tbuckley/cabot-search huggingface dataset:
Deficit Accumulation Frailty Trajectories of Older Breast Cancer Survivors and Non-Cancer Controls: The Thinking and Living With Cancer Study
Authors: Jeanne S Mandelblatt, Xingtao Zhou, Brent J Small, Jaeil Ahn, Wanting Zhai, Tim Ahles, Martine Extermann, Deena Graham, Paul B Jacobsen, Heather Jim, Brenna C McDonald, Sunita J Patel, James C Root, Andrew J Saykin, Harvey Jay Cohen, Judith E Carroll
Journal: JNCI Journal of the National Cancer Institute (2021)

We evaluated deficit accumulation and how deficits affected cognition and physical activity among breast cancer survivors and non-cancer controls.Newly diagnosed nonmetastatic survivors (n = 353) and matched non-cancer controls (n = 355) ages 60-98 years without neurological impairments were assessed presystemic therapy (or at enrollment for controls) from August 2010 to December 2016 and followed for 36 months. Scores on a 42-item index were analyzed in growth-mixture models to determine deficit accumulation trajectories separately and combined for survivors and controls. Multilevel models tested associations between trajectory and cognition (FACT-Cog and neuropsychological tests) and physical activity (IPAQ-SF) for survivors and controls.Deficit accumulation scores were in the robust range, but survivors had higher scores (95% confidence intervals [CI]) than controls at 36 months (0.18, 95% CI = 0.16 to 0.19, vs 0.16, 95% CI = 0.14 to 0.17; P = .001), and averages included diverse deficit trajectories. Survivors who were robust but became frailer (8.8%) had similar baseline characteristics to those remaining robust (76.2%) but experienced a 9.6-point decline self-reported cognition (decline of 9.6 vs 3.2 points; P = .04) and a 769 MET minutes per week decline in physical activity (P < .001). Survivors who started and remained prefrail (15.0%) had self-reported and objective cognitive problems. At baseline, frail controls (9.5%) differed from robust controls (83.7%) on deficits and self-reported cognition (P < .001). Within combined trajectories, frail survivors had more sleep disturbances than frail controls (48.6% [SD = 17.4%] vs 25.0% [SD = 8.2%]; P = .05).Most survivors and controls remained robust, and there were similar proportions on a frail trajectory. However, there were differences in deficit patterns between survivors and controls. Survivor deficit accumulation trajectory was associated with patient-reported outcomes. Additional research is needed to understand how breast cancer and its treatments affect deficit accumulation.
Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer
Authors: Chao Liu, Ruiqi Liu, Bojun Wang, Jie Lian, Yang Yao, Haoxiu Sun, Chunhui Zhang, Lin Fang, Xin Guan, Jiaqi Shi, Shuling Han, Fei Zhan, Shengnan Luo, Yuanfei Yao, Tongsen Zheng, Yanqiao Zhang
Journal: Journal for ImmunoTherapy of Cancer (2021)

Immune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflammatory mediators, mobilize myeloid cells and reshape the tumor environment. In the present study, we aimed to investigate the role of IL-17A in resistance to antitumor immunity and to explore the feasibility of anti-IL-17A combined with anti-PD-1 therapy in MSS CRC murine models.The expression of programmed cell death-ligand 1 (PD-L1) and its regulation by miR-15b-5p were investigated in MSS CRC cell lines and tissues. The effects of miR-15b-5p on tumorigenesis and anti-PD-1 treatment sensitivity were verified both in vitro and in colitis-associated cancer (CAC) and APCmin/+ murine models. In vivo efficacy and mechanistic studies were conducted using antibodies targeting IL-17A and PD-1 in mice bearing subcutaneous CT26 and MC38 tumors.Evaluation of clinical pathological specimens confirmed that PD-L1 mRNA levels are associated with CD8+ T cell infiltration and better prognosis. miR-15b-5p was found to downregulate the expression of PD-L1 at the protein level, inhibit tumorigenesis and enhance anti-PD-1 sensitivity in CAC and APCmin/+ CRC models. IL-17A led to high PD-L1 expression in CRC cells through regulating the P65/NRF1/miR-15b-5p axis. Combined IL-17A and PD-1 blockade had efficacy in CT26 and MC38 tumors, with more cytotoxic T lymphocytes cells and fewer myeloid-derived suppressor cells in tumors.IL-17A increases PD-L1 expression through the p65/NRF1/miR-15b-5p axis and promotes resistance to anti-PD-1 therapy. Blocking IL-17A improved the efficacy of anti-PD-1 therapy in MSS CRC murine models. IL-17A might serve as a therapeutic target to sensitize patients with MSS CRC to ICI therapy.
3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer
Authors: Barrie Peck, Philip Bland, Ioanna Mavrommati, Gareth Muirhead, Hannah Cottom, Patty T. Wai, Sarah L. Maguire, Holly E. Barker, Eamonn Morrison, Divya Kriplani, Lu Yu, Amy Gibson, Giulia Falgari, Keith Brennan, Gillian Farnie, Richard Buus, Rebecca Marlow, Daniela Novo, Eleanor Knight, Naomi Guppy, Daniela Kolarevic, Snezana Susnjar, Natasa Medic Milijic, Kalnisha Naidoo, Patrycja Gazinska, Ioannis Roxanis, Sunil Pancholi, Lesley-Ann Martin, Erle M. Holgersen, Maggie C.U. Cheang, Farzana Noor, Sophie Postel-Vinay, Gerard Quinn, Simon McDade, Lukas Krasny, Paul Huang, Frances Daley, Fredrik Wallberg, Jyoti S. Choudhary, Syed Haider, Andrew N. Tutt, Rachael Natrajan
Journal: Cancer Research (2021)

Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model
Targeted therapies in cholangiocarcinoma: Assessment of US oncologist practice patterns.
Authors: Kinjal Parikh, Davecia Ragoonath Cameron, Tristin Abair, Patrick Kugel, Arndt Vogel
Journal: Journal of Clinical Oncology (2021)

347 Background: Chemotherapy is a mainstay treatment modality for patients with advanced cholangiocarcinoma (CCA). Recent developments and new approvals have led to changing paradigms, incorporating the use of targeted therapies for patients with progressive disease. Given the need for a greater understanding of the molecular alterations, varying targets, and available and emerging therapies, education is needed to assess knowledge regarding these recent advances in unresectable CCA. The goal of this activity was to increase the knowledge of self-assess the learning needs of oncologists in treating patients with unresectable CCA. Methods: The education included 25 multiple choice questions in a continuing medical education (CME)-certified clinical practice assessment to assess practice gaps. The questions were designed to measure knowledge, competence, confidence, and attitudes of oncologists regarding clinical evidence, role of molecular testing, and place in the treatment paradigm for targeted therapies in unresectable CCA. The self-assessment was made available online to physicians as a learning tool to gain foundational knowledge, as well as receive feedback about their performance as compared to other test-takers, to improve self-awareness of their own personal educational gaps. The activity launched 6/24/20, and data are reported through 8/31/20. Results: A total of 1,009 learners, including 758 physicians, participated in the activity. Of the 104 oncologists that participated, a majority practiced in the community setting, saw patients with a range of cancers, and were not confident about using targeted therapies or recognizing targets for biomarker testing. Oncologists demonstrated the following gaps related to: NGS sequencing and biomarkers: 21% do not use; 32% use upon progressive disease; 35% did not realize that not all panels detect FGFR2 fusions; 20% do not test for biomarkers; 29% and 56% test for IDH or FGFR, respectively; 60% recognize the incidence of IDH1 mutations; Clinical trial (FIGHT202 and ClarIDHy): 45% were able to identify biomarker eligibility for pemigatinib; 9% were able to identify pemigatinib OS outcomes; 30% were able to recognize most common grade 3 AE of pemigatinib; 51% recognized the PFS endpoint with ivosidenib; 34% were able to identify eligibility for ivosidenib; 55% recognized most common AEs of ivosidenib. Conclusions: This CME-certified clinical practice assessment identified gaps in knowledge, competence, and confidence regarding testing and use of targeted therapies and emerging data in patients with unresectable CCA. As new data emerges and the number of targets and targeted therapies expand, continued education remains important to continue to optimize patient care.
Phase I Trial of DNA Methyltransferase Inhibitor Guadecitabine Combined with Cisplatin and Gemcitabine for Solid Malignancies Including Urothelial Carcinoma (SPIRE)
Authors: Simon J. Crabb, Sarah Danson, James W.F. Catto, Syed Hussain, Danna Chan, Denise Dunkley, Nichola Downs, Ellice Marwood, Laura Day, Geoff Saunders, Michelle Light, Amy Whitehead, Deborah Ellis, Naveed Sarwar, Deborah Enting, Alison Birtle, Bernadette Johnson, Robert Huddart, Gareth Griffiths
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers. Patient and Methods: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2–4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1–5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228. Results: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1–5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred. Conclusions: The guadecitabine RP2D was 20 mg/m2, days 1–5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.
Solidarity and universal preparedness for health after covid-19
Authors: Göran Tomson, Sara Causevic, Ole Petter Ottersen, Stefan Swartling Peterson, Sabina Rashid, Rhoda Kitti Wanyenze, Alicia Ely Yamin
Journal: BMJ (2021)

<b>Göran Tomson and colleagues</b> argue that our ability to control pandemics requires global action to counter inequalities from demographic, environmental, technological, and other megatrends
Change in Reported Adherence to Nonpharmaceutical Interventions During the COVID-19 Pandemic, April-November 2020
Authors: Matthew A. Crane, Kenneth M. Shermock, Saad B. Omer, John A. Romley
Journal: JAMA (2021)

This study uses national survey data to describe overall and regional trends in adherence to protective behaviors (mask wearing, physical distancing, staying at home, others) among US adults during the COVID-19 pandemic from April to November 2020.
FDG-Avid Erythema Nodosum Lesions of Behçet Disease Demonstrated on FDG PET/CT
Authors: Selin Kesim, Salih Ozguven, Tunc Ones, Halil Turgut Turoglu, Tanju Yusuf Erdil
Journal: Clinical Nuclear Medicine (2021)

Behçet disease is a rare multisystemic vasculitis that can affect all sizes and types of blood vessels. Recurrent painful erythematous nodular lesions called erythema nodosum are the most common skin lesions of Behçet disease. Herein, we present 18F-FDG PET/CT images of erythema nodosum lesions in a patient with Behçet disease.
FRI0540 DIFFERENT ASSOCIATION BETWEEN BONE MINERAL DENSITY AND OSTEOARTHRITIS ACCORDING TO THE SITE OF OSTEOARTHRITIS
Authors: J. Lee, Y. Eun, I. Y. Kim, S. Y. Kang, S. Lee, H. S. Cha, E. M. Koh, H. Kim
Journal: Annals of the Rheumatic Diseases (2020)

Background: Osteoarthritis (OA) and osteoporosis (OP) are both high prevalence at old age, and there are various reports on the association between the two diseases. Some studies have shown that high bone mineral density (BMD) is a risk factor for OA incidence, while others have mentioned the possibility of OP contributing to onset of hip OA. Recent study described that higher BMD reduce the risk of hip OA and raise the risk of knee OA. So, the relationship between BMD and OA or the effects of BMD on different OA site are not clear yet. Objectives: In this study, we investigated the association between BMD and radiographic OA using representative sample data of Korean adults. Methods: The study included 6345 subjects aged 50 years or older who underwent BMD measurements using dual-energy X-ray absorptiometry and X-rays of at least one site of the spine, hip, and knee in the Korean National Health and Nutrition Examination Survey conducted in 2010-2011. OA was defined according to radiographic finding (KL grade ≥ 2). Weighted multivariable logistic regression was used to analyze the association between BMD and OA. Since gender differences are evident, men and women were analyzed separately. Results: Spine OA was about 60% in both men and women, and hip OA was about 35% in men but only 1% in women. Knee OA was 76% in women and 58% in men. In men, the risk of OA increased 1.24 times as BMD increased by 1 g/cm 2 . By site, knee and spine OA were statistically significant in relation to BMD, but hip OA was not statistically significant. In women, the association between BMD and knee and hip OA was insignificant. In spine OA, the risk of OA increased 1.2 times when BMD increased by 1 g/cm 2 . Conclusion: In conclusion, high BMD increased the risk of knee and spine OA in men, but did not affect hip OA. In women, high BMD increased the risk of spine OA. Differences in the mechanism of OA development by site are thought to be possible explanations for the differences in the association between BMD and OA. Disclosure of Interests: None declared
Mass screening for chronic hepatitis B: A population health registry approach
Authors: S. Grandhe, I. Martinez, S. MacDonald, K. Slapnik, E. Chak
Journal: Hepatology (2020)

Background: Screening and linkage to care for patients living with chronic hepatitis B (CHB) is suboptimal Electronic health record-based tools allow identification of at-risk populations and for action to be taken for many patients at once We designed processes for mass screening via bulk lab ordering and bulk patient messaging which may be used to screen for CHB and alert patients of their need for testing simultaneously Methods: We piloted a hepatitis B (HBV) screening program at a single family medicine clinic We created a population registry of Asian patients at risk, but never tested for CHB based on surname, ethnicity, and primary language (Group 1) Healthy Planet (HP) is an electronic population management module from Epic Systems (Epic Systems Corporation, Verona, WI) Using HP, we placed bulk orders for hepatitis B surface antigen (HBsAg), hepatitis B core antibody total, and hepatitis B surface antibody for at risk patients (“opt-out” screening) To prompt patients to present to the laboratory, electronic messages were sent to patients using an electronic patient portal Depending on the results of the blood tests, patients were placed into 2 other groups: HBsAg positive (Group 2) or HBsAg negative (Group 3) (see Image) For HBsAg positive patients, a patient navigator was used to order follow up blood testing and hepatology referral The primary outcome of the program was completion of the aforementioned HBV screening tests as measured before and after program initiation Results: Prior to our screening program, HBsAg completion rate among Asian patients in our health system was 7 4% On February 22, 2020, 430 HBV tests were ordered for patients in Group 1 and 90 tests were completed (20 9%) within the first 4 months of observation (283% increase from baseline) One of the 90 tests were HBsAg positive (1 1%) For this patient, follow up labs have been ordered and hepatology referral has been placed On March 19, 2020, a shelter-in-place (SIP) order was enacted in Sacramento County for the COVID-19 pandemic and the screening program was placed on hold 19 tests were completed in the first month (prior to SIP), 8 in the second month (SIP declared), and 23 in the third month (Stage 2 reopening), and 40 in the fourth month Conclusion: Utilizing electronic population health registries may increase mass screening for CHB Screening was increased 283% compared to baseline despite interruption from the COVID-19 pandemic Image Legend: HBV Population Health Registry Workflow Abbreviations: ALT: Alanine aminotransferase;BM: bulk message;BO: bulk order;HBeAg/AB: hepatitis B e antigen and antibody;HBsAg: hepatitis B surface antigen;HBV: hepatitis B virus;VL: viral load  (Table Presented)
Abstract 377: Predictors of Recovery in Out-Of-Hospital Post-Arrest Patients With Mild to Moderate Early Cerebral Edema
Authors: Zachary Fuller, John Faro, Clifton W Callaway, Jonathan Elmer
Journal: Circulation (2019)

Introduction: Some patients develop cerebral edema after cardiac arrest. Those with mild-to-moderate edema may or may not recover. Whether modifiable processes of care can improve outcomes in these patients is unknown. Methods: We conducted a retrospective cohort study of adults resuscitated from out-of-hospital arrest (OHCA) at a single center from 2010-2018. We included those with mild-to-moderate cerebral edema, defined as gray to white matter attenuation ratio (GWR) 1.2-1.4 on CT imaging obtained within 24h. We excluded patients who were awake, arrests due to trauma or neurological catastrophe, those with no CT imaging within 24h, and those who died or had limitations of care within 6 hours. We used Pittsburgh Cardiac Arrest Category (PCAC) to adjust for illness severity and considered as additional predictors the following values in the first 24 hours of admission: GWR, lab values affecting serum osmolality (sodium, glucose, blood urea nitrogen (BUN)), total osmolality, change in osmolality from 0 to 24 hours, cardiac etiology of arrest, targeted temperature to 33C (vs 36C), average mean arterial pressure (MAP) and sedative medications used. Our primary outcome was awakening from coma. We used unadjusted and adjusted logistical regression for analysis. Results: Of 1500 total OHCAs, 513 met inclusion criteria. Mean (SD) age was 58 (16) years, most (62%, 317 of 513) were male, and 35% (179 of 513) arrested from ventricular tachycardia or fibrillation. In adjusted models, higher mean glucose (OR 0.89 95% CI 0.83-0.96, p=0.002) and increasing serum osmolality (OR 0.90, 95% CI 0.82-0.98, p=0.018) were negatively associated with awakening, as was increased PCAC. Other predictors including BUN, MAP, target temperature and sedative choice were not associated with outcome in adjusted models. Associations were consistent in the subgroups with moderate (GWR 1.2 to &lt;1.3) and mild (GWR 1.3-1.4) edema. Conclusions: Illness severity, but not modifiable processes of care, were associated with recovery among post-arrest patients with mild-to-moderate cerebral edema.
THU0123 Apoptosis markers in rheumatoid arthritis
Authors: M Szmyrka, J Szechinski
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Disregulated apoptosis of T lymphocytes was postulated as one of the potential patomechanisms of rheumatoid arthritis. In peripheral blood of RA patients atypical clones of T cells were identified, overexpressing Bcl-2 protein and apoptosis resistant. Experimental treatment inducing apoptosis of joint infiltrating T cells and synovial fibroblasts resulted in disease remission in animal models. <h3>Objectives</h3> The objective of the study was to examine the expression of apoptosis regulatory proteins (p53, Bcl-2, Bax and Fas) in peripheral blood and synovial fluid lymphocytes as well as sFas concentrations in patients with RA and to compare it with expression in other arthritides. We analized the correlation with disease clinical characteristics and treatment. The other aim was to determine the relation of those markers expression in blood and synovial fluid lymphocytes from the same patients. <h3>Methods</h3> Study covered 77 RA patients, 18 OA patients 10 patients with other arthritides and healthy control group. Immunocytochemical analysis was performed with indirect immunoperoxidase test. sFas concentration was measured with ELISA test. <h3>Results</h3> In RA patients with advanced joint destruction and active disease high overexpression of Bcl-2 was found (over 80%of cells) which correlated to ESR (r = 0.63, p = 0.027). Bcl-2 expression was significantly higher in RA patients with limited disease than in pts with extra articular disease (p = 0.02) No significant difference in other apoptosis markers expression among examined groups was found. We did not observe its relation to disease duration, RF seropositivity, clinical stage or treatment. Serum sFas concentration was significantly higher in extra articular RA (p = 0.009). <h3>Conclusion</h3> The above results may indirectly suggest the role of lymphocyte apoptosis defect in RA pathogenesis, which demands further investigation.
Cell-type-specific nicotinic input disinhibits mouse barrel cortex during active sensing
Authors: Célia Gasselin, Benoît Hohl, Arthur Vernet, Sylvain Crochet, Carl C.H. Petersen
Journal: Neuron (2021)

Fast synaptic transmission relies upon the activation of ionotropic receptors by neurotransmitter release to evoke postsynaptic potentials. Glutamate and GABA play dominant roles in driving highly dynamic activity in synaptically connected neuronal circuits, but ionotropic receptors for other neurotransmitters are also expressed in the neocortex, including nicotinic receptors, which are non-selective cation channels gated by acetylcholine. To study the function of non-glutamatergic excitation in neocortex, we used two-photon microscopy to target whole-cell membrane potential recordings to different types of genetically defined neurons in layer 2/3 of primary somatosensory barrel cortex in awake head-restrained mice combined with pharmacological and optogenetic manipulations. Here, we report a prominent nicotinic input, which selectively depolarizes a subtype of GABAergic neuron expressing vasoactive intestinal peptide leading to disinhibition during active sensorimotor processing. Nicotinic disinhibition of somatosensory cortex during active sensing might contribute importantly to integration of top-down and motor-related signals necessary for tactile perception and learning.
Identification of Novel Targets for Antibody or Chimeric Antigen Receptor (CAR) Based Immunotherapy in AML: Characterizing the Surfaceome from Primary Patient Samples
Authors: Thomas Koehnke, Liu Xilong, Sascha Haubner, Christina Krupka, Victor Solis-Mezarino, Franz Herzog, Wolfgang Hiddemann, Marion S. Subklewe
Journal: Blood (2017)