tbuckley/cabot-search huggingface dataset:
Molecular determinants associated with long-term response to apalutamide (APA) in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Felix Y Feng, Clemente Aguilar-Bonavides, Justin Lucas, Shibu Thomas, Michael Gormley, Sharon Anne McCarthy, Sabine Doris Brookman-May, Spyros Triantos, Suneel Mundle, Matthew Raymond Smith, Eric Jay Small
Journal: Journal of Clinical Oncology (2021)

8 Background: SPARTAN, a phase 3 placebo (PBO)-controlled study in patients (pts) with nmCRPC, showed that APA plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival compared with PBO + ADT. This exploratory analysis investigated potential biological signatures of pts with long-term responses to APA and PBO. Methods: The biomarker cohort of SPARTAN was characterized as long-term responders (LTR) or early progressors (EP) based on time to metastasis, and separated into quartiles for APA and PBO groups. Pts progressing in the first quartile (APA, 21; PBO, 17), with shortest time to metastatic event, were classified as EP, those progressing in the last quartile (APA, 39; PBO, 20) as LTR. Gene expression profiles were generated from 233 archival primary prostate tumors. Predefined gene signatures indicative of cancer biology were compared between LTR and EP groups within the APA and PBO arms using 2 sample t tests. Signatures associated with LTR and EP were identified using p values of less than 0.05. Results: Median time to metastatic progression was 40.5 months in APA pts and 22 months in PBO pts in the LTR group and 7.3 and 3.6 months in APA and PBO pts, respectively, in the EP group. Signatures categorized into 3 general mechanistic classes (immune regulation, proliferation, and hormone dependence) associated with LTR on APA included increased T cell activity reflected by T cell activation ( p = 0.0045), stimulation ( p = 0.0642), cytokine response ( p = 0.0489), and interferon production (gamma response p = 0.0227 ), and decreased T cell exclusion ( p = 0.0652), low proliferative capacity ( p = 0.0435), and increased hormonal dependence ( p = 0.0485). High risk (DECIPHER p = 0.0406, metastatic potential p = 0.0077), hormone nonresponsive (basal p = 0.0115; androgen receptor activity-low, p = 0.0437), and neuroendocrine-like tumors ( p = 0.0125) were associated with early progression on treatment with PBO. Conclusions: Although the data require confirmation in larger studies, these molecular determinants may have utility in selecting pts with nmCRPC who may derive the most benefit from APA and other androgen signaling inhibitors. Clinical trial information: NCT01946204.
Abstract PO040: Protease inhibitors of HGF activation prevent HGF-dependent tumor progression and overcome resistance to anti-cancer therapy
Authors: Jorine J.L.P. Voss, Vishnu Damalanka, Matthew Mahoney, Lidija Klampfer, James W. Janetka
Journal: Cancer Research (2021)

Abstract Overproduction of Hepatocyte Growth Factor (HGF) in the tumor microenvironment by tumor-associated fibroblasts or cancer cells is associated with poor patient outcomes and is a common cause of therapeutic resistance. HGF signals via the MET receptor, which results in the activation of downstream signaling pathways that promote cell survival, proliferation, migration, scattering, and invasion of cancer cells. HGF is secreted as an inactive precursor, pro-HGF, and proteolytic processing into its active form by one of the serine proteases, matriptase, hepsin, or HGF Activator (HGFA), is the rate-limiting step in HGF/MET signaling. The expression of these proteases is upregulated in cancer, whereas the activity of endogenous inhibitors of HGF-activating proteases, HGF-Activation Inhibitors (HAI-1/HAI-2), is reduced in cancer. We have developed small-molecule inhibitors of the three HGF-activating proteases, matriptase, hepsin, and HGFA. We refer to these inhibitors as synthetic HGF-Activation Inhibitors (sHAI), because they mimic the activity of HAI-1/HAI-2. The activity of sHAI was tested in in vitro models of therapeutic resistance and in in vivo models of HGF-driven lung cancer progression. ZFH7116 and VD2173, two lead SHAI compounds, are both potent inhibitors of the HGF-activating proteases and have good drug-like pharmacokinetic (PK) properties. We demonstrated that ZFH7116 and VD2173 inhibit proteolytic activation of pro-HGF to its active form. Both compounds overcome HGF-mediated resistance to EGFR and MET-targeted therapy in lung and colon cancer models of therapeutic resistance. Furthermore, ZFH7116 and VD2173 inhibit HGF-dependent growth of lung cancer cells in mice. Overall, our data demonstrate that inhibitors of HGF activation, such as ZFH7116 and VD2173, prevent HGF-dependent tumor growth, and overcome HGF-mediated resistance to targeted anti-cancer therapy. As such, they represent a unique way of inhibiting oncogenic HGF/MET signaling. Citation Format: Jorine J.L.P. Voss, Vishnu Damalanka, Matthew Mahoney, Lidija Klampfer, James W. Janetka. Protease inhibitors of HGF activation prevent HGF-dependent tumor progression and overcome resistance to anti-cancer therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO040.
Abstract 17799: Have We Abandoned Therapeutic Hypothermia Prematurely?
Authors: Janet Bray, Jason Bloom, Dion Stub, Louise Segan, Biswadev Mitra, Karen Smith, Judith Finn, Stephen Bernard
Journal: Circulation (2015)

Introduction: Following the recent Targeted Temperature Management (TTM) Trial, many worldwide cardiac arrest centers have adjusted target temperatures from 330C to 360C. The aim of this study was to examine quality of post-arrest care in an expert cardiac center following the adoption of a TTM protocol. Methods: We conducted an audit of consecutive ventricular fibrillation out-of-hospital cardiac arrest (VF-OHCA) patients of presumed cardiac etiology, admitted to a quaternary referral cardiac hospital in Australia. Results: Over the two-year period there were 70 VF-OHCAs admitted (28 before TTM change and 42 after). Patient demographics, arrest features including witnessed arrest, bystander CPR and arrest duration were all similar, between the two periods. Post-arrest care including cardiology consults (93% vs 100%, p=0.15), coronary angiography (79% vs. 76%, p=0.82) and documented orders for TTM were all equivalent. Compliance, however, with temperature management was significantly worse in the 360C period; the average time at target temperature was significantly lower in this time (22hrs vs. 8hrs, p&lt;0.001). 50% of patients recorded temperatures &gt;37.1o in the first 24-hours in the 360C, compared to 0% of patients during the 330C period. Survival to hospital discharge (75% vs 69%, p = 0.59) and rates of discharge to home among (59% vs 45%, p = 0.32) were similar between 330C and 360C periods. After adjustment for arrest duration, an abnormal temperature (&gt;37.10C) in the first 24hours following hospital admission was associated with hypoxic brain injury (AOR=4.55, 95%CI: 1.08-19.09, p=0.039). Conclusion: Revision of the TTM protocol in an expert cardiac centre was associated with significant non-compliance with target temperatures, leading to increased febrile patients in the post arrest period and possible poorer outcomes.
Circulating clonally expanded T cells reflect functions of tumor-infiltrating T cells
Authors: Liliana E. Lucca, Pierre-Paul Axisa, Benjamin Lu, Brian Harnett, Shlomit Jessel, Le Zhang, Khadir Raddassi, Lin Zhang, Kelly Olino, James Clune, Meromit Singer, Harriet M. Kluger, David A. Hafler
Journal: The Journal of Experimental Medicine (2021)

Understanding the relationship between tumor and peripheral immune environments could allow longitudinal immune monitoring in cancer. Here, we examined whether T cells that share the same TCRαβ and are found in both tumor and blood can be interrogated to gain insight into the ongoing tumor T cell response. Paired transcriptome and TCRαβ repertoire of circulating and tumor-infiltrating T cells were analyzed at the single-cell level from matched tumor and blood from patients with metastatic melanoma. We found that in circulating T cells matching clonally expanded tumor-infiltrating T cells (circulating TILs), gene signatures of effector functions, but not terminal exhaustion, reflect those observed in the tumor. In contrast, features of exhaustion are displayed predominantly by tumor-exclusive T cells. Finally, genes associated with a high degree of blood-tumor TCR sharing were overexpressed in tumor tissue after immunotherapy. These data demonstrate that circulating TILs have unique transcriptional patterns that may have utility for the interrogation of T cell function in cancer immunotherapy.
Glycemic Outcome Associated With Insulin Pump and Glucose Sensor Use in Children and Adolescents With Type 1 Diabetes. Data From the International Pediatric Registry SWEET
Authors: Roque Cardona-Hernandez, Anke Schwandt, Hessa Alkandari, Heiko Bratke, Agata Chobot, Nicole Coles, Sarah Corathers, Damla Goksen, Peter Goss, Zineb Imane, Katrin Nagl, Stephen M.P. O’Riordan, Craig Jefferies
Journal: Diabetes Care (2021)

OBJECTIVE Insulin delivery methods, glucose-monitoring modalities, and related outcomes were examined in a large, international, diverse cohort of children and adolescents with type 1 diabetes from the Better Control in Pediatric and Adolescent Diabetes: Working to Create Centers of Reference (SWEET) -Registry. RESEARCH DESIGN AND METHODS Participants with type 1 diabetes of ≥1 year, aged ≤18 years, and who had documented pump or sensor usage during the period August 2017–July 2019 were stratified into four categories: injections–no sensor (referent); injections + sensor; pump–no sensor; and pump + sensor. HbA1c and proportion of patients with diabetic ketoacidosis (DKA) or severe hypoglycemia (SH) were analyzed; linear and logistic regression models adjusted for demographics, region, and gross domestic product per capita were applied. RESULTS Data of 25,654 participants were analyzed. The proportions of participants (adjusted HbA1c data) by study group were as follows: injections–no sensor group, 37.44% (8.72; 95% CI 8.68–8.75); injections + sensor group, 14.98% (8.30; 95% CI 8.25–8.35); pump–no sensor group, 17.22% (8.07; 95% CI 8.03–8.12); and pump + sensor group, 30.35% (7.81; 95% CI 7.77–7.84). HbA1c was lower in all categories of participants who used a pump and/or sensor compared with the injections–no sensor treatment method (P &amp;lt; 0.001). The proportion of DKA episodes was lower in participants in the pump + sensor (1.98%; 95% CI 1.64–2.48; P &amp;lt; 0.001) and the pump–no sensor (2.02%; 95% CI 1.64–2.48; P &amp;lt; 0.05) groups when compared with those in the injections–no sensor group (2.91%; 95% CI 2.59–3.31). The proportion of participants experiencing SH was lower in pump–no sensor group (1.10%; 95% CI 0.85–1.43; P &amp;lt; 0.001) but higher in the injections + sensor group (4.25%; 95% CI 3.65–4.95; P &amp;lt; 0.001) compared with the injections–no sensor group (2.35%; 95% CI 2.04–2.71). CONCLUSIONS Lower HbA1c and fewer DKA episodes were observed in participants using either a pump or continuous glucose monitoring (CGM) or both. Pump use was associated with a lower rate of SH. Across SWEET centers, use of pumps and CGM is increasing. The concomitant use of pump and CGM was associated with an additive benefit.
Only the best instruments should be used to measure core outcomes
Authors: J. Kottner, J. Schmitt
Journal: British Journal of Dermatology (2021)

Linked Article: van Zuuren et al. Br J Dermatol 2021; 185:36–51. The development and use of Core Outcome Sets (COS) is increasingly recognized as an important aspect to improve the quality and usefulness of clinical trial evidence. In dermatology, several COS have been published or are under development.1 The Cochrane Skin-Core Outcome Set Initiative (CS-COUSIN, http://cs-cousin.org/) supports the development of COS in dermatology and offers guidance and support for COS development groups. Currently, 21 COS groups are affiliated with CS-COUSIN, among them the Acne Core Outcomes Research Network (ACORN). In COS development, the selection and prioritization of critical outcome domains is a crucial first step which is followed by the selection of outcome measurement instruments (OMIs) per domain. Guidance on how to best select core outcome domains is available to support this complex and challenging process.2 However, the appropriate selection of OMIs is at least as challenging as selecting core domains.3 In the last decade substantial advances have been made in COS development in dermatology. High-quality empirical evidence is needed to support OMI development and selection to achieve the overall goal to make trial results comparable and to reduce research waste.10 The current example of ACORN and the review published in this issue of the BJD illustrate that COS development and eventually COS implementation is a long journey, that can succeed only with endurance, strong international cooperation and methodological rigour.
Serum Monocyte-Chemoattractant Protein–1 Could Be an Indicator of Coronary Artery Calcium Score—Reply
Authors: Marios K. Georgakis, Martin Dichgans
Journal: JAMA Cardiology (2021)

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Abstract 64: An Integrated Model for <i>Titin</i> Truncation Mutation Interpretation
Authors: Jun Zou, Diana Tran, Angelo Pelonero, Rahul C Deo
Journal: Circulation Research (2016)

Background: We recently discovered a conserved internal promoter in the Titin gene, which explains why truncating mutations in the C-terminal two thirds of the zebrafish ttna protein result in more severe disease, recapitulating a puzzling observation in human dilated cardiomyopathy (DCM) patients. Here we focus on the contribution of alternative splicing to the DCM phenotype, both in zebrafish Titin truncation mutants and in the context of an integrative model for Titin mutation interpretation. Methods and Results: Using CRISPR/Cas9, we disrupted an alternatively spliced exon in the I-band of Titin , normally present in zebrafish heart but absent in skeletal muscle. The resulting mutants had, on average, a milder cardiac phenotype than those with mutations in constitutive exons but also showed striking inter-sibling variability in disease expression, ranging from intact cardiac blood flow to severe early demise. The mutant exon demonstrated nonsense-altered splicing and disease severity paralleled selective deficiency in Titin transcript level, implying that variability in mutated exon inclusion coupled with nonsense-mediated decay (NMD) modulated phenotype. We next amassed Titin mutation information from 1785 human DCM cases and &gt;68,000 controls to model mutation distribution and found three variance components 1) splicing; 2) internal isoform disruption; and 3) targeting of the C-terminal 2000 amino acids. An integrated model demonstrated strong predictive performance with an area under the receiver operating characteristic curve of 0.79 and correctly identified the highest risk individuals. Conclusions: We conclude that genetically targeted models and large-scale human data can be complementary in overcoming the challenges of genetic data interpretation.
Randomized, Double-Blind Comparison of Half-Dose Versus Full-Dose Edoxaban in 14,014 Patients With Atrial Fibrillation
Authors: Jan Steffel, Christian T. Ruff, Ophelia Yin, Eugene Braunwald, Jeong-Gun Park, Sabina A. Murphy, Stuart Connolly, Elliott M. Antman, Robert P. Giugliano
Journal: Journal of the American College of Cardiology (2021)

In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, the lower dose edoxaban regimen (LDER) and the higher dose edoxaban regimen (HDER) were noninferior to well-managed warfarin for stroke prevention in atrial fibrillation. The objective of the present analysis of the ENGAGE AF TIMI-48 trial was to comprehensively compare the net clinical outcome (NCO) of LDER (30 mg once daily, dose reduced to 15 mg in selective patients) versus HDER (60 mg once daily, dose reduced to 30 mg in selective patients). This study performed a pre-specified analysis of the ENGAGE AF-TIMI 48 trial, comparing patients on LDER versus HDER. The pre-defined primary NCO (stroke/systemic embolism [SEE], major bleeding, death) was less frequent with LDER (7.26% vs. 8.01%; hazard ratio: 0.90; 95% confidence interval: 0.84 to 0.98; p = 0.014). The secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) and tertiary pre-defined NCOs (stroke, SEE, life-threatening bleeding, or all-cause mortality) were similar between the 2 dosing regimens. Patients randomized to LDER versus HDER had a significantly higher risk of stroke/SEE (2.04% vs. 1.56%; hazard ratio: 1.31; 95% confidence interval: 1.12 to 1.52; p < 0.001). Conversely, major bleeding, intracranial hemorrhage, major gastrointestinal bleeding, and life-threatening bleeding occurred significantly less frequently with LDER compared with those of HDER. These findings were supported by multiple pharmacokinetic findings. In the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the 2 dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation. (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48]; NCT00781391)
Arginine is a key player in fibroblasts during the course of IPF development
Authors: Yi Wang, Jianping Zhao, Huilan Zhang, Cong-Yi Wang
Journal: Molecular Therapy (2021)

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by the activation of invasive fibroblasts, which are involved in the uncontrolled production and deposition of extracellular matrix (ECM) in the lung parenchyma. No therapeutic approach is, thus far, available to halt or reverse the process of IPF, although nintedanib and pirfenidone, two US Food and Drug Administration (FDA)-approved drugs, have shown that it is possible to slow the decline of lung function without a noticeable effect upon overall mortality.
gapseq: informed prediction of bacterial metabolic pathways and reconstruction of accurate metabolic models
Authors: Johannes Zimmermann, Christoph Kaleta, Silvio Waschina
Journal: Genome biology (2021)

Genome-scale metabolic models of microorganisms are powerful frameworks to predict phenotypes from an organism's genotype. While manual reconstructions are laborious, automated reconstructions often fail to recapitulate known metabolic processes. Here we present gapseq ( https://github.com/jotech/gapseq ), a new tool to predict metabolic pathways and automatically reconstruct microbial metabolic models using a curated reaction database and a novel gap-filling algorithm. On the basis of scientific literature and experimental data for 14,931 bacterial phenotypes, we demonstrate that gapseq outperforms state-of-the-art tools in predicting enzyme activity, carbon source utilisation, fermentation products, and metabolic interactions within microbial communities.
Tumor Microenvironment Triggered Cascade‐Activation Nanoplatform for Synergistic and Precise Treatment of Hepatocellular Carcinoma
Authors: Fuli Xin, Ming Wu, Zhixiong Cai, Xiaolong Zhang, Zuwu Wei, Xiaolong Liu, Jingfeng Liu
Journal: Advanced Healthcare Materials (2021)

Abstract Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancy cancers, which remains a major global health problem. At present, over 50% of patients with HCC have implemented systemic therapies, such as interventional therapy or local chemotherapy that are scarcely effective and induce serious side effects to the remaining normal liver, further limiting their clinical outcomes. Herein, a tumor microenvironment triggered cascade‐activation nanoplatform (A‐NP Lap/TPZ ) is prepared based on β ‐lapachone ( β ‐Lap) and tirapazamine (TPZ) for the synergistic therapy of HCC. The A‐NP Lap/TPZ exerts its targeting effect by binding to the receptor of tumor cells with an external aptamer. In the tumor microenvironment, the nanoplatform can realize H 2 O 2 ‐triggered disassembly to release β ‐Lap and TPZ. The released β ‐Lap generates ROS to induce tumor cell apoptosis under the catalysis of the tumor cell over‐expressed NAD(P)H‐quinone oxidoreductase‐1 (NQO1) enzyme. In this process, oxygen is consumed to intensify tumor hypoxia, and eventually cascade activates TPZ to exert the anti‐tumor effect. The studies in vitro and in vivo consistently demonstrate that the as‐prepared A‐NP Lap/TPZ nanoplatform possesses an excellent synergistic anti‐tumor effect. This design of nanoplatform with cascade activation effect provides a promising strategy for HCC treatment.
A novel method of papilla fixation for difficult biliary cannulation without using a pancreatic duct guidewire: non-guidewire fixation method
Authors: Mamoru Takenaka, Koichiro Kawano, Reiko Kawano, Takao Katoh, Katsuhisa Nishi, Masatoshi Kudo
Journal: Endoscopy (2021)

Biliary cannulation in patients with periampullary diverticula is challenging due to high mobility and an unusual orientation of the papilla. Although papilla fixation using a pancreatic duct guidewire (PGW) has been performed in such cases, the procedure requires the placement of a guidewire in the pancreatic duct and takes times [1] [2] [3] [4] ([Fig. 1]). The risk of PGW-induced postoperative pancreatitis has also been reported [5]. To overcome these challenges, we developed a novel method for difficult biliary cannulation without using a PGW, involving papilla fixation with a unique double-lumen catheter