tbuckley/cabot-search huggingface dataset:
Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma
Authors: Nurulhuda Mustafa, Adina Huey Fang Nee, Jing Yuan Chooi, Sabrina Hui Min Toh, Tae-Hoon Chung, Viknesvaran Selvarajan, Shuangyi Fan, Siok Bian Ng, Michelle Poon, Esther Chan, Joanne Lee, Yen Lin Chee, Anand D Jeyasekharan, Longen Zhou, Jennifer Yang, Wee Joo Chng
Journal: Journal for ImmunoTherapy of Cancer (2021)

The potential therapeutic efficacy of daratumumab in natural killer T-cell lymphoma (NKTL) was highlighted when its off-label usage produced sustained remission in a patient with highly refractory disease. This is corroborated recently by a phase II clinical trial which established that daratumumab monotherapy is well tolerated and displayed encouraging response in relapsed/refractory NKTL patients. However, little is known regarding the molecular factors central to the induction and regulation of the daratumumab-mediated antitumor response in NKTL. CD38 expression was studied via immunohistochemistry, multiplex immunofluorescence and correlated with clinical characteristics of the patient. The therapeutic efficacy of daratumumab was studied in vitro via CellTiter-Glo (CTG) assay, complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), and in vivo, via a patient-derived xenograft mouse model of NKTL, both as a single agent and in combination with L-asparaginase. Signaling mechanisms were characterized via pharmacologic treatment, RNA silencing, flow cytometry and corroborated with public transcriptomic data of NKTL. Epstein-Barr virus-positive NKTL patients significantly express CD38 with half exhibiting high expression. Daratumumab effectively triggers Fc-mediated ADCC and CDC in a CD38-dependent manner. Importantly, daratumumab monotherapy and combination therapy with L-asparaginase significantly suppresses tumor progression in vivo. Ablation of complement inhibitory proteins (CIP) demonstrate that CD55 and CD59, not CD46, are critical for the induction of CDC. Notably, CD55 and CD59 expression were significantly elevated in the late stages of NKTL. Increasing the CD38:CIP ratio through sequential CIP knockdown, followed by CD38 upregulation via All-Trans Retinoic Acid treatment, potently augments complement-mediated lysis in cells previously resistant to daratumumab. The CD38:CIP ratio consistently demonstrates a statistically superior correlation to antitumor efficacy of daratumumab than CD38 or CIP expression alone. This study characterizes CD38 as an effective target for a subset of NKTL patients and the utilization of the CD38:CIP ratio as a more robust identifier for patient stratification and personalisation of treatment. Furthermore, elucidation of factors which sensitize the complement-mediated response provides an alternative approach toward optimizing therapeutic efficacy of daratumumab where CDC remains a known limiting factor. Altogether, these results propose a strategic rationale for further evaluation of single or combined daratumumab treatment in the clinic for NKTL.
Abstract 251: Mixed Lineage Kinase 3 Functions as a Protein Kinase G I Alpha Antiremodeling Substrate in the Heart
Authors: Timothy D Calamaras, Robert A Baumgartner, Guang-rong Wang, Angela M Lane, Mark Aronovitz, Roger J Davis, Richard H Karas, Robert M Blanton
Journal: Circulation Research (2016)

Background: cGMP-dependent protein kinase G I α (PKGIα) via its leucine zipper (LZ) domain prevents adverse cardiac remodeling. Identifying and characterizing PKGIα-LZ dependent substrates may reveal novel therapeutic targets in the myocardium. We previously identified the LZ-containing Mixed Lineage Kinase 3 (MLK3) as a potential PKGIα substrate. Further, MLK3 whole body knockout mice had increased LV hypertrophy and dysfunction after pressure overload. In this study we sought to further explore the PKGIα-MLK3 interaction, and to investigate MLK3 in human cardiomyopathy. Results: We first tested for a direct interaction between PKGIα and MLK3. Using affinity purified recombinant proteins we observed co-precipitation of PKGIα and MLK3 that was disrupted by mutation of the PKGIα LZ domain (LZ mutation: MLK3 binding decreased by 61.61% ±13.6, n=4). In mouse heart the interaction between native MLK3 and PKGIα was observed by co-immunoprecipitation (n=3). PKGIα phosphorylated MLK3 at the activation loop in vitro, which was attenuated by inhibiting PKGIα kinase function (n=3). We next tested if MLK3 regulates hypertrophy of cultured cardiomyocytes. Adult rat ventricular cardiomyocytes treated with the MLK3 inhibitor URMC-099 (100 nM, 48 hrs) exhibited increased cell size compared to vehicle treated cells (23.3% increase ± 3.64 SEM vs DMSO vehicle, n=3, 50 cells per treatment). Finally, we examined MLK3 expression in hearts from human patients with non-ischemic or hypertrophic cardiomyopathy. Compared to normal LV samples (NDRI, n=4), MLK3 expression was markedly elevated in both non-ischemic and hypertrophic cardiomyopathy LV samples (MLK3/GAPDH: non-ischemic: 6.26 ADU ± 0.85, n=9, hypertrophic: 6.97 ADU ± 1.42, n=8). Conclusion: These data support a model in which PKGIa directly binds and activates MLK3, leading in the cardiomyocyte to repression of cellular hypertrophy. Our findings in tissue from human failing hearts further suggest that MLK3 upregulation may act as a compensatory anti-remodeling signal in the setting of cardiac dysfunction, which ultimately becomes overwhelmed by pro-remodeling signals. More broadly our findings support that identifying PKGIa LZ-dependent substrates can reveal novel anti-remodeling molecules.
Prospective Study of Fertility Preservation in Young Women With Breast Cancer in Mexico
Authors: Cynthia Villarreal-Garza, Fernanda Mesa-Chavez, Alejandra Plata de la Mora, Melina Miaja-Avila, Marisol Garcia-Garcia, Alan Fonseca, Sylvia de la Rosa-Pacheco, Marlid Cruz-Ramos, Manuel Rolando García Garza, Alejandro Mohar, Enrique Bargallo-Rocha
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: Despite the risk of treatment-related infertility, implementation of fertility-preservation (FP) strategies among young patients with breast cancer is often suboptimal in resource-constrained settings such as Mexico. The “Joven &amp; Fuerte: Program for Young Women With Breast Cancer” strives to enhance patient access to supportive care services, including FP measures through alliances with assisted-reproduction units and procurement of coverage of some of these strategies. This study describes patients from Joven &amp; Fuerte who have preserved fertility, and assesses which characteristics were associated with the likelihood of undergoing FP. Methods: Women aged ≤40 years with recently diagnosed breast cancer were prospectively accrued. Sociodemographic and clinicopathologic data were collected from patient-reported and provider-recorded information at diagnosis and 1-year follow-up. Descriptive statistics, chi-square test, and simple logistic regression were used to compare patients who preserved fertility with those who did not. Results: In total, 447 patients were included, among which 53 (12%) preserved fertility, representing 38% of the 140 women who desired future biologic children. Oocyte/embryo cryopreservation was the most frequently used method for FP (59%), followed by temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy (26%), and use of both GnRHa and oocyte/embryo cryopreservation (15%). Younger age, higher educational level, being employed, having private healthcare insurance, and having one or no children were associated with a significantly higher likelihood of preserving fertility. Conclusions: By facilitating referral and seeking funds and special discounts for underserved patients, supportive care programs for young women with breast cancer can play a crucial role on enhancing access to oncofertility services that would otherwise be prohibitive because of their high costs, particularly in resource-constrained settings. For these efforts to be successful and widely applied in the long term, sustained and extended governmental coverage of FP options for this young group is warranted.
Semaglutide’s Success Could Usher in a “New Dawn” for Obesity Treatment
Authors: Jennifer Abbasi
Journal: JAMA (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 14231: Differential DNA Methylation in Marfan Syndrome is Associated With Inflammation and Cardiac Contraction
Authors: Cassandra Malecki, Elizabeth N Robertson, Kiersten A Liddy, Alex Sahagian, Callum Gover, Yaxin Lu, Murat Kekic, Donna Lai, Brett D Hambly, Richmond W Jeremy
Journal: Circulation (2019)

Introduction: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in FBN1 (fibrillin-1). Cardiovascular (CVS) manifestations of MFS include thoracic aorta dilatation and disse...
Association Between Neuronal Autoantibodies and Cognitive Impairment in Patients With Lung Cancer
Authors: Frederik Bartels, Mona-Marie Wandrey, Annette Aigner, Timo Strönisch, Kimberley Farmer, Kristin Rentzsch, Antje Tessmer, Christian Grohé, Carsten Finke
Journal: JAMA Oncology (2021)

<h3>Importance</h3> Paraneoplastic neurological syndromes are associated with neuronal autoantibodies, and some of these autoantibodies are associated with neuropsychological symptoms. The most common underlying tumor is lung cancer. The association of neuronal autoantibodies with cognitive deficits has not been systematically investigated in patients with small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC). <h3>Objective</h3> To assess the frequency of neuronal autoantibodies in patients with lung cancer and analyze their association with cognitive function. <h3>Design, Setting, and Participants</h3> This prospective, cross-sectional study included 167 patients with lung cancer (both SCLC and NSCLC) recruited at a single lung cancer center in Berlin, Germany, between June 2015 and April 2016. Detailed neuropsychological testing was performed in a carefully selected subgroup of 97 patients (from which patients with potential confounding factors were excluded). Investigators were blinded to patients’ autoantibody status and cognitive test results. Data were analyzed from May 2016 to December 2019. <h3>Main Outcomes and Measures</h3> Prevalence of neuronal autoantibodies and their association with cognitive impairment. The evaluation of autoantibodies as potential risk factors for cognitive impairment was performed using bayesian logistic regression models. <h3>Results</h3> Among 167 patients with lung cancer (median age, 66.0 years [interquartile range, 59.0-72.0 years]; 105 men [62.9%]), 127 had NSCLC, and 40 had SCLC. Brain-directed autoantibodies were detected in 61 of 167 patients (36.5%); 33 patients (19.8%) had known autoantibodies and 28 patients (16.8%) had autoantibodies against currently unknown antigens that were detected through immunohistochemical analysis. Cognitive impairment was found in 65 of 97 patients (67.0%). Among patients with SCLC, the odds of cognitive impairment for those with any autoantibodies was 11-fold higher (odds ratio [OR], 11.0; 95% credible interval [CrI], 1.2-103.6) than that of autoantibody-negative patients, and the increased odds were independent of age, sex, and neurological deficit. Among patients with NSCLC, those with immunoglobin A autoantibodies targeting the<i>N</i>-methyl-d-aspartate receptor had a relevantly increased odds of verbal memory deficits (OR, 182.8; 95% CrI, 3.1-10 852.4). Autoantibodies against currently unknown antigens were also associated with increased odds of cognitive impairment (OR, 2.8; 95% CrI, 0.6-12.1). <h3>Conclusions and Relevance</h3> In this prospective, cross-sectional study, more than one-third of patients with lung cancer had neuronal autoantibodies that were found to be associated with cognitive impairment. These autoantibodies might represent a potentially treatable mechanism of immune-mediated cognitive impairment among patients with lung cancer.
Polyploidy control in hepatic health and disease
Authors: Valentina C. Sladky, Felix Eichin, Thomas Reiberger, Andreas Villunger
Journal: Journal of Hepatology (2021)

A balanced increase in DNA content (ploidy) is observed in some human cell types, including bone-resorbing osteoclasts, platelet-producing megakaryocytes, cardiomyocytes or hepatocytes. The impact of increased hepatocyte ploidy on normal physiology and diverse liver pathologies is still poorly understood. Recent findings suggest swift genetic adaptation to hepatotoxic stress and the protection from malignant transformation as beneficial effects. Herein, we discuss the molecular mechanisms regulating hepatocyte polyploidisation and its implication for different liver diseases and hepatocellular carcinoma. We report on centrosomes' role in limiting polyploidy by activating the p53 signalling network (via the PIDDosome multiprotein complex) and we discuss the role of this pathway in liver disease. Increased hepatocyte ploidy is a hallmark of hepatic inflammation and may play a protective role against liver cancer. Our evolving understanding of hepatocyte ploidy is discussed from the perspective of its potential clinical application for risk stratification, prognosis, and novel therapeutic strategies in liver disease and hepatocellular carcinoma.
Abstract 232: Restless Leg Syndrome and its Association with Iliofemoral Venous Disease
Authors: Navya Reddy, Nagender Reddy
Journal: Circulation Research (2016)

Background: Restless leg syndrome (RLS) is one of the most common sleep disorders, affecting between 5% and 10% of the U.S. population (1). However it has an unclear etiology, and is often over-medicated without a resulting qualitative improvement in lifestyle. It has not been determined whether iliofemoral or iliocaval venous disease, resulting from either thrombotic lesions or external compression, has an association with RLS. Methods: A total of 510 patients treated for iliofemoral venous compression syndrome (IVCS) with angioplasty and stenting were documented to have concomitant RLS per NIH screening criteria,2 prior to endovenous revascularization. 367 of the following patients were selected for retrospective research analysis based on pre-procedural selection criteria which included: IVCS with &gt; 60% luminal stenosis, confirmed RLS &gt; 1 year with or without current treatment, diminished quality of life, and clinical signs and symptoms of chronic venous disease. Patients with Diabetes, End stage renal disease, current pregnancy, and Rheumatic disease were excluded from this study. Patients with thrombotic lesions of the iliofemoral veins were also excluded. Following revascularization, patients were followed at 6 weeks, 3 months, and 6 months with doppler evaluation and asked to rate the severity of their RLS using a scale developed by the International Restless Leg Syndrome study group (3). Results: Of the 367 patients studied, 52% of patients had improvement of their RLS symptoms at 3 months, 90% reported significant relief with cessation of medication(s) within 6 months, and 10% did not have any statistically significant improvement by 6 months (p &lt; 0.001). Conclusion: This study demonstrates a strong relationship between deep vein outflow obstruction, with either iliocaval or iliofemoral stenosis, and RLS. It is suspected that a large population suffers from iliofemoral venous disease, and including this subset of patients in the differential diagnosis for RLS can allow for earlier treatment of IVCS and prevention of RLS.
Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma
Authors: Laura A. Genovesi, Amanda Millar, Elissa Tolson, Matthew Singleton, Emily Hassall, Marija Kojic, Caterina Brighi, Emily Girard, Clara Andradas, Mani Kuchibhotla, Dharmesh D. Bhuva, Raelene Endersby, Nicholas G. Gottardo, Anne Bernard, Christelle Adolphe, James M. Olson, Michael D. Taylor, Melissa J. Davis, Brandon J. Wainwright
Journal: Genome Medicine (2021)

Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects. We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB. Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB. Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.
Acridine‐Based Covalent Organic Framework Photosensitizer with Broad‐Spectrum Light Absorption for Antibacterial Photocatalytic Therapy
Authors: Cuiping Zhang, Jiangna Guo, Xiuyang Zou, Siyu Guo, Yu Guo, Rongwei Shi, Feng Yan
Journal: Advanced Healthcare Materials (2021)

Antibiotic resistance is considered as one of the serious public health issues. Antibacterial photocatalytic therapy, a clinically proven antibacterial therapy, is gaining increasing attention in recent years owing to its high efficacy. Here, an acridine-based covalent organic framework (COF) photosensitizer, named TPDA, with multiple active sites is synthesized via Schiff base condensation between 2,4,6-triformylphloroglucinol (TFP) and 3,6-diaminoacridine (DAA). Owing to the increased conjugation effect of the COF skeleton and outstanding light harvesting ability of DAA, TPDA exhibits a narrow optical band gap (1.6 eV), enhancing light energy transformation and conferring a wide optical absorption spectrum (intensity arbitrary unit > 0.8) ranging from the UV to near-infrared region. Moreover, TPDA shows high antibacterial activities against both gram-negative and gram-positive bacteria within a short time (10 min) of light irradiation and is found to efficiently protect fish from skin infections. Molecular dynamics simulation data show that the introduction of DAA and TFP facilitates the interaction between TPDA and bacteria and is conducive to reactive oxygen species migration, which further improves the antimicrobial performance. These findings indicate the potential of TPDA as a novel photosensitive material for photodynamic therapy.
New Pulmonary Infiltrates Observed on Computed Tomography-Based Image Guidance for Radiotherapy Warrant Diagnostic Workup for Coronavirus Disease 2019
Authors: Graham W. Warren, Vun-Sin Lim, Mudit Chowdhary, Gaurav Marwaha, Osama Mostafa Abd Elbadee, Esra Korkmaz Kirakli, Charlotte Billiet, Alexandra Giraldo Marin, Monica Ramos, Morten Hiul Suppli, Gwendolyn J. McGinnis, Alex A. Adjei
Journal: Journal of Thoracic Oncology (2021)
INTERBIO-21st Phenotypes—Additional Considerations
Authors: Tanis R. Fenton, William W. Hay, Seham Elmrayed
Journal: JAMA Pediatrics (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
The ACLS Score
Authors: Mickey Eisenberg
Journal: JAMA (1981)

We developed a score predictive of survival following out-of-hospital cardiac arrest from an analysis of factors associated with 611 cases. The score is calculated from four pieces of information readily obtainable by emergency personnel directly at the scene. The four items are as follows: A, arrest witnessed; C, cardiac rhythm; L, lay bystander cardiopulmonary resuscitation (CPR); S, speed (response time of paramedic unit). Among 22 patients with favorable findings on all four predictive variables (witnessed arrest, ventricular fibrillation, bystander CPR, paramedic response time less than four minutes), 15 (70%) were discharged alive. The ACLS score for this group of patients was 70%. Among 97 patients with the most unfavorable findings (whose ACLS score was O), one (1%) was discharged. We believe the score can provide emergency personnel with a realistic appraisal of the likelihood of successful resuscitation. (<i>JAMA</i>1981;246:50-52)