tbuckley/cabot-search huggingface dataset:
FROM BENIGN TO MALIGNANT DISEASE
Authors: Niccolò Bolli
Journal: HemaSphere (2022)

It is believed that every multiple myeloma (MM) case evolves from asymptomatic conditions called monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), even if these are not actually diagnosed before MM. MGUS is considered a pre-malignant condition and SMM an indolent cancer. However, this distinction was based on the clinical observation of their different rate of progression towards MM more than on actual biological studies. Recent next-generation sequencing (NGS) studies on MGUS/SMM show that these asymptomatic conditions share many of the driver genomic abnormalities of MM, indicating that the plasma cell clone has accumulated a notable oncogenic burden already in early clinical stages. However, one question is whether NGS can be exploited clinically to identify, among MGUS and SMM, patients at the highest risk of progression. Indeed, non-progressing MGUS/SMM show a distinct genomic spectrum of events, namely fewer hotspot gene mutations, segmental chromosomal deletions, complex rearrangements, and lower activity of the APOBEC family of DNA deaminases. Conversely, progressing MGUS/SMM show a genomic profile that is not different -on average- to the one of active MM at diagnosis, suggesting that current diagnostic criteria, mostly based on clinical and laboratory surrogates of disease burden, do not capture the actual disease biology. Also, using genomic techniques to estimate the time of acquisition of the first clonal event in the patient, it can be extrapolated that non-progressing MGUS/SMM arose closer to the day of sampling than active MM, where a decades-long subclinical evolution can be inferred. Looking at evolution of SMM into MM, two main patterns can be observed: one where the tumor does not change, implying it biologically is a MM from the start and early treatment may be beneficial; and another where the genomic composition of the tumor changes, implying the tumor was actually indolent at the time of diagnosis and treatment strategy may be aimed at eradication before the acquisition of aggressive subclones. Recent evidence suggests there is an advantage when treating SMM early, and studies are evaluating whether a more aggressive diagnosis approach -or even MGUS screening- may be beneficial for the patient. However, this will need to be paralleled by a better understanding of the biology of the tumor, and genomic prognostication may help better prognostication and treatment choices in MGUS/SMM patients.
Beyond knowledge versus belief: The contents of mental-state representations and their underlying computations
Authors: Mika Asaba, Aaron Chuey, Hyowon Gweon
Journal: Behavioral and Brain Sciences (2021)

Abstract Moving beyond distinguishing knowledge and beliefs, we propose two lines of inquiry for the next generation of theory of mind (ToM) research: (1) characterizing the contents of different mental-state representations and (2) formalizing the computations that generate such contents. Studying how children reason about what others think of the self provides an illuminating window into the richness and flexibility of human social cognition.
PARP-1 suppresses adiponectin expression through poly(ADP-ribosyl)ation of PPARγ in cardiac fibroblasts
Authors: Dan Huang, Chongzhe Yang, Yan Wang, Yuhua Liao, Kai Huang
Journal: Cardiovascular Research (2021)

Cardiovascular Research, Volume 81, Issue 1, 1 January 2009, Pages 98–107, https://doi.org/10.1093/cvr/cvn264 The Editor’s attention was drawn to this paper by a reader regarding concerns around Figures 6A and 1B and Figures 4B and 4C. After conducting in-house analysis, we concluded that there was no wrongdoing in relation to Figures 6A and 1B. We agreed that a correction should be made to Figures 4B and 4C. The Editorial Office received an erratum request from the first authors of the paper, regarding Figures 4B and 4C, which was subsequently withdrawn. This matter will now be reviewed by the ESC family Journal Ethics committee. The Editors of Cardiovascular Research have decided to place an expression of concern related to this paper to inform readers appropriately whilst we wait for the outcome of the investigation.
Cemented or Uncemented Hemiarthroplasty for Intracapsular Hip Fracture
Authors: Miguel A. Fernandez, Juul Achten, Nicholas Parsons, Xavier L. Griffin, May-Ee Png, Jenny Gould, Alwin McGibbon, Matthew L. Costa
Journal: New England Journal of Medicine (2022)

Controversy exists over the use of bone cement in hip fractures treated with hemiarthroplasty. Only limited data on quality of life after cemented as compared with modern uncemented hemiarthroplasties are available.We conducted a multicenter, randomized, controlled trial comparing cemented with uncemented hemiarthroplasty in patients 60 years of age or older with an intracapsular hip fracture. The primary outcome was health-related quality of life measured with the use of utility scores on the EuroQol Group 5-Dimension (EQ-5D) questionnaire at 4 months after randomization (range of scores, -0.594 to 1, with higher scores indicating better quality of life; range for minimal clinically important difference, 0.050 to 0.075).A total of 610 patients were assigned to undergo cemented hemiarthroplasty and 615 to undergo modern uncemented hemiarthroplasty; follow-up data were available for 71.6% of the patients at 4 months. The mean EQ-5D utility score was 0.371 in patients assigned to the cemented group and 0.315 in those assigned to the uncemented group (adjusted difference, 0.055; 95% confidence interval [CI], 0.009 to 0.101; P = 0.02). The between-group difference at 1 month was similar to that at 4 months, but the difference at 12 months was smaller than that at 4 months. Mortality at 12 months was 23.9% in the cemented group and 27.8% in the uncemented group (odds ratio for death, 0.80; 95% CI, 0.62 to 1.05). Periprosthetic fractures occurred in 0.5% and 2.1% of the patients in the respective groups (odds ratio [uncemented vs. cemented], 4.37; 95% CI, 1.19 to 24.00). The incidences of other complications were similar in the two groups.Among patients 60 years of age or older with an intracapsular hip fracture, cemented hemiarthroplasty resulted in a modestly but significantly better quality of life and a lower risk of periprosthetic fracture than uncemented hemiarthroplasty. (Funded by the National Institute for Health Research; WHiTE 5 ISRCTN number, ISRCTN18393176.).
Abstract 019: Estimated Benefits And Risks Of Lowering Sodium Through Potassium-enriched Salt Substitution In India: A Modeling Study
Authors: Matti Marklund, Rachita Gupta, Fikru T Tullu, Bruce Neal, Jason H Wu
Journal: Circulation (2022)

Objectives: To estimate the overall health impact in India of nationwide salt substitution (i.e., replacement of regular salt used at home for cooking or at the table with potassium-enriched reduced-sodium salt substitute). Methods: We used a comparative risk assessment framework to estimate 1) the number of cardiovascular disease (CVD) deaths averted due to blood pressure reductions in all adults, 2) the potential number of hyperkalemia deaths from increased potassium intake in individuals with advanced chronic kidney disease (CKD, estimated glomerular filtration rate &lt;60 mL/min per 1.73 m 2 ), and 3) the net averted deaths (calculated as the difference of 1 and 2) from nationwide salt substitution in India. We evaluated a conservative scenario, deriving key model inputs and assumptions from a large, long-term pragmatic trial recently concluded in rural China; and an optimistic scenario informed by findings from our recent salt substitution trial in India. The models incorporated existing data and corresponding uncertainties from randomised trials, national surveys, the Global Burden of Disease Study, and the CKD Prognosis Consortium. Sensitivity analyses were conducted to assess the robustness of the findings to alterations in model inputs and assumptions. Results: In the conservative scenario, salt substitution was estimated to result in a net ~191 000 (95% uncertainty interval: 69 683; 329 147) fewer CVD deaths annually in the overall population, and ~30 000 (1 052; 58 409) fewer deaths among 28 million individuals with advanced CKD (Figure). In the optimistic scenario, the corresponding numbers were ~343 000 (120 035; 537 134) and ~57 000 (14 253; 96 606). Net benefits were consistent in deterministic sensitivity analyses (Figure). Conclusions: Nationwide salt substitution in India was consistently estimated to result in substantial net benefits, preventing around 8-14% of annual CVD deaths in India. Even considering risks of hyperkalaemia, net benefits were also projected for individuals with CKD
Value of Neoadjuvant Radiation Therapy in the Management of Pancreatic Adenocarcinoma
Authors: William A. Hall, Laura A. Dawson, Theodore S. Hong, Manisha Palta, Joseph M. Herman, Douglas B. Evans, Susan Tsai, Cristina R. Ferrone, Jason B. Fleming, Daniel T. Chang, Christopher Crane, Albert C. Koong, Andrew Oar, Parag Parikh, Beth Erickson, Sarah Hoffe, Karyn A. Goodman
Journal: Journal of Clinical Oncology (2021)
Endoscopy International Open – recently published
Journal: Endoscopy (2022)

Comment on: Impact of ≥ 0.1-mm free resection margins on local intramural residual cancer after local excision of T1 colorectal cancerEndosc Int Open 2022; 10(04): E282-E290DOI: 10.1055/a-1736-6960 Comment on: Usefulness of optical enhancement endoscopy combined with magnification to improve detection of intestinal metaplasia in the stomachEndosc Int Open 2022; 10(04): E441-E447DOI: 10.1055/a-1759-2568 Comment on: Using fecal immunochemical test values below conventional cut-off to individualize colorectal cancer screeningEndosc Int Open 2022; 10(04): E413-E419DOI: 10.1055/a-1743-2651
Universal annotation of the human genome through integration of over a thousand epigenomic datasets
Authors: Ha Vu, Jason Ernst
Journal: Genome biology (2022)

Genome-wide maps of chromatin marks such as histone modifications and open chromatin sites provide valuable information for annotating the non-coding genome, including identifying regulatory elements. Computational approaches such as ChromHMM have been applied to discover and annotate chromatin states defined by combinatorial and spatial patterns of chromatin marks within the same cell type. An alternative "stacked modeling" approach was previously suggested, where chromatin states are defined jointly from datasets of multiple cell types to produce a single universal genome annotation based on all datasets. Despite its potential benefits for applications that are not specific to one cell type, such an approach was previously applied only for small-scale specialized purposes. Large-scale applications of stacked modeling have previously posed scalability challenges.
A forced marriage of IL-2 and PD-1 antibody nurtures tumor-infiltrating T cells
Authors: Erin A. Holcomb, Weiping Zou
Journal: Journal of Clinical Investigation (2022)

IL-2 is a pleiotropic cytokine. In this issue of the JCI, Ren et al. report on the development of a low-affinity IL-2 paired with anti–PD-1 (PD-1–laIL-2) that reactivates intratumoral CD8+ T cells, but not CD4+ Treg cells. PD-1–laIL-2 treatment synergized with anti–PD-L1 therapy to overcome tumor resistance to immune checkpoint blockade (ICB) in tumor-bearing mice. Rejection of rechallenged tumors following PD-1–laIL-2 therapy demonstrated the establishment of a potent T cell memory response. Furthermore, PD-1–laIL-2 therapy manifested no obvious toxicity. These findings suggest the potential of PD-1–laIL-2 therapy in treating patients with cancer.
Personalizing First-Line Management of Metastatic Renal Cell Carcinoma: Leveraging Current and Novel Therapeutic Options
Authors: Kelly N. Fitzgerald, Chung-Han Lee
Journal: Journal of the National Comprehensive Cancer Network (2022)

The treatment of metastatic renal cell carcinoma (RCC) has been revolutionized by advances in immunotherapeutic and targeted agents. Therapeutic approaches to RCC in these categories have recently evolved to include immune checkpoint inhibitors, novel vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors, and combinations of those agents. Multiple regimens within each category have been approved for use in the first-line treatment of clear cell and non-clear cell RCC. However, few of these regimens have been directly compared, leading to a new clinical challenge for physicians: how to select a first-line treatment regimen for an individual patient from among multiple approved options. In the modern era of RCC management, the initial treatment selection therefore becomes highly personalized and depends on numerous patient-specific factors, including histopathologic and clinical features of the disease, comorbid conditions, and psychosocial and economic factors. This review details current first-line treatment options for the management of metastatic RCC and proposes a framework whereby treatment selection can be optimized for individual patients.
Long-term use of immunosuppressive medicines and in-hospital COVID-19 outcomes: a retrospective cohort study using data from the National COVID Cohort Collaborative
Authors: Kathleen M Andersen, Benjamin A Bates, Emaan S Rashidi, Amy L Olex, Roslyn B Mannon, Rena C Patel, Jasvinder Singh, Jing Sun, Paul G Auwaerter, Derek K Ng, Jodi B Segal, Brian T Garibaldi, Hemalkumar B Mehta, G Caleb Alexander, Melissa A Haendel, Christopher G Chute
Journal: The Lancet Rheumatology (2021)

Many individuals take long-term immunosuppressive medications. We evaluated whether these individuals have worse outcomes when hospitalised with COVID-19 compared with non-immunosuppressed individuals.
Lifting the Illusion
Authors: Michelle Izmaylov
Journal: Annals of Internal Medicine (2022)

On Being a DoctorMarch 2022Lifting the IllusionMichelle Izmaylov, MDMichelle Izmaylov, MDVanderbilt University Medical Center Nashville, TennesseeSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-4215 Audio Reading - “Lifting the Illusion” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads “Lifting the Illusion” by Michelle Izmaylov, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I whisper abracadabra—a word that means I will create as I speak—and pull a radiant red flower out of the space between my ribs. I hold its dazzling beauty before your gaze, and you believe that, embodied in those pretty petals, I have spoken all the words inside my chest into existence. Yes, that's right: watch this flower and don't notice what I conjure in my second hand concealed behind my back, abracadabra, the power of a magician's careful sleight of hand.My first study in this art takes place in middle school, early, sitting beside my friend on the ... Author, Article, and Disclosure InformationAffiliations: Vanderbilt University Medical Center Nashville, TennesseeCorresponding Author: Michelle Izmaylov, MD, 1211 Medical Center Drive, Nashville, TN 37232; e-mail, michelle.l.izmaylov.[email protected]org. PreviousarticleNextarticle Advertisement Audio Reading - “Lifting the Illusion” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads “Lifting the Illusion” by Michelle Izmaylov, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics March 2022Volume 175, Issue 3Page: 452-453 ePublished: 15 March 2022 Issue Published: March 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Changes in target ability of nanoparticles due to protein corona composition and disease state
Authors: Wenwen Xu, Mingyu Xu, Yumeng Xiao, Lu Yu, Huiru Xie, Xuehua Jiang, Meiwan Chen, Huile Gao, Ling Wang
Journal: Asian Journal of Pharmaceutical Sciences (2022)

Many studies have shown the influence of protein corona (PC) on the active targeting capability of ligand-modified nanoparticles; however, the influence of clinical status on PC composition and targeting capacity is rarely discussed. In this study, when transferrin-modified PEGylated polystyrene nanoparticles (Tf-PNs) is intravenously injected into mice with non-small cell lung cancer (NSCLC) comorbid with type 2 diabetes mellitus (T2DM), more Tf-PNs accumulated in the tumor tissue than in those of NSCLC model mice. This indicated that PC derived from different states of disease changed the active targeting ability of Tf-PNs. To explain the occurrence of this phenomenon, our analysis of PC from different disease states revealed that Tf (transferrin) modification had no significant effect on the formation of PC, and that the PC from the NSCLC comorbid with T2DM model contained more proteins like fibrin and clusterin. This work demonstrates the impacts of comorbidity, such as with T2DM, on the active targeting capability of ligand-modified nanoparticles, and the results promote the application of nanoparticles for precision medicine.
Platelet Transcriptome Yields Progressive Markers in Chronic Myeloproliferative Neoplasms and Identifies Putative Targets of Therapy
Authors: Zhu Shen, Wenfei Du, Cecelia Perkins, Lenn Fechter, Vanita Natu, Holden T. Maecker, Jesse W Rowley, Jason Gotlib, James L Zehnder, Anandi Krishnan
Journal: Blood (2021)
Effectiveness of Covid-19 Vaccines over a 9-Month Period in North Carolina
Authors: Dan-Yu Lin, Yu Gu, Bradford Wheeler, Hayley Young, Shannon Holloway, Shadia-Khan Sunny, Zack Moore, Donglin Zeng
Journal: New England Journal of Medicine (2022)

The duration of protection afforded by coronavirus disease 2019 (Covid-19) vaccines in the United States is unclear. Whether the increase in postvaccination infections during the summer of 2021 was caused by declining immunity over time, the emergence of the B.1.617.2 (delta) variant, or both is unknown.We extracted data regarding Covid-19-related vaccination and outcomes during a 9-month period (December 11, 2020, to September 8, 2021) for approximately 10.6 million North Carolina residents by linking data from the North Carolina Covid-19 Surveillance System and the Covid-19 Vaccine Management System. We used a Cox regression model to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & Johnson-Janssen) vaccines in reducing the current risks of Covid-19, hospitalization, and death, as a function of time elapsed since vaccination.For the two-dose regimens of messenger RNA (mRNA) vaccines BNT162b2 (30 μg per dose) and mRNA-1273 (100 μg per dose), vaccine effectiveness against Covid-19 was 94.5% (95% confidence interval [CI], 94.1 to 94.9) and 95.9% (95% CI, 95.5 to 96.2), respectively, at 2 months after the first dose and decreased to 66.6% (95% CI, 65.2 to 67.8) and 80.3% (95% CI, 79.3 to 81.2), respectively, at 7 months. Among early recipients of BNT162b2 and mRNA-1273, effectiveness decreased by approximately 15 and 10 percentage points, respectively, from mid-June to mid-July, when the delta variant became dominant. For the one-dose regimen of Ad26.COV2.S (5 × 1010 viral particles), effectiveness against Covid-19 was 74.8% (95% CI, 72.5 to 76.9) at 1 month and decreased to 59.4% (95% CI, 57.2 to 61.5) at 5 months. All three vaccines maintained better effectiveness in preventing hospitalization and death than in preventing infection over time, although the two mRNA vaccines provided higher levels of protection than Ad26.COV2.S.All three Covid-19 vaccines had durable effectiveness in reducing the risks of hospitalization and death. Waning protection against infection over time was due to both declining immunity and the emergence of the delta variant. (Funded by a Dennis Gillings Distinguished Professorship and the National Institutes of Health.).
Exceptionally potent human monoclonal antibodies are effective for prophylaxis and treatment of tetanus in mice
Authors: Marco Pirazzini, Alessandro Grinzato, Davide Corti, Sonia Barbieri, Oneda Leka, Francesca Vallese, Marika Tonellato, Chiara Silacci-Fregni, Luca Piccoli, Eaazhisai Kandiah, Giampietro Schiavo, Giuseppe Zanotti, Antonio Lanzavecchia, Cesare Montecucco
Journal: Journal of Clinical Investigation (2021)

We used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for hyperimmune sera to treat tetanus in mice. By screening memory B cells from immune donors, we selected 2 tetanus neurotoxin-specific mAbs with exceptionally high neutralizing activities and extensively characterized them both structurally and functionally. We found that these antibodies interfered with the binding and translocation of the neurotoxin into neurons by interacting with 2 epitopes, whose identification pinpoints crucial events in the cellular pathogenesis of tetanus. Our observations explain the neutralization ability of these antibodies, which we found to be exceptionally potent in preventing experimental tetanus when injected into mice long before the toxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential for therapeutic use via intrathecal injection. As such, we believe these humAbs, as well as their Fab derivatives, meet the requirements to be considered for prophylactic and therapeutic use in human tetanus and are ready for clinical trials.
Extracellular Vesicles Protect the Neonatal Lung from Hyperoxic Injury through the Epigenetic and Transcriptomic Reprogramming of Myeloid Cells
Authors: Gareth R. Willis, Monica Reis, Ali Hashemi Gheinani, Angeles Fernandez-Gonzalez, Elizabeth S. Taglauer, Vincent Yeung, Xianlan Liu, Maria Ericsson, Eric Haas, S. Alex Mitsialis, Stella Kourembanas
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Mesenchymal stem/stromal cell (MSC)-small extracellular vesicle (MEx) treatment has shown promise in experimental models of neonatal lung injury. The molecular mechanisms by which MEx afford beneficial effects remain incompletely understood.