tbuckley/cabot-search huggingface dataset:
Haplo‐identical or mismatched unrelated donor hematopoietic cell transplantation for <scp>Fanconi</scp> anemia: Results from the <scp>Severe Aplastic Anemia Working Party</scp> of the <scp>EBMT</scp>
Authors: Josune Zubicaray, Daria Pagliara, Julian Sevilla, Dirk‐Jan Eikema, Paul Bosman, Mouhab Ayas, Marco Zecca, Akif Yesilipek, Savas Kansoy, Cécile Renard, Jean H. Dalle, Antonio Campos, Maura Faraci, Alphan Kupesiz, Frans J. W. Smiers, Andrea Velardi, Manuel Abecasis, Paola Corti, Franca Fagioli, Soledad González Muñiz, Gergely Kriván, Carlo Dufour, Antonio Risitano, Selim Corbacioglu, Régis Peffault de Latour
Journal: American Journal of Hematology (2021)

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p = .22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p = .046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p = .005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts.
Use of a biliary guidewire to assist placement of two over-the-scope clips for deep ulcer bleeding while preventing duodenal closure
Authors: Álvaro Martínez-Alcalá García, Felipe Martínez-Alcalá, Klaus Mönkemüller
Journal: Endoscopy (2021)

A 58-year-old woman with history of coronary artery disease presented with hematochezia and melena. In addition to aspirin and atorvastatin she was taking ibuprofen for headaches. On presentation she was in hypovolemic shock. Her laboratory data was remarkable for a hemoglobin concentration of 5 g/dL and mild leukocytosis (13 000/µL). The remaining laboratory data was normal. After initial fluid resuscitation with intravenous saline and after receiving transfusion with 2 units of units of packed red blood cells, the patient underwent endoscopy. A large, deep prepyloric ulcer with a visible vessel compressing the pyloric channel was seen ([Fig. 1]; [Video 1]). An over-the-scope clip (OTSC 11/6/t; Ovesco, Tübingen, Germany) was deployed. However, the OTSC only grasped part of the fibrotic ulcer. Therefore, a decision was made to place a second OTSC (12/6t). Because the ulcer was partly closing the duodenal entrance, a 0.035-inch biliary guidewire was advanced into the duodenum to (a) maintain visibility of the gastric outlet and (b) prevent closure of the duodenal bulb while the second OTSC was being applied ([Video 1]). Application of the second OTSC was uneventful. Final inspection of the site revealed adequately placed clips and a patent duodenum. The patient had an uneventful recovery, her food intake was well tolerated, and she was discharged home in stable condition 48 hours later.
Abstract 16222: Electrocardiographic Manifestations of Right Ventricular Strain in Covid-19 Patients on Ventilatory Support or With Documented Pulmonary Embolism
Authors: Usman Naseer, Gregory Petrossian, Amit Chopra, Andrew Coates, Mikhail Torosoff
Journal: Circulation (2020)

Background: A significant number of COVID-19 patients require mechanical ventilation and suffer from thrombotic events, including pulmonary embolism. Prevalence of ECG changes associated with right ventricular strain in COVID-19 patients on mechanical ventilatory support and with pulmonary embolism have not been well described. Material: Data on 106 consecutive patients with COVID-19 infection, treated at a single academic medical center, was collected. Standard 12-lead ECGs were reviewed for evidence of RV strain, including S wave in lead I (S1), Q wave in lead III (Q3), inverted T wave in lead III (T3), right atrial enlargement (RAE), and right bundle branch block (RBBB). Results: The study cohort included 37% females, 62+/-15 years old, with histories of diabetes in 28%, myocardial infarction in 10%, CHF in 6%, PVD in 4%, and cancer in 6%. Of the study cohort, 34 (32%) of patients required mechanical ventilation and pulmonary embolism was documented in 4 patients, 2 of whom were on mechanical ventilation, a total of 36 patients, Vented-PE group. Thirty-three patients (30.8% of the study cohort) expired. In Vented-PE patients, prevalence of Q3 (41.7% vs. 19.7% in the rest of the cohort, p=0.016) was significantly increased, which due to supine position at the time of ECG. The prevalence of S1 (33.3 vs. 29.6%, p=0.691), T3 (44 vs. 30%, p=0.127), RBBB (3 vs. 10%, p=0.188), and RAE (2.8 vs. 1.4%, p=0.621) was not significantly different between Vented-PE group and the rest of the cohort. Similarly, except for significantly more common in survivors T3 (5.6 vs. 40.4%, p=0.004), there were no significant differences in prevalence of S1 (44.4 vs. 28.1%, p=0.171), Q3 (233.3 vs 25.8%, p=0.514), RBBB (11.1 vs. 6.7%, p=0.520), or RAE (0 vs. 2.2%, p=0.521) between patients who expired and live discharges, respectively. Conclusions: In COVID-19 patients, 12 lead ECG evidence of RV strain has low prevalence and does not allow to differentiate patients who require mechanical ventilation, suffer from pulmonary embolism, or expire. RV strain should not be ruled out in these patients solely based on the normal ECG. Additional imaging studies should be considered in eligible patients with high index of suspicion for the right ventricular strain.
REVA as A Well-Curated Database for Human Expression-Modulating Variants
Authors: Yu Wang, Fang-Yuan Shi, Yu Liang, Ge Gao
Journal: Genomics Proteomics & Bioinformatics (2021)

More than 90% of disease- and trait-associated human variants are noncoding. By systematically screening multiple large-scale studies, we compiled REVA, a manually curated database for over 11.8 million experimentally tested noncoding variants with expression-modulating potentials. We provided 2424 functional annotations that could be used to pinpoint the plausible regulatory mechanism of these variants. We further benchmarked multiple state-of-the-art computational tools and found that their limited sensitivity remains a serious challenge for effective large-scale analysis. REVA provides high-quality experimentally tested expression-modulating variants with extensive functional annotations, which will be useful for users in the noncoding variant community. REVA is freely available at http://reva.gao-lab.org.
Abstract SP161: Context-dependent functions and inter-tumoral heterogeneity of tumor-associated myeloid cells.
Authors: X Zhang
Journal: Cancer Research (2021)

Abstract Tumor-associated myeloid cells, including macrophages (TAMs) and neutrophils (TANs) have been extensively studied. Their pleotropic roles were observed in multiple steps of tumor progression and metastasis, and sometimes appeared to be inconsistent across different studies. In this talk, we will discuss evidence supporting the mutual influence between cancer cells and TAMs/TANs. We will review the immunosuppressive roles of these myeloid cells as well as their direct interactions with cancer cells. We will stress an emerging theme in recent studies: the precise myeloid functions may be determined by multiple factors including plasticity of these cells, mutual cooperation/competition among different cell types, and co-evolution between immune microenvironment and cancer traits. These factors together contribute to the heterogeneity of immune cells across tumors, an additional layer of heterogeneity beyond tumor-intrinsic characteristics. Citation Format: X Zhang. Context-dependent functions and inter-tumoral heterogeneity of tumor-associated myeloid cells. [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 SP161.
Cardiac Remodeling During Pregnancy With Metabolic Syndrome
Authors: Yijun Yang, Justin Kurian, Giana Schena, Jaslyn Johnson, Hajime Kubo, Joshua G. Travers, Chunya Kang, Anna Maria Lucchese, Deborah M. Eaton, Maoting Lv, Na Li, Lorianna G. Leynes, Daohai Yu, Fengzhen Yang, Timothy A. McKinsey, Raj Kishore, Mohsin Khan, Sadia Mohsin, Steven R. Houser
Journal: Circulation (2021)

The heart undergoes physiological hypertrophy during pregnancy in healthy individuals. Metabolic syndrome (MetS) is now prevalent in women of child-bearing age and might add risks of adverse cardiovascular events during pregnancy. The present study asks if cardiac remodeling during pregnancy in obese individuals with MetS is abnormal and whether this predisposes them to a higher risk for cardiovascular disorders.
The microbiome in IPF: tissue is not the issue
Authors: Philip L Molyneaux
Journal: Thorax (2021)

The first line of defence in the airways is the epithelium. In health there are numerous mechanisms to repel invaders and facilitate repair of this barrier. However, when these mechanisms are ineffective, absent or simply become exhausted, fibrosis can ensue.1 For many years epidemiological studies have highlighted potential environmental triggers which could target and damage the epithelium in idiopathic pulmonary fibrosis (IPF), but more recently we have come to understand the role of bacteria, and specifically the role of the ever-present respiratory microbiota in fibrogenesis.

The dysbiosis of the lower airway microbiota in IPF has now been well described. There are clear associations with both the content and quantity of bacteria and clinical disease behaviour, with the most consistent signal related to the overall bacterial burden.2–5 This relationship is not simply the result of extensive anatomical changes or related to the extent of fibrosis6 and is specific to IPF.7 However, the potential mechanisms by …
Assessment and Management of Cardiovascular Risk Factors Among US Veterans With Prostate Cancer
Authors: Lova Sun, Ravi B. Parikh, Rebecca A. Hubbard, John Cashy, Samuel U. Takvorian, David J. Vaughn, Kyle W. Robinson, Vivek Narayan, Bonnie Ky
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Cardiovascular disease is a leading cause of mortality in patients with prostate cancer, and androgen deprivation therapy (ADT) may worsen cardiovascular risk. Adherence to guideline-recommended assessment and management of cardiovascular risk factors (CVRFs) in patients initiating ADT is unknown. <h3>Objective</h3> To describe CVRF assessment and management in men with prostate cancer initiating ADT and overall. <h3>Design, Setting, and Participants</h3> A cross-sectional analysis of 90 494 men treated within the US Veterans Health Administration diagnosed with prostate cancer between January 1, 2010, and December 31, 2017, was conducted. Participants included men with a history of atherosclerotic cardiovascular disease (ASCVD), and treatment with ADT within 1 year of diagnosis. Data analysis was conducted from September 10, 2019, to July 1, 2020. <h3>Main Outcomes and Measures</h3> Rates of comprehensive CVRF assessment, uncontrolled CVRFs, and untreated CVRFs. Comprehensive CVRF assessment was defined as recorded measures for blood pressure, cholesterol, and glucose levels; CVRF control as blood pressure lower than 140/90 mm Hg, low-density lipoprotein cholesterol 130 mg/dL, and hemoglobin A<sub>1c</sub>less than 7%; and CVRF treatment as receipt of cardiac risk–reducing medications. Multivariable risk difference regression assessed the association between ASCVD and initiation of ADT and these outcomes. <h3>Results</h3> Of 90 494 veterans, median age was 66 years (interquartile range, 62-70 years); and 22 700 men (25.1%) received ADT. Overall, 68.1% (95% CI, 67.8%-68.3%) of the men received comprehensive CVRF assessment; 54.1% (95% CI. 53.7%-54.4%) of those assessed had uncontrolled CVRFs, and 29.6% (95% CI, 29.2%-30.0%) of those with uncontrolled CVRFs were not receiving corresponding cardiac risk–reducing medication. Compared with the reference group of patients without ASCVD not receiving ADT, patients with ASCVD not receiving ADT had a 10.4% (95% CI, 9.5%-11.3%) higher probability of comprehensive CVRF assessment, 4.0% (95% CI, 2.9%-5.1%) lower risk of uncontrolled CVRFs, and 22.2% (95% CI, 21.1%-23.3%) lower risk of untreated CVRFs. Similar differences were observed in patients with ASCVD receiving ADT. In contrast, patients without ASCVD receiving ADT had only a 3.0% (95% CI, 2.1%-3.9%) higher probability of comprehensive CVRF assessment, 2.6% (95% CI, 1.6%-3.5%) higher risk of uncontrolled CVRFs, and 5.4% (95% CI, 4.2%-6.6%) lower risk of untreated CVRFs. <h3>Conclusions and Relevance</h3> These findings suggest that veterans with prostate cancer had a high rate of underassessed and undertreated CVRFs, and ADT initiation was not associated with substantial improvements in CVRF assessment or management. These findings highlight gaps in care and the need for interventions to improve CVRF mitigation in this population.
Degradation of AHR by PROTACS : A novel approach for cancer chemoprevention
Authors: Dinesh Puppala, Hyosung Lee, Kyung Bo Kim, Hollie Swanson
Journal: Cancer Research (2007)

321  Activation of the aryl hydrocarbon receptor (AHR) leads to many adverse biological effects including tumor promotion, epithelial hyperplasia, endocrine disruption and immunodeficiency. Emerging evidence also links activation of the AHR to the development of type II diabetes. The AHR is thought to mediate its biological effects via its upregulation of a number of target genes. Agonists of the AHR includes dioxin (2, 3, 7, 8 tetrachlorodibenzo-p-dioxin) and polyhalogenated aromatic hydrocarbons found in cigarette smoke and other air pollutants. Our hypothesis is that blocking the actions of the AHR via appropriate AHR antagonists is a valid approach to be used for treatment of a number of human disease states. In the current project we have focused on the development of an AHR antagonist using the PROTACS (PROteolysis TArgeting Chimeric moleculeS) approach. PROTACS is a novel approach of tagging small recognition sequences of a specific E3 ubiquitin ligase complex on to a known ligand for the receptor of interest (AHR) for targeting its degradation via the 26S proteosomal pathway. PROTACS contain a ligand for the AHR, a recognition sequence for the pVHL E3 ubiquitin ligase complex and a linker moiety. The initial, parent compound that serves as the AHR ligand in these studies is apigenin. Here, we demonstrate the design, efficacy and specificity of apigenin bound PROTAC molecules. The design of the apigenin-Protacs was initiated by synthesizing apigenin derivatives that retained binding to the AHR and antagonistic activity. The Apigenin-PROTACS proved to be capable of degrading the AHR in both HepG2 (human hepatoma) and NHK (Primary human keratinocytes) cells in a time-dependent and concentration-dependent manner. These initial experiments demonstrate that the PROTAC approach can be effective in inhibiting the actions of the AHR blocking AHR-mediated effects.
Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia
Authors: Bernd B. Zeisig, Tsz Kan Fung, Magdalena Zarowiecki, Chiou Tsun Tsai, Huacheng Luo, Boban Stanojevic, Claire Lynn, Anskar Y. H. Leung, Jan Zuna, Marketa Zaliova, Martin Bornhauser, Malte von Bonin, Boris Lenhard, Suming Huang, Ghulam J. Mufti, Chi Wai Eric So
Journal: Science Translational Medicine (2021)

Chemoresistance remains the major challenge for successful treatment of acute myeloid leukemia (AML). Although recent mouse studies suggest that treatment response of genetically and immunophenotypically indistinguishable AML can be influenced by their different cells of origin, corresponding evidence in human disease is still largely lacking. By combining prospective disease modeling using highly purified human hematopoietic stem or progenitor cells with retrospective deconvolution study of leukemia stem cells (LSCs) from primary patient samples, we identified human hematopoietic stem cells (HSCs) and common myeloid progenitors (CMPs) as two distinctive origins of human AML driven by Mixed Lineage Leukemia (MLL) gene fusions (MLL-AML). Despite LSCs from either MLL-rearranged HSCs or MLL-rearranged CMPs having a mature CD34-/lo/CD38+ immunophenotype in both a humanized mouse model and primary patient samples, the resulting AML cells exhibited contrasting responses to chemotherapy. HSC-derived MLL-AML was highly resistant to chemotherapy and expressed elevated amounts of the multispecific anion transporter ABCC3. Inhibition of ABCC3 by shRNA-mediated knockdown or with small-molecule inhibitor fidaxomicin, currently used for diarrhea associated with Clostridium difficile infection, effectively resensitized HSC-derived MLL-AML toward standard chemotherapeutic drugs. This study not only functionally established two distinctive origins of human LSCs for MLL-AML and their role in mediating chemoresistance but also identified a potential therapeutic avenue for stem cell-associated treatment resistance by repurposing a well-tolerated antidiarrhea drug already used in the clinic.
αPD-1-mesoCAR-T cells partially inhibit the growth of advanced/refractory ovarian cancer in a patient along with daily apatinib
Authors: Juemin Fang, Na Ding, Xianling Guo, Yan Sun, Zhiwei Zhang, Bailu Xie, Zhong Li, Hui Wang, Wei Mao, Zhicai Lin, Fei Qin, Min Yuan, Wenqi Chu, Huanlong Qin, Qijun Qian, Qing Xu
Journal: Journal for ImmunoTherapy of Cancer (2021)

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies in China. In particular, advanced/refractory ovarian cancer lacks effective targeted therapies due to the immunosuppressive and proangiogenic tumor microenvironment. Mesothelin (MSLN) has been found to be highly expressive in most EOC. Targeting MSLN by antibodies or chimeric antigen receptor-modified T (CAR-T) cells and immune checkpoint blockades as well as apatinib, an anti-angiogenic drug, have been used in patients with refractory ovarian cancer. Apatinib was reported to promote the infiltration of CD8 + T cells in lung cancer. However, the combination therapy of CAR-T secreting anti-PD-1 antibody with apatinib in EOC has not been reported. Case presentation Here we report a case of refractory EOC in a patient who had relapsed after multiline chemotherapy. The patient received autologous T cells that contained sequences encoding single-chain variable fragments specific for MSLN and full-length antibody for PD-1 (αPD-1). The modified T cells were called αPD-1-mesoCAR-T cells. After infusion, the copy number and PD-1 antibody secretion of the CAR-T cells were increased in the blood. By application of multimodality tumor tracking, MRI of the liver showed shrinkage of metastatic nodules from average diameter of 71.3–39.1 mm at month 2. The patient achieved partial response and survived more than 17 months. IL-6 levels in the patient fluctuated from the baseline to 2–4-folds after treatment, but side effects were mild with only grade 1 hypertension and fatigue. Conclusion αPD-1-mesoCAR-T cell therapy combined with apatinib demonstrates a potential therapeutic effect on advanced refractory ovarian cancer. Trial registration number NCT03615313 .
Combined Analysis of Concordance between Liquid and Tumor Tissue Biopsies for <i>RAS</i> Mutations in Colorectal Cancer with a Single Metastasis Site: The METABEAM Study
Authors: Yoshinori Kagawa, Elena Elez, Jesús García-Foncillas, Hideaki Bando, Hiroya Taniguchi, Ana Vivancos, Kiwamu Akagi, Ariadna García, Tadamichi Denda, Javier Ros, Tomohiro Nishina, Iosune Baraibar, Yoshito Komatsu, Davide Ciardiello, Eiji Oki, Toshihiro Kudo, Takeshi Kato, Takeharu Yamanaka, Josep Tabernero, Takayuki Yoshino
Journal: Clinical Cancer Research (2021)

Abstract Purpose: OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in the RAS status by metastatic sites in patients with a single metastatic site. Experimental Design: Data from previous Spanish and Japanese studies investigating the concordance of the RAS status between OncoBEAM™ and tissue biopsy in 221 patients with metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, peritoneal, or lung metastases and evaluated the concordance rates according to the metastatic site and the association between the concordance rate and tumor burden. Results: Patients had metastases in the liver (n = 151), peritoneum (n = 25), or lung (n = 45) with concordance rates of 91% (95% confidence interval, 85%–95%), 88% (68%–97%), and 64% (49%–78%), respectively. Factors associated with concordance included the baseline longest diameter and lesion number (P = 0.004), and sample collection interval (P = 0.036). Concordance rates ≥90% were observed in the following groups: liver metastases alone, regardless of the baseline longest diameter and lesion number; peritoneal metastases alone in patients with a baseline longest diameter ≥20 mm; and lung metastases alone in patients with a baseline longest diameter ≥20 mm and/or number of lesions ≥10. Conclusions: Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients' RAS status with only peritoneal or lung metastases.
Recent advances in drug delivery applications of cubosomes, hexosomes, and solid lipid nanoparticles
Authors: Anan Yaghmur, Huiling Mu
Journal: Acta Pharmaceutica Sinica B (2021)

The use of lipid nanocarriers for drug delivery applications is an active research area, and a great interest has particularly been shown in the past two decades. Among different lipid nanocarriers, ISAsomes (Internally self-assembled somes or particles), including cubosomes and hexosomes, and solid lipid nanoparticles (SLNs) have unique structural features, making them attractive as nanocarriers for drug delivery. In this contribution, we focus exclusively on recent advances in formation and characterization of ISAsomes, mainly cubosomes and hexosomes, and their use as versatile nanocarriers for different drug delivery applications. Additionally, the advantages of SLNs and their application in oral and pulmonary drug delivery are discussed with focus on the biological fates of these lipid nanocarriers in vivo. Despite the demonstrated advantages in in vitro and in vivo evaluations including preclinical studies, further investigations on improved understanding of the interactions of these nanoparticles with biological fluids and tissues of the target sites is necessary for efficient designing of drug nanocarriers and exploring potential clinical applications.
Corrigendum to “MR and PET-CT monitoring of tissue-engineered vascular grafts in the ovine carotid artery” [Biomaterials 216 (2019) 119228]
Authors: Frederic Wolf, Vera Paefgen, Oliver Winz, Marianne Mertens, Sabine Koch, Nicolas Gross-Weege, Agnieszka Morgenroth, Anne Rix, Heike Schnoering, Khaled Chalabi, Stefan Jockenhoevel, Twan Lammers, Felix Mottaghy, Fabian Kiessling, Petra Mela
Journal: Biomaterials (2021)