tbuckley/cabot-search huggingface dataset:
Development of a quantitative PD-L1 assay using laser capture microdissection (LCM)-based reverse phase protein microarray (RPPA) workflow: Implications for precision medicine.
Authors: Mariaelena Pierobon, Elisa Baldelli, K. Alex Hodge, Maria Isabella Sereni, Vienna Ludovini, Guido Bellezza, Lucio Crino, Lance A. Liotta, Emanuel Petricoin
Journal: Journal of Clinical Oncology (2018)

35 Background: FDA approved IHC-based companion/complementary assays are routinely used to measure PD-L1 for treatment selection. However, IHC cut-point values vary across platforms and are based on subjective analysis that requires antigen retrieval methods. Even in highly selected populations of PD-L1 “positive” patients, clinical benefits are seen only in subgroups of patients. We tested the feasibility of utilizing LCM and RPPA as a new methodology for quantitative, operator independent measurements of PD-L1 on tumor cells. Methods: PD-L1 quantification by RPPA was compared to IHC on 23 lung cancers (LC). Tumor cells were isolated from the surrounding microenvironment using LCM. The E1L3N clone from Cell Signaling was used to quantify PD-L1 expression by RPPA and IHC. Reproducibility across antibody clones was then assessed on LCM procured tumor epithelia from 10 FFPE LC and 71 snap-frozen ovarian cancers (OC). PD-L1 measurements were compared between the Cell Signaling E1L3N and the Ventana SP-142 clone. A quantitative PD-L1 calibrated assay was developed and assessed with the pilot population data. Results: Of the 23 LC, 5 were PD-L1 positive by IHC. The 5 IHC-positive patients had the greatest level of PD-L1 expression by RPPA indicating that the RPPA platform correlates with IHC. However, RPPA quantification showed a dynamic range ~ 4-fold across IHC negative samples. Correlation between PD-L1 detection with the E1L3N and the SP-142 clone in the OC was significant (R 2 = 0.85), indicating great concordance across clones. Results were confirmed in the 10 LC samples (R 2 = 0.87). Conclusions: The LCM-RPPA workflow captures PD-L1 expression on a continuous quantitative scale. This quantitative output correlated with IHC although it captures a much broader dynamic range in both IHC negative and positive populations. PD-L1 quantification by LCM-RPPA may be less dependent upon the clone used for the detection than IHC. Because the detection is unconstrained by antigen retrieval issues as well as subjectivity of IHC interpretation, this approach may generate a more accurate cut-point of therapeutic response prediction.
A tumor growth rate/overall survival model for atezolizumab as an early predictor of OS in patients with first or second line metastatic urothelial carcinoma.
Authors: Rene Bruno, Laurent Claret, Benjamin Wu, Jin Y Jin, Helen Winter, Na Cui, Christina Louise Derleth, Xiaodong Shen, Sandhya Girish, Jonathan E. Rosenberg, Thomas Powles
Journal: Journal of Clinical Oncology (2018)

62 Background: Standard early endpoints are often poor predictors of overall survival (OS) for immunotherapies. There is a need for new intermediate endpoints to support upcoming combination studies with immune checkpoint inhibitors. We investigated the predictive performance of on-treatment tumor growth rate (TGR) estimates to predict OS in atezolizumab clinical trials in patients (pts) with metastatic urinary carcinoma (mUC). Methods: Atezolizumab showed durable response, prolonged OS and good tolerability supporting its therapeutic use in mUC (Rosenberg, Lancet 2016; Balar, lancet 2017; Powles, EACR-AACR-SIC 2017). A multivariate model linking baseline patient characteristics and TGR (estimated using time profile of sum of longest diameters (SLD) of target lesions, RECIST 1.1) to OS was developed using phase 2 data (IMvigor210) and validated to predict phase 3 trial (IMvigor211). Results: To estimate TGR, patients needed to have at least one post-baseline measurement: n = 365/429 (85%) in IMvigor210 (102 in cohort 1, 1L cisplatin-ineligible and 263 in cohort 2, prior platinum-treated 2L+) and n = 745/902 treated (83%) in IMvigor211 (prior platinum-treated 2/3L). A lognormal model with independent baseline prognostic factors (alkaline phosphatase, ECOG performance status and number of metastatic sites) and estimated TGR was developed. The model predicted OS distributions in the two IMvigor210 cohorts in all comers as well as by PD-L1 expression on tumor-infiltrating immune cells (IC). In IMvigor211, SLD profiles in atezolizumab and chemotherapy arms crossed at about 40 weeks with more initial shrinkage in chemotherapy-treated pts but slower overall TGR in atezolizumab-treated pts. The IMvigor210 OS model predicted OS hazard ratio (HR) in IMvigor211 in all comers with post-baseline tumor scans (model-predicted HR [prediction interval]: 0.80 [0.70-0.92] vs. 0.74 observed) as well as by IC status: 0.66 [0.50-0.87] vs. 0.70 observed in IC23. Conclusions: Model-based TGR is a promising exploratory endpoint and is being investigated to support early decisions in signal-seeking atezolizumab combination trials in mUC.
Maternal thyroid function and child educational attainment: prospective cohort study
Authors: Scott M Nelson, Caroline Haig, Alex McConnachie, Naveed Sattar, Susan M Ring, George D Smith, Debbie A Lawlor, Robert S Lindsay
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To determine if first trimester maternal thyroid dysfunction is a critical determinant of child scholastic performance and overall educational attainment. <h3>Design</h3> Prospective cohort study. <h3>Setting</h3> Avon Longitudinal Study of Parents and Children cohort in the UK. <h3>Participants</h3> 4615 mother-child pairs with an available first trimester sample (median 10 weeks gestation, interquartile range 8-12). <h3>Exposures</h3> Free thyroxine, thyroid stimulating hormone, and thyroid peroxidase antibodies assessed as continuous measures and the seven clinical categories of maternal thyroid function. <h3>Main outcome measures</h3> Five age-specific national curriculum assessments in 3580 children at entry stage assessment at 54 months, increasing up to 4461 children at their final school assessment at age 15. <h3>Results</h3> No strong evidence of clinically meaningful associations of first trimester free thyroxine and thyroid stimulating hormone levels with entry stage assessment score or Standard Assessment Test scores at any of the key stages was found. Associations of maternal free thyroxine or thyroid stimulating hormone with the total number of General Certificates of Secondary Education (GCSEs) passed (range 0-16) were all close to the null: free thyroxine, rate ratio per pmol/L 1.00 (95% confidence interval 1.00 to 1.01); and thyroid stimulating hormone, rate ratio 0.98 (0.94 to 1.02). No important relationship was observed when more detailed capped scores of GCSEs allowing for both the number and grade of pass or when language, mathematics, and science performance were examined individually or when all educational assessments undertaken by an individual from school entry to leaving were considered. 200 (4.3%) mothers were newly identified as having hypothyroidism or subclinical hypothyroidism and 97 (2.1%) subclinical hyperthyroidism or hyperthyroidism. Children of mothers with thyroid dysfunction attained an equivalent number of GCSEs and equivalent grades as children of mothers with euthyroidism. <h3>Conclusions</h3> Maternal thyroid dysfunction in early pregnancy does not have a clinically important association with impaired child performance at school or educational achievement.
A Perspective on Physiologic Assessment of Coronary Stenoses in Series
Authors: Morton J. Kern, Arnold H. Seto
Journal: JAMA Cardiology (2018)

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 Cardiology 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 Cardiology journal
Vesicular carriers containing phenylethyl resorcinol for topical delivery system; liposomes, transfersomes and invasomes
Authors: Thanaporn Amnuaikit, Tunyaluk Limsuwan, Pasarat Khongkow, Prapaporn Boonme
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Topical administration of phenylethyl resorcinol (PR) has attracted much attention as skin lightening agent with potent anti-tyrosinase activity. Two novel types of elastic carriers were developed to overcome the limitation of PR as topical delivery by increasing the solubility, stability and decreasing skin irritation compared to conventional liposomes. In addition, it also promotes skin penetration of PR to reach deep skin layer at the target site. The lead formulations were obtained from the invasomes containing 1% (w/v) d-limonene mixed with 10% (v/v) absolute ethanol as the skin enhancer, and transfersomes containing 15% (w/w) sodium deoxycholate (SDC) as edge activator. All formulations gave a vesicle size < 500 nm, polydispersity index (PDI) < 0.3, high zeta potential, entrapment efficiency > 50%, and good stability on storage at 30 °C at 75% RH for 4 months. Transfersomes have a lower degree of deformability (6.63%) than invasomes (25.26%). In contrast, the liposomes as rigid vesicles do not show a deformable property. This characteristic affects the skin permeation, and thus, transfersomes with high elastic property provided a significantly higher cumulative amount, steady state flux (
Abstract MS1-1: Targeting DNA repair deficiency in triple negative breast cancers (TNBC) with G-quadruplex stabilisers
Authors: S Aparicio
Journal: Cancer Research (2018)

Abstract Triple negative breast cancers (TNBC) represent a heterogeneous group of patients where pathway targeted interventions are lacking. We have recently identified new subgroups of TNBC tumours based on patterns of genomic instability, suggesting that deficiencies in DNA repair or genome maintenance could be exploited in specific subgroups of TNBC patients. We recently discovered synthetic lethal activity for small molecules that bind and stabilise G-quadruplex (G4) structures in the human genome. Stabilized G4 structures are considered "at risk" during DNA replication, leading to single strand and double strand breaks in the absence of DNA repair. This has specific application in cancers with DNA repair deficiency. We have shown that loss of homologous recombination repair capacity in breast cancers is associated with ∼ 1 log order increase in sensitivity to G4 binders. Moreover this activity has been observed in platinum pre-treated tumours, and in PARP insensitive tumours. Recently through CRISPR screening approaches we have defined additional DNA repair lesions that confer synthetic lethality to G4 binders. This mechanism of G4 stabilisation is now being tested in a phase 1/2 clinical trial of CX5461 in breast cancer patients. Citation Format: Aparicio S. Targeting DNA repair deficiency in triple negative breast cancers (TNBC) with G-quadruplex stabilisers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr MS1-1.
Using aorta lesion attenuation difference (ALAD) on preoperative contrast-enhanced CT scan to differentiate between malignant and benign renal tumors.
Authors: Joseph Grajo, Russell Terry, Justin Ruoss, Jonathan Pavlinec, Blake Noennig, Shahab Bozorgmehri, Mike Blute, Paul Crispen, Li-Ming Su
Journal: Journal of Clinical Oncology (2018)

606 Background: To evaluate the ability of Aorta−Lesion−Attenuation−Difference (ALAD) to differentiate malignant renal tumors from renal oncocytomas. Methods: A retrospective review of preoperative CT scans and surgical pathology from robotic assisted partial nephrectomy specimens obtained by a single surgeon was performed. ALAD was calculated by measuring the difference in Hounsfield units (HU) between the aorta and the lesion of interest on the same image slice in the nephrographic phase on preoperative CT scan. The discriminative ability of ALAD to differentiate malignant pathology from oncocytoma was evaluated by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under curve (AUC) using ROC analysis. Results: A total of 218 preoperative CT scans and corresponding pathology reports were reviewed. Pathology review revealed 22 oncocytomas (10.1%), 11 chromophobe RCC (5%), 37 papillary RCC (17%), and 148 clear cell RCC (67.9%). ALAD was able to differentiate malignant pathology from oncocytoma using a HU threshold of 24 with a sensitivity of 84%, specificity of 86%, PPV of 98%, and NPV of 33%. The AUC for malignant pathology versus oncocytoma was 0.86 (95% CI 0.77−0.96). Subgroup analysis showed that ALAD was able to differentiate chromophobe RCC from oncocytoma using a HU threshold of 24 with a sensitivity of 100%, specificity of 86%, PPV of 75%, and a NPV of 100%. The AUC for chromophobe RCC versus oncocytoma was 0.98 (95% CI 0.91−1.00). Conclusions: ALAD measurements based upon preoperative CT scans provide good discrimination between malignant renal tumors and oncocytomas, potentially decreasing the need for biopsy in certain patients. ALAD also discriminates well between chromophobe RCC and oncocytoma, which may aid in the management of patients with indeterminate diagnoses of oncocytic neoplasm on biopsy. Further validation of ALAD will be necessary prior to routine use in clinical practice.
ROLE OF DIABETES AND INSULIN USE IN THE RISK OF STROKE AND ACUTE MYOCARDIAL INFARCTION IN PATIENTS WITH ATRIAL FIBRILLATION: A MEDICARE ANALYSIS
Authors: Ghanshyam Palamaner Subash Shantha, Amgad Mentias, Chakradhari Inampudi, Oluwaseun Adeola, Chad Ward, Kongkiat Chaikriangkrai, Nimesh Patel, Alexander Mazur, Abhishek Deshmukh, Michael Giudici, Frank Pelosi, Hakan Oral, Rajan Sah, Mary Vaughan Sarrazin
Journal: Journal of the American College of Cardiology (2018)
Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke
Authors: Stefan Roth, Vikramjeet Singh, Steffen Tiedt, Lisa Schindler, Georg Huber, Arie Geerlof, Daniel J. Antoine, Antoine Anfray, Cyrille Orset, Maxime Gauberti, Antoine Fournier, Lesca M. Holdt, Helena Erlandsson Harris, Britta Engelhardt, Marco E. Bianchi, Denis Vivien, Christof Haffner, Jürgen Bernhagen, Martin Dichgans, Arthur Liesz
Journal: Science Translational Medicine (2018)

Stroke induces a multiphasic systemic immune response, but the consequences of this response on atherosclerosis-a major source of recurrent vascular events-have not been thoroughly investigated. We show that stroke exacerbates atheroprogression via alarmin-mediated propagation of vascular inflammation. The prototypic brain-released alarmin high-mobility group box 1 protein induced monocyte and endothelial activation via the receptor for advanced glycation end products (RAGE)-signaling cascade and increased plaque load and vulnerability. Recruitment of activated monocytes via the CC-chemokine ligand 2-CC-chemokine receptor type 2 pathway was critical in stroke-induced vascular inflammation. Neutralization of circulating alarmins or knockdown of RAGE attenuated atheroprogression. Blockage of β3-adrenoreceptors attenuated the egress of myeloid monocytes after stroke, whereas neutralization of circulating alarmins was required to reduce systemic monocyte activation and aortic invasion. Our findings identify a synergistic effect of the sympathetic stress response and alarmin-driven inflammation via RAGE as a critical mechanism of exacerbated atheroprogression after stroke.
Government issues rules on sharing confidential patient information
Authors: Matthew Limb
Journal: BMJ (2013)

The government has issued rules setting out the duties of doctors and other healthcare staff when sharing confidential patient information.

The health secretary for England, Jeremy Hunt, said that better sharing of patient data that relied on “implied consent” would improve people’s care and that a range of safeguards would guard against misuse. “This new approach will mean that frontline staff will be confident about when to share information with other members of a person’s care team and how to do so safely,” he said.

In a report issued on 13 September the government responded to the …
Editor’s Choice: Stepping off the treadmill
Authors: Tom Moberly
Journal: BMJ (2015)

This week BMJ Careers reports on another rise in the proportion of junior doctors who choose to step off the training treadmill after completing the foundation programme.

As Abi Rimmer reports (http://careers.bmj.com/careers/advice/Nearly\_half\_of\_trainees\_chose\_not\_to\_progress\_straight\_to\_specialty\_training\_in_2015), 48% of those leaving the foundation programme in 2015 moved straight into specialty training. This number has risen sharply since 2011, when around a …
GMC should deal forcefully with repeatedly dishonest doctors
Authors: Peter T Wilmshurst
Journal: BMJ (2018)

I am very sorry that Jack Adcock died and for the distress that his death caused his family.1

I have read that Hadiza Bawa-Garba is a conscientious doctor who made mistakes in the care of Jack Adcock. Had she not made those mistakes he might have survived. There were also system problems …
The NHS is failing to look after its staff and patients, expert warns
Authors: Abi Rimmer
Journal: BMJ (2014)

The NHS is failing to look after its staff properly as well as its patients, a psychotherapist who specialises in group behaviour has warned.

Gerhard Wilke, an organisational consultant and group analyst, raised the issue at an event in London at which doctors and other clinicians discussed their experience of working in the NHS. He said that the NHS and its staff had developed a “learned helplessness.”

“What we need to do is move out of that and to start to act,” he said. “The NHS used to be the ‘good enough’ mother of the nation, where it had the delegated task of looking after the staff and the patients. What …
RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study
Authors: J.B. Bachet, O. Bouché, J. Taieb, O. Dubreuil, M.L. Garcia, A. Meurisse, C. Normand, J.M. Gornet, P. Artru, S. Louafi, F. Bonnetain, A. Thirot-Bidault, I. Baumgaertner, R. Coriat, D. Tougeron, T. Lecomte, F. Mary, T. Aparicio, L. Marthey, V. Taly, H. Blons, D. Vernerey, P. Laurent-Puig
Journal: Annals of Oncology (2018)
Application-based perioperative management of the radical cystectomy patient.
Authors: Meredith Metcalf, Jill Hamilton-Reeves, Martin DeRuyter, David Bishop, Lauren Hand, Jeffrey M. Holzbeierlein, Eugene Lee
Journal: Journal of Clinical Oncology (2018)

480 Background: Radical cystectomy patients are a vulnerable population, with up to 65% suffering complications and 26% readmitted within 90 days. Perioperative education, early identification of patients at risk, and discharge transitions remain central to improving outcomes. This project aimed to examine the feasibility of using LifeScience Technologies tablet-based application (LST app) for perioperative patient education, transition care communications, and post-discharge monitoring. Methods: We initiated a prospective feasibility pilot trial (NCT NCT02942121) in 20 patients undergoing radical cystectomy. Participants were provided an iPad preloaded with the LST app and equipment to measure vital signs during the study. Patient education videos tailored to each individual based on gender and diversion type were sent via the app for viewing preoperatively. Postoperatively participants were asked to log medication compliance and vital signs. Vital equipment was wirelessly transmittable, and the study team was alerted to any abnormal patient data. Compliance with watching videos and recording vital signs was the primary aim of the study. Results: Twenty patients were enrolled between 2/2017 and 10/2017. Two patients discontinued due to difficulty with electronics, two due to oncologic restaging, and two await surgery. Patients watched 155/235 (66%) of assigned education videos. On average, each video was viewed 2.1 times (range 0-3.7), and 16/18 (89%) of all videos were watched more than once. Excluding the patients who did not complete the trial, compliance in video watching was 143/193 (74%). Complete vital signs were logged on 181/227 (70%) of patient study days. Excluding patients who did not complete the trial, compliance in vital sign recording was 175/216 (81%). Conclusions: Tablet-based applications are emerging as adjuncts to traditional clinical practice. This protocol demonstrates patient compliance with assigned tasks and was feasible for extending educational content beyond the office while allowing for repetition of viewing, vital for improving comprehension and recall. Additionally, patients were compliant with recording vitals while at home, demonstrating feasibility of this novel technology. Clinical trial information: NCT02942121.
USEFULNESS OF BLOOD PRESSURE VARIABILITY MARKERS DERIVED FROM AMBULATORY BLOOD PRESSURE MONITORING IN DETECTING AUTONOMIC FAILURE
Authors: Hamza Lodhi, Peri-Okonny Poghni, Kevin Schesing, Kamal Phelps, Christian Ngo, Debbie Arbique, Hillary Evans, Ayodele Aigbe, Angela Price, Steven Vernino, Lauren Phillips, Pravin Khemani, Yuichiro Yano, Sandeep Das, Tao Wang, Wanpen Vongpatanasin
Journal: Journal of the American College of Cardiology (2018)
Trenchlike Ulcer on a Newborn’s Scalp
Authors: Lisa M. Cotter, Kathleen Ellison, Scott A. Norton
Journal: JAMA Dermatology (2018)

A neonate in her second week of life had a thick serosanguineous crust adhering to the scalp; extending laterally in both directions was a deep, trenchlike ulcer with no drainage. What is your diagnosis?
Overheard in a corridor of power
Authors: Jamie Wilson
Journal: BMJ (2007)

We welcome your rapid responses, whether in direct response to an article in Career Focus or as a way of sharing your own ideas. As long as it isn9t libellous or offensive, we9ll post it on our website. We print a selection of rapid reponses here and the writer of the best each month wins an <i>Oxford Handbook</i> of their choice. Letter of the month prize is donated by OUP.
Young medics are more likely to move abroad than within UK, thanks to NHS reform and pension changes
Authors: Helen Jaques
Journal: BMJ (2012)

Junior doctors and medical students are more likely than they were two years ago to express a wish to move abroad after training or to work overseas permanently, with many citing changes to the structure of the NHS and pensions as influencing their attitudes to their career path.

When the BMA asked junior doctors and medical students to compare their career intentions with their views in May 2010, just over half (51%) of the respondents said that they were more likely than two years ago to want to work overseas for a spell after training, and over a …
TREM-1 multimerization is essential for its activation on monocytes and neutrophils
Authors: Kevin Carrasco, Amir Boufenzer, Lucie Jolly, Helene Le Cordier, Guanbo Wang, Albert JR Heck, Adelheid Cerwenka, Emilie Vinolo, Alexis Nazabal, Alexandre Kriznik, Pierre Launay, Sebastien Gibot, Marc Derive
Journal: Cellular and Molecular Immunology (2018)