tbuckley/cabot-search huggingface dataset:
Intradermal vaccination of MUC1 transgenic mice with MUC1/IL-18 plasmid DNA inhibits experimental pulmonary metastases
Authors: Frank Shi, George R. Gunn, Linda Snyder, Theresa J. Goletz
Journal: Cancer Research (2004)

1278  MUC1 (mucin 1) is a transmembrane glycoprotein normally expressed on the ductal epithelia of the pancreas, breast, prostate, colon, and lung. However, in adenocarcinomas of these organs, this self-antigen is over-expressed and aberrantly glycosylated, thereby making it a promising tumor-associated antigen. Immunotherapy targeting tumor cells expressing this form of MUC1 could have great therapeutic value. Towards this end, we developed a DNA vaccine comprised of two plasmids encoding MUC1 (pMUC1) and interleukin-18 (pIL-18), and found that it protects MUC1 transgenic mice from subcutaneous tumor challenge by inducing MUC1-specific cellular immunity. We have now examined the possibility of targeting pulmonary metastases with pMUC1/pIL-18 DNA immunization in both preventive and therapeutic settings in MUC1 transgenic mice. We found that intradermal vaccination of pMUC1 DNA alone was insufficient to elicit anti-tumor effects, as measured by incidence of lung metastasis and number of tumor nodules. However, co-administration of pMUC1 with an adjuvant plasmid encoding IL-18 (pIL-18) prior to tumor challenge dramatically reduced the incidence of experimental tumor metastases in the lung. Mice immunized with pMUC1/pIL-18 also showed a prolonged survival compared to control mice. Furthermore, mice immunized with pMUC1/pIL-18 were protected from challenge with MUC1+ tumor cells, but not from MUC1- tumors, indicating that the anti-tumor effect is antigen-specific. Finally, pMUC1/pIL-18 DNA vaccination was effective in treating pre-established pulmonary metastases. Collectively, these results demonstrate that vaccination with pMUC1/pIL-18 breaks tolerance to MUC1 and induces antigen-specific immunity with protective and therapeutic benefit. This suggests that pMUC1/pIL-18 DNA vaccination may provide clinical benefit for cancer patients with MUC1+ tumors.
TMOD-40. IN VIVO EVALUATION OF O6-METHYLGUANINE-DNA-METHYLTRANSFERASE (MGMT) PROMOTER METHYLATION STATUS FOR DE NOVO GLIOBLASTOMA PATIENTS USING DEEP LEARNING FEATURES
Authors: Saima Rathore, MacLean Nasrallah, Hamed Akbari, Gaurav Shukla, Stephen Bagley, Christopher Watt, Sung Min Ha, Elizabeth Mamourian, Chiharu Sako, Zev Binder, Donald O’Rourke, Christos Davatzikos
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND High expression of O6-methylguanine-DNA methyltransferase (MGMT) in glioblastoma is associated with resistance to temozolomide, as tumor cells lacking MGMT activity are significantly more sensitive to the cytotoxic effects of temozolomide. The MGMT promoter methylation status (MGMTpms) is typically determined as MGMT-methylated or MGMT-unmethylated. Some single-center studies have reported results ranging from 70–95% detection rates using MRI. We aim to further validate these findings using a multi-institutional data set. We hypothesize that transfer learning based features when integrated via machine learning may lead to non-invasive determination of MGMTpms. METHODS A total of 270 patients were included across the 3 institutions (Hospital of the University of Pennsylvania (HUP), Jefferson University Hospital (JUH); the TCIA). JUH and TCIA datasets comprised conventional modalities (T1,T2,T2-FLAIR,T1-Gd), whereas HUP dataset had additional modalities (DSC,DTI) as well. We used transfer learning and adapted a convolutional neural network (CNN) model pre-trained on 1.2 million 3-channel images of the ImageNet to extract deep learning features from the given images. A support vector machine multivariately integrated these features towards a non-invasive marker of MGMTpms. RESULTS The cross-validated accuracy of our MGMT marker in classifying the mutation status in individual patients was 86.95%, 81.56%, and 82.43%, respectively, in HUP, JUH, and TCIA. Our marker revealed MGMT-methylated tumors with lower neovascularization and cell density, when compared with MGMT-unmethylated tumors. MGMT-unmethylated tumors were found to be more lateralized to the right hemisphere, when compared with MGMT-methylated tumors. CONCLUSION Our findings suggest that transfer learning features when integrated via machine learning allow robust prediction of MGMTpms on mpMRI acquired within multiple institutions. The proposed non-invasive MGMT marker may contribute to (i) MGMTpms determination for patients with inadequate tissue/inoperable tumors, (ii) stratification of patients into clinical trials, (iii) patient selection for targeted therapy, and (iv) personalized treatment planning.
Inhibition of Canonical WNT Signaling in the Bone Marrow Niche Prevents the Development of Disease in a Mouse MDS Model with Apc Haploinsufficiency
Authors: Angela Stoddart, Jianghong Wang, Chunmei Hu, Anthony A. Fernald, Elizabeth M. Davis, Jason X. Cheng, Michelle M. Le Beau
Journal: Blood (2016)
Differential co-expression-based detection of conditional relationships in transcriptional data: comparative analysis and application to breast cancer
Authors: Dharmesh D. Bhuva, Joseph Cursons, Gordon K. Smyth, Melissa J. Davis
Journal: Genome biology (2019)

Abstract Background Elucidation of regulatory networks, including identification of regulatory mechanisms specific to a given biological context, is a key aim in systems biology. This has motivated the move from co-expression to differential co-expression analysis and numerous methods have been developed subsequently to address this task; however, evaluation of methods and interpretation of the resulting networks has been hindered by the lack of known context-specific regulatory interactions. Results In this study, we develop a simulator based on dynamical systems modelling capable of simulating differential co-expression patterns. With the simulator and an evaluation framework, we benchmark and characterise the performance of inference methods. Defining three different levels of “true” networks for each simulation, we show that accurate inference of causation is difficult for all methods, compared to inference of associations. We show that a z -score-based method has the best general performance. Further, analysis of simulation parameters reveals five network and simulation properties that explained the performance of methods. The evaluation framework and inference methods used in this study are available in the dcanr R/Bioconductor package. Conclusions Our analysis of networks inferred from simulated data show that hub nodes are more likely to be differentially regulated targets than transcription factors. Based on this observation, we propose an interpretation of the inferred differential network that can reconstruct a putative causal network.
Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma
Authors: Ronan J. Kelly, Jeeyun Lee, Yung-Jue Bang, Khaldoun Almhanna, Mariela Blum-Murphy, Daniel V.T. Catenacci, Hyun Cheol Chung, Zev A. Wainberg, Michael K. Gibson, Keun-Wook Lee, Johanna C. Bendell, Crystal S. Denlinger, Cheng Ean Chee, Takeshi Omori, Rom Leidner, Heinz-Josef Lenz, Yee Chao, Marlon C. Rebelatto, Philip Z. Brohawn, Peng He, Jennifer McDevitt, Siddharth Sheth, Judson M. Englert, Geoffrey Y. Ku
Journal: Clinical Cancer Research (2019)

This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.
Twice Weekly Induction with Ixazomib-Lenalidomide-Dexamethasone (IRd) Combination Followed By Extended IRD Consolidation and Lenalidomide Maintenance in Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Phase 2 Study from the Intergroupe Francophone Du Myelome (IFM 2014-03)
Authors: Murielle Roussel, Benjamin Hebraud, Cyrille Hulin, Xavier Leleu, Thierry Facon, Eileen Boyle, Cyrille Touzeau, Brigitte Pegourie, Aurore Perrot, Anne-Marie Stoppa, Jean-Pierre Marolleau, Philippe Moreau, Herve Avet-Loiseau, Laure Devlamynck, Valerie Lauwers-Cances, Michel Attal
Journal: Blood (2019)
A seven-gene methylation markers panel: An epigenetic predictor of neoadjuvant chemotherapy sensitivity in triple-negative breast cancer
Authors: V.O. Sigin, A.I. Kalinkin, E. Ignatova, A.V. Sycheva, I.I. Vinogradov, M.I. Vinogradov, I.Y. Vinogradov, D.V. Zaletaev, V.V. Strelnikov, A.S. Tanas
Journal: Annals of Oncology (2019)
Mutations Affecting RNA Binding Proteins Are a Novel Feature of Mantle Cell Lymphoma
Authors: Krysta M Coyle, Prasath Pararajalingam, Sarah E Arthur, Nicole Thomas, Miguel Alcaide, Barbara Meissner, Merrill Boyle, Bruno M. Grande, Christopher Rushton, Leah Tooman, Graham W Slack, Andrew J. Mungall, Randy D. Gascoyne, Christian Steidl, Joseph M Connors, Diego Villa, Marco A. Marra, Nathalie Johnson, David W. Scott, Ryan D. Morin
Journal: Blood (2019)
State-of-the-Art Workup and Initial Management of Newly Diagnosed Molar Pregnancy and Postmolar Gestational Trophoblastic Neoplasia
Authors: Kevin M. Elias, Ross S. Berkowitz, Neil S. Horowitz
Journal: Journal of the National Comprehensive Cancer Network (2019)

Gestational trophoblastic disease refers to a series of interrelated tumors arising from the placenta, including benign molar pregnancies as well as the malignant conditions termed gestational trophoblastic neoplasia (GTN). GTN most commonly follows a molar pregnancy but may develop after any gestation. The wide availability of first trimester ultrasound and serum human chorionic gonadotropin (hCG) measurement has changed the presentation of molar pregnancy in recent decades from a second trimester to a first trimester disease, such that most patients have few symptoms at diagnosis. With identification of molar pregnancy at earlier gestations, accurate diagnosis increasingly relies on expert histopathology coupled with ancillary molecular and genetic techniques. However, earlier diagnosis has not changed the risk of postmolar GTN. Although most molar pregnancies are treated with dilation and curettage, hysterectomy may be appropriate in select cases when future fertility is not desired. After treatment of molar pregnancy, close surveillance with serial hCG monitoring is essential to diagnose GTN and identify the need for chemotherapy. Physicians following hCG levels should understand the performance characteristics of the test, including common causes of false-positive and false-negative results. After a diagnosis of postmolar GTN is made, selection of single-agent or multiagent chemotherapy depends on accurate assignment of the clinical stage and risk stratification by the International Federation of Gynecology and Obstetrics (FIGO) prognostic scoring system. Surgical treatment of postmolar low-risk GTN, including both second uterine curettage and hysterectomy, may decrease subsequent need for or duration of chemotherapy. Cure rates for postmolar low-risk GTN approach 100%, and subsequent pregnancy outcomes for patients reflect those of the general population.
ACTR-43. GENOMIC ANALYSIS OF RESPONDERS OF PHASE II TRIAL OF TEMOZOLOMIDE AND TRC-102 (BASE EXCISION REPAIR INHIBITOR) IN BEVACIZUMAB-NAÏVE GLIOBLASTOMA AT FIRST RECURRENCE
Authors: Manmeet Ahluwalia, Harshil Dhruv, Jaleh Fallah, Michael Berens, Jan Drappatz, Xiaobu Ye, Glenn Lesser, Timothy Cloughesy, Tobias Walbert, Matthias Holdhoff, David Peereboom, Louis Nabors, Patrick Wen, Stuart Grossman, Lisa Rogers
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Temozolomide forms O6-methylguanine (O6mG), 7-methylguanine (N7mG), and 3- methyladenine (N3mA) DNA adducts. The O6mG DNA adduct is repaired by MGMT. N7mG and N3mA DNA adducts are removed by the base excision repair (BER) pathway, initiated by N- methylpurine DNA glycosolase (MPG). TRC-102 is a BER inhibitor that binds to the apurinic site created through the action of MPG. METHODS A phase II study of adult glioblastoma in first recurrence was performed in the Adult Brain Tumor Consortium with temozolomide, 150 mg/ m2 and TRC-102, 150 mg (1–5/ 28 days). Primary objective included radiographic response rate. Secondary objectives included safety and PFS-6. Exploratory objectives included tumor expression of N-methylpurine DNA glycosylase (MPG). The study tested hypothesis that combination therapy will achieve 30% RR. To understand the context of vulnerability to TRC102 we performed RNA sequencing on treatment naïve tissue from 7 patients. RESULTS Nineteen patients were enrolled in first stage. Median age was 60 years (range: 48–76), 53% females, median KPS was 80 (range: 70–90). Median cycles of treatment was 2 (range: 1–12). No responses were observed. Median OS was 11.0 months (95% CI: 8–18 months), median PFS was 2.0 months (95% CI: 1.8–3.6 months). PFS-6 rate was 10.5 % (2/19). The combination was safe. MPG staining was negative in six, 1+ in five and 2+ in three patients. PFS of 11 + months in two patients (exceptional responders) was associated with MPG expression. Preliminary analysis on RNA sequencing revealed significant enrichment for DNA Damage Response pathways (MsigDB), chromosomal instability gene signature (CIN70 and CIN25), and proliferative gene signature (PCNA25) in these 2 patients. CONCLUSIONS TRC 102 with temozolomide has acceptable safety but did not meet the primary endpoint of response. Gene signature of MsigDB, CIN70, CIN25 and PCNA25 was seen in exceptional responders and biomarker driven study is planned.
Encyclopedic tumour analysis guided treatments with conventional drugs outperform available alternatives in refractory cancers
Authors: T. Crook, A. Vaid, S. Limaye, R. Page, D. Patil, D. Akolkar, V. Datta, A. Ghaisas, R. Patil, H. Singh, A. Srinivasan, S. Apurwa, R. Datar
Journal: Annals of Oncology (2019)
A Comparison of Two-Year Outcomes in ZUMA-1 (Axicabtagene Ciloleucel) and SCHOLAR-1 in Patients with Refractory Large B Cell Lymphoma
Authors: Sattva S Neelapu, Frederick L. Locke, Nancy L Bartlett, Lazaros J Lekakis, Patrick M Reagan, David B. Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan O. Oluwole, Tanya Siddiqi, Yi Lin, Michael Crump, John Kuruvilla, Eric Van Den Neste, Umar Farooq, Lynn Navale, Venita DePuy, Jenny J. Kim, Christian Gisselbrecht
Journal: Blood (2019)
Don’t accept racist abuse, Hancock tells NHS staff
Authors: Abi Rimmer
Journal: BMJ (2019)

The secretary of health and social care in England has written to NHS staff to express his horror at the incidents of racial abuse that they face.

In a letter sent on 5 November, Hancock said that he wanted to send a clear message that this sort of abuse was unacceptable and would not be tolerated.1

“If you face abuse, do not accept it. If you see a colleague being abused, do not ignore it. If you know of an employee facing this, do not stand for it,” Hancock wrote. “The government takes a zero tolerance policy approach to dealing with racist abuse whenever it arises. Things should be no different in our NHS.”

Hancock also made reference to the case of the Blackpool trauma and orthopaedic surgeon Radhakrishna Shanbhag. Speaking to ITV News on 31 October, Shanbhag described how he felt after a patient had asked for a white surgeon instead of him.2 “It made me reconsider my position in the NHS because I thought, do I want to put up with this at this stage, after I have given my life, blood, sweat, and tears to the …
Risk Factors for E-Cigarette, or Vaping, Product Use–Associated Lung Injury (EVALI) Among Adults Who Use E-Cigarette, or Vaping, Products — Illinois, July–October 2019
Authors: Livia Navon, Christopher M. Jones, Isaac Ghinai, Brian A. King, Peter A. Briss, Karen A. Hacker, Jennifer E. Layden
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

The United States is experiencing an unprecedented outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) (1). All EVALI patients have used e-cigarette, or vaping, products, and most (≥85%) have reported using products containing tetrahydrocannabinol (THC) (2,3), the principal psychoactive component of cannabis. To examine whether e-cigarette, or vaping, product use behaviors differed between adult EVALI patients and adults who use these products but have not developed lung injury, the Illinois Department of Public Health (IDPH) conducted an online public survey during September-October 2019 targeting e-cigarette, or vaping, product users in Illinois. Among 4,631 survey respondents, 94% reported using any nicotine-containing e-cigarette, or vaping, products in the past 3 months; 21% used any THC-containing products; and 11% used both THC-containing products and nicotine-containing products. Prevalence of THC-containing product use was highest among survey respondents aged 18-24 years (36%) and decreased with increasing age. E-cigarette, or vaping, product use behaviors of 66 EVALI patients aged 18-44 years who were interviewed as part of the ongoing outbreak investigation were compared with a subset of 519 survey respondents aged 18-44 years who reported use of THC-containing e-cigarette, or vaping, products. Compared with these survey respondents, EVALI patients had higher odds of reporting exclusive use of THC-containing products (adjusted odds ratio [aOR] = 2.0, 95% confidence interval [CI] = 1.1-3.6); frequent use (more than five times per day) of these products (aOR = 3.1, 95% CI = 1.6-6.0), and obtaining these products from informal sources, such as a dealer, off the street, or from a friend (aOR = 9.2, 95% CI = 2.2-39.4). The odds of using Dank Vapes, a class of largely counterfeit THC-containing products, was also higher among EVALI patients (aOR = 8.5, 95% CI = 3.8-19.0). These findings reinforce current recommendations not to use e-cigarette, or vaping, products that contain THC and not to use any e-cigarette, or vaping, products obtained from informal sources. In addition, because the specific compound or ingredient causing lung injury is not yet known, CDC continues to recommend that persons consider refraining from use of all e-cigarette, or vaping, products while the outbreak investigation continues (1).
Wound-closure with Adhesive Tape
Authors: J. T. Burrowes
Journal: BMJ (1964)

MEDILlHdue to neuromuscular block of respiratory muscles, since they could have completely recovered.With the existing knowledge, could I suggest another explanation of the events in the case reported by Dr. Ross and his colleagues ?The presence of curare-like block on E.M.G. could be due to recurarization as a result of 180 mg. of gallamine, used in a patient with poor circulation, poor renal function, and a very low serum calcium level.The respiratory inadequacy at the end of operation in spite of 2.5 mg. of neostigmine could be attributed to the existence of metabolic acidosis, maintained and accentuated by superadded respiratory acidosis with or without partial recurarization.Oral neomycin has a distinct advantage of its own in the prevention of complications after elective surgery on the colon ; therefore, before surgeons can accept the suggestion that "neomycin should be kept to a minimum" more convincing proof is required.-Iam, etc.,
Treatment of Myeloma Patients Progressing on Lenalidomide-Based Maintenance after ASCT Performed As Part of 1st, 2nd or 3rd Line Therapy: Real-World Results from the National Myeloma Canada Research Network (MCRN) Database
Authors: Donna E Reece, Esther Masih-Khan, Eshetu G Atenafu, Victor Jimenez-Zepeda, Arleigh McCurdy, Kevin Song, Richard Leblanc, Michael Sebag, Darrell J White, Hannah Cherniawsky, Tony Reiman, Julie Stakiw, Martha L Louzada, Rami Kotb, Muhammad Aslam, Engin Gul, Christopher P Venner
Journal: Blood (2019)
Rates of colorectal cancer after negative colonoscopies vary by provider, study finds
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The rate at which people develop colorectal cancer within three years of a colonoscopy negative for cancer differs depending on which provider they use, with NHS screening providers performing better than non-NHS providers, a study has found.1

Researchers from across England looked at the rates of post colonoscopy colorectal cancer (PCCRC)—cases which follow a negative colonoscopy performed within three years—in England between 2005 and 2013, and compared how different providers performed.

They found that although the overall PCCRC three year rate decreased from 9.0% for colonoscopies performed in 2005 to 6.5% for those performed in 2013 (P<0.01), rates were lower (3.6%) for dedicated bowel cancer screening providers, and higher for non-NHS providers …
Differential Efficacy of Anti-Sickling and Anti-Inflammatory Mechanisms in a Fluorescent Intravital Microscopy Dorsal Skinfold Vaso-Occlusion Model in Sickle Cell Disease Townes Mice
Authors: Sarah Sturtevant, Alejandra Macias-Garcia, Sriram Krishnamoorthy, Arjan van der Flier, Alexandra Hicks, Melanie Demers
Journal: Blood (2019)
Determinants of Outcomes of FLT3mut Acute Myeloid Leukemia with First Salvage Therapy
Authors: Abhishek Maiti, Hagop M. Kantarjian, Guillermo Garcia-Manero, Marina Y Konopleva, Srdan Verstovsek, Michael Andreeff, Gautam M. Borthakur, Tapan M. Kadia, Naval G. Daver, Naveen Pemmaraju, Courtney D. DiNardo, Sherry A. Pierce, Lian-Chun Xiao, Xuelin Huang, William G. Wierda, Steven M. Kornblau, Farhad Ravandi, Jorge E. Cortes
Journal: Blood (2019)
Genome-Wide CRISPR Screening Identifies MAPK and Mtorc Pathways As Regulators of Sorafenib Resistance in Acute Myeloid Leukemia
Authors: Alisa Damnernsawad, Tamilla Nechiporuk, Daniel Bottomly, Stephen E Kurtz, Christopher A. Eide, Shannon K. McWeeney, Jeffrey W. Tyner
Journal: Blood (2019)
Quantitative Proteomics in Diffuse Large B-Cell Lymphoma Patients Reveal Novel Overexpressed Proteins and Potentially Druggable Targets in the ABC Subtype
Authors: Susanne Bram Ednersson, Mimmie Stern, Henrik Fagman, Gunilla Enblad, Ulf-Henrik Mellqvist, Herman Nilsson-Ehle, Sverker Hasselblom, Per-Ola Andersson
Journal: Blood (2019)