tbuckley/cabot-search huggingface dataset:
Development and analyses of CPT-11 resistant sublines of human colorectal adenocarcinoma cell line, SW-948
Authors: Kevin P. Raisch, Zhi Qiang Huang, Dongquan Chen, Murray A. Stackhouse, James A. Bonner, Donald J. Buchsbaum
Journal: Cancer Research (2005)

1493  Irinotecan (CPT-11), a camptothecin analog, is converted to the active topoisomerase I inhibitor, SN-38, by carboxylesterase. CPT-11 is widely used for the treatment of advanced colorectal carcinoma. CPT-11 refractory colorectal cancer patients have shown benefit by treatment with anti-EGFR mAb, cetuximab, when given alone or in combination with CPT-11. In order to study current and novel treatment options for CPT-11 refractory colorectal cancer, two CPT-11 resistant colorectal cancer cell sublines were isolated from the parental cell line, SW-948. Two methods were used to develop sublines resistant to CPT-11. First, SW-948 cells were initially exposed to a high dose (2-fold higher than the IC50 dose) of CPT-11 to obtain the resistant cell line, SW948CPTH. Second, SW-948 cells were initially exposed to a low dose (4-fold lower than the IC50 dose) of CPT-11 to obtain the resistant cell line, SW948CPTL. Both methods used a stepwise increase and continuous exposure to CPT-11 on the cells. The cells were monitored for drug resistance by clonogenic assay. Upon attaining an increased resistance of ≥10-fold in the IC50 dose of CPT-11compared to the parental cell line, the drug was removed and the cells were monitored for retention of CPT-11 resistance for >100 days. Cross-resistance testing to other topoisomerase I inhibitors showed increased resistance to CPT (SW948CPTH) and SN-38 (SW948CPTH and SW948CPTL) but not lapachone (SW948CPTH). Cross-resistance studies to other chemotherapeutic agents showed increased resistance to cisplatin and etoposide by SW948CPTL but not 5-FU by either subline. Microarray analyses showed the differential expression of 464 (p≤0.01) or 1488 (p≤0.05) genes when comparing the SW948CPTH to SW-948 cells and 27 (p≤0.01) or 333 (p≤0.05) genes when comparing the SW948CPTL to SW-948 cells. Ninety-eight (p≤0.05) genes were identified that were differentially expressed in both SW948CPTH and SW948CPTL cells compared to the parental cell line. SW948CPTL cells were found to overexpress the p-glycoprotein (p-gp) gene and protein by microarray and FACS analyses, respectively. Verapamil was shown to increase the intracellular concentration of CPT-11 in SW948CPTL cells. SW948CPTH cells were found to overexpress the single-strand break repair gene, XRCC1, and protein by microarray analysis and immunoblot, respectively. Immunoblot analysis indicated the EGFR expression was similar in the parental cell line and each subline, however erbB-2 gene and protein expression was increased in SW948CPTH cells. Exposure of the parental cell line and each subline to cetuximab was shown to reduce the expression of XRCC1 protein in SW948CPTH and SW948CPTL cells. The mechanism of CPT-11 drug resistance in SW948CPTL cells involves p-gp whereas the mechanism of CPT-11 drug resistance in SW948CPTH cells may involve one or more genes, one of which may be the XRCC1 gene.
AB1073 DYNAMICS OF X-RAY CHANGES IN THE HIP JOINTS WITH EARLY AXIAL SPONDYLOARTHRITIS PATIENTS.
Authors: E. Agafonova, T. Dubinina, S. Erdes, D. Rumiantceva
Journal: Annals of the Rheumatic Diseases (2020)

Background: in almost half of patients with ankylosing spondylitis (AS) in Russia, damage to the hip joints (HJ) is detected, but the rate of its progression has not been studied. Objectives: to evaluate the radiological progression of coxitis in patients with early axial spondylarthritis (axSpA) for two years. Methods: the study involved the patients of the Moscow cohort CORSAIR (Early Spondyloarthritis Cohort), which was formed in V.A. Nasonova Research Institute of Rheumatology. We analyzed 62 patients with a diagnosis of axSpa (ASAS criteria 2009), observed for at least 2 years and having survey images of the pelvic bones during inclusion in the cohort and 2 years after the start of observation. The average age at the time of inclusion in the cohort was 29.2 ± 6.4 years with an average disease duration of 23.8 ± 16.2 months, 32 men and 30 women, 92% of patients positive for HLA-B27. All patients received standard anti-inflammatory therapy. Results: when including out of 62 patients in the study, only one (2%) patient showed X-ray changes in HJ, Fig. 1 (a; b)). After 2 years of follow-up, the number of patients with radiological changes in HJ increased to 13 (21%), Fig. 1 (a; b). Patients were divided into two groups depending on the presence of radiological progression in HJ. A comparative analysis of the groups revealed that progression is more common in men and in younger people (p &lt;0.05). In other parameters presented in Table 1, the groups did not differ from each other. Parameter ΔBASRI hip=0 n=39 ΔBASRI hip &gt;0 n = 23 p Sex (m/w), n 15/24 17/6 &lt;0,05* Duration of the disease months., Me [25; 75 percentile] 22 [7;36] 24 [18,8;24,8] &gt;0,05 Age, years, Me [25; 75 percentile] 29 [25,5;32,5] 26,5 [23,2;28,7] &lt;0,05* BASDAI, Me [25; 75 percentile] 3,6 [2,1;5,2] 3,45 [1,1;5,2] &gt;0,05 BASFI, Me [25; 75 percentile] 1,5 [0,5;2,8] 0,7 [0,3;2,4] &gt;0,05 ASDAS (CRP), Me [25; 75 percentile] 2,5 [1,6;3,35] 2,4 [1,25;3,45] &gt;0,05 ESR, mm/h, Me [25; 75 percentile] 8 [6;22] 10 [5;28,75] &gt;0,05 CRP, mg/L, Me [25; 75 percentile] 5,3 [1,3;24,5] 5,2 [1,1; 23,4] &gt;0,05 Peripheral Arthritis, n% 12 (32%) 5 (22%) &gt;0,05 Conclusion: it has been shown that in some patients with axSpA already in the first years of the disease, radiological signs of HJ destruction are detected. The progression of coxitis was not dependent on the activity of the disease and was more often detected in men than in women. Disclosure of Interests: Ekaterina Agafonova: None declared, Tatiana Dubinina Speakers bureau: Novartis, BIOCAD, MSD, Pfaizer, Abbvie, UCB, Shandor Erdes: None declared, Daria Rumiantceva: None declared
Convalescent plasma treatment for SARS-CoV-2 infection: analysis of the first 436 donors in England, 22 April to 12 May 2020
Authors: Heli Harvala, Jennifer Mehew, Matthew L Robb, Samreen Ijaz, Steven Dicks, Monika Patel, Nicholas Watkins, Peter Simmonds, Tim Brooks, Rachel Johnson, Robin Gopal, David J Roberts, Maria Zambon
Journal: Eurosurveillance (2020)

Serological reactivity was analysed in plasma from 436 individuals with a history of disease compatible with COVID-19, including 256 who had been laboratory-confirmed with SARS-CoV-2 infection. Over 99% of laboratory-confirmed cases developed a measurable antibody response (254/256) and 88% harboured neutralising antibodies (226/256). Antibody levels declined over 3 months following diagnosis, emphasising the importance of the timing of convalescent plasma collections. Binding antibody measurements can inform selection of convalescent plasma donors with high neutralising antibody levels.
Frequent Retroviral Gene Co-option during the Evolution of Vertebrates
Authors: Jianhua Wang, Guan-Zhu Han
Journal: Molecular Biology and Evolution (2020)

Abstract Endogenous retroviruses are ubiquitous in the vertebrate genomes. On occasion, hosts recruited retroviral genes to mediate their own biological functions, a process formally known as co-option or exaptation. Much remains unknown about the extent of retroviral gene co-option in vertebrates, although more than ten retroviral gene co-option events have been documented. Here, we use a phylogenomic approach to analyze more than 700 vertebrate genomes to uncover retroviral gene co-option taking place during the evolution of vertebrates. We identify a total of 177 independent retroviral gene co-option events in vertebrates, a majority of which have not been reported previously. Among these retroviral gene co-option events, 93 and 84 involve gag and env genes, respectively. More than 78.0% (138 out of 177) of retroviral gene co-option occurred within mammals. The gag and env co-option events share a generally similar temporal pattern with less frequent retroviral gene co-option identified in the deep branches, suggesting that retroviral gene co-option might have not been maintained for very long time periods. Moreover, we find co-opted retroviral genes are subject to different selection pressure, implying potentially diverse cellular functionality. Our study provides a comprehensive picture of co-opted retroviral genes during the evolution of vertebrates and has implications in understanding the ancient evolution of vertebrate–retrovirus interaction.
Unexpected Features of Cardiac Pathology in COVID-19 Infection
Authors: Sharon E. Fox, Guang Li, Aibek Akmatbekov, Jack L. Harbert, Fernanda S. Lameira, J. Quincy Brown, Richard S. Vander Heide
Journal: Circulation (2020)

heart failure ◼ SARS virus ◼ severe acute respiratory syndrome T his Research Letter expands our previous report of 10 hearts 1 by adding an additional 12 hearts (for a total of 22 hearts) from deaths confirmed attributable to coronavirus disease 2019 (COVID-19) infection.We identify key gross and microscopic changes that challenge the notion that typical myocarditis is present in severe acute respiratory syndrome coronavirus 2 infection.We speculate on alternative mechanisms for cardiac injury that should be investigated to provide a better understanding of the cardiac manifestations of COVID-19.In each case, consent for autopsy was granted by the next of kin.These studies were determined exempt by the institutional review board at LSU Health Sciences Center and Tulane University.Representative sections of the left and right ventricles were submitted for routine histology.All sections were stained with hematoxylin and eosin and examined by an experienced cardiovascular pathologist.A subset of the sections was selected for additional immunostaining for lymphocytes, endothelial cells, and DNA/RNA using CD4, CD8, and CD31 antibodies and DRAQ5 (Bio status)/StrandBrite Green (ATT Bioquest) labeling, respectively.
Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age
Authors: Elias K. Mai, Kaya Miah, Uta Bertsch, Jan Dürig, Christof Scheid, Katja C. Weisel, Christina Kunz, Markus Munder, Hans-Walter Lindemann, Maximilian Merz, Dirk Hose, Anna Jauch, Anja Seckinger, Steffen Luntz, Sandra Sauer, Stephan Fuhrmann, Peter Brossart, Ahmet Elmaagacli, Martin Goerner, Helga Bernhard, Martin Hoffmann, Marc S. Raab, Igor W. Blau, Mathias Hänel, Axel Benner, Hans J. Salwender, Hartmut Goldschmidt
Journal: Leukemia (2020)

Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61-65 years (S2, n = 107) and 66-70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/<0.001). With respect to progression-free survival (log-rank p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray's p = 0.83) and non-relapse mortality (Gray's p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.
The value of serology testing to manage SARS-CoV-2 infections
Authors: Laia Fernández-Barat, Ruben López-Aladid, Antoni Torres
Journal: European Respiratory Journal (2020)

<b>Validated serology tests are a good complement for the SARS-CoV-2 RNA test, allow rapid epidemiological control and reveal immune status before and after vaccination.</b>https://bit.ly/3eKAc6h
Blocking inflammation on the way: Rationale for CXCR2 antagonists for the treatment of COVID-19
Authors: Lars M. Koenig, Daniel F.R. Boehmer, Philipp Metzger, Max Schnurr, Stefan Endres, Simon Rothenfusser
Journal: The Journal of Experimental Medicine (2020)

An exacerbated and unbalanced immune response may account for the severity of COVID-19, the disease caused by the novel severe acute respiratory syndrome (SARS) coronavirus 2, SARS-CoV-2. In this Viewpoint, we summarize recent evidence for the role of neutrophils in the pathogenesis of COVID-19 and propose CXCR2 inhibition as a promising treatment option to block neutrophil recruitment and activation.
Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY-232): A Multicenter, Phase 1b Study
Authors: Kevin J. Harrington, Anthony Kong, Nicolas Mach, Jason A. Chesney, Beatriz Castelo Fernandez, Danny Rischin, Ezra E.W. Cohen, Hoi-Shen Radcliffe, Burak Gumuscu, Jonathan Cheng, Wendy Snyder, Lillian L. Siu
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone. Patients and Methods: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety. Results: Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3–24.2). One DLT of T-VEC–related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0–5.8] and 5.8 months (95% Cl, 2.9–11.4), respectively. Conclusions: The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).
FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex–driven autoimmunity
Authors: Jonathan J. Hubbard, Michal Pyzik, Timo Rath, Lisa K. Kozicky, Kine M.K. Sand, Amit K. Gandhi, Algirdas Grevys, Stian Foss, Susan C. Menzies, Jonathan N. Glickman, Edda Fiebiger, Derry C. Roopenian, Inger Sandlie, Jan Terje Andersen, Laura M. Sly, Kristi Baker, Richard S. Blumberg
Journal: The Journal of Experimental Medicine (2020)

IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) γ-receptors (FcγRs). Of these, the highly prevalent FcγRIIa (CD32a) histidine (H)-131 variant (CD32aH) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32aR) variant, CD32aH more avidly bound human (h) IgG1 IC and formed a ternary complex with the neonatal Fc receptor (FcRn) under acidic conditions. In primary human and mouse cells, both CD32a variants required FcRn to induce innate and adaptive immune responses to hIgG1 ICs, which were augmented in the setting of CD32aH. Conversely, FcRn induced responses to IgG IC independently of classical FcγR, but optimal responses required FcRn and FcγR. Finally, FcRn blockade decreased inflammation in a rheumatoid arthritis model without reducing circulating autoantibody levels, providing support for FcRn's direct role in IgG IC-associated inflammation. Thus, CD32a and FcRn coregulate IgG IC-mediated immunity in a manner favoring the CD32aH variant, providing a novel mechanism for its disease association.
Critical Illness Secondary to Synthetic Cannabinoid Ingestion
Authors: Ismini Kourouni, Bashar Mourad, Hassan Khouli, Janet M. Shapiro, Joseph P. Mathew
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Synthetic cannabinoids (SCs), commonly known as<i>K2</i>,<i>spice</i>, or<i>fake weed</i>, are cheap, artificially manufactured recreational drugs that have emerged as a major public health threat in various regions of the US. <h3>Objective</h3> To describe the clinical manifestations of SC intoxication. <h3>Design, Setting, and Participants</h3> This case series assessed adults admitted to the intensive care unit from 2014 to 2016 with acute life-threatening complications of SC use. Data analysis was completed in October 2016. <h3>Exposures</h3> Use of SCs such as K2, spice, or other synthetic versions of cannabinoids. <h3>Main Outcomes and Measures</h3> Data collected included patient demographic data, medical history, presenting symptoms, physical findings, laboratory and imaging data, and intensive care unit and hospital course. <h3>Results</h3> Thirty patients (mean age, 41 years [range, 21-59 years]; 24 men [80%]) with SC ingestion were admitted to the intensive care unit over a 2-year period. Thirteen patients were undomiciled. The majority had a history of polysubstance abuse, psychiatric illness, or personality disorder. The admission diagnoses were coma (10 patients [33%]), agitation (10 patients [33%]), and seizure (6 patients [20%]). Eighteen patients (60%) had acute respiratory failure, and tracheal intubation was required in 21 patients (70%) for either airway protection or acute respiratory failure. Rhabdomyolysis was noted in 8 patients (26%). A man developed transient cerebral edema with loss of gray-white differentiation but had complete recovery. A woman with history of asthma died of acute respiratory distress syndrome. All patients underwent routine toxicology testing, which was unrevealing in 16 cases and revealed coingestion in the remainder. Sixteen patients (53%) left the hospital against medical advice. <h3>Conclusions and Relevance</h3> Ingestion of SCs can lead to life-threatening complications, including severe toxic encephalopathy, acute respiratory failure, and death. Synthetic cannabinoids are undetectable in routine serum and urine toxicology testing but can be suspected on the basis of history and clinical presentation, which may include extreme agitation or coma. Frontline clinicians must be aware of the presentation and be vigilant in suspecting SC intoxication.
Brown adipose tissue-derived exosomes mitigate the metabolic syndrome in high fat diet mice
Authors: Xueying Zhou, Zhelong Li, Meihao Qi, Ping Zhao, Yunyou Duan, Guodong Yang, Lijun Yuan
Journal: Theranostics (2020)

The ever-increasing incidence of obesity and related disorders impose serious challenges on public health worldwide. Brown adipose tissue (BAT) has strong capacity for promoting energy expenditure and has shown great potential in treating obesity. Exosomes are nanovesicles that share the characteristics of their donor cells. Whether BAT derived exosomes (BAT-Exos) might exert similar metabolic benefits on obesity is worthy of investigation. Methods: Obese mice were established by high-fat-diet (HFD) feeding and were treated with Seum-Exos or BAT-Exos isolated from young healthy mice. Blood glucose, glucose tolerance and blood lipids were tested in mice with indicated treatments. Histology examinations were performed on adipose tissue, liver and heart by HE staining and/or Oil Red O staining. Echocardiography was performed to evaluate cardiac function of mice. In vivo distribution of exosomes was analyzed by fluorescence labeling and imaging and in vitro effects of exosomes were evaluated by cell metabolism analysis. Protein contents of BAT-Exos were analyzed by mass spectrometry. Results: The results showed that BAT-Exos reduced the body weight, lowered blood glucose and alleviated lipid accumulation in HFD mice independently of food intake. Echocardiography revealed that the abnormal cardiac functions of HFD mice were significantly restored after treatment with BAT-Exos. Cell metabolism analysis showed that treatment with BAT-Exos significantly promoted oxygen consumption in recipient cells. Protein profiling of exosomes demonstrated that BAT-Exos were rich in mitochondria components and involved in catalytic processes. Conclusions: Collectively, our study showed that BAT-Exos significantly mitigated the metabolic syndrome in HFD mice. Detailed elucidation of the reactive molecules and mechanism of action would provide new insights in combating obesity and related disorders.
Abstract 9960: Patterns of Oral Anticoagulant Treatment Among Non-valvular Atrial Fibrillation Patients With End-stage Renal Disease Treated With Dialysis
Authors: Allison Keshishian, Daniel Wiederkehr, Xiaoyan Li, Jack Mardekian, Neeraja Balachander, Cristina Russ, Lisa Rosenblatt, Amol Dhamane, Janvi Sah, Xuemei Luo
Journal: Circulation (2019)

Introduction: Patients with non-valvular atrial fibrillation (NVAF) and end-stage renal disease (ESRD) are at an increased risk of stroke and bleeding, which is further elevated by dialysis treatme...
Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma
Authors: Xiaohua Liu, Yu Zhang, Yalei Li, Juan Wang, Huaqian Ding, Wenjing Huang, Chunyong Ding, Hongchun Liu, Wenfu Tan, Ao Zhang
Journal: Acta Pharmaceutica Sinica B (2020)

Medulloblastoma (MB) is a common yet highly heterogeneous childhood malignant brain tumor, however, clinically effective molecular targeted therapy is lacking. Modulation of hedgehog (HH) signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4 (BRD4) has recently spurred new interest as potential treatment of HH-driven MB. Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog (GLI) protein, the BRD4 inhibitor 2 was selected as the lead for further structural optimization, which led to the identification of compounds 25 and 35 as the high potency HH inhibitors. Mechanism profiling showed that both compounds suppressed HH signaling by interacting with the transcriptional factor GLI, and were equally potent against the clinical resistant mutants and the wild type of smoothened (SMO) receptor with IC50 values around 1 nmol/L. In the resistant MB allograft mice, compound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg (TGI = 83.3%) and 10 mg/kg (TGI = 87.6%) doses. Although further modification is needed to improve the pharmacokinetic (PK) parameters, compound 25 represents an efficacious lead compound of GLI inhibitors, possessing optimal safety and tolerance to fight against HH-driven MB.
MARKED IMPROVEMENTS IN SURVIVAL OF PATIENTS WITH STAGE II-IV RECTAL CANCER IN THE NETHERLANDS 1989-2006; AN ANALYSIS OF CHANGES IN TREATMENT AND SURVIVAL
Authors: M. Elferink, L.N. van Steenbergen, P. Krijnen, V.E.P.P. Lemmens, H.J. Rutten, C.A.M. Marijnen, I.D. Nagtegaal, H.E. Karim-Kos, E. de Vries, S. Siesling
Journal: Annals of Oncology (2010)