tbuckley/cabot-search huggingface dataset:
Intracellular uptake of nanocrystals: Probing with aggregation-induced emission of fluorescence and kinetic modeling
Authors: Jifen Zhang, Clairissa D. Corpstein, Tonglei Li
Journal: Acta Pharmaceutica Sinica B (2020)

Nanocrystal formulations have been explored to deliver poorly water-soluble drug molecules. Despite various studies of nanocrystal formulation and delivery, much more understanding needs to be gained into absorption mechanisms and kinetics of drug nanocrystals at various levels, ranging from cells to tissues and to the whole body. In this study, nanocrystals of tetrakis (4-hydroxyphenyl) ethylene (THPE) with an aggregation-induced emission (AIE) property was used as a model to explore intracellular absorption mechanism and dissolution kinetics of nanocrystals. Cellular uptake studies were conducted with KB cells and characterized by confocal microscopy, flow cytometry, and quantitative analyses. The results suggested that THPE nanocrystals could be taken up by KB cells directly, as well as in the form of dissolved molecules. The cellular uptake was found to be concentration- and time-dependent. In addition, the intracellular THPE also could be exocytosed from cells in forms of dissolved molecules and nanocrystals. Kinetic modeling was conducted to further understand the cellular mechanism of THPE nanocrystals based on first-order ordinary differential equations (ODEs). By fitting the kinetic model against experimental measurements, it was found that the initial nanocrystal concentration had a great influence on the dynamic process of dissolution, cellular uptake, and exocytosis of THPE nanocrystals. As the nanocrystal concentration increased in the culture media, dissolution of endocytosed nanocrystals became enhanced, subsequently driving the efflux of THPE molecules from cells.
Redox-Resistant SERCA [Sarco(endo)plasmic Reticulum Calcium ATPase] Attenuates Oxidant-Stimulated Mitochondrial Calcium and Apoptosis in Cardiac Myocytes and Pressure Overload–Induced Myocardial Failure in Mice
Authors: Jena B. Goodman, Fuzhong Qin, Robert J. Morgan, Jordan M. Chambers, Dominique Croteau, Deborah A. Siwik, Ion Hobai, Marcello Panagia, Ivan Luptak, Markus Bachschmid, XiaoYong Tong, David R. Pimentel, Richard A. Cohen, Wilson S. Colucci
Journal: Circulation (2020)

Background: SERCA [sarco(endo)plasmic reticulum calcium ATPase] is regulated by oxidative posttranslational modifications at cysteine 674 (C674). Because sarcoplasmic reticulum (SR) calcium has been shown to play a critical role in mediating mitochondrial dysfunction in response to reactive oxygen species, we hypothesized that SERCA oxidation at C674 would modulate the effects of reactive oxygen species on mitochondrial calcium and mitochondria-dependent apoptosis in cardiac myocytes. Methods: Adult rat ventricular myocytes expressing wild-type SERCA2b or a redox-insensitive mutant in which C674 is replaced by serine (C674S) were exposed to H 2 O 2 (100 µmol/Lμ). Free mitochondrial calcium concentration was measured in adult rat ventricular myocytes with a genetically targeted fluorescent probe, and SR calcium content was assessed by measuring caffeine-stimulated release. Mice with heterozygous knock-in of the SERCA C674S mutation were subjected to chronic ascending aortic constriction. Results: In adult rat ventricular myocytes expressing wild-type SERCA, H 2 O 2 caused a 25% increase in mitochondrial calcium concentration that was associated with a 50% decrease in SR calcium content, both of which were prevented by the ryanodine receptor inhibitor tetracaine. In cells expressing the C674S mutant, basal SR calcium content was decreased by 31% and the H 2 O 2 -stimulated rise in mitochondrial calcium concentration was attenuated by 40%. In wild-type cells, H 2 O 2 caused cytochrome c release and apoptosis, both of which were prevented in C674S-expressing cells. In myocytes from SERCA knock-in mice, basal SERCA activity and SR calcium content were decreased. To test the effect of C674 oxidation on apoptosis in vivo, SERCA knock-in mice were subjected to chronic ascending aortic constriction. In wild-type mice, ascending aortic constriction caused myocyte apoptosis, LV dilation, and systolic failure, all of which were inhibited in SERCA knock-in mice. Conclusions: Redox activation of SERCA C674 regulates basal SR calcium content, thereby mediating the pathologic reactive oxygen species–stimulated rise in mitochondrial calcium required for myocyte apoptosis and myocardial failure.
Clonal tracing reveals diverse patterns of response to immune checkpoint blockade
Authors: Shengqing Stan Gu, Xiaoqing Wang, Xihao Hu, Peng Jiang, Ziyi Li, Nicole Traugh, Xia Bu, Qin Tang, Chenfei Wang, Zexian Zeng, Jingxin Fu, Cliff Meyer, Yi Zhang, Paloma Cejas, Klothilda Lim, Jin Wang, Wubing Zhang, Collin Tokheim, Avinash Das Sahu, Xiaofang Xing, Benjamin Kroger, Zhangyi Ouyang, Henry Long, Gordon J. Freeman, Myles Brown, X. Shirley Liu
Journal: Genome biology (2020)

Abstract Background Immune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but only a minority of cancer patients respond. Multiple studies have sought to identify general biomarkers of ICB response, but elucidating the molecular and cellular drivers of resistance for individual tumors remains challenging. We sought to determine whether a tumor with defined genetic background exhibits a stereotypic or heterogeneous response to ICB treatment. Results We establish a unique mouse system that utilizes clonal tracing and mathematical modeling to monitor the growth of each cancer clone, as well as the bulk tumor, in response to ICB. We find that tumors derived from the same clonal populations showed heterogeneous ICB response and diverse response patterns. Primary response is associated with higher immune infiltration and leads to enrichment of pre-existing ICB-resistant cancer clones. We further identify several cancer cell-intrinsic gene expression signatures associated with ICB resistance, including increased interferon response genes and glucocorticoid response genes. These findings are supported by clinical data from ICB treatment cohorts. Conclusions Our study demonstrates diverse response patterns from the same ancestor cancer cells in response to ICB. This suggests the value of monitoring clonal constitution and tumor microenvironment over time to optimize ICB response and to design new combination therapies. Furthermore, as ICB response may enrich for cancer cell-intrinsic resistance signatures, this can affect interpretations of tumor RNA-seq data for response-signature association studies.
PD1 blockade enhances K<sup>+</sup>channel activity, Ca<sup>2+</sup>signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer
Authors: Hannah S Newton, Vaibhavkumar S Gawali, Ameet A Chimote, Maria A Lehn, Sarah M Palackdharry, Benjamin H Hinrichs, Roman Jandarov, David Hildeman, Edith M Janssen, Trisha M Wise-Draper, Laura Conforti
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immunotherapy has emerged as a promising treatment modality for head and neck squamous cell carcinoma (HNSCC). Pembrolizumab, an anti-programmed death 1 antibody, is an immunotherapy agent currently approved for metastatic HNSCC and curative intent clinical trials. Although clinical responses to pembrolizumab are promising, many patients fail to respond. However, it is well known that T cell cytotoxicity and chemotaxis are critically important in the elimination of HNSCC tumors. These functions depend on ion channel activity and downstream Ca
<i>Echinacea</i>for Preventing and Treating the Common Cold
Authors: Marlies Karsch-Völk, Bruce Barrett, Klaus Linde
Journal: JAMA (2015)

<h3>Clinical Question</h3> Are<i>Echinacea</i>products associated with a reduced incidence and a shorter duration of common colds compared with placebo? <h3>Bottom Line</h3> Individual prophylaxis trials show no association with prevention of the common cold, but exploratory meta-analysis suggests that<i>Echinacea</i>products may be associated with a small reduction in cold incidence. In treatment trials, there was no association of<i>Echinacea</i>products with a shorter duration of colds.
Effects of hyperkalaemia and non‐adherence to renin–angiotensin–aldosterone system inhibitor therapy in patients with heart failure in <scp>Italy</scp>: a propensity‐matched study
Authors: Maurizio Volterrani, Valentina Perrone, Diego Sangiorgi, Elisa Giacomini, Ferdinando Iellamo, Luca Degli Esposti
Journal: European Journal of Heart Failure (2020)

Aims The aims of this study were to evaluate if the risk of cardiovascular events and all‐cause mortality was higher in the presence of hyperkalaemia (HK) in patients with heart failure (HF) treated with renin–angiotensin–aldosterone system inhibitors (RAASi), and to investigate in this cohort the increased risk of cardiovascular events and all‐cause mortality among HK patients with non‐optimal adherence to RAASi therapy. Methods and results In this retrospective cohort study based on administrative databases of five Italian Local Health Units, all adult patients with a HF diagnosis between January 2010 and December 2017 were included only if they were prescribed RAASi therapy during the first 3 months after the index date, that corresponded to the date of first HF diagnosis during the inclusion period. Patients were considered to have HK if serum potassium level was ≥5.5 mmol/L. A propensity score matching was applied before evaluation of hazard ratios. Patients with HK were 37% ( P &lt; 0.001) and 70% ( P &lt; 0.001), respectively, more at risk of cardiovascular events and of dying for all‐cause mortality compared to non‐HK patients. Among the HK group, patients non‐adherent to RAASi therapy had a 39% ( P = 0.105) higher risk of cardiovascular events and a twofold increased risk ( P &lt; 0.001) of all‐cause death. Conclusion Findings from this real‐world study showed that in a cohort of HF patients under RAASi therapy, subjects with HK had an enhanced risk of cardiovascular events or death compared to patients without HK. Moreover, in HK patients, sub‐optimal adherence to RAASi therapy was associated with an increased risk of all‐cause mortality.
Novel Agents for Metastatic Triple-Negative Breast Cancer: Finding the Positive in the Negative
Authors: Neelima Vidula, Leif W. Ellisen, Aditya Bardia
Journal: Journal of the National Comprehensive Cancer Network (2021)

Metastatic triple-negative breast cancer (TNBC) is associated with a poor prognosis, and the development of better therapeutics represents a major unmet clinical need. Although the mainstay of treatment of metastatic TNBC is chemotherapy, advances in genomics and molecular profiling have helped better define subtypes of TNBC with distinct biologic drivers to guide the therapeutic development of targeted therapies, including AKT inhibitors for PI3K/AKT-altered TNBC, checkpoint inhibitors for PD-L1–positive TNBC, and PARP inhibitors for BRCA1/2 mutant TNBC. This progress may ultimately convert TNBC from a disease traditionally defined by the absence of therapeutically actionable receptors to one that is defined by the presence of discrete molecular targets with therapeutic implications. Furthermore, antibody drug conjugates have emerged as an important therapeutic strategy to target genomically complex tumors that lack actionable oncogenes but have overexpressed actionable surface receptors such as trop-2. In this article, we discuss promising novel agents for advanced TNBC, some of which have been incorporated into current clinical practice, and others that will likely change the therapeutic landscape and redefine the TNBC terminology in the near future.
Association of Laminar Airflow During Primary Total Joint Arthroplasty With Periprosthetic Joint Infection
Authors: Qiaojie Wang, Chi Xu, Karan Goswami, Timothy L. Tan, Javad Parvizi
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Whether laminar airflow (LAF) in the operating room is effective for decreasing periprosthetic joint infection (PJI) after total joint arthroplasty remains a clinically important yet controversial issue. <h3>Objective</h3> To investigate the association between operating room LAF ventilation systems and the risk of PJI in patients undergoing total joint arthroplasty. <h3>Design, Setting, and Participants</h3> A retrospective cohort study was conducted of 6972 consecutive patients undergoing primary total knee arthroplasty or total hip arthroplasty at 2 surgical facilities within a single institution from January 1, 2013, to September 15, 2017, with a minimum of 1 year of follow-up. All procedures were performed by 5 board-certified arthroplasty surgeons. Statistical analysis was performed from January 1, 2014, to September 15, 2018. <h3>Exposure</h3> Patients underwent total joint arthroplasty in operating rooms equipped with either LAF or turbulent airflow. <h3>Main Outcomes and Measures</h3> Patient characteristics were extracted from clinical records. Periprosthetic joint infection was defined according to Musculoskeletal Infection Society criteria within 1 year of the index arthroplasty. A multivariable logistic regression model was performed to explore the potential association between LAF and risk of PJI at 1 year, and then a sensitivity analysis using propensity score matching was performed to further validate the findings. <h3>Results</h3> A total of 6972 patients (2797 who underwent total knee arthroplasty and 4175 who underwent total hip arthroplasty; 3690 women [52.9%]; mean [SD] age, 63.9 [10.7] years) were included. The incidence of PJI within 1 year for patients from the facility without LAF was similar to that of patients from the facility with LAF (0.4% [12 of 3027] vs 0.5% [21 of 3945]). In the multivariable logistic regression analysis, after all confounding factors were taken into account, the use of LAF was not associated with a reduction of the risk of PJI (adjusted odds ratio, 0.94; 95% CI, 0.40-2.19;<i>P</i> = .89). After propensity score matching, there was no significant difference in the incidence of PJI within 1 year for patients who underwent total joint arthroplasty at these 2 sites. <h3>Conclusions and Relevance</h3> This study suggests that the use of LAF in the operating room was not associated with a reduced incidence of PJI after primary total joint arthroplasty. With an appropriate perioperative protocol for infection prevention, LAF does not seem to play a protective role in PJI prevention.
The Need for Evidence Regarding Cannabidiol
Authors: Wilson M. Compton, Emily B. Einstein
Journal: JAMA Network Open (2020)

Eric C. Leas, PhD, MPH; Erik M. Hendrickson, MPH, MA; Alicia L. Nobles, PhD, MS; Rory Todd, BA; Davey M. Smith, MD, MAS; Mark Dredze, PhD; John W. Ayers, PhD, MA
Trends in the Use of Buprenorphine in US Emergency Departments, 2002-2017
Authors: Taeho Greg Rhee, Gail D’Onofrio, David A. Fiellin
Journal: JAMA Network Open (2020)

provided for opioid use disorder and the lack of information on dosing, route of administration, formulation, or prescriptions written for ongoing treatment after ED discharge.It appears that the sampling strategy or data collection method in 2012-2013 was different from that used in other years because less buprenorphine use was captured.Despite the limitations, the present study found increased use of buprenorphine in ED settings, a promising strategy for narrowing the treatment gap.Potential barriers to ED adoption of buprenorphine treatment initiation for untreated opioid use disorder have been identified, 6 and research on strategies to address these should be prioritized.
A Wnt-Induced Phenotypic Switch in Cancer-Associated Fibroblasts Inhibits EMT in Colorectal Cancer
Authors: Mohammed H. Mosa, Birgitta E. Michels, Constantin Menche, Adele M. Nicolas, Tahmineh Darvishi, Florian R. Greten, Henner F. Farin
Journal: Cancer Research (2020)

Tumor progression is recognized as a result of an evolving cross-talk between tumor cells and their surrounding nontransformed stroma. Although Wnt signaling has been intensively studied in colorectal cancer, it remains unclear whether activity in the tumor-associated stroma contributes to malignancy. To specifically interfere with stromal signals, we generated Wnt-independent tumor organoids that secrete the Wnt antagonist Sfrp1. Subcutaneous transplantation into immunocompetent as well as immunodeficient mice resulted in a strong reduction of tumor growth. Histologic and transcriptomic analyses revealed that Sfrp1 induced an epithelial-mesenchymal transition (EMT) phenotype in tumor cells without affecting tumor-intrinsic Wnt signaling, suggesting involvement of nonimmune stromal cells. Blockage of canonical signaling using Sfrp1, Dkk1, or fibroblast-specific genetic ablation of β-catenin strongly decreased the number of cancer-associated myofibroblasts (myCAF). Wnt activity in CAFs was linked with distinct subtypes, where low and high levels induced an inflammatory-like CAF (iCAF) subtype or contractile myCAFs, respectively. Coculture of tumor organoids with iCAFs resulted in significant upregulation of EMT markers, while myCAFs reverted this phenotype. In summary, we show that tumor growth and malignancy are differentially regulated via distinct fibroblast subtypes under the influence of juxtacrine Wnt signals. SIGNIFICANCE: This study provides evidence for Wnt-induced functional diversity of colorectal cancer-associated fibroblasts, representing a non-cell autonomous mechanism for colon cancer progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5569/F1.large.jpg.
Efficacy and safety of tranexamic acid in acute traumatic brain injury: a systematic review and meta-analysis of randomized-controlled trials
Authors: Kumait Al Lawati, Sameer Sharif, Said Al Maqbali, Hussein Al Rimawi, Andrew Petrosoniak, Emilie P. Belley-Cote, Sunjay V. Sharma, Justin Morgenstern, Shannon M. Fernando, Julian J. Owen, Michelle Zeller, David Quinlan, Waleed Alhazzani, Bram Rochwerg
Journal: Intensive Care Medicine (2020)
Rational Selection of CRISPR-Cas9 Guide RNAs for Homology-Directed Genome Editing
Authors: Kristina J. Tatiossian, Robert D.E. Clark, Chun Huang, Matthew E. Thornton, Brendan H. Grubbs, Paula M. Cannon
Journal: Molecular Therapy (2020)

Homology-directed repair (HDR) of a DNA break allows copying of genetic material from an exogenous DNA template and is frequently exploited in CRISPR-Cas9 genome editing. However, HDR is in competition with other DNA repair pathways, including non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ), and the efficiency of HDR outcomes is not predictable. Consequently, to optimize HDR editing, panels of CRISPR-Cas9 guide RNAs (gRNAs) and matched homology templates must be evaluated. We report here that CRISPR-Cas9 indel signatures can instead be used to identify gRNAs that maximize HDR outcomes. Specifically, we show that the frequency of deletions resulting from MMEJ repair, characterized as deletions greater than or equal to 3 bp, better predicts HDR frequency than consideration of total indel frequency. We further demonstrate that tools that predict gRNA indel signatures can be repurposed to identify gRNAs to promote HDR. Finally, by comparing indels generated by S. aureus and S. pyogenes Cas9 targeted to the same site, we add to the growing body of data that the targeted DNA sequence is a major factor governing genome editing outcomes.
Producing and using timely comparative evidence on drugs: lessons from clinical trials for covid-19
Authors: Huseyin Naci, Aaron S Kesselheim, John-Arne Røttingen, Georgia Salanti, Per O Vandvik, Andrea Cipriani
Journal: BMJ (2020)

Huseyin Naci and colleagues call for greater collaboration among trialists, meta-analysts, and guidance developers to improve the evidence base for new treatments
FRI0172 Long-term follow-up of paediatric patients with positive anti-phospholipid antibodies
Authors: A Ince, A Roumany, U Daud, PH Pepmueller, TL Moore
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Long-term outcome data of Anti-Phospholipid syndrome (APLS) in paediatric patient population is very limited. There are no established criteria for making a diagnosis of Paediatric Anti- Phospholipid syndrome (APLS). Adult APLS criteria includes the major criteria of fetal loss, which is not pertinent to the pedriatric population. <h3>Objectives</h3> To evaluate the clinical outcome of paediatric patients who either had a positive Lupus Anticoagulant (LAC), moderately high titer of anti-cardiolipin antibodies (ACLA) or anti-b<sub>2</sub> glycoprotein-1 antibodies on more than one occasion. <h3>Methods</h3> We identified 19 patients (17 females, 2 males), mean age of disease onset was 11.7 years (range 7–16 years). Patients were followed-up a median of 96 months (range 12–204 months). <h3>Results</h3> Seven patients had only IgG ACLA, one had only IgM ACLA, two had both IgG and IgM ACLA, one had IgG and IgA ACLA, and one had all three ACLA's present. One patient had significantly positive LAC and IgM ACLA and four patients had positive results for both anti-β 2 glycoprotein and ACLA. Out of 17 patients, 11 had a diagnosis of Systemic Lupus Erythematosus (SLE) and 6 patients did not have any other connective tissue disease (CTD) diagnosis. On clinical presentation, 4 patients had headaches (HA),&nbsp;4 had livedo reticularis, and 8 had both HA and livedo reticularis. At initial presentation,&nbsp;1 patient had venous thrombosis,&nbsp;1 had chorea nad one had both arterial and venous thrombosis with no previous CTD diagnosis. One patient with SLE presented with arterial thrombosis. In the follow-up period, one patient had a miscarriage and chose not to become pregnant again. All patients were placed on low-dose aspirin (ASA) [81 mg/d] and hrdroxychloroquine (HCQ) if they had a diagnosis of SLE. Patients who had an event at presentation were treated with warfarin for 6 months and then switched to ASA alone after 6 months. There were no events noted in patients who were treated after their initial presentation to our clinic. <h3>Conclusion</h3> This long-term follow-up shows that: 1) Livedo reticularis and HA are common initial presentations of APLS, but,&nbsp;2) Prognosis has been very good with treatment with ASA and HCQ in the paediatric APLS group.