tbuckley/cabot-search huggingface dataset:
Colchicine treatment in community healthcare setting to prevent severe COVID-19
Authors: Emanuel Della-Torre, Giuseppe A Ramirez, Lorenzo Dagna, Moreno Tresoldi
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the article from Scarsi and colleagues about the efficacy of colchicine in hospitalised patients with severe COVID-19.1 Colchicine is an ‘old drug’ originally approved for the treatment of gout and subsequently repositioned in numerous disease settings characterised by systemic inflammation and uncontrolled activation of the innate immune response.2 3 During the recent outbreak of SARS-CoV-2 infection, uncontrolled release of major proinflammatory cytokines such as interleukin (IL)-1 and IL-6 soon emerged as a major pathological feature of COVID-19 as well as a predictor of patients’ morbidity and mortality.4 5

Based on this evidence, hospitalised patients with severe COVID-19 are currently being treated with anti-cytokine biological drugs including the IL-1 receptor antagonist anakinra, the anti-granulocyte-macrophage colony-stimulating factor mavrilimumab and the IL-6 receptor blockers tocilizumab and sarilumab.6–9 Yet, although these targeted approaches have provided encouraging results in preliminary retrospective cohorts, they do not seem to induce a prompt recovery as optimistically expected, likely because administered at …
Disparities in the excess risk of mortality in the first wave of COVID-19: Cross sectional study of the English sentinel network
Authors: Simon de Lusignan, Mark Joy, Jason Oke, Dylan McGagh, Brian Nicholson, James Sheppard, Oluwafunmi Akinyemi, Gayatri Amirthalingam, Kevin Brown, Rachel Byford, Gavin Dabrera, Else Krajenbrink, Harshana Liyanage, Jamie LopezBernal, Cecilia Okusi, Mary Ramsay, Julian Sherlock, Mary Sinnathamby, Ruby S.M. Tsang, Victoria Tzortziou Brown, John Williams, Maria Zambon, Filipa Ferreira, Gary Howsam, F.D. Richard Hobbs
Journal: Journal of Infection (2020)
Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma
Authors: Jonas Ecker, Venu Thatikonda, Gianluca Sigismondo, Florian Selt, Gintvile Valinciute, Ina Oehme, Carina Müller, Juliane L Buhl, Johannes Ridinger, Diren Usta, Nan Qin, Cornelis M van Tilburg, Christel Herold-Mende, Marc Remke, Felix Sahm, Frank Westermann, Marcel Kool, Robert J Wechsler-Reya, Lukas Chavez, Jeroen Krijgsveld, Natalie Jäger, Stefan M Pfister, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2020)

The sensitivity of myelocytomatosis oncogene (MYC) amplified medulloblastoma to class I histone deacetylase (HDAC) inhibition has been shown previously; however, understanding the underlying molecular mechanism is crucial for selection of effective HDAC inhibitors for clinical use. The aim of this study was to investigate the direct molecular interaction of MYC and class I HDAC2, and the impact of class I HDAC inhibition on MYC function.Co-immunoprecipitation and mass spectrometry were used to determine the co-localization of MYC and HDAC2. Chromatin immunoprecipitation (ChIP) sequencing and gene expression profiling were used to analyze the co-localization of MYC and HDAC2 on DNA and the impact on transcriptional activity in primary tumors and a MYC amplified cell line treated with the class I HDAC inhibitor entinostat. The effect on MYC was investigated by quantitative real-time PCR, western blot, and immunofluorescence.HDAC2 is a cofactor of MYC in MYC amplified medulloblastoma. The MYC-HDAC2 complex is bound to genes defining the MYC-dependent transcriptional profile. Class I HDAC inhibition leads to stabilization and reduced DNA binding of MYC protein, inducing a downregulation of MYC activated genes (MAGs) and upregulation of MYC repressed genes (MRGs). MAGs and MRGs are characterized by opposing biological functions and by distinct enhancer-box distribution.Our data elucidate the molecular interaction of MYC and HDAC2 and support a model in which inhibition of class I HDACs directly targets MYC's transactivating and transrepressing functions.
Effect of artificial intelligence-based triaging of breast cancer screening mammograms on cancer detection and radiologist workload: a retrospective simulation study
Authors: Karin Dembrower, Erik Wåhlin, Yue Liu, Mattie Salim, Kevin Smith, Peter Lindholm, Martin Eklund, Fredrik Strand
Journal: The Lancet Digital Health (2020)

BackgroundWe examined the potential change in cancer detection when using an artificial intelligence (AI) cancer-detection software to triage certain screening examinations into a no radiologist work stream, and then after regular radiologist assessment of the remainder, triage certain screening examinations into an enhanced assessment work stream. The purpose of enhanced assessment was to simulate selection of women for more sensitive screening promoting early detection of cancers that would otherwise be diagnosed as interval cancers or as next-round screen-detected cancers. The aim of the study was to examine how AI could reduce radiologist workload and increase cancer detection.MethodsIn this retrospective simulation study, all women diagnosed with breast cancer who attended two consecutive screening rounds were included. Healthy women were randomly sampled from the same cohort; their observations were given elevated weight to mimic a frequency of 0·7% incident cancer per screening interval. Based on the prediction score from a commercially available AI cancer detector, various cutoff points for the decision to channel women to the two new work streams were examined in terms of missed and additionally detected cancer.Findings7364 women were included in the study sample: 547 were diagnosed with breast cancer and 6817 were healthy controls. When including 60%, 70%, or 80% of women with the lowest AI scores in the no radiologist stream, the proportion of screen-detected cancers that would have been missed were 0, 0·3% (95% CI 0·0–4·3), or 2·6% (1·1–5·4), respectively. When including 1% or 5% of women with the highest AI scores in the enhanced assessment stream, the potential additional cancer detection was 24 (12%) or 53 (27%) of 200 subsequent interval cancers, respectively, and 48 (14%) or 121 (35%) of 347 next-round screen-detected cancers, respectively.InterpretationUsing a commercial AI cancer detector to triage mammograms into no radiologist assessment and enhanced assessment could potentially reduce radiologist workload by more than half, and pre-emptively detect a substantial proportion of cancers otherwise diagnosed later.FundingStockholm City Council.
A combined bioinformatics, experimental and clinical approach to identify novel cardiac‐specific heart failure biomarkers: is <scp>Dickkopf</scp>‐3 (<scp>DKK3</scp>) a possible candidate?
Authors: Arnold Piek, Navin Suthahar, Adriaan A. Voors, Rudolf A. de Boer, Herman H.W. Silljé
Journal: European Journal of Heart Failure (2020)

ABSTRACT Aims Cardiac specificity provides an advantage in correlating heart failure (HF) biomarker plasma levels with indices of cardiac function and remodelling, as shown for natriuretic peptides. Using bioinformatics, we explored the cardiac specificity of secreted proteins and investigated in more detail the relationship of Dickkopf‐3 ( DKK3 ) gene expression and DKK3 plasma concentrations with cardiac function and remodelling in (pre)clinical studies. Methods and results The cardiac specificity of secreted proteins was determined using RNAseq data for a large panel of organs and tissues. This showed that natriuretic peptides ( NPPA and NPPB ) are highly cardiac‐specific (&gt;99%), whereas other HF biomarkers, including galectin‐3 (Gal‐3, LGALS3 ) and growth differentiation factor‐15 ( GDF‐15 ), lack cardiac specificity (&lt;4%). DKK3 was cardiac‐enriched (44%), warranting further investigation. In three different HF mouse models, cardiac Dkk3 expression was altered, but DKK3 plasma concentrations were not. In humans, DKK3 plasma concentrations were higher in HF patients ( n = 2090) in comparison with age‐ and sex‐matched controls without HF ( n = 240) (46.4 ng/mL vs. 36.3 ng/mL; P &lt; 0.001). Multivariate regression analysis revealed that DKK3 was strongly associated with HF risk factors and comorbidities, including age, kidney function and atrial fibrillation. After correction for existing prediction models, DKK3 did not independently predict HF outcome [all‐cause mortality/HF hospitalization, hazard ratio 1.13 (0.79–1.61) per DKK3 doubling; P = 0.503]. Conclusions Of actively secreted HF biomarkers, only natriuretic peptides showed high cardiac specificity. Despite a cardiac specificity of 44%, secreted DKK3 had limited additional diagnostic and prognostic value.
Duckbill-type antireflux self-expandable metal stent placement for post-choledochojejunostomy reflux cholangitis
Authors: Takehiko Koga, Susumu Hijioka, Yasutake Ishikawa, Kimiteru Ito, Shota Harai, Takuji Okusaka, Yutaka Saito
Journal: Endoscopy (2020)

Reflux cholangitis is a common complication of choledochojejunostomy [1] [2]. Intestinal content reflux is considered a possible cause for this complication when there is no stenosis at the choledochojejunal anastomosis [3] [4] [5], and post-choledochojejunostomy reflex cholangitis (PCRC) is not an indication for endoscopic procedures (e. g., stenting). Here, we discuss using antireflux self-expandable metal stents (ARMS) to treat a patient with PCRC.
Abstract 6362: TH1901, a novel curcumin-peptide conjugate for the treatment of Sortilin-positive (SORT1+) cancer
Authors: Borhane Annabi, Michel Demeule, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Christian Marsolais, Richard Béliveau
Journal: Cancer Research (2020)

Abstract Rational: Phytochemicals are compounds found in plant foods that can help prevent the occurrence of chronic diseases like cancer. Several studies, over the last decade on the impact of phytochemicals in cancer treatment, have provided experimental evidence that curcumin contains antiproliferative, antiangiogenic, and apoptotic properties. Further evidence suggested that curcumin also suppresses tumor/colon cancer cell progression and angiogenesis by stimulating apoptosis and regulating immune response. Increased expression of the scavenging receptor Sortilin (SORT1), has been clinically observed in numerous invasive tumor biopsies. Procedures: In light of this, we developed a peptide conjugation platform and a new SORT1 receptor-mediated strategy to increase cell targeting selectivity and cell delivery of anticancer agents. As a proof-of-concept for phytochemicals, curcumin was conjugated to a SORT1-binding proprietary peptide (TH19P01). Curcumin-TH19P01 conjugate (TH1901) and unconjugated curcumin were tested on the proliferation of various cancer cells. Results: TH1901 showed a stronger anti-proliferation activity against cancer cells, with IC50 values up to 100-fold greater when compared to unconjugated curcumin. In addition, higher accumulation of fluorescence was detected for TH1901 indicating a more efficient cell internalization and release of curcumin from the conjugate. TH1901 uptake was reduced in the presence of SORT1 ligands neurotensin and progranulin as well as of free peptide confirming a preferential SORT1-mediated uptake of TH1901 in ES-2 ovarian cancer cells. Fluorescence microscopy showed that, in contrast to unconjugated curcumin, TH1901 induced cell apoptosis, and showed a stronger effect than unconjugated curcumin on TNF-alpha-induced intracellular signaling pathways involved in pro-inflammation processes. Interestingly, conjugation of curcumin also increased its in vitro stability in solution. In vivo, intraperitoneal administration of TH1901 (60 mg/kg/twice a week) inhibited growth of SORT1+ HT-29 colorectal cancer cell subcutaneous xenograft tumors, whereas at an equivalent dose unconjugated curcumin (15 mg/kg/twice a week) had no effect. Conclusion: Overall, these proof-of-concept experiments support the future development of this flexible and innovative platform to generate novel anticancer treatments. Citation Format: Borhane Annabi, Michel Demeule, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Christian Marsolais, Richard Béliveau. TH1901, a novel curcumin-peptide conjugate for the treatment of Sortilin-positive (SORT1+) cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6362.
The application of label-free imaging technologies in transdermal research for deeper mechanism revealing
Authors: Danping Zhang, Qiong Bian, Yi Zhou, Qiaoling Huang, Jianqing Gao
Journal: Asian Journal of Pharmaceutical Sciences (2020)

The penetration behavior of topical substances in the skin not only relates to the transdermal delivery efficiency but also involves the safety and therapeutic effect of topical products, such as sunscreen and hair growth products. Researchers have tried to illustrate the transdermal process with diversified theories and technologies. Directly observing the distribution of topical substances on skin by characteristic imaging is the most convincing approach. Unfortunately, fluorescence labeling imaging, which is commonly used in biochemical research, is limited for transdermal research for most topical substances with a molecular mass less than 500 Da. Label-free imaging technologies possess the advantages of not requiring any macromolecular dyes, no tissue destruction and an extensive substance detection capability, which has enabled rapid development of such technologies in recent years and their introduction to biological tissue analysis, such as skin samples. Through the specific identification of topical substances and endogenous tissue components, label-free imaging technologies can provide abundant tissue distribution information, enrich theoretical and practical guidance for transdermal drug delivery systems. In this review, we expound the mechanisms and applications of the most popular label-free imaging technologies in transdermal research at present, compare their advantages and disadvantages, and forecast development prospects.
IL-31 induces antitumor immunity in breast carcinoma
Authors: Tal Kan, Erik Feldman, Michael Timaner, Ziv Raviv, Shai Shen-Orr, Ami Aronheim, Yuval Shaked
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immunomodulatory agents that induce antitumor immunity have great potential for treatment of cancer. We have previously shown that interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent. Here, we characterize the immunomodulatory effect of IL-31 in breast cancer. Methods In vivo breast carcinoma models including EMT6 and PyMT cell lines were used to analyze the effect of IL-31 on the composition of various immune cells in the tumor microenvironment using high-throughput flow cytometry. In vitro studies using isolated cytotoxic T cells, CD4 + T cells, myeloid-derived suppressor cells (MDSCs) and macrophages were carried out to study IL-31 immunological activity. The generation of recombinant IL-31 bound to IgG backbone was used to test IL-31 therapeutic activity. Results The growth rate of IL-31-expressing breast carcinomas is decreased in comparison with control tumors due, in part, to antitumor immunomodulation. Specifically, cytotoxic T cell activity is increased, whereas the levels of CD4 + T cells, MDSCs, and tumor-associated macrophages are decreased in IL-31-expressing tumors. These cellular changes are accompanied by a cytokine profile associated with antitumor immunity. In vitro, IL-31 directly inhibits CD4 + Th0 cell proliferation, and the expression of Th2 canonical factors GATA3 and IL-4. It also promotes CD8 + T cell activation through inhibition of MDSC activity and motility. Clinically, in agreement with the mouse data, alterations in immune cell composition in human breast cancer biopsies were found to correlate with high expression of IL-31 receptor A (IL-31Ra) . Furthermore, high coexpression of IL-31Ra, IL-2 and IL-4 in tumors correlates with increased survival. Lastly, to study the therapeutic potential of IL-31, a recombinant murine IL-31 molecule was fused to IgG via a linker region (IL-31-L-IgG). This IL-31-L-IgG therapy demonstrates antitumor therapeutic activity in a murine breast carcinoma model. Conclusions Our findings demonstrate that IL-31 induces antitumor immunity, highlighting its potential utility as a therapeutic immunomodulatory agent.
Phase I study of chidamide (CS055/HBI-8000), a novel histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas
Authors: M. Dong, Z. Ning, M. J. Newman, J. Xu, G. Dou, H. Cao, Y. Shi, M. A. Gingras, X. Lu, F. Feng
Journal: Journal of Clinical Oncology (2009)

3529 Background: Chidamide (CS055/HBI-8000) is a new benzamide type of histone deacetylase (HDAC) inhibitor with low nanomolar activity against HDAC1, 2, 3 and 10. This Phase I study evaluated the safety and tolerability of chidamide in patients (pts) with advanced solid tumors and lymphomas. Methods: 31 pts with refractory or relapsed advanced solid tumors (22) and lymphomas (9) were enrolled in this study. Escalating doses of 5, 10, 17.5, 25, 32.5 and 50 mg Chidamide (each with 3 to 7 pts) were administered orally either twice or three times per week for 4 consecutive weeks every 6 weeks. Results: No dose limiting toxicities (DLTs) were identified in the 2 x per week cohorts (22 pts) up to 50 mg; G2 and G3 hematological toxicities (leukopenia/neutropenia and thrombocytopenia) were observed at 50 mg. DLTs were reported as G3 diarrhea or vomiting in 2 pts in the 3 x per week cohort at 50 mg. Common adverse events were G1/G2, fatigue (n = 11), thrombocytopenia (n = 9), anorexia (n = 8), nausea/vomiting (n = 7), leukopenia/neutropenia (n = 6), hypochromia (n = 6), and diarrhea (n = 5). No cystitis, pericarditis, pericardial effusion or prolonged QTc intervals were observed. Single dose PK analysis in pts with 25, 32.5 and 50 mg revealed T1/2 of 16.8–18.3 h, Tmax of 1–2 h in most cases, and a dose-related increase in Cmax and AUC. Multiple dose PK analysis in pts with 32.5 mg 3 x per week suggested drug accumulation with this regimen. Significant induction of histone (H3) acetylation was observed in peripheral white blood cells, which lasted for 2–3 days in most pts after single dosing. 25 pts with total treatment cycles of 49 (range 1–6) were evaluable for efficacy. 4 pts with T-cell lymphomas (4/5 evaluable) and 1 pt with submandibular adenoid cystic carcinoma achieved PR, and 11 pts (2 B-cell lymphomas and 9 solid tumors) experienced SD. Conclusions: Chidamide was well-tolerated in pts with advanced solid tumors and lymphomas in the tested regimens. In addition, the compound exhibited a relatively long half-life, a long-lasting biomarker response and encouraging antitumor activity at well-tolerated doses. The overall phase I results recommend the 2 x per week regimen for phase II studies. [Table: see text]
Implementation of genomic predictors of chemotherapy response for guiding preoperative therapy in a prospective breast cancer trial
Authors: P. K. Marcom, M. B. Datto, W. T. Barry, J. Geradts, T. L. Foster, H. K. Dressman, J. Olson, A. Potti, G. Ginsburg, J. R. Nevins
Journal: Journal of Clinical Oncology (2009)

11057 Background: Personalized approaches to breast cancer therapy depend on genomic assays. While assays based on fixed tissues offer greater convenience, the spectrum of biology interrogated is limited. Full-transcriptome assays using microarrays are more challenging, but have the advantage of providing multiple prognostic and predictive signatures in one assay. We have created a clinical infrastructure with the objective of obtaining full genome expression data on breast cancer samples as a clinical assay for use in a prospective trial. Methods: “Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer” is a prospective trial validating genomic signatures for predicting response to doxorubicin (A) or docetaxel (T) treatment in HER2 negative cancers. Fresh-frozen cores are reviewed by the study pathologist for tumor content. RNA is then extracted and probe generated to hybrize to an Affymetrix U133Plus2.0 microarray. Microarray data quality is determined using summary metrics for U133Plus2.0 arrays and principal component analysis (PCA) plots. The data is then used for predicting A or T sensitivity. Results: Thirteen cancers have been analyzed in the context of the above trial. Histologic type was lobular for 1, and predominantly ductal for 12 (10 ER positive, 3 ER negative). Median tumor size was 3.4 cm (range, 1.8–5.7). Microarray analysis was successful on 11 tumors (84%), providing data of sufficient quality to make predictions of A and T sensitivity. One sample hybridization failed QC as detected by PCA analysis, and one sample had insufficient RNA. The median “tissue to array data” time and “study consent to initiation of treatment” time were 5 days (range, 3–8) and 14 days (range, 11–36), respectively. Conclusions: Our initial experience shows that full-genome expression analysis on frozen tumor using an Affymetrix platform is feasible as a clinical assay for breast cancer. The resulting data is being used in a prospective marker validation protocol for predicting chemosensitivity. The data can also be analyzed for a variety of other potential prognostic and predictive signatures for guiding therapy. No significant financial relationships to disclose.
Use of the Sport Concussion Assessment Tool 5 (SCAT5) in professional hockey, part 1: cross-cultural normative data
Authors: Ruben J Echemendia, Joanie Thelen, Willem Meeuwisse, Michael G Hutchison, Paul Comper, John Rizos, Jared M Bruce
Journal: British Journal of Sports Medicine (2020)

Objectives This paper provides comprehensive normative data stratified by language preference and age on the components of the National Hockey League (NHL) Sport Concussion Assessment Tool 5 (SCAT5) in a multilingual sample of professional ice hockey players and compares the findings from a paper form of the NHL SCAT5 with an electronic (App) version of the tool. Methods A total of 1924 male NHL and American Hockey League (AHL) players (ages 17–41) were assessed during preseason medical evaluations (baseline); 1881 were assessed with the NHL SCAT5 App via tablet and 43 received the paper version of the NHL Modified SCAT5. Results No significant differences between the App and paper modes of administration emerged in a subsample of English preference players. Significant SCAT5 differences among language preference groups emerged on measures of cognitive functioning (Immediate Memory,Concentration). No language preference differences emerged on the Delayed Recall component. Using age as a continuous variable, older participants outperformed younger players on Immediate Memory, Delayed Recall and Concentration. Players wearing skates demonstrated significantly more modified Balance Error Scoring System (mBESS) total errors than barefoot players. Normative data tables for language preference groups are presented. Conclusions Significant differences were found between English and non-English language preference groups on the components of SCAT5, which suggest that language-specific normative data, rather than aggregated normative data, are preferable when interpreting test scores. Similarly, age-specific normative data tables may provide greater precision in data interpretation. Due to clear ceiling effects on the mBESS single leg and tandem stances, players should not be tested while wearing skates.