tbuckley/cabot-search huggingface dataset:
717. UCART19, an Allogeneic “Off-the-Shelf” Adoptive T-Cell Immunotherapy Against CD19+ B-Cell Leukemias
Authors: Laurent Poirot, Brian Philip, Cécile Schiffer-Mannioui, Sophie Derniame, Hong Zhan, Sian Stafford, Roman Galetto, Stephan Reynier, Sylvain Arnould, Agnès Gouble, Waseem Qasim, Martin Pule, Julianne Smith
Journal: Molecular Therapy (2015)

Autologous T-cells engineered to express chimeric antigen receptors (CARs) that target specific tumor antigens are known to be of high potential in treating different kinds of cancer. However, they must be generated on a “per patient” basis, thereby limiting the population of patients that could benefit from this approach. In particular, immune homeostasis may be affected in heavily pre-treated patients, such that autologous T-cells may be low in number, not fully functional, or unable to expand, thereby restricting the amount of cells that could be manufactured. The use of allogeneic T-cells isolated from healthy third party donors could constitute an easy-to-scale-up alternative, producible in advance, with potential for standardized quality controls, better batch consistency, and immediate availability for administration to a larger number of patients. In this context, we have developed a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic “off-the-shelf” engineered CD19-CAR+ T-cell–based frozen products. Our platform involves the use of transcription activator-like effector nucleases (TALEN), which mediate the simultaneous inactivation of two genes through genome editing. The knockout of the TCR alpha gene eliminates TCR expression and is intended to abrogate the donor T-cell's potential for graft-versus-host disease (GvHD), while knocking out the CD52 gene makes donor T-cells resistant to the lymphodepleting agent alemtuzumab. In addition, our T-cells are engineered to co-express the RQR8 gene as a safety feature, with the aim of rendering them sensitive to the monoclonal antibody rituximab.We have obtained proof-of-concept for the application of this approach by manufacturing TCR/CD52-deficient RQR8+ and cD19-CAR+ T-cells (UCART19) using a good manufacturing practice-compatible process and have demonstrated that the resulting UCART19 cells were functional using in vitro assays. Furthermore we have demonstrated the ability of UCART19 cells to engraft into an orthotopic human CD19+ lymphoma xenograft immunodeficient mouse model. UCART19 cells exhibited antitumor activity equivalent to that of standard CD19 CAR T-cells. We also demonstrated that UCART19 cells did not mediate alloreactivity in a xeno-GvHD mouse model. Finally, the effectiveness of the rituximab-induced depletion mechanism of RQR8+ cells was shown in an immunocompetent mouse model. This valuable dataset supports the development of allogeneic CAR T-cells, and UCART19 will be investigated in an exploratory, first-in-human, clinical trial where refractory/relapsed CD19+ B-cell leukemia patients are to be enrolled.
Association of elevated C-reactive protein with oncologic outcomes in renal CELL carcinoma: A multicenter analysis.
Authors: Sunil Hemant Patel, Margaret Frances Meagher, Kazutaka Saito, Dattatraya Patil, Ahmet Bindayi, Ahmed Eldefrawy, Stephen Ryan, Brittney Cotta, Kendrick Yim, Ryan Nasseri, Zachary Hamilton, Yosuke Yasuda, Yasuhisa Fujii, Viraj A. Master, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2019)

596 Background: C-reactive protein (CRP) is a systemic inflammatory marker which has been associated with overall survival (OS) in Renal Cell Carcinoma (RCC) patients in Asia. Data supporting utility of CRP as a predictive marker in non-Asian populations are sparse and controversial. We analyzed utility of pre-treatment CRP as a predictor of survival and oncological outcomes in a multicenter cohort of RCC patients. Methods: Retrospective international 3 center analysis of patients of patients with RCC with pretreatment CRP values from 2006-2017. CRP &gt; 0.5mg/dl was used as threshold for elevation and the cohort was subdivided into two groups for descriptive analysis (normal-CRP ≤0.5 and elevated-CRP &gt; 0.5). Primary outcome was recurrence-free survival (RFS). Secondary outcome was overall survival (OS). Kaplan-Meier (KMA) and multivariable analyses (MVA) were utilized to delineate survival outcomes and their predictors. Results: Overall 2695 patients were analyzed (1791 Male/904 female, CRP≤0.5 1198/CRP &gt; 0.5 1496; mean follow-up 36 months). Patients with elevated CRP had higher incidence of hypertension (p = 0.001), BMI (p &lt; 0.001), and tumor size (3.91 cm vs. 6.05 cm, p &lt; 0.001). MVA for RFS demonstrated elevated CRP (OR = 0.542, p = 0.005), increasing tumor size (OR = 0.915, p &lt; 0.001), and high tumor grade (OR = 0.322 p &lt; 0.001) to be independent risk factors. MVA for all-cause mortality demonstrated elevated CRP (OR = 12.396, p = 0.005), increasing tumor size (OR = 1.126, p &lt; 0.001), high tumor grade (OR = 2.474, p &lt; 0.001), and receipt of PN (OR = 1.826, p = 0.001) to be independent risk factors. For normal vs. elevated CRP, KMA revealed 5-year RFS of 90% vs. 85% (p = 0.001), 95% vs 85% (p = 0.163), 85% vs 62% (p = 0.001), 50% vs 60% (p = 0.513) for Stages 1, 2, 3, and 4, respectively. KMA revealed 5-year OS of 98% vs 80% (p = 0.001), 95% vs 80% (p = 0.103), 95% vs 65% (p = 0.001), 99% vs 40% (p &lt; 0.001) for Stages 1, 2, 3, and 4, respectively. Conclusions: Pre-treatment CRP was an independent predictor of recurrence free survival and overall survival in a multicenter cohort of RCC patients. While further confirmation is requisite, our findings suggest incorporation of CRP into nomographic and risk stratification protocols.
Abstract 15278: Cell-free DNA Released From Ischemic Myocardium Contributes Importantly to Myocardial Reperfusion Injury
Authors: Yikui Tian, Eric J Charles, Irving L Kron, Brent A French, Zequan Yang
Journal: Circulation (2016)

Introduction: Increasing evidence shows that damage associated molecular patterns (DAMPs) such as cell-free DNA (cfDNA) may play critical roles in mediating ischemia/reperfusion injury (IRI). Hypot...
A New Class of Medicines through DNA Editing
Authors: Matthew H. Porteus
Journal: New England Journal of Medicine (2019)

Interview with Dr. Matthew H. Porteus on therapeutic editing of the human genome. (12:58)Download Therapeutic editing of the human genome has long been a holy grail of genetic medicine. Different approaches are founded on a bedrock of basic laboratory discovery. This article describes the history, applications, and limitations of genome editing for clinical application.
Targeted delivery of hesperetin to cartilage attenuates osteoarthritis by bimodal imaging with Gd2(CO3)3@PDA nanoparticles via TLR-2/NF-κB/Akt signaling
Authors: Zhengxiao Ouyang, Tingting Tan, Chunfeng Liu, Juan Duan, Wanchun Wang, Xiaoning Guo, Qing Zhang, Zhihong Li, Qianli Huang, Pengcheng Dou, Tang Liu
Journal: Biomaterials (2019)
A phase I study of RX-3117, an oral agent activated by uridine cytidine kinase 2, to treat subjects with advanced solid tumors.
Authors: Drew Warren Rasco, Amita Patnaik, Anthony W. Tolcher, Kyriakos P. Papadopoulos, Christine Peterson, Ely Benaim
Journal: Journal of Clinical Oncology (2015)

TPS2605 Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117’s efficacy in xenograft models (Colo-205, H460, H69 and CaSki), which are moderately sensitive or resistant to gemcitabine, indicates that RX-3117 may have the potential to treat tumors that do not respond to gemcitabine or have become gemcitabine resistant. Methods: This phase I, open-label, multicenter study evaluates the efficacy and safety of RX-3117 in subjects with solid tumors). RX-3117 is administered 3 times a week for 3 weeks with 1 week off during each 4 week cycle. Dose escalation starts with an accelerated design treating 1 subject per dose followed by a standard 3 + 3 design using a modified Fibonacci sequence after the occurrence of a single related Grade 2 or greater adverse event. The primary endpoint is the overall safety profile characterized by the type, frequency, severity, timing of onset, duration and relationship to study therapy of any adverse events, or abnormalities of laboratory tests or electrocardiograms, any dose limiting toxicities that occur during Cycle 1, serious adverse events, or adverse events leading to study treatment discontinuation. Secondary endpoints include pharmacokinetic parameters (e.g., time to maximum observed concentration [Tmax], maximum observed plasma concentration [Cmax], trough concentration [Ctrough], area under the concentration-time curve [AUC]) and Indices of anti-tumor activity (e.g., overall response rate , time to response, duration of response, and progression-free survival). Exploratory endpoints are baseline biomarker expression/concentration, including (but not limited to) concentrative nucleoside transporter 2; equilibrative nucleoside transporter 1; uridine-cytidine kinase 1 and 2; DNA methyltransferase 1, 3a and 3b; and ribonucleotide reductases 1 and 2. Target recruitment is approximately 30 subjects. Eligible subjects must have confirmed histologic or cytologic evidence of metastatic or locally advanced solid neoplasm that has failed to respond to standard therapy, progressed despite standard therapy or for which standard therapy does not exist. Clinical trial information: NCT02030067.
Pregabalin and gabapentin: what impact will reclassification have on doctors and patients?
Authors: Ingrid Torjesen
Journal: BMJ (2019)

From 1 April 2019 pregabalin and gabapentin will be reclassified as class C controlled substances in the UK. The change, announced in October 2018, is expected to prompt a decline in the use of the drugs as prescribing, dispensing, and collecting them becomes more onerous for doctors, pharmacists, and patients.

The reclassification will make it illegal to supply pregabalin and gabapentin through repeat dispensing. Pharmacists will need to dispense the drugs within 28 days of a prescription being written, and doctors will have to hand sign prescriptions,12 unless a system for electronic prescription of controlled drugs is agreed and rolled out.3 NHS England sent guidance to GP practices about the changes last month (see box).

After representation from community pharmacy groups4 it has been decided that pregabalin and gabapentin will be exempt from safe custody regulations, meaning that they will not be required to be kept in controlled drug cabinets.

The reclassification has been prompted by a growing number of deaths associated with misuse of the two drugs: the number linked to pregabalin …
Steps in developing Watson for Oncology, a decision support system to assist physicians choosing first-line metastatic breast cancer (MBC) therapies: Improved performance with machine learning.
Authors: Julia Fu, Ayca Gucalp, Marjorie Glass Zauderer, Andrew S. Epstein, Mark G. Kris, Jeffrey Keesing, Aryeh Caroline, Mark Megerian, Thomas Eggebraaten, Robert DeLima, Marie Setnes, Patrick Wildt, Andrew David Seidman
Journal: Journal of Clinical Oncology (2015)

566 Background: IBM Watson for Oncology (WFO), trained by Memorial Sloan Kettering (MSK), is a cognitive computing system designed to apply machine learning, informed by MSK expertise, to enhance clinical decision making. We expanded the initial adjuvant therapy prototype to include MBC. Patients with MBC share many common attributes (e.g. age, performance status, receptor status, prior therapy) but receive widely varying therapies. Accuracy of WFO treatment recommendations for similar cases can be improved with machine learning features built on highly influential attributes. Methods: 101 manufactured MBC training cases were grouped by biologic characteristics and then analyzed for variation. A set of clinical attributes characterizing disease burden was posited to be influential in selecting the initial systemic therapy for MBC recommended by MSK breast medical oncologists (e.g. endocrine therapy vs chemotherapy for a patient with hormone receptor (HR)+MBC). WFO learned weights characterizing each attribute's importance (e.g. site(s), extent, and size of metastatic lesions, degree of symptoms) through iterative experiments on training cases, and incorporated them into a "disease burden score"). Model performance as quantified by a combination of precision and recall (F1 Score) defined as (2 * true positives) / [(2 * true positives) + (false positives) + (false negatives)], was measured with and without the use of the disease burden score. Results: Activation of the disease burden score feature yielded a relative improvement in F1 Score of 11.5% across all cases (n = 101) from 73.6% to 82.1%; 28.8% among HR+ HER2+ cases (n = 32); 9.6% among HR+ HER2- cases (n = 29); 2.8% among HR- HER2+ cases (n = 17) and -1.4% among HR- HER2- cases (n = 23). Conclusions: Using training data and medical logic, WFO's machine learning model can assign weights to attributes and features to select therapy for patients that better align with the nuanced decision-making of MSK breast medical oncologists than rules alone. WFO's machine-learned disease burden score is a useful driver of treatment recommendations for HR+ and/or HER2+ MBC.
Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol
Authors: Kausik K. Ray, Harold E. Bays, Alberico L. Catapano, Narendra D. Lalwani, LeAnne T. Bloedon, Lulu R. Sterling, Paula L. Robinson, Christie M. Ballantyne
Journal: New England Journal of Medicine (2019)

Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy.We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks.The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL cholesterol level at baseline was 103.2±29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of -16.5% from baseline (difference vs. placebo in change from baseline, -18.1 percentage points; 95% confidence interval, -20.0 to -16.1; P<0.001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy.In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. (Funded by Esperion Therapeutics; CLEAR Harmony ClinicalTrials.gov number, NCT02666664.).
Disturbances in quality of life among BRCA mutation carriers.
Authors: Aileen Caceres, Rebecca McLamara, Olga Ivanov, Cynthia Buffington
Journal: Journal of Clinical Oncology (2015)

e12522 Background: The high risk for primary and secondary breast and ovarian cancer among BRCA mutation carriers, coupled with lifelong cancer surveillance, preventative surgical procedures and/or cancer treatment may adversely affect Quality of Life (QoL). In the present study, we have: 1) measured the QoL of BRCA mutation carriers (survivors and previvors) and their non-affected controls and, 2) identified other lifestyle conditions affected by, or contributing to, QoL disturbances. Methods: The study population included 33 breast and ovarian cancer survivors with BRCA mutations, 44 BRCA mutation previvors, and 23 controls. Quality of life (QoL) was assessed by the RAND-36 QoL Questionnaire which consists of 8 scales related to physical and emotional QoL: general health perception, physical functioning, limitations due to physical issues, pain, emotional well-being, function emotional, energy/fatigue, and social functioning. QoL scores were statistically analyzed in regard to cancer status (survivors, previvors, controls) and in association with lifestyle measures, i.e. anxiety, sex, sleep, diet, activity, health (vitals, disease). Results: We found that emotional QoL composite scores for both of the BRCA mutation groups (survivors, previvors) were significantly (p < 0.05) below those of the controls, i.e. 70.5, 71.4, 81.5, and controls, respectively. The disturbances in emotional QoL were significantly (p < 0.05) associated with anxiety, poor sleep quality, sexual inactivity, calorie intake, and health status. For physical QoL, only the BRCA cancer survivors scored significantly (p < 0.01) below the controls, i.e. 74.0, 84.8, and 87.8 for the survivors, previvors, and controls, respectively. Poor physical QoL was associated significantly (p < 0.01) with physical inactivity, a disproportionately low amount of lean tissue relative to body fat, and health status. Conclusions: BRCA previvors have disturbances in emotional QoL and BRCA survivors have low QoL for both emotional and physical issues. Based upon these findings, we conclude that QoL needs to be assessed for all BRCA mutation carriers and attempts made to identify and appropriately address emotional and physical issues.
Association of serum androgen and drug levels with response to abiraterone.
Authors: Elahe A. Mostaghel, Rana R. McKay, Eunpi Cho, Zhenwei Zhang, Brett Marck, Alvin M. Matsumoto, Nima Sharifi, Mary-Ellen Taplin, Peter Nelson, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2019)

208 Background: The association of serum ABI and androgen levels with clinical efficacy in men with CRPC is not well understood. Methods: We measured androgens, ABI and its key metabolites (D4A and 5α) in serum at 4, 8, and 12 weeks (wks) in 29 men with CRPC treated with ABI (for associations with PSA response and time to radiographic progression (TTP)); in 58 men from a study of ABI without prednisone; and in 22 men with localized PCa treated with neoadjuvant ABI for 3 months prior to definitive therapy (including prostate levels). Results: Median (Med) TTP was 36 mo (4-104). 52% had a PSA response (decline &gt;30% at wk12), and 34% early progression (TTP &lt; 6 mo). There was no difference in ABI (at wk4 or average of wks 4/8/12) in men with v without PSA response, or in men with early v late TTP. D4A and 5α at wk4 were higher in early v late progressors (2.9 v 1.5 ng/ml, p=0.05; 10.35 v 6.7 ng/ml, p=0.08). TTP was longer in the lowest v highest quartile of drug levels (ABI: 4wk 48 v 30 wks; 8wk 60 v 16 wks; D4A: 4wk 40 v 16 wks; 8wk 60 v 28 wks; 5a: 8wk 41 v 16 wks, p&lt;0.05 all). The lowest quartile of pre-ABI androgens had shorter TTP (DHEAS 24 v 52 wks; T 30 v 52 wks, p&lt;0.05 both). In both CRPC studies, men with pre-ABI DHEAS &gt; Med had 2-5x higher levels of all steroids (DHEAS 110 v 22 ug/dl, DHEA 184 v 49 ng/dl, AED 46 v 26 ng/dl, and T 9 v 4.9 ng/dl, p&lt;0.05 all). While markedly suppressed by ABI in both groups, levels remained detectable and higher in the ‘high’ group (DHEAS 5.4 v 1.6 ug/dl; DHEA 1.3 v 0.6 ng/dl; p&lt;0.05 both) regardless of ABI levels (37.4 ng/ml, 2.75-89; 36.8 ng/ml, 8.7-121, p=ns). Androgens in serum and prostate after neoadjuvant ABI were higher in men with pre-ABI eugonadal serum DHEAS levels &gt; v &lt; Med, regardless of serum or tissue ABI levels on treatment. Conclusions: In men with pre-ABI serum DHEAS &lt; Med, androgens were suppressed even at low serum ABI levels, whereas in men with pre-ABI DHEAS &gt; Med, levels were not completely suppressed even at high ABI levels, explaining the minimal impact of dose escalated ABI and observed noninferiority of low dose ABI previously reported in men with CRPC. The shorter TTP in the highest quartiles of ABI, D4A and 5α may reflect increased conversion to the AR agonist metabolite 5α. Men with pre-ABI DHEAS &gt; Med may warrant stratification to more potent/combination therapy. Clinical trial information: NCT01503229.
Phosphoproteomics Reveals the GSK3-PDX1 Axis as a Key Pathogenic Signaling Node in Diabetic Islets
Authors: Francesca Sacco, Anett Seelig, Sean J. Humphrey, Natalie Krahmer, Francesco Volta, Alessio Reggio, Piero Marchetti, Jantje Gerdes, Matthias Mann
Journal: Cell Metabolism (2019)
Not All Weight Loss Created Equal
Authors: Brian Hodgens, Kenric M. Murayama
Journal: JAMA Surgery (2019)

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 Surgery 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 Surgery journal