tbuckley/cabot-search huggingface dataset:
Lesson of the Week: Delayed diagnosis of Kawasaki disease presenting with massive lymphadenopathy and airway obstruction
Authors: D. Burgner, M. Festa, D. Isaacs
Journal: BMJ (1996)

Kawasaki disease is an acute, self limiting febrile illness of infants and young children. In children under 5 years of age the incidence varies from about 3-6 per 100 000 in Europe1 to 90 per 100 000 in Japan.2 It causes coronary artery lesions in about 20% of untreated patients, up to 2% of whom die.3 Diagnosis is based on the presence of a prolonged fever (of more than five days duration) plus four of the following five signs: conjunctival injection, changes in the mucous membranes, changes in the peripheries (erythema of the palms and soles and swelling of the hands and feet), rash, and lymphadenopathy. The clinical features may be supplemented by non-specific laboratory investigations—for example, thrombocytosis and an increased erythrocyte sedimentation rate—but there is no specific diagnostic test. Prompt diagnosis permits early treatment with intravenous immunoglobulin, which reduces the incidence of coronary artery lesions by up to two thirds.4 5

Lymphadenopathy is …
Presence of JAK2V617F Mutation in Endothelial Cells from Budd-Chiari Syndrome Patients Is Not Correlated with Ph-Negative Myeloproliferative Neoplasm
Authors: Ricardo Helman, Welbert Oliveira Pereira, Paulo Vidal Campregher, Luciana Cavalheiro Marti, Nelson Hamerschlak, Isabel Bello, Sandra Saemi Nakashima, Carlos S Chiattone, Fabio P S Santos
Journal: Blood (2014)
Effect of Bone Marrow–Derived Mononuclear Cell Treatment, Early or Late After Acute Myocardial Infarction
Authors: Daniel Sürder, Robert Manka, Tiziano Moccetti, Viviana Lo Cicero, Maximilian Y. Emmert, Catherine Klersy, Sabrina Soncin, Lucia Turchetto, Marina Radrizzani, Michel Zuber, Stephan Windecker, Aris Moschovitis, Ines Bühler, Sebastian Kozerke, Paul Erne, Thomas F. Lüscher, Roberto Corti
Journal: Circulation Research (2016)

Intracoronary delivery of autologous bone marrow-derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction (AMI).To demonstrate long-term efficacy of BM-MNC treatment after AMI.In a multicenter study, we randomized 200 patients with large AMI in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were either administered 5 to 7 days (early) or 3 to 4 weeks (late) after AMI. Cardiac magnetic resonance imaging was performed at baseline and after 12 months. The current analysis investigates the change from baseline to 12 months in global LV ejection fraction, LV volumes, scar size, and N-terminal pro-brain natriuretic peptide values comparing the 2 treatment groups with control in a linear regression model. Besides the complete case analysis, multiple imputation analysis was performed to address for missing data. Furthermore, the long-term clinical event rate was computed. The absolute change in LV ejection fraction from baseline to 12 months was -1.9±9.8% for control (mean±SD), -0.9±10.5% for the early treatment group, and -0.7±10.1% for the late treatment group. The difference between the groups was not significant, both for complete case analysis and multiple imputation analysis. A combined clinical end point occurred equally in all the groups. Overall, 1-year mortality was low (2.25%).Among patients with AMI and LV dysfunction, treatment with BM-MNC either 5 to 7 days or 3 to 4 weeks after AMI did not improve LV function at 12 months, compared with control. The results are limited by an important drop out rate.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.
Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced adrenocortical carcinoma from the JAVELIN solid tumor phase Ib trial: Safety and clinical activity.
Authors: Christophe Le Tourneau, Christopher J. Hoimes, Corrine Zarwan, Deborah Jean Lee Wong, Sebastian Bauer, Martin Wermke, Rainer Claus, Kevin M. Chin, Anja von Heydebreck, Jean-Marie Cuillerot, James L. Gulley
Journal: Journal of Clinical Oncology (2016)

4516 Background: Avelumab* is a fully human anti-PD-L1 IgG1 antibody under clinical investigation in multiple cancers. We report safety and clinical activity of single-agent avelumab in patients (pts) with metastatic adrenocortical carcinoma (mACC), a rare malignancy for which there are limited therapeutic options (NCT01772004). Methods: Pts with mACC who had progressed after platinum-based therapy and were unselected for PD-L1 expression were treated with avelumab at 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Prior and ongoing treatment with mitotane was permitted. Tumors were assessed every 6 wks (RECIST 1.1). Objective response rate (ORR) and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Results: As of Oct 23, 2015, 37 pts were treated with avelumab (median 8 wks [range 2-48]) and followed for a median of 13 wks (range 0-58). Median age was 50 y (range 23-71), ECOG PS was 0 (37.8%) or 1 (62.2%), and median number of prior treatments for metastatic disease was 1 (range 0-5). Treatment-related (TR) AEs occurred in 23 pts (62.2%); the most common (> 10%) were nausea (6 [16.2%]), fatigue (5 [13.5%]), pyrexia (5 [13.5%]), and infusion-related reaction (5 [13.5%]), all of grade 1/2. Grade ≥3 TRAEs occurred in 5 pts (13.5%; each 1 event): hyperkalemia, increased ALT, GGT, or transaminase, sepsis, spinal cord infection, and pneumonitis. Potential immune-related TRAEs occurred in 4 pts (10.8%): 3 pts with grade 1/2 events and 1 pt with grade 3 pneumonitis that resolved. There were no treatment-related deaths. Among 19 pts with ≥13 wks f/u, unconfirmed ORR was 10.5% (2 partial responses; 95% CI: 1.3, 33.1). Stable disease was observed in 5 pts (26.3%); disease control rate was 36.8% (7/19). Median PFS was 7.6 wks (95% CI: 5.9, 23.9), and PFS rate at 12 wks was 30.3% (95% CI: 12.3, 50.7). Conclusions: Avelumabshowed an acceptable safety profile and clinical activity in pts with mACC, a dataset representing the first study to date of an anti-PD-(L)1 agent in this rare tumor type. Analyses of activity, including response correlated with PD-L1 expression, are ongoing. *Proposed INN. Clinical trial information: NCT01772004.
Abstract 3737: Inhibition of O-GlcNAc transferase in tamoxifen resistant breast cancer cells
Authors: Anna Barkovskaya, Lina Prasmickaite, Ian G. Mills, Gunhild M. Mælandsmo, Siver A. Moestue, Harri M. Itkonen
Journal: Cancer Research (2016)

Abstract O-linked N-acetyl-glucosamine transferase (OGT) is an enzyme that catalyzes addition of the O-GlcNAc modification to a wide range of intracellular proteins. The O-GlcNAc modification is a product of the hexosamine biosynthetic pathway, which requires glucose and glutamine as substrates. Uptake of both of these nutrients is often up-regulated in cancer, which in turn leads to an increase in the total protein O-GlcNAcylation. Increased OGT expression has also been reported in most cancer types, including the most frequently diagnosed cancer in women, breast cancer. Many of the breast cancers rely on estrogen receptor alpha (ERα) for proliferation and have shown a strong response to the ERα inhibition, most commonly achieved by treatment with tamoxifen. However, while efficient, prolonged exposure to tamoxifen commonly causes resistance and relapse of the disease. It is therefore vital to uncover mechanisms which contribute to the resistance in order to develop adequate treatment strategy for these patients. Here, we have investigated the effect of targeting OGT in an isogenic pair of ERα-positive tamoxifen-sensitive MCF7 and tamoxifen-resistant TAMR breast cancer cell lines. OGT inhibition decreased viability and triggered cell death in both cell lines. These responses were associated with over 50% reduction in ERα expression in both MCF7 and TAMR cells. Reduced O-GlcNAcylation has previously been reported to induce endoplasmic reticulum stress and activation of transcription factor C/EBP homologous protein (CHOP), which promotes cell death. Targeting OGT resulted in a strong increase of CHOP expression, which appeared more prominent in the TAMR cells. Finally, targeting OGT induced a very pronounced cell cycle arrest in the G2/M phase in the TAMR cells, while the MCF7 cell lined showed a very modest response. Taken together, these results indicate that targeting OGT leads to a differential response in the tamoxifen-sensitive and resistant breast cancer cells. Currently, we are using an expanded panel of tamoxifen-resistant cell lines to perform expression microarrays, metabolic flux assays and DNA damage response analysis in order to uncover the cause of the differential response to OGT targeting. This may help us identify potential therapeutic combinations that might be suitable for treatment of tamoxifen-resistant cancers. Citation Format: Anna Barkovskaya, Lina Prasmickaite, Ian G. Mills, Gunhild M. Mælandsmo, Siver A. Moestue, Harri M. Itkonen. Inhibition of O-GlcNAc transferase in tamoxifen resistant breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3737.
Abstract 3873: Single cell cisplatin measurements by ICP-MS
Authors: Lauren Amable, Stan Smith, Chady Stephan
Journal: Cancer Research (2016)

Abstract Cisplatin, carboplatin, and oxaliplatin are the most widely used class of cancer chemotherapy drugs in the Western world. Many cancers are initially sensitive to platinum treatment but drug resistance frequently occurs. Cellular uptake of cisplatin is related to tumor burden, thus lower intracellular cisplatin levels are associated with a decreased tumor response. Traditional methods to assess cisplatin uptake in cells involves digesting a cell population and measuring the total platinum content. This approach does not reflect the distribution and individual cellular variation of cisplatin uptake. Here, we present a new method, single cell inductively coupled plasma-mass spectrometry (SC-ICP-MS) to quantitate the platinum concentration within individual cells. Experiments were performed using the A2780 cisplatin-sensitive and the corresponding cisplatin-resistant A2780-CP70 ovarian cancer cell lines. Time course experiments were performed to measure the change of cisplatin uptake over time. Serum starvation experiments were also performed to examine if differences in cisplatin uptake were dependent on the cell cycle. SC-ICP-MS was performed by injecting cell suspensions and analyzing the platinum 195 isotope. Individual cellular cisplatin levels were collected and a histogram representing the cell population was generated using the instrument software (Syngistix Nano Application). Other metals, such as zinc, iron, and copper, were analyzed to measure the variation between cell lines after treatment. We observed a heterogeneous distribution of cisplatin concentrations within the sample reflecting that cisplatin uptake differs from cell to cell. Serum starvation affected the uptake of cisplatin within cells, changing the cisplatin distribution curve. SC-ICP-MS was also effective in measuring other metals within individual cells and differences were observed between the A2780 and A2780-CP70 cell lines. In conclusion, single cell ICP-MS analysis allows for the quantitation of cisplatin within individual cells. The heterogeneous distribution of cisplatin uptake more closely reflects what occurs within tumor cells. SC-ICP-MS allows for the development of strategies to increase cisplatin uptake, translating to better clinical responses. Citation Format: Lauren Amable, Stan Smith, Chady Stephan. Single cell cisplatin measurements by ICP-MS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3873.
Abstract 4972: Detection of PSMA on circulating tumor cells from blood of prostate cancer patients using anti-PSMA Centyrin
Authors: Bhavesh Vaidya, Peter Vulfson, Renouard Sanders, Donna Klein, Shalom Goldberg, Steve Jacobs, Chandra Rao
Journal: Cancer Research (2016)

Abstract Prostate specific membrane antigen (PSMA), a transmembrane glycoprotein, is a clinically validated marker of prostate cancer. PSMA is overexpressed in primary and metastatic prostate cancer when compared to normal prostate tissue which makes it an attractive target for immunotherapy. Several antibodies are being considered to target PSMA for the development of an anticancer drug. The expression levels of PSMA on tumor cells may play a role in response to treatment with anti PSMA drugs. Therefore, it is important to monitor PSMA expression on tumor cells before and during treatment. We used CellSearch® CTC assay to determine the presence of PSMA on circulating tumor cells (CTCs) using anti PSMA Centyrin as a biomarker. Centyrins are a class of alternative scaffold molecules which are proteins of small size (∼ 10 kDa). They are engineered to bind to target molecules with high specificity and sensitivity. The anti PSMA Centyrin was tested for specificity and sensitivity using tissue cultured tumor cell lines spiked into normal healthy blood and then compared to anti PSMA antibody. The anti PSMA Centyrin showed 100% positivity with the high PSMA expressing cell line (LNCap), 25% positivity with the low PSMA expressing cell line (22Rv1) and 0% positivity with the PSMA negative cell line (PC3-9). The anti PSMA Centyrin was further tested with prostate patient blood samples to determine the expression levels of PSMA on CTCs. The patient samples which contain CTCs are positive for anti PSMA Centyrin and the percentage of CTCs positive for PSMA ranged from 25-100%. Thus, PSMA expression on CTCs can be determined using CellSearch® system and anti PSMA Centyrin as a biomarker in a clinical trial. Citation Format: Bhavesh Vaidya, Peter Vulfson, Renouard Sanders, Donna Klein, Shalom Goldberg, Steve Jacobs, Chandra Rao. Detection of PSMA on circulating tumor cells from blood of prostate cancer patients using anti-PSMA Centyrin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4972.
Abstract 5278: NGS-SWIFT: A cloud-based variant analysis framework using control-accessed sequencing data from dbGaP/SRA
Authors: Chunlin Xiao, Eugene Yaschenko, Stephen Sherry
Journal: Cancer Research (2016)

Abstract Genetic variation analysis plays an important role in elucidating the causes of various human diseases. The drastically reduced costs of genome sequencing driven by next generation sequence technologies now make it possible to analyze genetic variations with hundreds or thousands of samples simultaneously, but with the cost of ever increasing local storage requirements. The tera- and peta-byte scale footprint for sequence data imposes significant technical challenges for data management and analysis, including the tasks of collection, storage, transfer, sharing, and privacy protection. Currently, each analysis group must download all the relevant sequence data into a local file system before variation analysis is initiated. This heavy-weight transaction not only slows down the pace of the analysis, but also creates financial burdens for researchers due to the cost of hardware and time required to transfer the data over typical academic internet connections. To overcome such limitations and explore the feasibility of analyzing control-accessed sequencing data in cloud environment while maintaining data privacy and security, here we introduce a cloud-based analysis framework that facilitates variation analysis using direct access to the NCBI Sequence Read Archive through NCBI SRA Toolkit, which allows the users to programmatically access data housed within SRA with encryption and decryption capabilities and converts it from the SRA format to the desired format for data analysis. A customized machine image (ngs-swift) with preconfigured tools, including NCBI SRA Toolkit and NGS Software Development Kit, and resources essential for variant analysis has been created for instantiating an EC2 instance or instance cluster on Amazon cloud. Performance of this framework has been evaluated using dbGaP study phs000710.v1.p1 (1000Genome Dataset in dbGaP, http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id = phs000710.v1.p1), and compared with that from traditional analysis pipeline, and security handling in cloud environment when dealing with control-accessed sequence data has been addressed. We demonstrate that with this framework, it is cost effective to make variant calls without first transferring the entire set of aligned sequence data into a local storage environment, thereby accelerating variant discovery using control-accessed sequencing data. Citation Format: Chunlin Xiao, Eugene Yaschenko, Stephen Sherry. NGS-SWIFT: A cloud-based variant analysis framework using control-accessed sequencing data from dbGaP/SRA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5278.
Abstract 3388: Genetic prediction of VEGF-A plasma levels in cancer patients
Authors: Federico Innocenti, Chen Jiang, Alexander Sibley, Amy Etheridge, Yoichi Furukawa, Michiaki Kubo, Hedy L. Kindler, Alan P. Venook, Herber I. Hurwitz, Andrew B. Nixon, Kouros Owzar
Journal: Cancer Research (2016)

Abstract ABSTRACT Background: Angiogenesis is an essential event in tumor growth, progression and metastasis and is strongly regulated by multiple VEGF ligands and receptors. We sought to discover genetic variants that could predict levels of circulating angiogenic proteins in cancer patients prior to receiving therapy. Methods: EDTA plasma was collected at baseline (before treatment) in 216 treatment naïve pancreatic cancer patients (CALGB 80303, discovery) and 149 treatment naïve colorectal cancer patients (CALGB 80203, validation). Thirty-one angiogenic factors were measured by a multiplexed ELISA assay. Genetic variants associated with levels of each of the 31 proteins were selected from a genome-wide genotyping of 484,523 common variants in CALGB 80303. Using a cut off of p&amp;lt;10−8 for association, variants were selected from CALGB 80303, genotyped in CALGB 80203 and associations tested with the same protein levels. The Jonckheere-Terpstra test was used. Additionally, mRNA was extracted from formalin-fixed, paraffin-embedded primary tumors from patients in CALGB 80203 and tissue levels of VEGF-A analyzed by RT-PCR. Results: In CALGB 80303, three genetic variants passed the p&amp;lt;10−8 cut off for significance: rs2284284 for MCP1, rs7504372 for VEGFC, and rs7767396 for VEFG-A levels. Of these, only rs7767396 (A&amp;gt;G) for VEFG-A levels was validated in CALGB 80203 (p = 1.23×10−5). Patients with the AA genotype exhibited 2.2-fold higher VEGF-A levels than AG patients, who had 1.2-fold higher levels than GG patients. rs7767396 was not associated with VEGF-A mRNA levels from the primary tumors of patients in CALGB 80203 (p&amp;gt;0.05). rs7767396 is a common variant (frequency of 49% in Europeans), is located about 150 Kb 3’ to the VEGFA gene, and is predicted by HaploReg to disrupt the binding motifs of two transcription factors, NF-AT1 and ZBRK1. Conclusions: A common genetic variant predicts the levels of circulating VEGF-A in cancer patients. A similar effect has been also shown in non-cancerous individuals (Debette S et al., Circ Res, 2011). Due to the central role of VEFG-A in the pathophysiology of many conditions, genetic testing could predict patients who have high versus low levels, potentially helping to guide the use of anti-angiogenesis therapies. Citation Format: Federico Innocenti, Chen Jiang, Alexander Sibley, Amy Etheridge, Yoichi Furukawa, Michiaki Kubo, Hedy L. Kindler, Alan P. Venook, Herber I. Hurwitz, Andrew B. Nixon, Kouros Owzar. Genetic prediction of VEGF-A plasma levels in cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3388.
Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases
Authors: Nobuhiro Inatomi, Jun Matsukawa, Yuuichi Sakurai, Kazuyoshi Otake
Journal: Pharmacology & Therapeutics (2016)

Acid-related diseases (ARDs), such as peptic ulcers and gastroesophageal reflux disease, represent a major health-care concern. Some major milestones in our understanding of gastric acid secretion and ARD treatment reached during the last 50years include 1) discovery of histamine H2-receptors and development of H2-receptor antagonists, 2) identification of H+,K+-ATPase as the parietal cell proton pump and development of proton pump inhibitors (PPIs), and 3) identification of Helicobacter pylori (H. pylori) as the major cause of peptic ulcers and development of effective eradication regimens. Although PPI treatments have been effective and successful, there are limitations to their efficacy and usage, i.e. short half-life, insufficient acid suppression, slow onset of action, and large variation in efficacy among patients due to CYP2C19 metabolism. Potassium-competitive acid blockers (P-CABs) inhibit H+,K+-ATPase in a reversible and K+-competitive manner, and exhibit almost complete inhibition of gastric acid secretion from the first dose. Many pharmaceutical companies have tried to develop P-CABs, but most of their clinical development has been discontinued due to safety concerns or a similar efficacy to PPIs. Revaprazan was developed in Korea and was the first P-CAB approved for sale. Vonoprazan, approved in 2014 in Japan, has a completely different chemical structure and higher pKa value compared to other P-CABs, and exhibits rapid onset of action and prolonged control of intragastric acidity. Vonoprazan is an effective treatment for ARDs that is especially effective in healing reflux esophagitis and for H. pylori eradication. P-CABs, such as vonoprazan, promise to further improve the management of ARDs.