tbuckley/cabot-search huggingface dataset:
Abstract 9185: Diagnostic Utility of R-R Interval Variations Under Deep Breathing Load in Patients With Cardiac Amyloidosis
Authors: Yasuhiro Nagayoshi, Hiroaki Kawano, Naritsugu Sakaino, Taiki Nishihara, Kei Morikawa, Shinsuke Hanatani, Hiroki Usuku, Kenichi Tsujita
Journal: Circulation (2021)

Introduction: Autonomic disorder is one of important characteristics of cardiac amyloidosis. However, the prevalence of autonomic disorder in wild-type transthyretin amyloidosis (ATTR wt ) remains to be elucidated. Analysis of coefficient of variation of R-R interval (CVR-R) is a non-invasive method to measure the autonomic nervous system. In normal subjects, CVR-R values are higher during deep breathing load than those at rest. Diminished response of CVR-R to deep breathing reflects the parasympathetic nervous system disorder. We aimed to assess autonomic disorder of ATTRwt and investigate the utility of CVR-R for the detection of ATTRwt from other cardiac disease. Methods: Fifty patients with chronic heart failure (HF) patients aged &gt;70 were investigated. The etiology of HF was as follows: ATTR wt , n=10; previous myocardial infarction (MI), n=20; and left ventricular hypertrophy (LVH) due to other disease (e.g. aortic stenosis); n=20. Serum cardiac troponin I and plasma brain natriuretic peptide (BNP) were measured in all patients. Cardiac function was evaluated by echocardiography. We measured CVR-R at rest (CVR-R rest ), CVR-R with deep breaths (CVR-R beath ) and their change rate (CVR-R diff rate ). Relative change formula is CVR-R diff rate = (CVR-R beath - CVR-R rest )/ CVR-R rest . Results: There was no difference in age among the three groups. Plasma BNP levels, troponin I levels and left ventricular mass index were significantly higher in ATTR wt group. There was no difference in CVR-R rest levels among the three groups. CVR-R diff rate levels in ATTR wt group were significantly lower (ATTR wt : -8.77 [-43.8-10.9]; LVH: 67.4 [38.7-89.4]; MI: 83.7 [60.4-142.9], respectively). In the ROC analysis to identify ATTR wt in HF, the best cutoff value for CVR-R diff rate was 1.197 (AUC: 0.848). Conclusions: Autonomic nervous disorder is frequently observed in the patients with ATTR wt . Measurement of CVR-R is convenient support tool for detection of ATTRwt.
EVI1-Positive AML Cells Show Distinct Features and High Dependency on ETS Transcription Factor ERG
Authors: Yosuke Masamoto, Akira Chiba, Toshiaki Takezaki, Toshiya Hino, Hiroki Hayashida, Hideaki Mizuno, Tomohiko Sato, Mineo Kurokawa
Journal: Blood (2021)
74 Tumor microenvironment based on PD-L1 and CD8 T-cell infiltration correlated with the response of MSS mCRC patients treated vactosertib in combination with pembrolizumab
Authors: Tae Won Kim, Keun-Wook Lee, Joong Bae Ahn, Young Suk Park, Chan-Young Ock, Hyejoo Park, Jiyeon Ryu, Bitna Oh, Bo-Kyoung Kim, Sunjin Hwang, Ki Baik Hahm, Seong-Jin Kim
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The expression of PD-L1 and tumor-infiltrating CD8 T cells were reported to have a decisive effect on the immunotherapy response (PMID: 26819449). Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) shows a limited clinical benefit to immunotherapy alone known to be having an ‘immune-cold’ microenvironment. To understand the basis of the clinical responses to anti-PD-1 and TGF-β inhibitor combination therapy in MSS mCRC, we conducted a comprehensive analysis of survival outcome, whole transcriptome sequencing (WTS) data, and multiplex immunohistochemistry (mIHC) data from a combination treatment of vactosertib and pembrolizumab. Methods Clinical outcomes were evaluated by RECIST v1.1 and iRECIST. Tumor tissue biopsy samples for WTS and mIHC were obtained in screening and cycle 2 post-treatment time point. CD274(PD-L1) and CD8A expression cut-off were calculated as a median value in the merged data set of TCGA Pan-cancer and MP-VAC-204 study. Having over median value defined as a high group and under median value as a low group. Tumor immune status by a combination of gene expression (high or low) was classified into four subtypes (1: CD274 high, CD8A high; 2: CD274 low, CD8A low; 3: CD274 high, CD8A low; 4: CD274 low, CD8A high). Tumor tissue slides stained with PD-L1, CD8, and granzyme B (GZB) in tumor nest and stroma. Results Among 43 patients whose WTS data are available, thus included in the analysis, 9 patients were responders (7 PRs and 2 iPRs). Subtype 2 showed a major proportion in the MP-VAC-204 CRC patients (1: 14%, 2: 58%, 3: 12%, 4: 16%). Responders were observed in subtype 2 and 4 (24% and 14%, RECIST). The CD8A expression and median overall survival (mOS) showed a significantly positive correlation (**P=0.0028) and there was no significance in the correlation of CD274 and mOS. mOS was significantly longer in high expression of CD8A patients (*P=0.0083, Not reached vs 9.9 months, hazard ratio 8.812 [95% CI 3.19–24.31]). After the combination treatment, CD8 and GZB positive T cells were increased significantly in both tumor nest and stroma. Conclusions Our study suggests a high level of CD8 T cells, even in the case of low PD-L1 expression, is significantly correlated with the improved clinical outcomes in MSS mCRC patients treated with vactosertib and pembrolizumab. The increases in CD8 T cells both in tumor nest and stroma after the combined inhibition of PD-1 and TGF-β pathway may contribute to the survival benefit. Further clinical investigations are warranted. (Clinical trial information: NCT03724851 )
The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases
Authors: Moxin Wu, Manqing Zhang, Xiaoping Yin, Kai Chen, Zhijian Hu, Qin Zhou, Xianming Cao, Zhiying Chen, Dan Liu
Journal: Translational Neurodegeneration (2021)

Abstract Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accompanied by amyloid-β (Aβ) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark in AD, is recognized as the main cause of the cognitive impairments. Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD. Pathological tau, which is detached from axonal microtubules and mislocalized into pre- and postsynaptic neuronal compartments, is suggested to induce synaptic dysfunction in several ways, including reducing mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing the maturation of dendritic spines at postsynaptic terminals, disrupting mitochondrial transport and function in synapses, and promoting the phagocytosis of synapses by microglia. Here, we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD. We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.
Bone Mineral Density Remains Stable in Pyruvate Kinase Deficiency Patients Receiving Long-Term Treatment with Mitapivat
Authors: Hanny Al-Samkari, Rachael F. Grace, Andreas Glenthoej, Oliver Andres, Wilma Barcellini, Frédéric Galactéros, Kevin H.M. Kuo, D. Mark Layton, Marta Morado, Vip Viprakasit, Yan Dong, Feng Tai, Liz Grekas, Karishma Khoja, Sarah Gheuens, Bryan McGee, John B. Porter, Eduard J. Van Beers
Journal: Blood (2021)
Characteristics of Cost-effectiveness Studies for Oncology Drugs Approved in the United States From 2015-2020
Authors: Alyson Haslam, Mark P. Lythgoe, Emma Greenstreet Akman, Vinay Prasad
Journal: JAMA Network Open (2021)

Increasingly, cost-effectiveness analyses are being done to determine the value of rapidly increasing oncology drugs; however, this assumes that these analyses are unbiased.To analyze the characteristics of cost-effectiveness studies and to determine characteristics associated with whether an oncology drug is found to be cost-effective.This retrospective cross-sectional study included 254 cost-effectiveness analyses for 116 oncology drugs that were approved by the US Food and Drug Administration from 2015 to 2020.Each drug was analyzed for the incremental cost-effectiveness ratio per quality-adjusted life year, the funding of the study, the authors' conflict of interest, the threshold of willingness-to-pay, from what country's perspective the analysis was done, and whether a National Institute for Health and Care Excellence cost-effectiveness analysis had been done.The main outcome was the odds of a study concluding that a drug was cost-effective.There were 116 drug approvals with 254 studies and country perspectives. Of the country perspectives, 132 (52%) were from the US. Forty-seven of 78 drugs with cost-effective studies had been shown to improve overall survival, whereas 15 of 38 of drugs without a cost-effectiveness study had been shown to improve overall survival. Having a study funded by a pharmaceutical company was associated with higher odds of a study concluding that a drug was cost-effective than studies without funding (odds ratio, 41.36; 95% CI, 11.86-262.23).In this cross-sectional study, pharmaceutical funding was associated with greater odds that an oncology drug would be found to be cost-effective. These findings suggest that simply disclosing potential conflict of interest is inadequate. We encourage cost-effectiveness analyses by independent groups.
Very Elderly Patients with Myeloproliferative Neoplasms: Phenotypic Distinctions and Prognostic Determinants of Complications and Mortality
Authors: Judith Jolin, Michael Harnois, Luigina Mollica, Pierre Laneuville, Robert Delage, Harold J. Olney, Shireen Sirhan, Lambert Busque, Natasha Szuber
Journal: Blood (2021)
Clinical Manufacture of FT819: Use of a Clonal Multiplexed-Engineered Master Induced Pluripotent Stem Cell Line to Mass Produce Off-the-Shelf CAR T-Cell Therapy
Authors: Xu Yuan, Raedun Clarke, Yi-Shin Lai, Chia-Wei Chang, Bi-Huei Yang, Gloria Hsia, Ramzey Abujarour, Tom Lee, Sjoukje van der Stegen, Helena Shaked, Abubakar Jalloh, Stephanie Moreno, Jason ORourke, Eric Sung, Alma Gutierrez, Betsy Rezner, Meghan Eberhart, Rebecca Magdaleno, Xiuyan Wang, Brigitte Senechal, Devanjan S. Sikder, Dell Farnan, Mark Plavsic, Jerome Bressi, Isabelle Rivière, Bahram Valamehr
Journal: Blood (2021)
Gilteritinib Can be Safely Combined with Atezolizumab for the Treatment of Relapsed or Refractory <i>FLT3</i>-Mutated AML: Results of a Phase 1 Study
Authors: Jessica K. Altman, Bhavana Bhatnagar, Sameem Abedin, Amanda Przespolewski, Prapti A. Patel, Gary J. Schiller, Stanley Gill, Dhruva Patel, Linyi Fan, Ramon V. Tiu, Stephen A. Strickland
Journal: Blood (2021)
Preliminary Results from a Phase I Study of HMPL-523, a Selective Oral Syk Inhibitor, in Patients with Relapsed or Refractory Lymphoma
Authors: Paolo Strati, Dominik Chraniuk, Eva González-Barca, Michal Taszner, Rathi Pillai, Caly Chien, Shivani Nanda, Mark Rudinski, Vijayvel Jayaprakash, Marjo Hahka-Kemppinen, Marek Kania
Journal: Blood (2021)
Impact of the COVID-19 Pandemic on in-Person Visit Rates Among Patients with Hematologic Malignancies in the United States
Authors: Gaurav Goyal, Krystal W. Lau, Xiaoliang Wang, Amy J. Davidoff, Scott F. Huntington, Omer Hassan Jamy, Gregory Calip, Harsh Shah, Deborah M. Stephens, Rebecca A. Miksad, Ravi Parikh, Samuel Takvorian, Natalia Neparidze, Erlene K Seymour
Journal: Blood (2021)
Abstract 11271: Three-Dimensional Deep-Tissue Imaging of the Right Ventricle Reveals Decreased Capillary-Cardiomyocyte Contact Surface in Decompensated Right Heart Failure
Authors: Kenzo Ichimura, Mario Boehm, Fan Zhang, Adam Andruska, Melanie J Dufva, Sushma Reddy, Vitaly O Kheyfets, Ross Metzger, Edda F Spiekerkoetter
Journal: Circulation (2021)

Introduction: Right ventricular (RV) function determines the prognosis of pulmonary hypertension. Capillary rarefaction using 2D imaging has been proposed as the hallmark of RV failure, although this paradigm is controversially discussed. By applying 3D deep-tissue imaging, we characterized the adaptive and maladaptive response of the capillaries in the pressure-overloaded RV in hypertrophy and failure. Methods and Results: Mice subjected to pulmonary artery banding (PAB) were harvested after 3 weeks (w) (compensated RV hypertrophy) and 7w post-surgery (decompensated RV failure). Hearts were sectioned into 250 μm and capillaries were stained with isolectin B4. Samples were imaged with confocal microscopy and reconstructed into 3D using Imaris imaging software (Fig. A, n=4). In the RV free wall, mean capillary length decreased, and branching, tortuosity, mean and total capillary diameter increased 3w post-PAB. Mean and total diameter, and total length decreased at 7w resulting in a reduced capillary volume normalized to heart volume at 7w vs 3w, but not significantly reduced vs baseline suggesting that this is not the mechanism of RV failure (Fig. B). However, most strikingly we uncovered by sparsely labeling cardiomyocytes that the capillary-cardiomyocyte contact surface was maintained at w3, yet significantly decreased in areas of interstitial fibrosis in the decompensated RV at 7w compared to baseline and 3w (Fig. C, D). Conclusions: 3D deep-tissue imaging uncovered the remarkable adaptive response of the RV microvasculature in the pressure-overloaded RV to maintain an adequate capillary-cardiomyocyte contact by increasing capillary branching, length and diameter. These mechanisms failed in the decompensating RV when interstitial fibrosis impaired the capillary-cardiomyocyte interaction. Our method offers the unprecedented opportunity to study microvascular adaption in the pressure overloaded RV and is readily transferable to human tissue.
Overdiagnosis: it’s official
Authors: Steven Woloshin, Barnett Kramer
Journal: BMJ (2021)

Recently the US National Library of Medicine (NLM) unveiled new terms to be included in the medical subject headings (MeSH) vocabulary used to index, catalogue, and search journal articles, books, and other biomedical and health related information.1

#### One of the new terms is overdiagnosis

“The labeling of a person with a disease or abnormal condition that would not have caused the person harm if left undiscovered, creating new diagnoses by medicalizing ordinary life experiences, or expanding existing diagnoses by lowering thresholds or widening criteria without evidence of improved outcomes. Individuals derive no clinical benefit from overdiagnosis, although they may experience physical, psychological, or financial harm.”2

#### Why is this a big deal

At the core of advancement in any scientific field, including the study of disease overdiagnosis, is the ability to build on the existing knowledge base. That demands tools to facilitate systematic assessment of that knowledge. The MeSH taxonomy was developed as a key tool to meet that need.

#### What is MeSH?

NLM created MeSH in the 1960s to describe what journal articles are about. MeSH indexing “is a form of intelligent …
Serological Response to BNT162b2 Anti-Sars-Cov-2 mRNA Vaccine in Patients with Transfusion Dependent Thalassemia
Authors: Stefania Zucano, Francesco Tarantini, Angelantonio Vitucci, Antonio Palma, Daniela Campanale, Luigi Vimercati, Angela Maria Vittoria Larocca, Domenico Visceglie, Amalia Acquafredda, Silvio Tafuri, Pellegrino Musto
Journal: Blood (2021)
Activated but impaired IFN-γ production of mucosal-associated invariant T cells in patients with hepatocellular carcinoma
Authors: Wenyong Huang, Dongmei Ye, Wenjing He, Xiaoshun He, Xiaomin Shi, Yifang Gao
Journal: Journal for ImmunoTherapy of Cancer (2021)

Objective Mucosal-associated invariant T (MAIT) cells are innate T cells with immunoregulatory activity and were recently found to be associated with various tumor types. The role of intrasinusoidal MAIT cells in hepatocellular carcinoma (HCC) has not been fully characterized. Design Peripheral blood samples were obtained from patients with HCC and healthy controls. Liver-associated mononuclear cells (LMCs) were collected from liver perfusions of donors and patients with HCC undergoing liver transplantation. Blood and liver perfusates from patients with HCC were analyzed by flow cytometry for CD3 +CD161+Vα7.2+MAIT cell frequency, phenotype, and function. Results There were fewer MAIT cells in the peripheral blood and liver of patients with HCC than in the healthy controls. Interferon-γ (IFN-γ) production by these cells was also reduced. Peripheral MAIT cells showed upregulation of HLA-DR (Human Leukocyte Antigen DR） and the inhibitory molecule PD-1 (Programmed Cell Death Protein 1), but no significant differences in upregulation were found in intrasinusoidal MAIT cells. MAIT cells were significantly enriched in the liver relative to that in the peripheral blood of patients with HCC. High levels of activation markers and exhaustion markers including HLA-DR, CD69, and PD-1 were observed in LMCs of patients with HCC but not in the peripheral blood. Single-cell RNA sequencing revealed that intrasinusoidal MAIT cells exhibited distinct features in patients with HCC and the controls. Conclusion Our study showed that alterations in MAIT cells are associated with HCC. The distinct activity and function of MAIT cells in the peripheral blood and liver of patients with HCC might suggest a potential role of these cells in disease pathogenesis.
Abstract 13814: Prediction of Transthyretin Cardiac Amyloidosis in Heart Failure With Preserved Ejection Fraction: Artificial Intelligence Electrocardiogram versus Traditional Risk Scores
Authors: Daniel Davies, Dennis Murphree, Christopher Scott, Francisco Lopez-jimenez, Abraham Baez Suarez, Zachi Attia, Suraj Kapa, Daniel D Borgeson, Paul A FRIEDMAN, Dispenzieri Angela, Martha Grogan, Margaret M Redfield, Omar F Abouezzeddine
Journal: Circulation (2021)

Introduction: Transthyretin cardiac amyloidosis (TTR-CA) can cause heart failure with preserved EF (HFpEF). We previously reported a clinical/echo-based score (TCAS) and defined a cut-off that predicted risk of TTR-CA in HFpEF. Herein, we assess the comparative performance of an artificial-intelligence ECG-based screening tool (AI-ECG). Hypothesis: AI-ECG successfully identifies TTR-CA in HFpEF cohorts across a range of TTR-CA prevalence Methods: Referral HFpEF cohort was constructed from a referral population of HFpEF patients (EF ≥ 40%) undergoing 99m Tc-pyrophosphate scintigraphy (PYP) at Mayo Clinic (2013-2020, n=484, 38% with TTR-CA). Community HFpEF cohort was prospectively screened with PYP (n=275; age ≥ 60, LV wall thickness (WT) ≥ 12 mm, 4% with TTR-CA). TCAS was built using a multivariable logistic regression model and converted to a simple point score comprised of age (60-69, 70-79, ≥ 80: +2, +3, +4 points respectively), male sex (+2), relative WT &gt; 0.57 (+2), posterior WT ≥ 12 mm (+1), EF &lt; 60% (+1), and hypertension diagnosis (-1). TCAS was validated in the community cohort. A deep neural network trained to predict cardiac amyloidosis from a single 12-lead ECG, was applied to both referral and community cohorts. Patients were excluded if ECG was not available ≤ 12 months before PYP or if used in development of the AI-ECG. Standard ROC methods were applied. Youden’s index was used to define optimal cut-off. Results: Predictive characteristics of AI-ECG were strong and compared favorably with TCAS across a range of true TTR-CA prevalence (Table). Conclusions: Using a single ECG, AI-ECG effectively predicts TTR-CA with an excellent negative predictive value to rule out TTR-CA and a positive predictive value sufficient to warrant specific TTR-CA testing. This was particularly evident in the community. AI-ECG holds promise for simple, cost-effective global screening of at-risk populations, especially those with limited access to advanced cardiac imaging.
Monocytes from Patients with Polycythemia Vera Express Molecules Related to Stress Erythropoiesis and Have Increased Erythrocyte Phagocytosis
Authors: Marina Dorigatti Borges, Renata Sesti-Costa, Dulcinéia Martins de Albuquerque, Carolina Lanaro, Kleber Yotsumoto Fertrin, Fernando Ferreira Costa
Journal: Blood (2021)
Analyses of the Kinetics and Phenotype of Multiple Intraclonal CXCR4/CD5 B Cell Subsets Suggest Differences in Life Cycle Transitioning in CLL
Authors: Andrea Nicola Mazzarello, Mark Fitch, Anita Ng, Sabreen Bhuiya, Esha Sharma, Andrew Shih, Martina Cardillo, Steven L Allen, Jonathan E Kolitz, Jacqueline Barrientos, Kanti R Rai, Marc Hellerstein, Nicholas Chiorazzi
Journal: Blood (2021)
Safety and preliminary efficacy of the Gam-COVID-Vac vaccine and outcomes of SARS-CoV-2 infection in Russian patients with genitourinary malignancies
Authors: Ilya Tsimafeyeu, Maria Volkova, Galina Alekseeva, Maria Berkut, Alexander Nosov, Igor Myslevtsev, Andrey Andrianov, Andrey Semenov, Pavel Borisov, Ruslan Zukov, Vadim Goutnik, Sergey Savchuk, Natalia Dengina, Timur Mitin
Journal: Journal of Hematology & Oncology (2021)

Abstract Background To our knowledge, there is no clinical data pertaining to COVID-19 outcomes and safety of COVID-19 vaccination in Russian patients with genitourinary (GU) malignancies. Aim of our analysis was to describe the characteristics of the COVID-19 infection course as well as preliminary safety and efficacy of Gam-COVID-Vac vaccine in patients with active GU malignancies. Methods Patients were retrospectively identified at nine cancer centers in different regions. Patients were included if COVID-19 was diagnosed by a polymerase chain reaction. Data from additional patients with GU cancers who had no positive SARS-CoV-2 RT-PCR test before vaccination and who received two doses of Gam-COVID-Vac (Sputnik V) between 11 February and 31 August 2021 were collected for safety assessment. Anonymized data were collected through an online registry covering demographics, treatments, and outcomes. Results The Gam-COVID-Vac vaccine was well tolerated; no grade 3–5 toxicities were reported in 112 vaccinated metastatic GU cancer patients. The most common grade 1 adverse events (81%) were injection site reactions (76%), flu-like illness (68%), and asthenia (49%). Five patients experienced grade 2 chills (4.5%) and 3 patients had grade 2 fever (2.7%). With median follow-up of 6.2 months, two COVID-19 cases were confirmed by RT-PCR test in the vaccine group (of 112 participants; 1.8%). Eighty-eight patients with COVID-19 disease were included in the analysis. The average age as of the study enrollment was 66 (range 39–81) and the majority of patients were male with renal cell carcinoma (RCC). Thirty-six patients (41%) had evidence of metastatic disease, of these 22 patients were receiving systemic therapy. More than half of patients required hospitalization. Fifty-four patients (61%) experienced complications. Sixteen patients who developed COVID-19 pneumonia required mechanical ventilator support. Sixteen patients (18%) died in a median of 23.5 days after the date of COVID-19 diagnosis was established. The 3-month survival rate was 82%. Clinical and/or radiographic progression of cancer during COVID-19 infection or the subsequent 3 months was observed in 10 patients (11.4%). Conclusion Patients with GU malignancies are at increased risk of mortality from COVID-19 infection when compared to the general population. Vaccination could be safe in GU cancer patients. Trial registration : retrospectively registered.