tbuckley/cabot-search huggingface dataset:
Abstract PS11-22: Lipophilic statins for prolonging dormancy and overall survival: A real-world retrospective investigation
Authors: Juan Luis Gomez Marti, Alan Wells
Journal: Cancer Research (2021)

Abstract Background: Micrometastases from breast cancer (BC) might undergo quiescence following adjuvant therapies. Oftentimes they reactivate, prompting metastatic relapse and aggressive, uncurable disease. It is necessary to find alternative, safe therapies that could be used as adjuvants for delaying the dormancy process and reduce metastatic breast cancer (MBC) progression. Prior epidemiological studies found prolonged overall survival from chronic statin use. However, the effectiveness of statin use through different stages of progression, including advanced MBC, has not yet been defined. Methods: A real-world, retrospective analysis of 1,016 deceased patients with MBC treated from 1999-2019 at the University of Pittsburgh Medical Center (UPMC). Lipophilic statin (atorvastatin and simvastatin) use and dosing were retrieved from medical records through an IRB-approved R3 request and merged with already available clinical variables. A total of 122 patients were included in the analysis as the statin use group. This included patients who were prescribed statins through the course of their breast cancer. For measuring time to relapse, only patients with statin prescription before being diagnosed with MBC were selected. Log-ranks were used to compute survival. Uni- and multi-variate Cox hazard models were also applied. Statistical analysis was computed using the package ggpubr on R v3.6.3.Results: Women who used statins were older at the time of detection of primary (60 vs 52 years of age, respectively) and MBC (66 vs 56 years of age, respectively). An almost 2-fold reduction was found in the onset of liver metastasis as first relapse in the statin group, compared to general population (5.7% vs 10.4%, respectively). Increased overall survival (OS) was found among statin users who had ER (+) (p&amp;lt;0.05), and HER2 (-) (p&amp;lt;0.05) BC. Statins were associated with an increase in time from diagnosis until relapse, in ER (+) (p=0.03) and HER2(-) (p=0.02) patients with BC. Patients with ER (-), HER2 (-) MBC also seemed to partially benefit from statin use (p=0.09). Multivariate analysis adjusted for age, ER-status, statin use, and adjuvant chemotherapy also predicted increased OS for patients using statins. No differences in survival were seen when measuring time from metastatic diagnosis to death, suggesting that statins may be effective in prolonging dormancy but lack benefit against relapsing MBC.Conclusion: Lipophilic statins may prolong dormancy and overall survival but not slow the progression of relapsing metastatic breast cancer. Citation Format: Juan Luis Gomez Marti, Alan Wells. Lipophilic statins for prolonging dormancy and overall survival: A real-world retrospective investigation [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-22.
Adenylosuccinate lyase is oncogenic in colorectal cancer by causing mitochondrial dysfunction and independent activation of NRF2 and mTOR-MYC-axis
Authors: Stephanie Taha-Mehlitz, Gaia Bianco, Mairene Coto-Llerena, Venkatesh Kancherla, Glenn R. Bantug, John Gallon, Caner Ercan, Federica Panebianco, Serenella Eppenberger-Castori, Marco von Strauss, Sebastian Staubli, Martin Bolli, Ralph Peterli, Matthias S. Matter, Luigi M. Terracciano, Markus von Flüe, Charlotte K.Y. Ng, Savas D Soysal, Otto Kollmar, Salvatore Piscuoglio
Journal: Theranostics (2021)

Rationale: Adenylosuccinate lyase (ADSL) is an essential enzyme for de novo purine biosynthesis. Here we sought to investigate the putative role of ADSL in colorectal carcinoma (CRC) carcinogenesis and response to antimetabolites. Methods: ADSL expression levels were assessed by immunohistochemistry or retrieved from The Cancer Genome Atlas (TCGA) dataset. The effects of ADSL silencing or overexpression were evaluated on CRC cell proliferation, cell migration and cell-cycle. In vivo tumor growth was assessed by the chicken chorioallantoic membrane (CAM). Transfected cell lines or patient-derived organoids (PDO) were treated with 5-fluorouracil (5-FU) and 6-mercaptopurine (6-MP) and drug response was correlated with ADSL expression levels. Metabolomic and transcriptomic profiling were performed to identify dysregulated pathways and ADSL downstream effectors. Mitochondrial respiration and glycolytic capacity were measured using Seahorse; mitochondrial membrane potential and the accumulation of ROS were measured by FACS using MitoTracker Red and MitoSOX staining, respectively. Activation of canonical pathways was assessed by immunohistochemistry and immunoblotting. Results: ADSL expression is significantly increased in CRC tumors compared to non-tumor tissue. ADSL-high CRCs show upregulation of genes involved in DNA synthesis, DNA repair and cell cycle. Accordingly, ADSL overexpression accelerated progression through the cell cycle and significantly increased proliferation and migration in CRC cell lines. Additionally, ADSL expression increased tumor growth in vivo and sensitized CRCs to 6-MP in vitro, ex vivo (PDOs) and in vivo (CAM model). ADSL exerts its oncogenic function by affecting mitochondrial function via alteration of the TCA cycle and impairment of mitochondrial respiration. The KEAP1-NRF2 and mTORC1-cMyc axis are independently activated upon ADSL overexpression and may favor the survival and proliferation of ROS-accumulating cells, favoring DNA damage and tumorigenesis. Conclusions: Our results suggest that ADSL is a novel oncogene in CRC, modulating mitochondrial function, metabolism and oxidative stress, thus promoting cell cycle progression, proliferation and migration. Our results also suggest that ADSL is a predictive biomarker of response to 6-mercaptopurine in the pre-clinical setting.
Pre-flight exercise and bone metabolism predict unloading-induced bone loss due to spaceflight
Authors: Leigh Gabel, Anna-Maria Liphardt, Paul A Hulme, Martina Heer, Sara R Zwart, Jean D Sibonga, Scott M Smith, Steven K Boyd
Journal: British Journal of Sports Medicine (2021)

Bone loss remains a primary health concern for astronauts, despite in-flight exercise. We examined changes in bone microarchitecture, density and strength before and after long-duration spaceflight in relation to biochemical markers of bone turnover and exercise.Seventeen astronauts had their distal tibiae and radii imaged before and after space missions to the International Space Station using high-resolution peripheral quantitative CT. We estimated bone strength using finite element analysis and acquired blood and urine biochemical markers of bone turnover before, during and after spaceflight. Pre-flight exercise history and in-flight exercise logs were obtained. Mixed effects models examined changes in bone and biochemical variables and their relationship with mission duration and exercise.At the distal tibia, median cumulative losses after spaceflight were -2.9% to -4.3% for bone strength and total volumetric bone mineral density (vBMD) and -0.8% to -2.6% for trabecular vBMD, bone volume fraction, thickness and cortical vBMD. Mission duration (range 3.5-7 months) significantly predicted bone loss and crewmembers with higher concentrations of biomarkers of bone turnover before spaceflight experienced greater losses in tibia bone strength and density. Lower body resistance training volume (repetitions per week) increased 3-6 times in-flight compared with pre-spaceflight. Increases in training volume predicted preservation of tibia bone strength and trabecular vBMD and thickness.Findings highlight the fundamental relationship between mission duration and bone loss. Pre-flight markers of bone turnover and exercise history may identify crewmembers at greatest risk of bone loss due to unloading and may focus preventative measures.
Correspondence on ‘Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry’
Authors: Laurent Arnaud, Hervé Devilliers
Journal: Annals of the Rheumatic Diseases (2021)

We read with great interest the recent paper “Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry” published in the Annals by Strangfeld et al .1

Given the current epidemiological situation, all evidence indicate that the best option for preventing both morbidity and mortality in the initial phase of the COVID-19 vaccination programme is to directly protect persons who are most at risk. Based on the author’s findings,1 and previously published data,2 not all patients with rheumatic disease are at increased risk of severe COVID-19 and COVID-19-related …
Abstract 17167: Outcomes Of Laser Lead Extraction In Patients With Structural Congenital Heart Disease: A Single-center Experience
Authors: Harris U Onugha, Adryan Perez, Darren Tsang, Roger G Carrillo
Journal: Circulation (2019)

Outcomes of Laser Lead Extraction in Patients with Structural Congenital Heart Disease: A Single-Center Experience Background: Patients with congenital heart disease are at increased risk for intra...
REDUCED SURVIVAL POST-ENDOSCOPY FOR UPPER GASTROINTESTINAL BLEEDING IN THE COVID-19 ERA IS A SECONDARY EFFECT OF THE RESPONSE TO THE GLOBAL PANDEMIC
Authors: O. Tavabie, J. Clough, J. Blackwell, M. Bashyam, H. Martin, A. Soubieres, N. Direkze, D. Graham, C. Groves, S. Preston, S. DeMartino, U. Gill, B. Hayee, D. Joshi
Journal: Gut (2020)
A Uniform Computational Approach Improved on Existing Pipelines to Reveal Microbiome Biomarkers of Nonresponse to Immune Checkpoint Inhibitors
Authors: Fyza Y. Shaikh, James R. White, Joell J. Gills, Taiki Hakozaki, Corentin Richard, Bertrand Routy, Yusuke Okuma, Mykhaylo Usyk, Abhishek Pandey, Jeffrey S. Weber, Jiyoung Ahn, Evan J. Lipson, Jarushka Naidoo, Drew M. Pardoll, Cynthia L. Sears
Journal: Clinical Cancer Research (2021)

Abstract Purpose: While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%–30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations. Experimental Design: We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n = 303 unique patients) using a uniform computational approach. Results: Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (P &amp;lt; 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (n = 105). Conclusions: Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.
Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity
Authors: Yuzhu Hou, Hua L. Liang, Xinshuang Yu, Zhida Liu, Xuezhi Cao, Enyu Rao, Xiaona Huang, Liangliang Wang, Lei Li, Jason Bugno, Yanbin Fu, Steven J. Chmura, Wenjun Wu, Sean Z. Luo, Wenxin Zheng, Ainhoa Arina, Jessica Jutzy, Anne R. McCall, Everett E. Vokes, Sean P. Pitroda, Yang-Xin Fu, Ralph R. Weichselbaum
Journal: Science Translational Medicine (2021)

Tumor-induced CD45-Ter119+CD71+ erythroid progenitor cells, termed "Ter cells," promote tumor progression by secreting artemin (ARTN), a neurotrophic peptide that activates REarranged during Transfection (RET) signaling. We demonstrate that both local tumor ionizing radiation (IR) and anti-programmed death ligand 1 (PD-L1) treatment decreased tumor-induced Ter cell abundance in the mouse spleen and ARTN secretion outside the irradiation field in an interferon- and CD8+ T cell-dependent manner. Recombinant erythropoietin promoted resistance to radiotherapy or anti-PD-L1 therapies by restoring Ter cell numbers and serum ARTN concentration. Blockade of ARTN or potential ARTN signaling partners, or depletion of Ter cells augmented the antitumor effects of both IR and anti-PD-L1 therapies in mice. Analysis of samples from patients who received radioimmunotherapy demonstrated that IR-mediated reduction of Ter cells, ARTN, and GFRα3, an ARTN signaling partner, were each associated with tumor regression. Patients with melanoma who received immunotherapy exhibited favorable outcomes associated with decreased expression of GFRα3. These findings demonstrate an out-of-field, or "abscopal," effect mediated by adaptive immunity, which is induced during local tumor irradiation. This effect, in turn, governs the therapeutic effects of radiation and immunotherapy. Therefore, our results identify multiple targets to potentially improve outcomes after radiotherapy and immunotherapy.
Abstract PS19-23: Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer
Authors: Ai Amioka, Takayuki Kadoya, Satoshi Sueoka, Yoshie Kobayashi, Shinsuke Sasada, Akiko Emi, Norio Masumoto, Masaoki Ito, Morihito Okada
Journal: Cancer Research (2021)

Abstract Purpose: We previously showed that Wnt5a-positive breast cancer belongs to a subgroup of estrogen receptor (ER)-positive breast cancers and its prognosis is worse than that of Wnt5a-negative breast cancer. In this study, we aimed to investigate the molecular mechanisms underlying the poor prognosis of patients with Wnt5a-positive breast cancer.Methods: A total of 151 patients with ER-positive invasive breast cancer were recruited for this study between January 2011 and February 2014. The association between Wnt5a expression and recurrence rate was examined. To identify the pathways associated with Wnt5a-positive breast cancer, we established a Wnt5a-expressing cell line (MCF-7/Wnt5a cells) and conducted DNA microarray analysis of MCF-7/Wnt5a cells. We also performed pathway analysis associated with Wnt5a expression, and evaluated the effects of Wnt5a in vitro using MCF-7/Wnt5a cells.Results: Data showed poorer relapse-free survival of patients with Wnt5a-positive breast cancer (P = 0.047). The median length of follow-up was 6.08 years (range, 0.027 to 8.47 years) for all patients. According to DNA microarray data, only the cytochrome P450 (CYP) pathway was significantly upregulated and related with Wnt5a (P = 0.0440). Moreover, MCF-7/Wnt5a cells were less sensitive to tamoxifen and paclitaxel, which are metabolic substrates of CYP (P &amp;lt; 0.05). Although the PI3K-AKT-mTOR signaling pathway is involved in the poor prognosis of ER-positive breast cancer, it was not associated with Wnt5a.Conclusions: In ER-positive breast cancer, Wnt5a expression upregulated the CYP metabolic pathway and decreased the sensitivity to tamoxifen and paclitaxel, the standard treatment options for ER-positive breast cancer. Citation Format: Ai Amioka, Takayuki Kadoya, Satoshi Sueoka, Yoshie Kobayashi, Shinsuke Sasada, Akiko Emi, Norio Masumoto, Masaoki Ito, Morihito Okada. Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-23.
Labour market position of young people and premature mortality in adult life: A 26-year follow-up of 569 528 Swedish 18 year-olds
Authors: Nora Döring, Michael Lundberg, Christina Dalman, Tomas Hemmingsson, Finn Rasmussen, Alma Sörberg Wallin, Susanne Wicks, Cecilia Magnusson, Anton Lager
Journal: The Lancet Regional Health - Europe (2021)

Throughout the industrialized world, demand for low skilled labour is falling. The length of schooling is increasing in response, but so is the proportion of individuals not finishing upper secondary school. The objective of this study was to evaluate the associations between labour market positions at age 18 and all-cause and suicide- and accident-specific mortality in later adulthood.Labour market positions at age 18 were categorized for all Swedes born 1972-77 (n=630 959) into four main groups: employed, successful students, students not about to qualify (SNAQs), and individuals not in employment, education or training (NEETs). Cox proportional hazard models were fitted to assess all-cause, suicide and accident mortality up to 2016 (ages 39-44), adjusting for high school grades, parental and own prior psychiatric diagnoses, and childhood socioeconomic status.SNAQs had substantially increased all-cause (men: HR=2.10; 95% CI 1.92-2.28, women: HR=1.64; 95% CI: 1.44-1.86), suicide (men: HR=2.16; CI: 1.86-2.51, women: HR=2.10; 95% CI 1.64-2.69), and accident specific (men: HR=2.08; 95% CI 1.77-2.44, women: 1.87; 95% CI 1.33;2.62) mortality risks compared to successful students. The risks were similar for NEETs. There was no increased risk among full-time employed compared to successful students.Expanding the educational system may be a natural response to falling demand for low skilled labour but not by far one that corrects the major societal challenge of it. Unless educational systems adequately respond to this challenge, only more inequality is to be expected ahead.This work was supported by a grant to FR and AL from the Swedish Research Council for Health, Working Life, and Welfare with contract number (2014-2009).
Copenhagen adduction exercise can increase eccentric strength and mitigate the risk of groin problems: but how much is enough!
Authors: Lasse Ishøi, Kristian Thorborg
Journal: British Journal of Sports Medicine (2021)

<h3>ABSTRACT</h3> Optimising the scale and deployment of community health workers (CHWs) is important for maximizing geographical accessibility of integrated primary health care (PHC) services. Yet little is known about approaches for doing so. We used geospatial analysis to model optimised scale-up and deployment of CHWs in Mali, to inform strategic and operational planning by the Ministry of Health and Social Development. Accessibility catchments were modelled based on travel time, accounting for barriers to movement. We compared geographic coverage of the estimated population, under-five deaths, and plasmodium falciparum (<i>Pf</i>) malaria cases across different hypothetical optimised CHW networks and identified surpluses and deficits of CHWs compared to the existing CHW network. A network of 15843 CHW, if optimally deployed, would ensure that 77.3% of the population beyond 5 km of the CSCom (community health centre) and CSRef (referral health facility) network would be within a 30-minute walk of a CHW. The same network would cover an estimated 59.5% of U5 deaths and 58.5% of <i>Pf</i> malaria cases. As an intermediary step, an optimised network of 4500 CHW, primarily filling deficits of CHW in the regions of Kayes, Koulikoro, Sikasso, and Ségou would ensure geographic coverage for 31.3% of the estimated population. There were no important differences in geographic coverage percentage when prioritizing CHW scale-up and deployment based on the estimated population, U5 deaths, or <i>Pf</i> malaria cases. Our geospatial analysis provides useful information to policymakers and planners in Mali for optimising the scale-up and deployment of CHW and, in turn, for maximizing the value-for-money of resources of investment in CHWs in the context of the country's health sector reform. Countries with similar interests in optimising the scale and deployment of their CHW workforce may look to Mali as an exemplar model from which to learn.
Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy
Authors: Nina M. Muñoz, Malea Williams, Katherine Dixon, Crystal Dupuis, Amanda McWatters, Rony Avritscher, Soraya Zorro Manrique, Kevin McHugh, Ravi Murthy, Alda Tam, Aung Naing, Sapna P. Patel, David Leach, Jeffrey D. Hartgerink, Simon Young, Punit Prakash, Patrick Hwu, Rahul A. Sheth
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Intratumoral delivery of immunotherapeutics represents a compelling solution to directly address local barriers to tumor immunity. However, we have previously shown that off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy and systemic toxicities. We have identified three variables that influence intratumoral drug delivery: injection technique, drug formulation and tumor microenvironment. The purpose of this study was to characterize the impact of modifications in each variable on intratumoral drug delivery and immunotherapy efficacy. Methods Intratumoral injections were performed in a hybrid image-guided intervention suite with ultrasound, fluoroscopy and CT scanning capabilities in both rat and mouse syngeneic tumor models. Intratumoral drug distribution was quantified by CT volumetric imaging. The influence of varying needle design and hydrogel-based drug delivery on the immune response to a stimulator of interferon genes (STING) agonist was evaluated using flow cytometry and single cell RNA sequencing. We also evaluated the influence of tumor stiffness on drug injection distribution. Results Variations in needle design, specifically with the use of a multiside hole needle, led to approximately threefold improvements in intratumoral drug deposition relative to conventional end-hole needles. Likewise, delivery of a STING agonist through a multiside hole needle led to significantly increased expression of type I interferon-associated genes and ‘inflammatory’ dendritic cell gene signatures relative to end-hole STING agonist delivery. A multidomain peptide-based hydrogel embedded with a STING agonist led to substantial improvements in intratumoral deposition; however, the hydrogel was noted to generate a strong immune response against itself within the target tumor. Evaluation of tumor stroma on intratumoral drug delivery revealed that there was a greater than twofold improvement in intratumoral distribution in soft tumors (B16 melanoma) compared with firm tumors (MC38 colorectal). Conclusions Injection technique, drug formulation and tumor stiffness play key roles in the accurate delivery of intratumoral immunotherapeutics.