tbuckley/cabot-search huggingface dataset:
Effects of a Knowledge-Translation Intervention on Early Dialysis Initiation: A Cluster Randomized Trial
Authors: Navdeep Tangri, Amit X. Garg, Thomas W. Ferguson, Stephanie Dixon, Claudio Rigatto, Selina Allu, Elaine Chau, Paul Komenda, David Naimark, Gihad E. Nesrallah, Steven D. Soroka, Monica Beaulieu, Ahsan Alam, S. Joseph Kim, Manish M. Sood, Braden Manns
Journal: Journal of the American Society of Nephrology (2021)

The Initiating Dialysis Early and Late (IDEAL) trial, published in 2009, found no clinically measurable benefit with respect to risk of mortality or early complications with early dialysis initiation versus deferred dialysis start. After these findings, guidelines recommended an intent-to-defer approach to dialysis initiation, with the goal of deferring it until clinical symptoms arise.To evaluate a four-component knowledge translation intervention aimed at promoting an intent-to-defer strategy for dialysis initiation, we conducted a cluster randomized trial in Canada between October 2014 and November 2015. We randomized 55 clinics, 27 to the intervention group and 28 to the control group. The educational intervention, using knowledge-translation tools, included telephone surveys from a knowledge-translation broker, a 1-year center-specific audit with feedback, delivery of a guidelines package, and an academic detailing visit. Participants included adults who had at least 3 months of predialysis care and who started dialysis in the first year after the intervention. The primary efficacy outcome was the proportion of patients who initiated dialysis early (at eGFR >10.5 ml/min per 1.73 m2). The secondary outcome was the proportion of patients who initiated in the acute inpatient setting.The analysis included 3424 patients initiating dialysis in the 1-year follow-up period. Of these, 509 of 1592 (32.0%) in the intervention arm and 605 of 1832 (33.0%) in the control arm started dialysis early. There was no difference in the proportion of individuals initiating dialysis early or in the proportion of individuals initiating dialysis as an acute inpatient.A multifaceted knowledge translation intervention failed to reduce the proportion of early dialysis starts in patients with CKD followed in multidisciplinary clinics.ClinicalTrials.gov, NCT02183987. Available at: https://clinicaltrials.gov/ct2/show/NCT02183987.
Genetically determined telomere length and multiple myeloma risk and outcome
Authors: Matteo Giaccherini, Angelica Macauda, Enrico Orciuolo, Marcin Rymko, Karolina Gruenpeter, Charles Dumontet, Malgorzata Raźny, Victor Moreno, Gabriele Buda, Katia Beider, Judit Varkonyi, Hervé Avet-Loiseau, Joaquín Martinez-Lopez, Herlander Marques, Marzena Watek, Maria Eugenia Sarasquete, Vibeke Andersen, Lionel Karlin, Anna Suska, Marcin Kruszewski, Niels Abildgaard, Marek Dudziński, Aleksandra Butrym, Arnold Nagler, Annette Juul Vangsted, Katalin Kadar, Tomczak Waldemar, Krzysztof Jamroziak, Svend Erik Hove Jacobsen, Lene Hyldahl Ebbesen, Michał Taszner, Grzegorz Mazur, Fabienne Lesueur, Matteo Pelosini, Ramon Garcia-Sanz, Artur Jurczyszyn, Delphine Demangel, Rui Manuel Reis, Elżbieta Iskierka-Jażdżewska, Miroslaw Markiewicz, Federica Gemignani, Edyta Subocz, Daria Zawirska, Agnieszka Druzd-Sitek, Anna Stępień, M. Henar Alonso, Juan Sainz, Federico Canzian, Daniele Campa
Journal: Blood Cancer Journal (2021)

Abstract Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the “teloscore” in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36–2.11; P = 2.97 × 10 −6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86–0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.
The immune response to SARS-CoV-2 and COVID-19 immunopathology – Current perspectives
Authors: J.L. Boechat, I. Chora, A. Morais, L. Delgado
Journal: Pulmonology (2021)

SARS-CoV-2 is a new beta coronavirus, similar to SARS-CoV-1, that emerged at the end of 2019 in the Hubei province of China. It is responsible for coronavirus disease 2019 (COVID-19), which was declared a pandemic by the World Health Organization on March 11, 2020. The ability to gain quick control of the pandemic has been hampered by a lack of detailed knowledge about SARS-CoV-2-host interactions, mainly in relation to viral biology and host immune response. The rapid clinical course seen in COVID-19 indicates that infection control in asymptomatic patients or patients with mild disease is probably due to the innate immune response, as, considering that SARS-CoV-2 is new to humans, an effective adaptive response would not be expected to occur until approximately 2-3 weeks after contact with the virus. Antiviral innate immunity has humoral components (complement and coagulation-fibrinolysis systems, soluble proteins that recognize glycans on cell surface, interferons, chemokines, and naturally occurring antibodies) and cellular components (natural killer cells and other innate lymphocytes). Failure of this system would pave the way for uncontrolled viral replication in the airways and the mounting of an adaptive immune response, potentially amplified by an inflammatory cascade. Severe COVID-19 appears to be due not only to viral infection but also to a dysregulated immune and inflammatory response. In this paper, the authors review the most recent publications on the immunobiology of SARS-CoV-2, virus interactions with target cells, and host immune responses, and highlight possible associations between deficient innate and acquired immune responses and disease progression and mortality. Immunotherapeutic strategies targeting both the virus and dysfunctional immune responses are also addressed.
Selective expansion of regulatory T cells using an orthogonal IL-2/IL-2 receptor system facilitates transplantation tolerance
Authors: Toshihito Hirai, Teresa L. Ramos, Po-Yu Lin, Federico Simonetta, Leon L. Su, Lora K. Picton, Jeanette Baker, Jian-Xin Lin, Peng Li, Kinya Seo, Juliane K. Lohmeyer, Sara B. Wagers, Melissa Mavers, Warren J. Leonard, Bruce R. Blazar, K. Christopher Garcia, Robert S. Negrin
Journal: Journal of Clinical Investigation (2021)

Adoptive transfer of Tregs has been shown to improve alloengraftment in animal models. However, it is technically challenging to expand Tregs ex vivo for the purpose of infusing large numbers of cells in the clinic. We demonstrate an innovative approach to engineering an orthogonal IL-2/IL-2 receptor (IL-2R) pair, the parts of which selectively interact with each other, transmitting native IL-2 signals, but do not interact with the natural IL-2 or IL-2R counterparts, thereby enabling selective stimulation of target cells in vivo. Here, we introduced this orthogonal IL-2R into Tregs. Upon adoptive transfer in a murine mixed hematopoietic chimerism model, orthogonal IL-2 injection significantly promoted orthogonal IL-2R+Foxp3GFP+CD4+ cell proliferation without increasing other T cell subsets and facilitated donor hematopoietic cell engraftment followed by acceptance of heart allografts. Our data indicate that selective target cell stimulation enabled by the engineered orthogonal cytokine receptor improves Treg potential for the induction of organ transplantation tolerance.
Desmosomal COP9 regulates proteome degradation in arrhythmogenic right ventricular dysplasia/cardiomyopathy
Authors: Yan Liang, Robert C. Lyon, Jason Pellman, William H. Bradford, Stephan Lange, Julius Bogomolovas, Nancy D. Dalton, Yusu Gu, Marcus Bobar, Mong-Hong Lee, Tomoo Iwakuma, Vishal Nigam, Angeliki Asimaki, Melvin Scheinman, Kirk L. Peterson, Farah Sheikh
Journal: Journal of Clinical Investigation (2021)

Dysregulated protein degradative pathways are increasingly recognized as mediators of human disease. This mechanism may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication, as destabilization/breakdown of the desmosomal proteome is a hallmark of genetic-based desmosomal-targeted diseases, such as the cardiac disease arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here, we uncovered a cardiac constitutive photomorphogenesis 9 (COP9) desmosomal resident protein complex, composed of subunit 6 of the COP9 signalosome (CSN6), that enzymatically restricted neddylation and targeted desmosomal proteome degradation. CSN6 binding, localization, levels, and function were affected in hearts of classic mouse and human models of ARVD/C affected by desmosomal loss and mutations, respectively. Loss of desmosomal proteome degradation control due to junctional reduction/loss of CSN6 and human desmosomal mutations destabilizing junctional CSN6 were also sufficient to trigger ARVD/C in mice. We identified a desmosomal resident regulatory complex that restricted desmosomal proteome degradation and disease.
Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft- versus-host disease
Authors: R Storb, HJ Deeg, ED Thomas, FR Appelbaum, CD Buckner, MA Cheever, RA Clift, KC Doney, N Flournoy, MS Kennedy
Journal: Blood (1985)
Emergency Department Visits for COVID-19 by Race and Ethnicity — 13 States, October–December 2020
Authors: Amanda R. Smith, Jourdan DeVies, Elise Caruso, Lakshmi Radhakrishnan, Michael Sheppard, Zachary Stein, Renee M. Calanan, Kathleen P. Hartnett, Aaron Kite-Powell, Loren Rodgers, Jennifer Adjemian
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Data from 13 states indicate that compared with White persons, Hispanic and American Indian or Alaska Native persons experienced 1.7 times the rate, and Black persons experienced 1.4 times the rate of emergency department care visits for COVID-19 during October–December 2020.
Incremental Financial and Health-Related Burden of Novel Drugs Used in the Treatment of Relapsed and/or Refractory Multiple Myeloma (RRMM): A Meta-Analysis of Phase III Randomized Controlled Trials (RCTs)
Authors: Binod Dhakal, Ravi Narra, Timothy Smunt, Angela Canadeo, Saurabh Chhabra, Anita d'Souza, Bishal Gyawali, Parameswaran Hari, Saroj Niraula
Journal: Blood (2017)
Safety of Fibroblast Activation Protein–Targeted Radionuclide Therapy by a Low-Dose Dosimetric Approach Using 177Lu-FAPI04
Authors: Serkan Kuyumcu, Bilal Kovan, Yasemin Sanli, Fikret Buyukkaya, Duygu Has Simsek, Zeynep Gözde Özkan, Emine Goknur Isik, Meltem Ekenel, Cuneyt Turkmen
Journal: Clinical Nuclear Medicine (2021)

Objectives This study is set out to estimate the radiation-absorbed doses to normal organs and tumor tissue using low-dose 177 Lu-FAPI04 dosimetry to determine the safety and theranostic potential of fibroblast activation protein–targeted radionuclide therapy. Patients and Methods Four patients with metastatic advanced-stage cancer were administered low-dose 177 Lu-FAPI04 for dosimetry measurements. Data acquisition for dosimetry of normal organs and tumors was performed by whole-body and 3D SPECT/CT imaging at 4, 24, 48, and 96 hours after administering 177 Lu-FAPI04. Blood samples were drawn at 5, 15, 30, 60, 60, 120, and 180 minutes, and at 24, 48, and 96 hours for bone marrow dosimetry calculations. Results Mean absorbed doses per megabecquerel were 0.25 ± 0.16 mGy (range, 0.11–0.47 mGy), 0.11 ± 0.08 mGy (range, 0.06–0.22 mGy), and 0.04 ± 0.002 mGy (range, 0.04–0.046 mGy) for kidneys, liver, and bone marrow, respectively. The respective maximum estimated amount of radioactivity to reach radiation-absorbed dose limits were 120.9 ± 68.6 GBq, 47.5 ± 2.8 GBq, 397.8 ± 217.1 GBq, and 52.4 ± 15.3 GBq for kidneys, bone marrow, liver, and total body. The mean absorbed dose per megabecquerel was 0.62 ± 0.55 mGy for bone metastases, 0.38 ± 0.22 mGy for metastatic lymph nodes, 0.33 ± 0.21 mGy for liver metastases, and 0.37 ± 0.29 for metastatic soft tissue. The maximum absorbed dose in a tumor lesion was 1.67 mGy/MBq for bone, 0.6 mGy/MBq for lymph node, 0.62 mGy/MBq for liver, and 1 mGy/MBq for soft tissue. Conclusions The mean absorbed dose to organs at risk with 177 Lu-FAPI04 is reasonably low, allowing for low tumor-absorbed dose rates by administering a higher dose. Further research on optimizing therapeutic efficacy and using alternative radioisotopes is necessary, along with an individualized dosimetric approach.
Transepithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome
Authors: Rob Mac Sweeney, Kiran Reddy, Jane C Davies, Mike Parker, Barry Kelly, J Stuart Elborn, John Conlon, Rejina M Verghis, Carolyn S Calfee, Michael A Matthay, Eric W F W Alton, Daniel F McAuley
Journal: Thorax (2021)

Impaired alveolar fluid clearance, determined in part by alveolar sodium transport, is associated with acute respiratory distress syndrome (ARDS). Nasal sodium transport may reflect alveolar transport. The primary objective of this prospective, observational study was to determine if reduced nasal sodium transport, as measured by nasal potential difference (NPD), was predictive of the development of and outcome from ARDS.NPD was measured in 15 healthy controls and in 88 patients: 40 mechanically ventilated patients defined as 'at-risk' for ARDS, 61 mechanically ventilated patients with ARDS (13 who were previously included in the 'at-risk' group) and 8 ARDS survivors on the ward.In at-risk subjects, maximum NPD (mNPD) was greater in those who developed ARDS (difference -8.4 mV; 95% CI -13.8 to -3.7; p=0.005) and increased mNPD predicted the development of ARDS before its onset (area under the curve (AUC) 0.75; 95% CI 0.59 to 0.89). In the ARDS group, mNPD was not significantly different for survivors and non-survivors (p=0.076), and mNPD was a modest predictor of death (AUC 0.60; 95% CI 0.45 to 0.75). mNPD was greater in subjects with ARDS (-30.8 mV) than in at-risk subjects (-24.2 mV) and controls (-19.9 mV) (p<0.001). NPD values were not significantly different for survivors and controls (p=0.18).Increased NPD predicts the development of ARDS in at-risk subjects but does not predict mortality. NPD increases before ARDS develops, is greater during ARDS, but is not significantly different for controls and survivors. These results may reflect the upregulated sodium transport necessary for alveolar fluid clearance in ARDS. NPD may be useful as a biomarker of endogenous mechanisms to stimulate sodium transport. Larger studies are now needed to confirm these associations and predictive performance.
Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204)
Authors: Hussein A Tawbi, Peter A Forsyth, F Stephen Hodi, Christopher D Lao, Stergios J Moschos, Omid Hamid, Michael B Atkins, Karl Lewis, Reena P Thomas, John A Glaspy, Sekwon Jang, Alain P Algazi, Nikhil I Khushalani, Michael A Postow, Anna C Pavlick, Marc S Ernstoff, David A Reardon, Igor Puzanov, Ragini R Kudchadkar, Ahmad A Tarhini, Anne Sumbul, Jasmine I Rizzo, Kim A Margolin
Journal: Neuro-Oncology (2021)

In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients.Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months).Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed.Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.
Human Germline Genome Editing: On the Nature of Our Reasons to Genome Edit
Authors: Robert Sparrow
Journal: The American Journal of Bioethics (2021)

Ever since the publication of Derek Parfit's Reasons and Persons, bioethicists have tended to distinguish between two different ways in which reproductive technologies may have implications for the welfare of future persons. Some interventions harm or benefit particular individuals: they are "person affecting." Other interventions determine which individual, of a number of possible individuals, comes into existence: they are "identity affecting" and raise the famous "non-identity problem." For the past several decades, bioethical debate has, for the most part, proceeded on the assumption that direct genetic modification of human embryos would be person affecting. In this paper, I argue that that genome editing is highly unlikely to be person affecting for the foreseeable future and, as a result, will neither benefit nor harm edited individuals.
3D Mapping Reveals a Complex and Transient Interstitial Matrix During Murine Kidney Development
Authors: Sarah N. Lipp, Kathryn R. Jacobson, David S. Hains, Andrew L. Schwarderer, Sarah Calve
Journal: Journal of the American Society of Nephrology (2021)

The extracellular matrix (ECM) is a network of proteins and glycosaminoglycans that provides structural and biochemical cues to cells. In the kidney, the ECM is critical for nephrogenesis; however, the dynamics of ECM composition and how it relates to 3D structure during development is unknown.
SARS-CoV-2–Specific Antibodies in Breast Milk After COVID-19 Vaccination of Breastfeeding Women
Authors: Sivan Haia Perl, Atara Uzan-Yulzari, Hodaya Klainer, Liron Asiskovich, Michal Youngster, Ehud Rinott, Ilan Youngster
Journal: JAMA (2021)

Hubert Blain, MD, PhD; Edouard Tuaillon, MD, PhD; Lucie Gamon; Amandine Pisoni; Stephanie Miot, MD, PhD; Marie-Christine Picot, MD, PhD; Jean Bousquet, MD, PhD
HOTAIR‐Loaded Mesenchymal Stem/Stromal Cell Extracellular Vesicles Enhance Angiogenesis and Wound Healing
Authors: Louis J. Born, Kai‐Hua Chang, Pouria Shoureshi, Frank Lay, Sameer Bengali, Angela Ting Wei Hsu, Sanaz Nourmohammadi Abadchi, John W. Harmon, Steven M. Jay
Journal: Advanced Healthcare Materials (2021)

Abstract Chronic wounds remain a substantial source of morbidity worldwide. An emergent approach that may be well‐suited to induce the complex, multicellular processes such as angiogenesis that are required for wound repair is the use of extracellular vesicles (EVs). EVs contain a wide variety of proteins and nucleic acids that enable multifactorial signaling. Here, the capability of EVs is leveraged to be engineered via producer cell modification to investigate the therapeutic potential of EVs from mesenchymal stem/stromal cells (MSCs) transfected to overexpress long non‐coding RNA HOX transcript antisense RNA (HOTAIR). HOTAIR is previously shown by the authors' group to be critical in mediating angiogenic effects of endothelial cell EVs, and MSCs are chosen as EV producer cells for this study due to their widely reported intrinsic angiogenic properties. The results indicate that MSCs overexpressing HOTAIR (HOTAIR‐MSCs) produce EVs with increased HOTAIR content that promote angiogenesis and wound healing in diabetic (db/db) mice. Further, endothelial cells exposed to HOTAIR‐MSC EVs exhibit increased HOTAIR content correlated with upregulation of the angiogenic protein vascular endothelial growth factor. Thus, this study supports EV‐mediated HOTAIR delivery as a strategy for further exploration toward healing of chronic wounds.
Abstract IA-007: Exploiting DNA repair defects in head and neck squamous cell carcinoma
Authors: Conchita Vens
Journal: Clinical Cancer Research (2021)

Abstract DNA damage repair pathways govern genomic integrity and determine cellular sensitivities to radiation and chemotherapeutic agents. Recent genetic studies highlight the identification of an increasing number of DNA repair gene defects in many different cancer types. DNA damage response and repair inhibitors on the other hand provide opportunities to exploit such defects inherent to cancer cells. Combined with radiotherapy they are highly effective radiosensitizers that show some tumor specificity in that they cause greater radiation dose enhancement in cells with repair defects. To optimize such potent combinations, robust and sensitive biomarkers are needed to 1) assess effectivity and guide clinical trial designs and 2) to identify repair defects in individual patients. Radiotherapy is a mainstay in the treatment of advanced HPV-negative head and neck squamous cell carcinoma (HNSCC). There is a need for improved treatment options in this patient population. Indicating particular crosslink repair sensitivity and frequent cancer cell repair defects, cumulative cisplatin dose is an important factor in determining patient outcomes after chemoradiotherapy. Indeed, preclinical and genetic data highlight the frequent manifestation of DNA crosslink repair defects in HNSCC. Genetic biomarkers have therefore been generated and tested to support the identification of patients in need for novel treatment options and of crosslink repair defects in HNSCC for combination with PARP inhibitors. Citation Format: Conchita Vens. Exploiting DNA repair defects in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-007.