tbuckley/cabot-search huggingface dataset:
Targeting brain tumor stem cells using a bispecific antibody directed against CD133+ and EGFRvIII+
Authors: A. Wong, S. Mitra, P. Gupta
Journal: Journal of Clinical Oncology (2009)

2022 Background: Using the marker CD133, cancer stem cells (CSCs) have been demonstrated for glioblastomas (GBMs) and medulloblastomas. However, CD133 is also present on normal neural stem cells. EGFRvIII is a tumor specific EGF receptor. We hypothesized that a recombinant bispecific antibody directed against CD133 and EGFRvIII would be a highly specific reagent. Methods: Single chain antibodies (scFv) were cloned for anti-EGFRvIII and anti-CD133 using existing hybridomas and published sequences. scFv were cloned into a bicistronic vector containing a human CH3 constant domain. The bispecific antibody (BsAb) contains the anti-CD133 (AC133) and anti-EGFRvIII single chain Fv; monospecific but bivalent reagents for anti-CD133 and anti-EGFRvIII were also constructed. Results: U87 cells were co-transfected with increasing amounts of CD133 and decreasing amounts of EGFRvIII cDNAs. The BsAb showed the highest binding for cells expressing both epitopes, whereas Di-EGFRvIII and Di-AC133 had the highest affinity for cells expressing high levels of individual antigens. When cells expressing both antigens were mixed with cells expressing high levels of either antigen alone, the BsAb only recognized CD133+/EGFRvIII+ cells. We then explored the efficiency of tumor cell killing. Using human CD16-expressing NK cells as the effectors at an effector:target ratio of 10:1 and an 83 nM antibody concentration, the BsAb induced 86% lysis of U87-EGFRvIII/CD133 cells, 42.5% in U87-vIII but only 27.3% in U87-CD133 cells. Di-EGFRvIII efficiently induced cytotoxicity in U87-EGFRvIII/CD133 and U87vIII cells but not in U87-CD133 cells. Di-CD133 was the least effective at inducing ADCC. Finally, we studied the ability of the BsAb to induce ADCC on tumor spheres and normal neurospheres. The BsAb showed at least 4X greater lysis on tumor spheres that were CD133+/EGFRvIII+ over normal neurospheres expressing CD133 alone at an E:T of 10:1. This was seen at concentrations as low as 0.83 nM. Conclusions: A recombinant bispecific antibody directed against CD133 and EGFRvIII is highly specific for cells that are positive for both antigens, but poorly targets cells expressing CD133 alone. It can potentially be used as a therapeutic agent for specifically targeting CD133+/EGFRvIII+ cancer stem cells. No significant financial relationships to disclose.
Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk
Authors: Mark R. Davies, Michael Martinec, Robert Walls, Roman Schwarz, Gary R. Mirams, Ken Wang, Guido Steiner, Andy Surinach, Carlos Flores, Thierry Lavé, Thomas Singer, Liudmila Polonchuk
Journal: Cell Reports Medicine (2020)

There is an increasing expectation that computational approaches may supplement existing human decision-making. Frontloading of models for cardiac safety prediction is no exception to this trend, and ongoing regulatory initiatives propose use of high-throughput in vitro data combined with computational models for calculating proarrhythmic risk. Evaluation of these models requires robust assessment of the outcomes. Using FDA Adverse Event Reporting System reports and electronic healthcare claims data from the Truven-MarketScan US claims database, we quantify the incidence rate of arrhythmia in patients and how this changes depending on patient characteristics. First, we propose that such datasets are a complementary resource for determining relative drug risk and assessing the performance of cardiac safety models for regulatory use. Second, the results suggest important determinants for appropriate stratification of patients and evaluation of additional drug risk in prescribing and clinical support algorithms and for precision health.
Revascularization Practices and Outcomes in Patients With Multivessel Coronary Artery Disease Who Presented With Acute Myocardial Infarction and Cardiogenic Shock in the US, 2009-2018
Authors: Rohan Khera, Eric A. Secemsky, Yongfei Wang, Nihar R. Desai, Harlan M. Krumholz, Thomas M. Maddox, Kendrick A. Shunk, Salim S. Virani, Deepak L. Bhatt, Jeptha Curtis, Robert W. Yeh
Journal: JAMA Internal Medicine (2020)

Cardiogenic shock after acute myocardial infarction (AMI) is associated with high mortality, particularly among patients with multivessel coronary artery disease. Recent evidence suggests that use of multivessel percutaneous coronary intervention (PCI) may be associated with harm. However, little is known about recent patterns of care and outcomes for this patient population.
Abstract 16196: Relationship of Right and Left Atrial Volumes by Sex and Age Group in Healthy Adults
Authors: Saadia Qazi, Philimon N Gona, Garima Arora, Carol Salton, Christopher J O’Donnell, Warren J Manning, Michael L Chuang
Journal: Circulation (2019)

Introduction: The ratio of right atrial (RA) to left atrial (LA) volume is predictive of outcome in pulmonary hypertension. We sought to determine normal LA/RA volume ratio by cardiovascular magnet...
Association of an anaplastic lymphoma kinase pathway signature with cell de‐differentiation, neoadjuvant chemotherapy response, and recurrence risk in breast cancer
Authors: Dingxie Liu, Yong Wu
Journal: Cancer Communications (2020)

Abstract Background Aberrant activation of anaplastic lymphoma kinase (ALK) signaling has been found to be involved in the tumorigenesis of multiple types of cancer. The aim of this study was to determine the role of this pathway in the pathogenesis of breast cancer. Methods An ALK pathway signature that we generated previously was used to compute the ALK pathway activity in 6381 breast cancer samples from 42 microarray datasets, and the associations between ALK pathway signature score and clinical variables were examined using logistic regression and survival analyses. Results Our results indicated that high ALK pathway activity was a significant risk factor for hormone receptor‐negative, high‐grade breast cancer in the 42 datasets. ALK pathway activity was positively associated with pathological complete response (pCR) in 15 datasets annotated with patient's neoadjuvant chemotherapy response information (overall odds ratio = 1.67, P &lt; 0.01), and this association was more significant in HER2‐negative and grade 1&amp;2 tumors than in HER2‐positive and grade 3 tumors. ALK pathway activity was also positively associated with recurrence risk in breast cancer patients from 30 datasets annotated with survival information (overall hazard ratio = 1.21, P &lt; 0.01), particularly in patients with age &gt; 50 years old, with positive lymph nodes, or with residual disease after neoadjuvant chemotherapy. Conclusions ALK may be involved in breast cancer tumorigenesis, and ALK pathway signature score may serve as a prognostic biomarker for breast cancer.
Preventing Opioid-Induced Constipation
Authors: Srishti Saha, Piyush Nathani, Arjun Gupta
Journal: JAMA Internal Medicine (2020)

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 Internal Medicine 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 Internal Medicine journal
Outcome of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with systemic therapy without cytoreductive nephrectomy (CN)
Authors: S. L. Richey, S. H. Culp, C. G. Wood, P. G. Corn, E. Jonasch, N. M. Tannir
Journal: Journal of Clinical Oncology (2009)

e16035 Background: Targeted therapies (TT) have replaced cytokines in the management of pts with mRCC. CN has been incorporated in the management of pts with mRCC but many pts are not suitable candidates for CN. The median overall survival (OS) time of pts treated with interferon alfa (IFN-α) without CN was 7.8 months (mos) [Flanigan et al. Journal of Urology 2004]. The median OS time for pts with mRCC treated with TT sequentially without CN is unknown. Methods: We retrospectively reviewed the medical records of pts with mRCC who did not undergo CN and who received one or more TT (bevacizumab, sorafenib, sunitinib, or temsirolimus) sequentially for at least one month with or without chemotherapy (gemcitabine + capecitabine or 5-FU). We calculated OS time from date of diagnosis until date of death or last follow up. We excluded pts who had embolization, radiofrequency ablation or cryotherapy of the primary tumor. Results: We identified 88 pts between Jan 2002 and Dec 2007. Median follow-up time is 9.7 mos (range: 1.2–49.2). Median OS time for all pts is 10.7 mos (95% CI: 7.6–15.4). 55 pts (62.5%) had clear-cell and 33 (37.5%) had non-clear cell histology, with median OS times of 15.1 mos (95% CI: 9.6–17.7) and 7.4 mos (95% CI: 4.4–13.0), respectively. ECOG performance status (PS) at time of diagnosis was correlated with OS (HR 1.54; 95% CI: 1.16–2.05; p&lt;0.01). Pts with PS 0, 1, 2, and 3 had median OS times of 22.8 mos (95% CI: 5.7,*), 16.5 mos (95% CI: 8.1–24.7), 7.6 mos (95% CI: 5.7–11.9), and 7.1 mos (95% CI: 3.3–9.6), respectively. Pts with clinical evidence of lymph node (LN) involvement had worse outcome,with median OS time of 7.6 mos (95% CI: 5.6–9.8) versus 17.2 mos (95% CI: 9.8–35.5) for pts without clinical evidence of LN involvement. Conclusions: In this analysis, median OS time for pts with mRCC treated in the modern era with TT without CN is superior to historical experience with IFN- α.Compromised PS, LN involvement, and non-clear cell histology were associated with worse outcome. This data is useful in the design of randomized trials investigating the role of CN in mRCC. [Table: see text]
Circulating Exosomes Control CD4+ T Cell Immunometabolic Functions via the Transfer of miR-142 as a Novel Mediator in Myocarditis
Authors: Ping Sun, Naixin Wang, Peng Zhao, Chao Wang, Hairu Li, Qi Chen, Ge Mang, Weiwei Wang, Shaohong Fang, Guoqing Du, Maomao Zhang, Jiawei Tian
Journal: Molecular Therapy (2020)

CD4
The Weak LINQ—Continuous Rhythm Monitoring During Sudden Death
Authors: Emily R. Siegel, James W. Salazar, Zian H. Tseng
Journal: JAMA Internal Medicine (2020)

This case report describes a person in their 70s found unconscious and unresponsive who had a history of hypertension, dyslipidemia, atrial fibrillation, seizure disorder, and coronary artery disease and an implantable loop recorder placed 6 months prior.
A randomised trial of treatment optimisation in patients with severe asthma using composite type-2 biomarkers to adjust corticosteroid dose versus a symptom/risk-based algorithm
Authors: Liam G. Heaney, John Busby, Catherine E. Hanratty, Ratko Djukanovic, Ashley Woodcock, Samantha M. Walker, Timothy C. Hardman, Joseph R> Arron
Journal: The Lancet Respiratory Medicine (2020)
SP0092 Regulation of neutrophil apoptosis during acute inflammation – a role for the bcl-2 family of apoptosis-associated genes
Authors: B Walzog, P Weinmann, P Gaehtgens
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Introduction</h3> The life-span of circulating polymorphonuclear neutrophils (PMN) is relatively short when compared to other leukocytes but it can be further shortened by accelerating apoptosis. This is thought to be critical for the control of acute inflammation since apoptosis allows the “silent” elimination of emigrated PMN and thereby prevents uncontrolled tissue damage. This study was undertaken to elucidate the mechanisms which determine the life-span of emigrated PMN during acute inflammation. <h3>Methods</h3> Apoptosis of isolated human PMN was investigated by (1) analysis of DNA content, (2) detection of DNA degradation, (3) analysis of nuclear morphology, and (4) measurement of CD16 expression on the cell surface. Gene expression was analysed by semi-quantitative RT-PCR and western blotting technique. Intraperitoneal thioglycollate injection in mice was used as an <i>in vivo</i> model for acute inflammation. <h3>Results</h3> Leukocyte adhesion molecules of the β2 integrin family (CD11/CD18) which are critically involved in the recruitment of PMN to sites of inflammation were found to potentiate TNFα-induced apoptosis of human PMN within 4 h and 8 h after stimulation. The effect required aggregation of the β2 integrin Mac-1 (CD11b/CD18) and was independent of Fc receptors. An enhancement of apoptosis was also observed after migration of PMN through an endothelial cell monolayer which stained positively for ICAM-1, the ligand for the β2 integrins LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) suggesting that PMN emigration promotes apoptosis. This was confirmed using an <i>in vivo</i> model of acute inflammation in mice. Moreover, inflammatory, i.e. emigrated PMN showed a differential expression of apoptosis-associated genes of the bcl-2 family when compared to circulating PMN: Whereas the pro-apoptotic factor bax-alpha was up-regulated, the expression of the anti-apoptotic bcl-XL was down-regulated in emigrated PMN. Since the bcl-2 family plays an important role in the regulation of apoptosis, this shift of balance between anti- and pro-apoptotic factors may be responsible for the enhancement of apoptosis in inflammatory PMN. <h3>Conclusions</h3> The present study suggests a physiologically relevant mechanism for the control of acute inflammation by promoting the turnover of previously emigrated PMN. This mechanism which involves the bcl-2 family of apoptosis-associated genes may be critical to subside local inflammatory processes <i>in vivo</i>. <h3>References</h3> Walzog B, Jeblonski F, Zakrzewicz A, Gaehtgens P. FASEB J. 1997;<b>11</b>:1177–86 Weinmann P, Gaehtgens P, Walzog B. Blood 1999;93:3106– 15 Walzog B, Gaehtgens P. News Physiol Sci. 2000;15:107–13
Proteomic, biomechanical and functional analyses define neutrophil heterogeneity in systemic lupus erythematosus
Authors: Kathleen R Bashant, Angel M Aponte, Davide Randazzo, Paniz Rezvan Sangsari, Alexander JT Wood, Jack A Bibby, Erin E West, Arlette Vassallo, Zerai G Manna, Martin P Playford, Natasha Jordan, Sarfaraz Hasni, Marjan Gucek, Claudia Kemper, Andrew Conway Morris, Nicole Y Morgan, Nicole Toepfner, Jochen Guck, Nehal N Mehta, Edwin R Chilvers, Charlotte Summers, Mariana J Kaplan
Journal: Annals of the Rheumatic Diseases (2020)

Low-density granulocytes (LDGs) are a distinct subset of proinflammatory and vasculopathic neutrophils expanded in systemic lupus erythematosus (SLE). Neutrophil trafficking and immune function are intimately linked to cellular biophysical properties. This study used proteomic, biomechanical and functional analyses to further define neutrophil heterogeneity in the context of SLE.Proteomic/phosphoproteomic analyses were performed in healthy control (HC) normal density neutrophils (NDNs), SLE NDNs and autologous SLE LDGs. The biophysical properties of these neutrophil subsets were analysed by real-time deformability cytometry and lattice light-sheet microscopy. A two-dimensional endothelial flow system and a three-dimensional microfluidic microvasculature mimetic (MMM) were used to decouple the contributions of cell surface mediators and biophysical properties to neutrophil trafficking, respectively.Proteomic and phosphoproteomic differences were detected between HC and SLE neutrophils and between SLE NDNs and LDGs. Increased abundance of type 1 interferon-regulated proteins and differential phosphorylation of proteins associated with cytoskeletal organisation were identified in SLE LDGs relative to SLE NDNs. The cell surface of SLE LDGs was rougher than in SLE and HC NDNs, suggesting membrane perturbances. While SLE LDGs did not display increased binding to endothelial cells in the two-dimensional assay, they were increasingly retained/trapped in the narrow channels of the lung MMM.Modulation of the neutrophil proteome and distinct changes in biophysical properties are observed alongside differences in neutrophil trafficking. SLE LDGs may be increasingly retained in microvasculature networks, which has important pathogenic implications in the context of lupus organ damage and small vessel vasculopathy.
FRI0040 Helicobacter pylori infection and nsaids gastric lesions in patients with rheumatoid arthritis
Authors: F Montrone, M Lazzaroni, M Antivalle, S Santandrea, G Bianchi Porro, M Carrabba
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Helycobacter pylori is present in about fifty percent of patients with NSAIDs associated gastric lesions. However, studies on the interaction between H. pylori and the occurrence of NSAIDs gastrotoxicity have yielded conflicting results. <h3>Objectives</h3> To investigate the correlation between H. pylori infection and the development of NSAIDs related gastric lesions. <h3>Methods</h3> Data were collected during our double blind clinical and gastroscopic study on the treatment of rheumatoid arthritis with diclofenac or amtolmetinguacyl. A total of 64 patients, aged 18–80 years, suffering from rheumatoid arthritis were randomised to diclofenac (50 mg tid) or amtolmetinguacyl 600 mg bid) for 4 weeks. Clinical and endoscopic evaluation were performed at baseline and at the end of the treatment. The gastroduodenal mucosa was graded according to the Lanza scale, and H. pylori status was assessed at baseline by histology (2 biopsy samples in the antrum, one at the augulus and two in the body of the stomach) and by rapid urease test (one sample in the gastric antrum). <h3>Results</h3> All but one of the patients reached the final visit and 59 underwent endoscopy. H. pylori infection was detected in 30 of the 59 patients (51%); this prevalence is not significantly different from the age-adjusted rate for control populations in western countries and is consistent with previous reports in rheumatoid arthritis and in arthritides of different aetiology. The gross appearance of gastroduodenal mucosa was graded as follows: grade 0, normal mucosa; grade 1, mucosal haemorrhage only; grade 2, one or two erosions; grade 3, numerous areas (3–10) of erosions; grade 4, large number of erosions (&gt; 10) or an ulcer. Considering together patients with endoscopic grading 0–1–2 (normal or minimal lesions) and grading 3–4 (numerous erosions or ulcer), 6/30 (20%) of the H. pylori positive patients and 9/29 (31%) of the H. pylori negative patients had endoscopic scores of 3 or 4 (p &lt; 0.05, CL -33+11%). In this trial 60% of significant gastric lesions (score 3–4) occurred in uninfected patients; this finding supports the hypothesis that most NSAIDs gastric lesions develop through mechanisms that do not require the presence of H. pylori. Our data are not in contrast with recent reports, suggesting that H. pylori not only is unimportant but may rather play a somewhat protective role. <h3>Conclusion</h3> In this study we did not find any statistically significant correlation between H. pylori status and NSAIDs gastrolesivity. However, most gastric lesions (60%) occurred in H. pylori negative patients, suggesting that the presence of the infection is not a risk factor for the occurrence of NSAIDs related gastric lesions.
Covid-19: Should doctors recommend treatments and vaccines when full data are not publicly available?
Authors: Raymond M Johnson, Peter Doshi, David Healy
Journal: BMJ (2020)

With knowledge of covid-19 less than a year old, treatment remains fraught with uncertainty. Preprint data and adaptive clinical trials are imperfect but can guide active decision making in life-or-death situations, says <b>Raymond M Johnson</b>. But <b>Peter Doshi</b> and <b>David Healy</b> argue that doctors and professional societies should state that, without complete data transparency, they will not endorse covid-19 products as being based on science
Appointment Wait Times for Specialty Care in Veterans Health Administration Facilities vs Community Medical Centers
Authors: Kevin N. Griffith, Nambi J. Ndugga, Steven D. Pizer
Journal: JAMA Network Open (2020)

ResultsThe VHA completed 6.9 million consultations in house and paid for an additional 869 000 consultations in the community for cardiology, gastroenterology, orthopedics, and urology from January 2013 to December 2019.The study sample consisted of 3 135 530 veterans, with mean (SD) age 62.0 (13.4) years; 2 873 521 (91.6%) were men.Mean wait times for VHA appointments declined during this period (Figure ), but the declines began before VCP implementation.Orthopedics experienced the largest decline in mean (SD) wait times, from 53.0 (22.4) days to 30.0 (14.7) days.Lesser declines were observed for urology (42.0 [18.5] days vs 34.0 [11.7] days) and gastroenterology (58.0 [23.3] days vs 51.0 [22.9] days).Cardiology wait times did not differ over time.
Outcome prediction based on single nucleotide polymorphisms (SNPs) in DNA repair paths in patients (pts) with esophageal adenocarcinoma (EAC) treated with preoperative (preop) cisplatin (C)-based chemoradiation (CRT): Results from the Eastern Cooperative Oncology Group (ECOG)
Authors: H. H. Yoon, M. Powell, K. Murphy, E. A. Montgomery, M. J. Hafez, G. Liu, A. A. Forastiere, A. B. Benson, L. R. Kleinberg, M. K. Gibson
Journal: Journal of Clinical Oncology (2009)

4530 Background: EAC has eluded cure even with platin-based CRT. Stratifying pts by likelihood of success is one approach to improving outcomes. We assessed whether SNPs in DNA repair paths are associated with complete pathologic response (pCR) in EAC pts who received C-based CRT followed by surgery. Methods: Patients and specimens: Pretreatment biopsy or post-CRT resection samples were obtained from pts (EAC, stage II-IVa) treated on a randomized phase II trial, E1201 (n=86), of preop CRT (RT to 45 Gy). Arm A: Preop C 30 mg/m 2 + irinotecan (I) 50 mg/m 2 days (d) 1, 8, 22, 29 with RT. Post-op C 30 mg/m 2 + I 65 mg/m 2 d 1, 8 q21 days x 3. Arm B: Preop C 30 mg/m 2 + paclitaxel (P) 50 mg/m 2 d 1, 8, 15, 22, 29 with RT. Post-op C 75 mg/m 2 + P 175 mg/m 2 d 1 q21 days x 3. Clinical outcome - pCR: (A) 14% [95% CI 5.5%, 28.5%]; (B) 16% [95% CI 6.7%, 30.1%]. Median overall survival (OS): (A) 34.9 m (months) [90% CI 23.5, not reached]; (B) 20.9 m [90% CI 17.4, 46.7]. Experimental procedure: Normal tissue was microdissected from unstained sections of paraffin-embedded tissue. DNA was extracted (Qiagen). Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight (Sequenom) for all SNPs. Each SNP was dichotomized a priori into: (1) major homozygote vs (2) minor (heterozygote plus minor homozygote) allele groups. Data analysis was performed centrally, with lab investigators blinded to clinical data. Exact logistic regression was used to derive ORs for non-pCR, using the major homozygote as the reference (2-sided p values). Results: Germline DNA was available in 68 pts; 60 were eligible and began therapy ( Table ). Conclusions: In this homogenous, well-defined cohort, the XRCC1 Arg399Gln minor allele group was associated with lower pCR (p=0.06). Lab data on a panel of additional SNPs have been collected and are under analysis for presentation at the meeting. [Table: see text] [Table: see text]