tbuckley/cabot-search huggingface dataset:
Long-term corneal recovery by simultaneous delivery of hPSC-derived corneal endothelial precursors and nicotinamide
Authors: Zongyi Li, Haoyun Duan, Yanni Jia, Can Zhao, Wenjing Li, Xin Wang, Yajie Gong, Chunxiao Dong, Bochao Ma, Shengqian Dou, Bin Zhang, Dongfang Li, Yihai Cao, Lixin Xie, Qingjun Zhou, Weiyun Shi
Journal: Journal of Clinical Investigation (2022)

Human pluripotent stem cells (hPSCs) hold great promise for the treatment of various human diseases. However, their therapeutic benefits and mechanisms for treating corneal endothelial dysfunction remain undefined. Here, we developed a therapeutic regimen consisting of the combination of hPSC-derived corneal endothelial precursors (CEPs) with nicotinamide (NAM) for effective treatment of corneal endothelial dysfunction. In rabbit and nonhuman primate models, intracameral injection of CEPs and NAM achieved long-term recovery of corneal clarity and thickness, similar with the therapeutic outcome of cultured human corneal endothelial cells (CECs). The transplanted human CEPs exhibited structural and functional integration with host resident CECs. However, the long-term recovery relied on the stimulation of endogenous endothelial regeneration in rabbits, but predominantly on the replacing function of transplanted cells during the 3-year follow-up in nonhuman primates, which resemble human corneal endothelium with limited regenerative capacity. Mechanistically, NAM ensured in vivo proper maturation of transplanted CEPs into functional CECs by preventing premature senescence and endothelial-mesenchymal transition within the TGF-β–enriched aqueous humor. Together, we provide compelling experimental evidence and mechanistic insights of simultaneous delivery of CEPs and NAM as a potential approach for treating corneal endothelial dysfunction.
Effectiveness of CoronaVac, ChAdOx1 nCoV-19, BNT162b2, and Ad26.COV2.S among individuals with previous SARS-CoV-2 infection in Brazil: a test-negative, case-control study
Authors: Thiago Cerqueira-Silva, Jason R Andrews, Viviane S Boaventura, Otavio T Ranzani, Vinicius de Araújo Oliveira, Enny S Paixão, Juracy Bertoldo Júnior, Tales Mota Machado, Matt D T Hitchings, Murilo Dorion, Margaret L Lind, Gerson O Penna, Derek A T Cummings, Natalie E Dean, Guilherme Loureiro Werneck, Neil Pearce, Mauricio L Barreto, Albert I Ko, Julio Croda, Manoel Barral-Netto
Journal: The Lancet Infectious Diseases (2022)
Knowledge<i>is</i>belief – and shaped by culture
Authors: Andrea Bender, John B. Gatewood
Journal: Behavioral and Brain Sciences (2021)

Abstract Phillips and colleagues claim that the representation of knowledge is more basic than the representation of belief, presupposing them to be categorically distinct mental states with distinct evolutionary purposes. We argue that the relationship between the two is much more complex, is further shaped by culture and language, and leaves its mark on manifestations of theory of mind and teaching.
De Quervain Subacute Thyroiditis With Moderate PSMA Uptake Mimicking Thyroid Metastasis of Renal Cell Carcinoma
Authors: Theresa Leder, Robert Drescher, Falk Gühne, Bernhard Theis, Martin Freesmeyer
Journal: Clinical Nuclear Medicine (2021)

PSMA-targeted PET/CT can be used for diagnosis and staging of clear cell renal cell carcinoma. A 68-year-old woman with suspected hepatic metastases from clear cell renal cell carcinoma underwent PET/CT with 68Ga-PSMA, which showed a focus of moderately increased tracer uptake in the right thyroid lobe. Sonography displayed a correlating hypoechogenic, ill-defined node (TIRADS 5). Right hemithyroidectomy was performed in the assumption of a solitary metastasis of renal cell carcinoma. Histologic examination revealed subacute granulomatous thyroiditis (De Quervain thyroiditis) without evidence of malignancy.
Abstract 056: Inflammatory Cytokines And Incident Hypertension In The REasons For Geographic And Racial Differences In Stroke (REGARDS) Study
Authors: Timothy B Plante, Stephen P Juraschek, George Howard, Virginia J Howard, Russell P Tracy, Suzanne E Judd, Debora Kamin Mukaz, Neil A Zakai, D Leann Long, Mary Cushman
Journal: Circulation (2022)

Background: Higher C-reactive protein (CRP) is a risk factor for incident hypertension, but this non-specific inflammatory biomarker does not provide insight into specific immune pathways of hypertension. Here, we studied the role of selected cytokines in risk of incident hypertension to better elucidate these pathways. Objective: To determine the risk for incident hypertension disease among adults by level of IL-1β, IL-6, TNF-α, and IFN-γ. Methods: REGARDS recruited 30,239 Black and White adults aged ≥45 years from the 48 contiguous states in 2003-07. The Biomarkers as Mediators of Racial Disparities in Risk Factors (BioMedioR) substudy included 4,400 sex-race stratified REGARDS participants who also attendd a visit in 2013-16. We excluded those in BioMedioR with prevalent hypertension: 140/90 mm Hg threshold or self-reported antihypertensive medication use. Serum ELISAs assessed cytokines. Modified Poisson regression estimated relative risk (RR) of incident hypertension by detectable threshold (IL-1β; &gt;0.06 pg/mL) or cytokine tertiles (tertile thresholds [33 rd &amp; 66 th %iles] in pg/mL: IL-6, 0.56 &amp; 0.94; TNF-α, 1.30 &amp; 1.69; IFN-γ, 4.01 &amp; 6.56). IL-1β was stratified on race because of a statistically significant interaction. Results: Among the 1,877 participants at risk for incident hypertension (mean [SD] age 62 [8] years, 36% Black race, 51% women), incident hypertension occurred in 31% of White adults and 45% of Black adults. With full adjustment ( Figure ), higher TNF-α and IFN-γ in everyone, and detectable IL-1β in White but not Black adults, were associated with greater incident hypertension risk. There was no association of higher IL-6 with incident hypertension. Conclusions: Among Black and White adults without prevalent hypertension, higher TNF-α, and IFN-γ, and detectable IL-1β (among White but not Black adults), were associated with greater risk of incident hypertension. Future basic and clinical research should study these inflammatory pathways toward developing hypertension prevention strategies.
Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: results of a systematic review and meta-regression
Authors: Daniel R Feikin, Melissa M Higdon, Laith J Abu-Raddad, Nick Andrews, Rafael Araos, Yair Goldberg, Michelle J Groome, Amit Huppert, Katherine L O'Brien, Peter G Smith, Annelies Wilder-Smith, Scott Zeger, Maria Deloria Knoll, Minal K Patel
Journal: The Lancet (2022)

Knowing whether COVID-19 vaccine effectiveness wanes is crucial for informing vaccine policy, such as the need for and timing of booster doses. We aimed to systematically review the evidence for the duration of protection of COVID-19 vaccines against various clinical outcomes, and to assess changes in the rates of breakthrough infection caused by the delta variant with increasing time since vaccination.
Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial
Authors: Gontran Verset, Ivan Borbath, Mark Karwal, Chris Verslype, Hans Van Vlierberghe, Adel Kardosh, Vittorina Zagonel, Per Stal, Debashis Sarker, Daniel H. Palmer, Arndt Vogel, Julien Edeline, Stephane Cattan, Masatoshi Kudo, Ann-Lii Cheng, Sadahisa Ogasawara, Bruno Daniele, Stephen L. Chan, Jennifer J. Knox, Shukui Qin, Abby B. Siegel, Michael Chisamore, Ken Hatogai, Anran Wang, Richard S. Finn, Andrew X. Zhu
Journal: Clinical Cancer Research (2022)

KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy.
Upfront Use of 177Lu-Labeled PSMA Radioligand Therapy and Treatment Response Assessment in Treatment-Naive Prostate Cancer
Authors: Dharmender Malik, Ishita B. Sen, Parul Thakral, Subha Shankar Das, Divya Manda, Virupakshappa CB
Journal: Clinical Nuclear Medicine (2021)

Prostatic malignancy is the most common type of nonskin cancer and associated with significant morbidity and mortality. Early androgen deprivation therapy (ADT) is the treatment of choice in metastatic prostate cancer, whereas ADT delays progression of disease, but it is associated with significant adverse effects and frequently impairs the quality of life. Therefore, there is growing interest in treatments to postpone ADT while achieving a good progression-free survival. We present a case of oligometastatic prostate cancer, who was treated upfront with 177Lu-labeled PSMA radioligand therapy and demonstrated excellent response to a single dose of 177Lu-PSMA-617.
PARPs: All for One and One for All? Enhancing Diversity in Clinical Trials
Authors: Shibani Nicum, Sarah P. Blagden
Journal: Clinical Cancer Research (2022)

Summary PARP inhibitors have revolutionized the management of ovarian cancer and are being licensed for other cancer indications. The clinical trials prompting licensing decisions in ovarian cancer were dominated by White participants, or participant ethnicity was not documented. To compensate for this, replicative studies like L-MOCA can be run in specific ethnic groups. In the future, strategies such as mandatory collection and publication of race and ethnicity data are essential alongside concerted efforts to widen the inclusivity of trial recruitment. See related article by Gao et al., p. 2278
Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences
Authors: Tenna Vesterman Henriksen, Noelia Tarazona, Amanda Frydendahl, Thomas Reinert, Francisco Gimeno-Valiente, Juan Antonio Carbonell-Asins, Shruti Sharma, Derrick Renner, Dina Hafez, Desamparados Roda, Marisol Huerta, Susana Roselló, Anders Husted Madsen, Uffe S. Løve, Per Vadgaard Andersen, Ole Thorlacius-Ussing, Lene Hjerrild Iversen, Kåre Andersson Gotschalck, Himanshu Sethi, Alexey Aleshin, Andres Cervantes, Claus Lindbjerg Andersen
Journal: Clinical Cancer Research (2021)

Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates.We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing.Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7-13.5; P < 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4-167; P < 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9-172; P < 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P < 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1-6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography.Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making.See related commentary by Morris and George, p. 438.
Cold atmospheric plasma for preventing infection of viruses that use ACE2 for entry
Authors: Peiyu Wang, Renwu Zhou, Rusen Zhou, Wenshao Li, Janith Weerasinghe, Shuxiong Chen, Bernd H. A. Rehm, Liqian Zhao, Francesca D. Frentiu, Zhifa Zhang, Kexin Yan, Mary Lor, Andreas Suhrbier, Derek J. Richard, Erik W. Thompson, Kostya Ken Ostrikov, Xiaofeng Dai
Journal: Theranostics (2022)

The mutating SARS-CoV-2 potentially impairs the efficacy of current vaccines or antibody-based treatments. Broad-spectrum and rapid anti-virus methods feasible for regular epidemic prevention against COVID-19 or alike are urgently called for.
The Shooting
Authors: Gillian Naro
Journal: Annals of Internal Medicine (2022)

On Being a DoctorMarch 2022The ShootingGillian Naro, MD, MEdGillian Naro, MD, MEdThomas Jefferson University Hospital Philadelphia, PennsylvaniaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-4391 Audio Reading - “The Shooting” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads “The Shooting” by Gillian Naro, MD, MEd 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 Every night, you will find admitting residents and float teams tucked away in the resident lounge at Thomas Jefferson University Hospital. These doctors are responsible for admissions, rapid response calls, and codes in the hospital at night. All of the internal medicine residents assigned to this shift work together in this one room.The atmosphere is exhausting and busy, yet there is a real spirit of friendship and mutual trust. On quiet nights, we will play games together and enjoy each other's company. On busy nights, most nights, we work together to manage a 1000-bed hospital's worth of patients. We ... Author, Article, and Disclosure InformationAffiliations: Thomas Jefferson University Hospital Philadelphia, PennsylvaniaCorresponding Author: Gillian Naro, MD, MEd, 833 Chestnut Street, Suite 220, Philadelphia, PA 19107; e-mail, Gillian.[email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “The Shooting” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads “The Shooting” by Gillian Naro, MD, MEd 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 Cited byFirearm Injury in the United States: Time to Confront It as the Epidemic It Has BecomeChristine Laine, MD, MPH and Sue S. Bornstein, MD March 2022Volume 175, Issue 3Page: 454 ePublished: 15 March 2022 Issue Published: March 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities
Authors: Ilias Christodoulou, Won Jin Ho, Andrew Marple, Jonas W Ravich, Ada Tam, Ruyan Rahnama, Adam Fearnow, Cambrynne Rietberg, Sean Yanik, Elena E Solomou, Ravi Varadhan, Michael A Koldobskiy, Challice L Bonifant
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The prognosis of patients with recurrent/refractory acute myelogenous leukemia (AML) remains poor and cell-based immunotherapies hold promise to improve outcomes. Natural Killer (NK) cells can elicit an antileukemic response via a repertoire of activating receptors that bind AML surface ligands. NK-cell adoptive transfer is safe but thus far has shown limited anti-AML efficacy. Here, we aimed to overcome this limitation by engineering NK cells to express chimeric antigen receptors (CARs) to boost their anti-AML activity and interleukin (IL)-15 to enhance their persistence. Methods We characterized in detail NK-cell populations expressing a panel of AML (CD123)-specific CARs and/or IL-15 in vitro and in AML xenograft models. Results CARs with 2B4.ζ or 4-1BB.ζ signaling domains demonstrated greater cell surface expression and endowed NK cells with improved anti-AML activity in vitro. Initial in vivo testing revealed that only 2B4.ζ Chimeric Antigen Receptor (CAR)-NK cells had improved anti-AML activity in comparison to untransduced (UTD) and 4-1BB.ζ CAR-NK cells. However, the benefit was transient due to limited CAR-NK-cell persistence. Transgenic expression of secretory interleukin (sIL)-15 in 2B4.ζ CAR and UTD NK cells improved their effector function in the setting of chronic antigen simulation in vitro. Multiparameter flow analysis after chronic antigen exposure identified the expansion of unique NK-cell subsets. 2B4.ζ/sIL-15 CAR and sIL-15 NK cells maintained an overall activated NK-cell phenotype. This was confirmed by transcriptomic analysis, which revealed a highly proliferative and activated signature in these NK-cell groups. In vivo, 2B4.ζ/sIL-15 CAR-NK cells had potent anti-AML activity in one model, while 2B4.ζ/sIL-15 CAR and sIL-15 NK cells induced lethal toxicity in a second model. Conclusion Transgenic expression of CD123-CARs and sIL-15 enabled NK cells to function in the setting of chronic antigen exposure but was associated with systemic toxicities. Thus, our study provides the impetus to explore inducible and controllable expression systems to provide cytokine signals to AML-specific CAR-NK cells before embarking on early-phase clinical testing.
Parental preferences for a mandatory vaccination scheme in England: A discrete choice experiment
Authors: Louise E. Smith, Ben Carter
Journal: The Lancet Regional Health - Europe (2022)

Mandatory vaccination has been mooted to combat falling childhood vaccine uptake rates in England. This study investigated parental preferences for a mandatory vaccination scheme.Discrete choice experiment. Six attributes were investigated: vaccine, child age group, incentive, penalty, ability to opt out, and compensation scheme. Mixed effects conditional logit regression models were used to investigate parental preferences and relative importance of attributes.Participants were 1,001 parents of children aged 5 years and under in England (53% female; mean age=33·6 years, SD=7·1; 84% white). Parental preferences were mostly based on incentives (30·7% relative importance; 80·9% [95% confidence interval 76·3-85·0%] preference for parent and 74·8% [71·0-78·3%] for child incentive; reference: no incentive) and penalties (25·4% relative importance; 69·5% [65·7-73·1%] preference for schemes where unvaccinated children cannot attend school or day care and 67·6% [63·6-71·4%] for those withholding financial benefits for parents of unvaccinated children; reference: £450 fine). Parents also preferred schemes that: offered a compensation scheme (18·1% relative importance; 66·4% [62·7-69·8%] preference; reference: not offered), mandated vaccination in children aged 2 years (versus 5 years; 11·4% relative importance; 42·6% [39·4-45·9%] preference; reference: 2 years), mandated the 6-in-1 vaccine (10·5% relative importance; 58·2% [54·6-61·7%] preference; reference: MMR), and that offered only medical exemptions (versus medical and religious belief exemptions; 4·0% relative importance; 45·5% [41·1-50·0%] preference; reference: medical exemptions).These findings can inform policymakers' decisions about how best to implement a mandatory childhood vaccination scheme in England.Data collection was funded by a British Academy/Leverhulme Small Research Grants (SRG1920\101118).
Phase II Study of Ponatinib in Advanced Gastrointestinal Stromal Tumors: Efficacy, Safety, and Impact of Liquid Biopsy and Other Biomarkers
Authors: Suzanne George, Margaret von Mehren, Jonathan A. Fletcher, Jichao Sun, Sen Zhang, Justin R. Pritchard, John Graeme Hodgson, David Kerstein, Victor M. Rivera, Frank G. Haluska, Michael C. Heinrich
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The purpose of this study is to evaluate ponatinib for advanced gastrointestinal stromal tumors (GIST). Patients and Methods: This single-arm phase II trial enrolled patients with metastatic and/or unresectable GIST with failure of prior tyrosine kinase inhibitor (TKI) treatment into two cohorts based on presence or absence of KIT exon 11 (ex11) primary mutations. Patients initially received ponatinib 45 mg once daily. Following a temporary clinical hold in October 2013, dose reductions were implemented to reduce risk of arterial occlusive events (AOE). Primary endpoint was 16-week clinical benefit rate (CBR) in KIT ex11–positive cohort. KIT mutations in circulating tumor DNA (ctDNA) were assessed. Results: Forty-five patients enrolled (30 KIT ex11–positive and 15 KIT ex11–negative); median follow-up was 14.7 and 13.6 months, respectively, as of August 1, 2016. Sixteen-week CBR was 36% (KIT ex11–positive; primary endpoint) and 20% (KIT ex11–negative). ctDNA analyses (n = 37) demonstrated strong concordance of primary KIT mutations between plasma and tumor. At least two secondary mutations were detected in 35% of patients overall and 54% of KIT ex11–positive patients. Changes from baseline in mutated ctDNA levels were consistent with clinical activity. Ponatinib was ineffective in patients with KIT exon 9 primary mutations. Resistance was associated with emergence of V654A. AOEs and venous thromboembolic events occurred in three and two patients, respectively. Six patients died; two deaths (pneumonia and pulmonary embolism) were considered possibly ponatinib-related. Conclusions: Ponatinib demonstrated activity in advanced GIST, particularly in KIT ex11–positive disease. ctDNA analysis confirmed heterogeneous resistance mutations in TKI-pretreated advanced GIST. Safety was consistent with previous studies.
The role of epistemic emotions in learning from others
Authors: Asli Erdemli, Catherine Audrin, David Sander
Journal: Behavioral and Brain Sciences (2021)

Phillips et al. discuss whether knowledge or beliefs are more basic representations of others' minds, focusing on the primary function of knowledge representation: learning from others. We discuss links between emotion and "knowledge versus belief," and particularly the role of emotions in learning from others in mechanisms such as "social epistemic emotions" and "affective social learning."