tbuckley/cabot-search huggingface dataset:
Use of a human ribonuclease variant, QBI-139, for the treatment of cancer.
Authors: L. E. Strong, J. A. Kink, B. Mei, M. N. Shahan, R. T. Raines
Journal: Journal of Clinical Oncology (2010)

TPS162 Background: A phase I trial has been initiated for QBI-139, a variant of the human pancreatic ribonuclease 1, which shares 95% sequence identity with the native protein. Unlike the native protein, the drug QBI-139 is able to evade the ribonuclease inhibitor protein found in the cytosol, allowing the ribonuclease to be active when the enzyme enters cancer cells. Treatment of cancer cells with QBI-139 results in apoptosis. QBI- 139 has shown efficacy in models of a variety of cancers, including colorectal, non-small cell lung, ovarian, pancreatic, and prostate cancers. A critical next step for QBI-139 is to identify indications for the next stage of clinical development given the agent's broad efficacy in model systems. Methods: Due to the range of activity, the phase I trial was designed for patients with advanced solid tumors. Patients receive QBI- 139 by intravenous infusion once weekly for three weeks with treatment repeating every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of three to six patients receive escalating doses of QBI-139 until the maximum tolerated dose (MTD) is determined. The trial is expected to enroll approximately 30 patients, with about half of the patients currently enrolled (January 2010). The primary outcomes of the trial are to evaluate the toxicity and tolerability of and the maximum tolerated dose for QBI-139 in patients with advanced refractory solid tumors. In addition, patient response to QBI- 139 will be measured using the RECIST criteria and the pharmacokinetics of QBI-139 will be evaluated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Quintessence Biosciences, Inc. Quintessence Biosciences, Inc. Quintessence Biosciences, Inc.
Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion
Authors: A Toma, O Kosmider, S Chevret, J Delaunay, A Stamatoullas, C Rose, O Beyne-Rauzy, A Banos, A Guerci-Bresler, S Wickenhauser, D Caillot, K Laribi, B De Renzis, D Bordessoule, C Gardin, B Slama, L Sanhes, B Gruson, P Cony-Makhoul, B Chouffi, C Salanoubat, R Benramdane, L Legros, E Wattel, G Tertian, K Bouabdallah, F Guilhot, A L Taksin, S Cheze, K Maloum, S Nimuboma, C Soussain, F Isnard, E Gyan, R Petit, J Lejeune, V Sardnal, A Renneville, C Preudhomme, M Fontenay, P Fenaux, F Dreyfus
Journal: Leukemia (2015)
Abstract 16253: Which is the Optimal Pharmacogenetic Algorithm for Guiding Warfarin Initiation? Comparison among 3 Leading Algorithms
Authors: Kimberly D Brunisholz, Stacey Knight, Benjamin D Horne, Joseph B Muhlestein, John F Carlquist, Chrissa Petersen, Dustin Siler, Jeffrey L Anderson
Journal: Circulation (2012)

Background: Warfarin therapy is limited by highly variable individual dose requirements, a narrow therapeutic window, and a high risk of adverse events associated with out-of-range prothrombin times. Several pharmacogenetic (PG) algorithms have been proposed to improve warfarin efficiency and safety. This study compared 3 leading algorithms: Gage (Washington University), International Warfarin Pharmacogenetics Consortium (IWPC), and CoumaGen-II for ability to predict stable maintenance dose (MD) in a large prospective study. Methods: Patients (pts) enrolled in the CoumaGen-II study (NCT00927862) were evaluated. Individual patient clinical and genetic (CYP2C9, VKORC1) information was entered into previously published and on-line Gage and IWPC algorithms and the prospectively defined CoumaGen-II algorithm and MDs computed. Absolute differences between computed MDs and actual MDs were compared. An empiric dose of 5mg/d served as a virtual control. Differences between algorithms were compared using Friedman’s...
Does body mass index predict cutaneous reactions to pegylated liposomal doxorubicin?
Authors: E. L. Fleming, D. S. Dizon, P. A. Disilvestro, R. G. Moore, C. Granai, M. E. Gordinier
Journal: Journal of Clinical Oncology (2004)

5140 Background: The dose limiting toxicity of pegylated liposomal doxorubicin (PLD) is palmar-plantar erythrodysesthesia (PPE). Some physicians may have a bias against using this drug in overweight patients, postulating that larger size increases the likelihood of drug deposition that may predispose to PPE. The aim of this study was to determine whether the body mass index (BMI) predicted frequency or severity of cutaneous reactions in patients receiving PLD. Methods: The records of all patients receiving PLD for a gynecologic malignancy between 1996 and 2003 were reviewed. Chemotherapy history, BMI at the start of PLD treatment, dose, infusion time, and adverse effects were collected. In addition, type and grade of skin reactions and treatments for them were extracted. Finally, history of potential predisposing factors was recorded, such as sun exposure, medical conditions, and allergies. The reason for drug discontinuation was also ascertained. Results: 103 patients were included in this analysis. 429 cycles of PLD were given with a median of 4 cycles per patient. The primary toxicity was skin reaction with 36% experiencing PPE. Of those with PPE, 54% had a Gr1 reaction, 32% had Gr2 reactions, and 14% had Gr3 reactions. There were no Gr4 reactions. The mean BMI in patients who had clinically significant skin reactions was identical to those who did not, 29 vs. 28.8, respectively. When patients were analyzed by subsets of weight, the incidence of skin reactions among patients of different weight groups was similar. Logistic regression revealed no relationship between BMI and grade of rash. None of the potential predisposing factors analyzed correlated with an increased incidence of cutaneous toxicity. Conclusions: Increased BMI is not associated with an increased risk of skin reactions or PPE. Among the patients treated with PLD, the rate of skin toxicity was 36% and was a major reason for discontinuing the drug. Further work is required to better define which of our patients is at risk for PPE. No significant financial relationships to disclose.
Abstract 9929: Novel Mutations Identified by Whole Exome Sequencing in Families With Congenital Heart Disease
Authors: Ashok Kumar Manickaraj, Orion Buske, Michael Brudno, Seema Mital
Journal: Circulation (2012)

Congenital heart disease (CHD) is a complex disorder with multifactorial etiology and high heritability. We used whole exome sequencing to identify novel variants associated with familial CHD. Methods: CHD patients were enrolled in a prospective biobank registry (n=2800). Whole exome sequencing was performed in 12 affected members with LV outflow tract defects and 7 non-affected members from 5 families using Illumina Hi-Seq 2000, and Agilent SureSelect Human All Exon v.2 Kit for sequence capture. Results: Sequence alignment to the reference human genome (GRCh37/hg19) identified over 48K single nucleotide variants (SNVs) and indels (average 820 novel coding variants per individual). SNVs were called using SOAP tools and SIFT, Polyphen and Mutation Taster algorithms were used to predict pathogenicity. Affected and unaffected members were compared using the dominant model to identify novel CHD-associated variants. We identified 216 novel SNVs that segregated within affected members (not seen in unaffected members). These included 82 potentially pathogenic variants on 69 genes expressed in the heart and/or vasculature. Of these, 51 were inherited and 31 were de novo. Novel inherited variants in two genes on the Eph (ephrin) family receptor interacting proteins segregated within 4 affected members from 2 families. Eph receptors form the largest subfamily of receptor tyrosine kinases that are components of cell adhesion, migration, and signalling pathways and are involved in organ development. Additional inherited and de novo variants are being further characterized to determine if they are related to cardiac developmental pathways. Conclusions: Next-generation sequencing can detect novel variants on susceptibility genes that identify new pathways involved in CHD causation. Replication in additional CHD families and candidate gene resequencing will help validate the association of observed variants with CHD.
NHS organ registry considers new way to stop families over-ruling relatives’ wish to donate
Authors: Gareth Iacobucci
Journal: BMJ (2016)

More than 500 UK families have blocked organ donation taking place since April 2010, despite knowing or being informed that their deceased relative was a registered donor, new figures have shown.

NHS Blood and Transplant, which released the figures, said that there had been 547 refusals in the past five years, about one in eight of those deceased people who were registered to donate organs. This resulted in an estimated 1200 people missing out …
Urologist is investigated by GMC after review by Royal College of Surgeons
Authors: Clare Dyer
Journal: BMJ (2015)

A consultant urologist who worked at Birmingham Heartlands Hospital is under investigation by the General Medical Council after a review by the Royal College of Surgeons recommended that his radical prostatectomy patients be recalled.

Arackal Manu Nair was suspended by Heart of England NHS Foundation Trust last year pending the review and later resigned. The Medical Practitioners Tribunal Service has placed interim conditions on his registration, including a requirement that he practise only in the NHS under supervision and a ban on performing laparoscopic prostatectomies and procedures involving GreenLight laser.

Manu Nair also operated at three private Birmingham hospitals: Spire Parkway, Spire Little Aston, and BMI …
Engaging human tumor microvascular endothelium to improve ionizing radiation outcomes in solid tumor treatment
Authors: S. N. Lewin, R. R. Barakat, A. Haimovitz-Friedman, R. Kolesnick, Z. Fuks, E. A. Poynor
Journal: Journal of Clinical Oncology (2006)

10097 Background: Recent genetic and pharmacologic mouse model studies have shown tumor microvascular endothelium is a primary target in single-dose radiotherapy, required for induction of tumor cell death. The goal of this study is to establish the human tumor microvascular response to ionizing radiation (IR), and to determine whether targeting this response with IR might improve solid tumor treatment. Methods: Fresh epithelial ovarian cancer (EOC) tissue was obtained and irradiated within 30 minutes from patients undergoing surgical resection. Tumors were sliced into 0.5cm fragments, bathed in Dulbecco’s Modification of Eagle’s Medium (DMEM) and irradiated ex vivo at 0, 7, 13, 17, 20, 25 Gy. Specimens were incubated at 37°C post-irradiation for 0, 2, 3, 4 hours, fixed in formalin and paraffin embedded. Immunohistochemistry using TUNEL-CD34 double staining was subsequently performed to detect apoptotic tumor endothelial cells. Results: 10 EOC specimens were initially studied. Tumor microvascular endothelium underwent a linear dose and time dependent apoptotic response mirroring the range reported in mouse models. Three to four hours post irradiation, 60% of endothelial cells underwent apoptosis at 17–25 Gy compared to a baseline rate of 5% in unirradiated controls. Response heterogeneity among the tumor samples was not seen. Of interest is our observation that a maximal apoptotic response obtained in glioblastoma, classically considered radioresistant, was only 30%. Conclusion: The endothelial compartment is an important target in EOC radiation response at the clinically-relevant dose range. Studies assessing endothelial cell radiosensitivity of human EOC and the impact of endothelial cell radiosensitizing agents may provide opportunities to improve radiation responsiveness of EOC. No significant financial relationships to disclose.
Peripheral-blood gene expression profiling in bladder cancer (BC) patients (pts)
Authors: A. B. Apolo, I. Osman, R. Shen, A. B. Olshen, D. F. Bajorin
Journal: Journal of Clinical Oncology (2008)

5076 Background: There is a compelling need for biomarkers in the diagnosis and surveillance of bladder cancer (BC). In a pilot study, we previously reported that gene expression profile signature in circulating blood cells (CBC) can distinguish BC pts from other genitourinary cancers and from healthy controls. Here, we take our hypothesis-generating study to the hypothesis-testing level in a larger independent cohort of pts that: 1) includes more stringent control subjects, i.e., bladder pathology other than cancer; and 2) seeks to develop a gene-signature from CBC that can distinguish the presence and extent of BC. Methods: 85 pts (28 superficial BC (sBC), 27 metastatic BC (mBC), and 30 pts with benign bladder pathology) were studied. RNA from CBC was isolated and purified total RNA was labeled and hybridized onto Illumina Human-6 v2 Expression BeadChips (48,000 transcript probes/sample). Expression data were log base 2 transformed and within-array standardized. Unsupervised hierarchical clustering of 4438 high variance genes was used to group samples. T-tests were used to compare the 3 groups of pts. The Benjamini-Hochberg method was used to adjust the resulting p-values for multiple comparisons. Genes were selected based on adjusted p-value (≤ 0.05) and fold change (≥1.5). Results: Clustering led to almost complete separation of BC and benign pts and partial separation of sBC and mBC pts. A subset of 600 genes (230 significantly over-expressed genes and 370 under-expressed genes) were strikingly different between mBC pts compared to benign pts. The top-ranking overexpressed genes include genes related to inflammatory responses such as: peptidoglycan recognition protein 1 (p=2.9×10−8), CD177 molecule (p=5.4×10−8) and haptoglobin (p=5.6×10−7). Top-ranking underexpressed genes included genes related to cell cycle regulation and molecular chaperones such as: CDC like kinase 1 (p=1.7×10−9), Purinergic receptor P2Y (p=1.7×10−9), and Chaperonin Subunit 6a (p=2.3×10−9). Conclusions: Our study reveals a distinct blood-based gene expression signature that differentiates between metastatic BC (pts) and those with benign bladder pathology conditions. Efforts are ongoing to validate a smaller set of high-ranking genes as a BC signature that can be used as a diagnostic/prognostic tool. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, GPC Biotech Bristol-Myers Squibb, Eli Lilly, Genentech™ BioOncology, Pfizer
Validation of genotyping of gastrointestinal stromal tumor in Japan
Authors: T. Takahashi, T. Nishida, S. Sakurai, T. Kanda, A. Sawaki, R. Wada, T. Hasegawa, S. Hirota
Journal: Journal of Clinical Oncology (2009)

e21502 Background: Most gastrointestinal stromal tumors (GIST) have activating mutations in the KIT or PDGFRA gene. Genotyping of GIST is important in Dx and Tx of GIST. Methods of genotyping using genomic DNA extracted from paraffin-embedded specimens are diverse and not standardized. We did validation study of genotyping using special reference to sequencing data obtained from cDNA from fresh GIST samples. Methods: Three DNA extraction methods (QIAamp, DEXPAT, or original) and four PCR methods (Ex Taq, AmpliTaq condition-1, AmpliTaq condition-2, or QIAGEN Tag) were compared using 20 paraffin-embedded specimens with special reference to sequencing data obtained from cDNA from corresponding 20 fresh GIST samples. After DNA extraction, KIT exon 9, 11, 13 and 17, and PDGFRA exon 12 and 18 were amplified by each PCR method using specific primers and directly sequenced. Results: In evaluation of PCR method, the protocol with Ex Taq showed 100% amplication of DNA and sequence agreement, the protocol with QIAGEN Tag 99%, and the protocol with AmpliTaq condition-2 86% agreement, and the protocol with AmpliTaq condition-1 showed much less amplication and higher disagreement. For the DNA extraction, the protocol with QIAamp showed best DNA extraction and its DNA sequence data were consistent with reference sequence in 98%, DNA sequence obtained using DEXPAT showed 33% consistency, and 89% of DNA sequence data obtained from an original method was agreed with reference data. Some modifications improved DNA amplication but inconsistent sequence data also increased probably due to miss-PCR. Conclusions: Each DNA extraction method had different quantity of DNA and four PCR methods showed different quality. Using this validation study, a standard genotyping method in Japan was established. No significant financial relationships to disclose.
Abstract 204: Single-molecule localization microscopy analysis of a cancer metastasis-specific miRNA on the nanoscale
Authors: Mohammed Abba, Olga Oleksiuk, Kerem Tezcan, Wladimir Schaufler, Felix Bestvater, Peter Altevogt, Mathias Hafner, Christoph Cremer, Heike Allgayer
Journal: Cancer Research (2015)

Abstract We propose a novel approach for the detection of small non-coding RNAs in cells by Single Molecule Localization Microscopy (SMLM). We describe a modified and upgraded SMLM-setup and apply this instrument in a first proof-of-principle concept to human cancer cell lines. Our method is able to visualize single microRNA molecules in fixed cells with a localization accuracy of 10-15 nm, is able to quantify numbers and analyse clustering and localization in particular subcellular sites, including exosomes. We compared metastatic-site derived and primary site derived human adenocarcinoma cultured colorectal cancer (CRC) cells, and (as a proof of principle) evaluated the metastatically relevant miR-31 as a first example. We observed that the subcellular distribution of miR-31 molecules in all cell lines was very heterogeneous with the largest subpopulation of optically acquired low-metastatic cells characterized by a low number of miR-31 molecules, as opposed to a significantly higher number in the majority of the highly metastatic cells. Citation Format: Mohammed Abba, Olga Oleksiuk, Kerem Tezcan, Wladimir Schaufler, Felix Bestvater, Peter Altevogt, Mathias Hafner, Christoph Cremer, Heike Allgayer. Single-molecule localization microscopy analysis of a cancer metastasis-specific miRNA on the nanoscale. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 204. doi:10.1158/1538-7445.AM2015-204
A Genetically Vulnerable Myocardium May Predispose to Myocarditis
Authors: Oscar Campuzano, Anna Fernández-Falgueras, Georgia Sarquella-Brugada, Olallo Sanchez, Sergi Cesar, Irene Mademont, Catarina Allegue, Jesus Mates, Alexandra Pérez-Serra, Monica Coll, Mireia Alcalde, Anna Iglesias, Coloma Tiron, María Ángeles Gallego, Carles Ferrer-Costa, Anna Hospital, Carme Escribano, Concha Dasí, Juan Carlos Borondo, Josep Castellà, Elena Arbelo, Jordi Medallo, Josep Brugada, Ramon Brugada
Journal: Journal of the American College of Cardiology (2015)
A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies
Authors: Harriet S. Walter, Simon A. Rule, Martin J. S. Dyer, Lionel Karlin, Ceri Jones, Bruno Cazin, Philippe Quittet, Nimish Shah, Claire V. Hutchinson, Hideyuki Honda, Kevin Duffy, Joseph Birkett, Virginia Jamieson, Nigel Courtenay-Luck, Toshio Yoshizawa, John Sharpe, Tomoya Ohno, Shinichiro Abe, Akihisa Nishimura, Guillaume Cartron, Franck Morschhauser, Christopher Fegan, Gilles Salles
Journal: Blood (2015)
Abstract 14456: Evaluation of Right Ventricular Function Using Real-Time Three-Dimensional Echocardiography in Patients with Chronic Thromboembolic Pulmonary Hypertension Treated with Percutaneous Transluminal Pulmonary Angioplasty
Authors: Konomi Sakata, Youichiro Uesugi, Gou Kimura, Kazuya Takemoto, Toshinori Minamishima, Kenichi Matsushita, Toru Sato, Hideaki Yoshino
Journal: Circulation (2012)

OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition characterized by a pulmonary vascular bed that is obstructed with the organized thrombi, promoting i...
Enhanced efficacy of ALT-803, an IL-15-based superagonist complex, in combination with immune checkpoint inhibitors in an orthotopic muscle invasive bladder tumor model in mice
Authors: Wenxin Xu, Karen Kage, Warren D Marcus, Robby Newman, Sarah Alter, Peter R Rhode, Hing C Wong
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Immune checkpoint therapy, which can target regulatory pathways of T cells to enhance antitumor immune responses, has led to important clinical advances and provides novel strategies for combination immunotherapies against cancer. ALT-803 is an IL-15 superagonist complex capable
Management of Recurrent Small Cell Lung Cancer
Authors: Bryan J. Schneider
Journal: Journal of the National Comprehensive Cancer Network (2008)

Small cell lung cancer remains one of the more frustrating malignancies for oncologists to treat. Although responses to initial platinum-based chemotherapy are high, most are not durable, and many patients are candidates for further palliative chemotherapy. Therapeutic options include reinduction or single-agent chemotherapy, depending on the duration of response to front-line treatment. Topotecan is the only approved agent for patients with relapsed disease. Several phase II studies have shown a modest benefit with other agents used today, although combination chemotherapy should be avoided because of increased toxicity. Palliative care should always be the focus, especially in patients with recurrent or chemorefractory small cell lung cancer and a poor performance status.
Correction of Description of MMR Vaccine Receipt Coding and Minor Errors in MMR Vaccine and Autism Study
Authors: Anjali Jain, Jaclyn Marshall, Ami Buikema, Tim Bancroft, Jonathan P. Kelly, Craig Newschaffer
Journal: JAMA (2016)

To the Editor This letter is in reference to our article “Autism Occurrence by MMR Vaccine Status Among US Children With Older Siblings With and Without Autism,” which was published in the April 21, 2015, issue of JAMA.1