tbuckley/cabot-search huggingface dataset:
Antibody-activated trans-endothelial delivery of mesoporous organosilica nanomedicine augments tumor extravasation and anti-cancer immunotherapy
Authors: Tinglei Huang, Shuang Li, Jianchen Fang, Fuli Li, Shuiping Tu
Journal: Bioactive Materials (2021)

Tumor vasculature constitutes a formidable hurdle for the efficient delivery of cancer nanomedicine into tumors. The leverage of passive pathway through inter-endothelial gaps in tumor blood vessels might account for limited extravasation of nanomedicine into tumor microenvironment (TME). Herein, Annexin A1 antibody-installed mesoporous organosilica nanoplatforms carrying immunotherapeutics of anti-PD-L1 antibody (aPD-L1) and Indoximod are developed to target at caveolar Annexin-A1 protein of luminal endothelial cells and to trigger the active trans-endothelial transcytosis of nanomedicine mediated by caveolae. Such strategy enables rapid nanomedicine extravasation across tumor endothelium and relatively extensive accumulation in tumor interstitium. aPD-L1 and Indoximod release from aPD/[email protected] in a reduction-responsive manner and synergistically facilitate the intratumoral infiltration of cytotoxic T lymphocytes and reverse the immunosuppressive TME, thus demonstrating substantial anti-tumor efficacy in subcutaneous 4T1 breast tumors and remarkable anti-metastatic capacity to extend the survival of 4T1 tumor metastasis model. Moreover, aPD/[email protected] nanomedicine also exhibits distinct superiority over the combination therapy of free drugs to potently attenuate the progression of urethane-induced orthotopic lung cancers. Collectively, aPD/[email protected] nanoplatforms with boosted delivery efficiency via antibody-activated trans-endothelial pathway and enhanced immunotherapeutic efficacy provides perspectives for the development of cancer nanomedicines.
SP0071 Complement gene mutations
Authors: M Botto, MC Pickering, MJ Walport
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Homozygous complement protein deficiencies are rare. However, the study of inherited deficiencies of complement proteins <i>in vivo</i> offer insights into the physiological activities of the complement system that are not readily available from <i>in vitro</i> analysis. The phenotype of complement deficiency varies according to the position of the missing component within the complement activation pathways. This demonstrates that different parts of the complement system subserve particular functions. For example, terminal complement component deficiency predisposes to recurrent Neisserial infections. Furthermore, individuals with classical pathway component deficiencies develop SLE. These observations have led to the hypothesis that the classical pathway protects against the development of SLE. However, the mechanism underlying this association has not been fully established. Recent findings obtained using animal models of complement deficiencies, suggest that the classical pathway plays an important role in promoting the physiological clearance of apoptotic cells. The discovery that apoptotic cells may be the source of autoantigens in SLE has lead to the hypothesis that complement deficiency may promote autoimmunity by impairing the clearance of apoptotic cells. To prevent host tissue injury and depletion of complement components, the complement system is tightly regulated by a series of proteins circulating in plasma and present on cell membranes. The major inhibitory protein of the alternative pathway is factor H (FH). Deficiency of this protein results in secondary depletion of C3 due to uncontrolled alternative pathway (AP) activation. This occurs commonly in individuals with C3 nephritic factor, an IgG autoantibody that stabilises the alternative pathway C3 convertase. Both individuals deficient in FH and those with C3 nephritic factor develop membranoproliferative glomerulonephritis (MPGN). To explore the mechanisms by which uncontrolled C3 activation predisposes to MPGN, we have developed an <i>in vivo</i> model of factor H deficiency. FH deficient mice have secondary C3 deficiency, show large amounts of C3 deposited preferentially on the glomerular basement membrane and develop MPGN. Both partial and complete FH deficiencies have been associated with haemolytic uraemic syndrome (HUS) and the pathogenesis is poorly understood. This animal model will allow us to investigate the mechanisms by which C3 dysregulation predisposes to glomerulonephritis and HUS. In conclusion, individuals and experimental models of complement deficiency prove to be an invaluable tool to investigate the role of the complement system in health and in disease. <h3>Reference</h3> Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol. 2001;76:227–324
Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence
Authors: Cihangir Duy, Meng Li, Matt Teater, Cem Meydan, Francine E. Garrett-Bakelman, Tak C. Lee, Christopher R. Chin, Ceyda Durmaz, Kimihito C. Kawabata, Eugen Dhimolea, Constantine S. Mitsiades, Hartmut Doehner, Richard J. D'Andrea, Michael W. Becker, Elisabeth M. Paietta, Christopher E. Mason, Martin Carroll, Ari M. Melnick
Journal: Cancer Discovery (2021)

Patients with acute myeloid leukemia (AML) frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA sequencing suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony-forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential. SIGNIFICANCE: Despite entering complete remission after chemotherapy, relapse occurs in many patients with AML. Thus, there is an urgent need to understand the relapse mechanism in AML and the development of targeted treatments to improve outcome. Here, we identified a senescence-like resilience phenotype through which AML cells can survive and repopulate leukemia.This article is highlighted in the In This Issue feature, p. 1307.
Multitasking guardian of mitochondrial quality: Parkin function and Parkinson’s disease
Authors: Iryna Kamienieva, Jerzy Duszyński, Joanna Szczepanowska
Journal: Translational Neurodegeneration (2021)

Abstract The familial form of Parkinson’s disease (PD) is linked to mutations in specific genes. The mutations in parkin are one of the most common causes of early-onset PD. Mitochondrial dysfunction is an emerging active player in the pathology of neurodegenerative diseases, because mitochondria are highly dynamic structures integrated with many cellular functions. Herein, we overview and discuss the role of the parkin protein product, Parkin E3 ubiquitin ligase, in the cellular processes related to mitochondrial function, and how parkin mutations can result in pathology in vitro and in vivo.
Preclinical PET imaging with the novel human antibody<sup>89</sup>Zr-DFO-REGN3504 sensitively detects PD-L1 expression in tumors and normal tissues
Authors: Marcus P Kelly, Sosina Makonnen, Carlos Hickey, T Cody Arnold, Jason T Giurleo, Richard Tavaré, Makenzie Danton, Christian Granados, Ishita Chatterjee, Drew Dudgeon, Marc W Retter, Dangshe Ma, William C Olson, Gavin Thurston, Jessica R Kirshner
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blocking antibodies including cemiplimab have generated profound clinical activity across diverse cancer types. Tumorous PD-L1 expression, as assessed by immunohistochemistry (IHC), is an accepted predictive marker of response to therapy in some cancers. However, expression is often dynamic and heterogeneous, and therefore not reliably captured by IHC from tumor biopsies or archival samples. Thus, there is significant need for accurate whole-body quantification of PD-L1 levels. Methods We radiolabeled the novel human anti-PD-L1 antibody REGN3504 with zirconium-89 ( 89 Zr) using the chelator p-SCN-Bn-Deferoxamine to enable non-invasive immuno-positron emission tomography (immuno-PET) of PD-L1 expression. PET imaging assessed the localization of 89 Zr-REGN3504 to multiple human tumor xenografts. Mice genetically humanized for PD-1 and PD-L1 were used to assess the biodistribution of 89 Zr-REGN3504 to normal tissues and the estimated human radiation dosimetry of 89 Zr-REGN3504 was also determined. Pharmacokinetics of REGN3504 was assessed in monkeys. Results Clear localization of 89 Zr-REGN3504 to human tumor xenografts was observed via PET imaging and ex vivo biodistribution studies demonstrated high (fourfold to sixfold) tumor:blood ratios. 89 Zr-REGN3504 specifically localized to spleen and lymph nodes in the PD-1/PD-L1 humanized mice. 89 Zr-REGN3504 immuno-PET accurately detected a significant reduction in splenic PD-L1 positive cells following systemic treatment with clodronate liposomes. Radiation dosimetry suggested absorbed doses would be within guidelines for other 89 Zr radiolabeled, clinically used antibodies. Pharmacokinetics of REGN3504 was linear. Conclusion This work supports the clinical translation of 89 Zr-REGN3504 immuno-PET for the assessment of PD-L1 expression. Future clinical studies will aim to investigate the utility of 89 Zr-REGN3504 immuno-PET for predicting and monitoring response to anti-PD-1 therapy.
Potential Utility of Event-Free Survival (EFS) As Surrogate Endpoint for Overall Survival (OS) in Relapsed Diffuse Large B-Cell Lymphoma (DLBCL) after Autologous Stem Cell Transplantation (ASCT): A Subgroup Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Randomized Phase III Trial
Authors: Shen Li, Annette E Hay, Michael Crump, Peter Anglin, Tara Baetz, Ralph Meyer, Armand Keating, Sue Robinson, Matthew Seftel, Caterina Stelitano, Marina S Djurfeldt, Lois E. Shepherd, Bingshu E. Chen, Sarit Assouline
Journal: Blood (2017)
Evaluating adherence to post-treatment follow-up of colorectal cancer at a reference center in Mexico: A retrospective analysis.
Authors: Jorge Humberto Hernandez-Felix, Mónica Isabel Meneses Medina, Mauricio Rivera Aguilar, Ana Karen Valenzuela, Vanessa Rosas Rosas Camargo, Alberto Cedro-Tanda, Fidel David Huitzil Melendez
Journal: Journal of Clinical Oncology (2021)

51 Background: Adequate post-treatment surveillance for colorectal cancer (CRC) is recommended by all major societies with the intention to improve overall survival. However, compliance is variable and has not been studied in our country. Our aim was to evaluate the adherence to post-treatment surveillance NCCN guidelines for CRC at our Institution in Mexico City. Methods: We retrospectively reviewed charts from patients with stage I-III CRC who were diagnosed between January 2014 and December 2016. Adherence to surveillance was evaluated for the first 3 years after completion of oncologic treatment or until recurrence, whichever came first. We used an adherence composite definition previously defined by Cooper et al, where adequate compliance with guidelines was considered if patients had ≥2 physician visits per year for 3 years, ≥2 CEA tests per year for 2 years, and at least one colonoscopy in the 3-years surveillance period. Results: We included 90 patients. Mean age at diagnosis was 62 ± 12.5 years, 53% (n=48) were male, 68% (n=62) had colon cancer and 31% (n=28) rectal cancer. According to AJCC7 19% (n=17) were Stage I, 39% (n=35) II, and 42%(n=38) III. Median score for Charslon index at diagnosis was 4 (IQR 3-6). Results of follow-up adherence are presented in Table. Just 12% (n=11) of patients had a PET/CT or any other non-indicated imaging study for surveillance. Recurrence rate at the 3rd year of surveillance was 6.6% (n=6). A bivariate analysis was performed to find clinical and demographic factors associated to adherence and individual components of surveillance, we did not find any significative association. Conclusions: At our institution compliance with follow-up guidelines for CRC is good and higher than reported by other centers, though individual components have a decreasing trend in adherence every year. This could be explained because in our Institution cancer surveillance is performed by a medical oncologist. The main limitation of our study is that it involves an individual reference center in Mexico; thus, extrapolating data may not be feasible. [Table: see text]
Application of unsupervised machine learning to identify and characterise hydroxychloroquine misinformation on Twitter
Authors: Tim K Mackey, Vidya Purushothaman, Michael Haupt, Matthew C Nali, Jiawei Li
Journal: The Lancet Digital Health (2021)

On July 27, 2020, former US President Donald Trump retweeted to his then 84 million Twitter followers an online video, published by the Breitbart website, promoting misinformation about the anti-malarial drug, hydroxychloroquine.1 The video, featuring Dr Stella Immanuel and a group called America's Frontline Doctors, falsely claimed that the combination of hydroxychloroquine, zinc, and azithromycin (an antibiotic) could cure COVID-19.1 Twitter subsequently removed President Trump's retweet, temporarily suspended and removed tweets from his son, Donald Trump Jr, and removed and suspended other accounts sharing this false information as a violation of its COVID-19 misinformation policy.
AB0031 Protein sulfhydryls and carbonyl content changes in sera of rheumatoid arthritis patients
Authors: M Serteser, D Evcik, T Köken
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Objectives</h3> Oxygen free radicals play a major role in the generation of acute and chronic inflammatory processes one of which is Rheumatoid Arthritis (RA). Biological thiols or sulfhydryls protect cells against oxidative stress. Introduction of carbonyls into proteins is the consequences of the protein oxydation. This study is planned to investigate the roles of oxygen free radicals in rheumatoid arthritis. <h3>Methods</h3> In this study; according to ACR criteria, a total of 29 RA patients (M/F = 7/22) aged between 31 to 68 years old are included. They were physically evaluated by the number of tender points. Rutin labaratory investigations (ESR, CRP, RF, biochemically parameters) were also evaluated. Control group were selected from healthy adults with same age. Than blood samples were investigated in biochemistry unit. Protein carbonyl content of the samples were determined according to the method described by Levine <i>et al</i> and the modified method was described by Koster <i>et al</i>. These two methods were used for determination of protein sulphydyrls. <h3>Results</h3> The sulfhydryl contents of RA patients were found significantly decreased than those in age and sex matched controls, 396,26 ± 42,33 mmol/L and 677,21 ± 59,98 mmol/L respectivelly (p &lt; 0,001). On the other hand the carbonyl contents of RA patients were found significantly increased than those in controls, 105,45 ± 14,26 mmol/L and 93,65 ± 10,49 mmol/L respectively (p &lt; 0,05). <h3>Conclusion</h3> These changes in oxidative stress markers could indicate the role of free radical attacks on proteins. <h3>References</h3> Levine RL, Garland D, Oliver CN, Amici A, <i>et al</i>. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 1990;186:464–78 Koster JF, Biemond P, Swaak JG. Intracellular and extracellular sulfhydryl levels in rheumatoid arthritis. Ann Rheum Dis. 1986;45:44–6
Arg206Cys substitution in <i>DNASE1L3</i> causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus
Authors: Latanya N Coke, Hongxiu Wen, Mary Comeau, Mustafa H Ghanem, Andrew Shih, Christine N Metz, Wentian Li, Carl D Langefeld, Peter K Gregersen, Kim R Simpfendorfer
Journal: Annals of the Rheumatic Diseases (2021)

<h3>Objectives</h3> To determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the <i>DNASE1L3</i>/<i>PXK</i> gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function. <h3>Methods</h3> Conditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants. <h3>Results</h3> Conditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in <i>PXK</i> (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced. <h3>Conclusions</h3> SLE risk association in the <i>DNASE1L3</i> locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function.
Difficulties in diagnosing acute rheumatic fever-arthritis may be short lived and carditis silent
Authors: L Williamson, P Bowness, A Mowat, I Ostman-Smith
Journal: BMJ (2000)

in the developed world.14 Although the criteria for diagnosis are well known, the clinical symptoms needed to make a diagnosis do not always arise concurrently and the initial illness may be mild and short lived. Isolated arthritis is the presenting symptom in 14-42% of patients.35 There may be no history of sore throat, or this symptom may not be mentioned by the patient,5 and the carditis may be silent6 7 The diag nosis will be missed if appropriate investigations are not carried out during the acute illness. These patients are susceptible to recurrent attacks of rheumatic fever, and damage to heart valves becomes increasingly severe with each subsequent attack.8 9 Children are affected more than adults and may present to their general practitioners or to accident and emergency, orthopaedic, rheumatology, or paediatric departments. To highlight potential diagnostic problems, we describe three cases of rheumatic fever in young people who presented to one musculoskeletal centre in a six month period.
Evaluating Clinical Applicability: The STICH Trial's Findings⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: A. Laurie W. Shroyer, Joseph F. Collins, Frederick L. Grover
Journal: Journal of the American College of Cardiology (2010)
Phase II trial of bintrafusp alfa in patients with metastatic MSI-H cancers following progression on immunotherapy.
Authors: Van K. Morris, Michael Lam, Xuemei Wang, Michael J. Overman, Benny Johnson, Bryan K. Kee, Robert A. Wolff, Arvind Dasari, Isabel R. Zorrilla, Alda Tam, Dipen M. Maru, Scott Kopetz
Journal: Journal of Clinical Oncology (2021)

79 Background: Microsatellite instability-high (MSI-H) tumors are characterized by deficient mismatch repair, high tumor mutation burden, and exceptional anti-tumor responses to immunotherapy. While durable disease control is often observed for advanced MSI-H cancers treated with immune checkpoint blockade (ICB), some patients (pts) experience treatment resistance. In melanoma and urothelial cancer, acquired resistance to ICB has been associated with increased signaling of the immunosuppressive TGF-β pathway. Bintrafusp alfa (BA) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking PD-L1. Methods: In this phase II study (NCT03436563), pts with MSI-H metastatic solid tumors who had progressed on prior ICB were eligible. Pts received 1200 mg BA intravenously every 14 days. Paired tumor biopsies were collected for biomarker analysis. The primary objective was to estimate response rate (RR) per iRECIST. Median progression-free survival (PFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Adverse events (AEs) were assessed according to CTCAE v5.0. Results: 15 pts [arising from the colon/rectum (12), pancreas (1), duodenum (1), appendix (1)] were enrolled. Median duration of prior ICB before progression was 7.2 months (range, 1.8-24). All pts were evaluable for toxicity, and 14 for response. There was 1 grade 3 treatment-related AE (adrenal insufficiency) and 1 grade 5 treatment-related immune AE (hepatic failure). Median number of doses with BA was 4 (interquartile range, 2-4). There were 3 pts with stable disease and 11 with progressive disease as best response. RR was 0% (95% confidence interval (CI), 0-24%), and disease control rate was 21% (95% CI, 5-51%). Median PFS and OS were 1.8 months (95% CI, 1.5-5.7) and 9.1 months (95% CI, 5.3-not estimable), respectively. One pt with colorectal cancer demonstrated sustained stable disease (20.5 months) with BA. Conclusions: Dual inhibition of TGF-β and PD-L1 by BA did not demonstrate significant anti-tumor activity in the majority of pts with MSI-H metastatic cancer who had progressed on prior ICB. One pt did experience prolonged clinical benefit from BA. Ongoing correlative studies may inform on the effect of TGF-β and PD-L1 modulation by BA within the tumor microenvironment. Clinical trial information: NCT03436563.