries, and that pericyte loss is sufficient to trigger transient tubular injury and permanent peritubular capillary rarefaction.
Expression of innate immune defence genes in healthy and onychomycotic nail and stratum corneum
Authors: D.K. Mercer, T. Sairi, E. Sroka, H. Lamont, Y. Lawrie, D.A. O'Neil
Journal: British Journal of Dermatology (2016)

Onychomycosis, a fungal infection of the nail, is predominantly caused by dermatophytes1. Our understanding of the pathogenic response to these fungi and their ability to establish chronic infection and evade immune clearance remains limited2. Evidence suggests an association between onychomycosis and immunosuppression3 but the nail plate represents a site of infection with negligible adaptive immune cell presence; the host response here led largely by components of the innate immune system4 including antimicrobial peptides (AMP). AMP are a cornerstone of innate host defence4, but their role in onychomycosis, is poorly understood. This study is the first detailed investigation of associations between innate immune defence gene expression and onychomycosis.

This article is protected by copyright. All rights reserved.
P1-239: A message of hope: creation of the Faces of Lung Cancer Project for increasing awareness of clinical trials
Authors: Gwendolyn P. Quinn, Bethany A. Bell-Ellison, Miriam Y. Bell, Vicki D. Caraway, Diane Conforte, Linda B. Graci, Alyssa Lewandowski, Andrea Y. Shaffer, Valerie L. Powell-Stafford, Amber L. Sapp, Cynthia O. Shimizu, Susan Vadaparampil, Elizabeth J. Vaughn, Charles Williams, Gerold Bepler, Zhong Zheng
Journal: Journal of Thoracic Oncology (2007)
C9-01: Positive pleural lavage cytology and recurrence pattern in patients with early stage non-small cell lung cancers
Authors: Yukitoshi Satoh, Sakae Okumura, Ken Nakagawa, Atsushi Horiike, Fumiyoshi Ohyanagi, Yoshio Okano, Makoto Nishio, Takeshi Horai, Hironori Ninomiya, Yuichi Ishikawa
Journal: Journal of Thoracic Oncology (2007)
P3-105: Response to erlotinib in the neoadjuvant setting for early stage non–small cell lung cancer (NSCLC): a case report
Authors: Ingrid Kappers, Jacobus A. Burgers, Herman Rijna, Henk E. Codrington, Anne-Marie Dingemans, Carla Weenink, Michel J. Wouters, Renato A. Valdes Olmos, Nico v. Zandwijk, Houke M. Klomp
Journal: Journal of Thoracic Oncology (2007)
Sorafenib in patients (pts) with advanced thyroid carcinoma (TC): A compassionate use program.
Authors: J. Capdevila, L. Iglesias, I. Halperin, A. Segura, M. Vaz, J. Corral, J. J. Grau, G. Obiols, R. Hitt, J. Tabernero
Journal: Journal of Clinical Oncology (2010)

5590 Background: Sorafenib (BAY 43-9006, Nexavar) is a potent oral, multi-targeted small molecule kinase inhibitor of Raf and VEGFR-2, and with less affinity of VEFGR-1 and -3, RET, PDGFR-β, Flt-3, c-KIT and FGFR-1. Sorafenib has shown activity in patients with advanced TC in preliminary reports. Methods: We have retrospectively analyzed pts with advanced TC with progressive disease after standard therapy that were treated with sorafenib 400 mg BID in a Spanish compassionate use program. The parameters evaluated included response rate (RR) by RECIST criteria, progression-free survival (PFS), and overall survival (OS) as well as the toxicity profile. Tumor markers (thyroglobulin, calcitonin, and CEA) were monitored and correlated with efficacy. Results: 30 pts (16 females and 14 males) have been enrolled, median age was 58 years (3-85). Tumor subtypes: medullary (MTC) in 12 pts (40%), follicular in 9 (30%), papillary in 6 (20%) and poorly differentiated/anaplastic in 3 (10%). Previous therapies were surgery (96%), radiotherapy (60%), radioiodine (40%), chemotherapy (30%) and somatostatin analogs (20%). 27 pts were evaluable for response: partial response (PR) in 9 pts (30%), stable disease (SD) in 13 pts (36%) (8 pts SD > 6 months) and progressive disease in 5 pts (16%). Disease control rate (PR+SD) was 74%. 6 PRs were observed in MTC (50% RR) and one PR for each other tumor subtype. Tumor markers were evaluated in 22 pts and a statistically significant correlation was observed between PR and a decrease in tumor marker levels >50% (p=.033). With a median follow-up of 11 months (3-30) the median PFS was 11.6 months and the median OS was 23.6 months. The main side effects observed were diarrhea (52%), hand-foot syndrome (HFS) (51%), stomatitis (49%), fatigue (46%), abdominal pain (32%), rash (32%), anorexia (22%) and hypertension (13%). Main grade 3-4 toxicities were HFS (19%), diarrhea (16%), fatigue (16%) and anorexia (16%). 9 patients (30%) required dose reduction due to toxicity. Conclusions: Sorafenib has antitumor activity in all TC subtypes. We report an enriched MTC population with a significantly higher RR compared to other histologies that warrants further development in this setting. No significant financial relationships to disclose.
The Geldanamycin Analogue Heat Shock Protein 90 (HSP90) Inhibitor 17-AAG in Lymphomas: Molecular Mechanisms of 17-AAG-Induced Cell Death in Hodgkin Disease and Non- Hodgkin Lymphoma Cell Lines.
Authors: Georgios V. Georgakis, Yang Li, Anas Younes
Journal: Blood (2004)
Beyond too little, too late and too much, too soon: a pathway towards evidence-based, respectful maternity care worldwide
Authors: Suellen Miller, Edgardo Abalos, Monica Chamillard, Agustin Ciapponi, Daniela Colaci, Daniel Comandé, Virginia Diaz, Stacie Geller, Claudia Hanson, Ana Langer, Victoria Manuelli, Kathryn Millar, Imran Morhason-Bello, Cynthia Pileggi Castro, Vicky Nogueira Pileggi, Nuriya Robinson, Michelle Skaer, João Paulo Souza, Joshua P Vogel, Fernando Althabe
Journal: The Lancet (2016)
The Niemann-Pick C1 Inhibitor NP3.47 Enhances Gene Silencing Potency of Lipid Nanoparticles Containing siRNA
Authors: Haitang Wang, Yuen Yi C Tam, Sam Chen, Josh Zaifman, Roy van der Meel, Marco A Ciufolini, Pieter R Cullis
Journal: Molecular Therapy (2016)

The therapeutic applications of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA), are hampered by inefficient delivery of encapsulated siRNA to the cytoplasm following endocytosis. Recent work has shown that up to 70% of endocytosed LNP-siRNA particles are recycled to the extracellular medium and thus cannot contribute to gene silencing. Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal membrane protein required for efficient extracellular recycling of endosomal contents. Here we assess the influence of NP3.47, a putative small molecule inhibitor of NPC1, on the gene silencing potency of LNP-siRNA systems in vitro. Intracellular uptake and colocalization studies revealed that the presence of NP3.47 caused threefold or higher increases in accumulation of LNP-siRNA in late endosomes/lysosomes as compared with controls in a variety of cell lines. The gene silencing potency of LNP siRNA was enhanced up to fourfold in the presence of NP3.47. Mechanisms of action studies are consistent with the proposal that NP3.47 acts to inhibit NPC1. Our findings suggest that the pharmacological inhibition of NPC1 is an attractive strategy to enhance the therapeutic efficacy of LNP-siRNA by trapping LNP-siRNA in late endosomes, thereby increasing opportunities for endosomal escape. The therapeutic applications of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA), are hampered by inefficient delivery of encapsulated siRNA to the cytoplasm following endocytosis. Recent work has shown that up to 70% of endocytosed LNP-siRNA particles are recycled to the extracellular medium and thus cannot contribute to gene silencing. Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal membrane protein required for efficient extracellular recycling of endosomal contents. Here we assess the influence of NP3.47, a putative small molecule inhibitor of NPC1, on the gene silencing potency of LNP-siRNA systems in vitro. Intracellular uptake and colocalization studies revealed that the presence of NP3.47 caused threefold or higher increases in accumulation of LNP-siRNA in late endosomes/lysosomes as compared with controls in a variety of cell lines. The gene silencing potency of LNP siRNA was enhanced up to fourfold in the presence of NP3.47. Mechanisms of action studies are consistent with the proposal that NP3.47 acts to inhibit NPC1. Our findings suggest that the pharmacological inhibition of NPC1 is an attractive strategy to enhance the therapeutic efficacy of LNP-siRNA by trapping LNP-siRNA in late endosomes, thereby increasing opportunities for endosomal escape.