tbuckley/cabot-search huggingface dataset:
Abstract LB-145: Investigation of T cell dynamic changes in tumor progression by using sing-cell data
Authors: Hongyi Zhang, Longchao Liu, Jiahui Chen, Bo Li
Journal: Cancer Research (2019)

Abstract Cancer immunotherapies have revolutionized the treatment of cancer. To better understand the dynamic changes of T cell states during tumor progression, we profiled TCR sequences and transcriptomes of ~40,000 T cells from matched xenograft MC38 cancer cell line and spleen samples of 12 mice. Comparing the gene expression profiles of T cells collected in 10-day and 20-day samples, we observed obvious differences of T cell composition, such as higher CD8 and lower CD4 T cells in 20-day tumors. Unsupervised clustering revealed two subsets of T cells specific to early tumors, recapitulating important markers, such as TCF7, which has recently been reported to be a valid predictor of immune checkpoint blockade therapies in melanoma. Additionally, a unique CD8 cluster, expressing markers of T cell activation and exhaustion, was found to appear only in late tumors. We also observed subpopulations of TCRαβ+ CD3+/CD4-/CD8- double negative (DN) T cells, which have not been well-characterized in the tumor microenvironment. Our analysis revealed three clusters of DN cells: 1) an effector-like group with FCER1G and XCL1 high expression, and high interferon production; 2) a regulatory population expressing high level of Foxp3 and IL2ra, which has been previously reported in autoimmune disorders; 3) a naïve-like population with CCR7 expression. These findings indicate that the DN T cell population may span a wide-spectrum of functionalities that similar to CD4 or CD8 single positive conventional T cells. Our study, for the first time, provided a high-resolution dynamic landscape of T cell state and identified rare T cell subgroups associated with cancer progression. Citation Format: Hongyi Zhang, Longchao Liu, Jiahui Chen, Bo Li. Investigation of T cell dynamic changes in tumor progression by using sing-cell data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-145.
Abstract 15422: Enhancing Endothelial Specific Insulin Signaling Confers Contrasting Temporal Effects on Vascular Function and Whole Body Glucose Homeostasis
Authors: Matthew C Gage, Stephen B Wheatcroft, Afroze Abbas, Helen Imrie, Hema Viswambharan, Stacey Galloway, Piruthivi Sukumar, Richard Cubbon, Jessica Smith, Stephane Schurmans, Monique Jacoby, Eléonore Dubois, Mark Kearney
Journal: Circulation (2013)

Background: The effects of enhanced endothelial insulin signaling on whole body glucose regulation and vascular function are poorly characterized. We generated mice with downregulated activity of a...
The Mouth and Pharynx
Authors: Elide A. Pastorello, Cristoforo Incorvaia, Claudio Ortolani
Journal: Allergy (1995)

•Symptoms appear immediately at the site of contact with the food when a susceptible allergic patients eats the offending food. •Allergy to fresh fruits and vegetables, associated with all kinds of pollinosis, is the more frequent cause of Oral Allergy Syndrome.
Response to brentuximab vedotin by CD30 expression: Results from five trials in PTCL, CTCL, and B-cell lymphomas.
Authors: Deepa Jagadeesh, Steven M. Horwitz, Nancy L. Bartlett, Ranjana H. Advani, Eric D. Jacobsen, Madeleine Duvic, Ashish Gautam, Shangbang Rao, Matthew Onsum, Michelle Fanale, Youn H. Kim
Journal: Journal of Clinical Oncology (2019)

7543 Background: Brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, has been evaluated in multiple trials in patients (pts) with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell lymphoma. We examined the ability of CD30 expression level to predict response to BV across these patient populations. Methods: Data were integrated from 275 pts with PTCL, CTCL, and B-cell lymphoma treated with BV from 5 prospective clinical trials. Study SGN35-012 evaluated BV plus rituximab or BV monotherapy in pts with relapsed/refractory non-Hodgkin lymphoma. The ALCANZA study compared BV to physician’s choice of methotrexate or bexarotene in pts with mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL). Three investigator-sponsored trials evaluated BV monotherapy in pts with relapsed PTCL, MF, and pcALCL (35-IST-030, 35-IST-001, 35-IST-002). Exploratory analyses were conducted to examine the relationship between CD30 expression and objective response rate (ORR) for pts with CD30 expression ≥10%, &lt;10%, or undetectable (0%) by IHC (malignant cells or lymphoid infiltrate; local review). Results: 143 pts had tumors with CD30 &lt;10%, including 58/143 with undetectable CD30. Activity with BV was observed at all levels of CD30 expression, including CD30=0 (Table). Analysis of the interaction between CD30 and duration of response is ongoing and will be presented in the final poster. ORR by CD30 expression, n/N (%). Clinical trial information: NCT01421667, NCT02588651, NCT01578499, NCT01352520, NCT01396070. Conclusions: CD30 expression levels ≥10%, &lt;10%, or undetectable did not predict response to BV in a range of CD30-expressing lymphomas: Clinical responses occurred in pts with CD30 low and CD30 undetectable lymphomas. Limitations of IHC, the dynamic nature and heterogeneity of cell-surface CD30 expression, and multiple mechanisms of action of BV may all contribute to this observation.[Table: see text]
Abstract LB-111: Epidermal growth factor receptor oncogenes expressed in glioblastoma are activated as covalent dimers and exhibit unique pharmacology
Authors: Matthew O'Connor, Theodore Nicolaides, Jie Zhang, Alexander Flohr, Roberto Iacone, Alexander V. Mayweg, David M. Epstein, Elizabeth Buck
Journal: Cancer Research (2019)

Abstract Mutation of either the intracellular catalytic domain or the extracellular domain of the receptor for epidermal growth factor (EGFR) drives oncogenicity. Extracellular domain EGFR mutations are highly expressed in patients with glioblastoma. Despite clinical success with targeting EGFR catalytic site mutants, no drugs have proven effective in glioblastoma patients expressing extracellular EGFR mutations. Herein, we define the molecular mechanism for oncogenic activation of families of extracellular EGFR mutations and reveal how this mechanism renders current generation small molecule ATP-site inhibitors ineffective. We demonstrate that a group of the most commonly expressed extracellular domain EGFR mutants expressed in glioblastomas is activated by disulfide-bond mediated covalent homodimerization, collectively referred to as locked dimerization (LoDi-EGFR oncogenes). Strikingly, current generation small molecules binding to the active kinase conformation potently inhibit catalytic site mutants, but induce covalent dimerization and activate LoDi-EGFR receptors, manifesting in paradoxical acceleration of proliferation. These data demonstrate how the locked-dimer mechanism of EGFR oncogenesis has profound impact on the activity of small molecules acting at the distal catalytic site, providing further evidence for “inside-out” allosteric signaling in EGFR. This provides a mechanistic understanding for the failure of current generation EGFR inhibitors to effectively treat LoDi-EGFR mutants in GBM and sets guidelines for discovery of selective LoDi-EGFR inhibitors. Citation Format: Matthew O'Connor, Theodore Nicolaides, Jie Zhang, Alexander Flohr, Roberto Iacone, Alexander V. Mayweg, David M. Epstein, Elizabeth Buck. Epidermal growth factor receptor oncogenes expressed in glioblastoma are activated as covalent dimers and exhibit unique pharmacology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-111.
Abstract 368: Next generation DNA aptamers with prolonged stability and antitumor activity
Authors: Paola AMERO, Cristian Rodriguez-Aguayo, Rajan R. Chaudhari, Shuxing Zhang, Anil K. Sood, Gabriel Lopez-Berestein
Journal: Cancer Research (2019)

Abstract Aberrations in Gas6/AXL signaling is associated with many human diseases including ovarian cancer, where in patients expressing high levels of AXL have shorter overall survival than patients expressing low levels. Aptamers are short synthetic oligonucleotides (DNA or RNA) that can bind with highest specificity to various other macromolecules such as peptides, proteins and carbohydrates, based on their tertiary structures. Aptamers are similar in their functionality to antibodies in their specificity; easier to manufacture than antibodies; have minimal side effects; and thus hold a high promise as therapeutics. The typical issues with the use of aptamers as therapeutic agents are their selectivity, stability, and bioavailability. We present the development of the next generation DNA aptamers, targeting p-AXL specifically to as a therapeutic in ovarian cancer (OC) by chemical modifications to their primary sequence. Improved bioavailability and stability, based on the comparative analysis the library of 17 DNA aptamers that differed in the position and number of fluoro- and thio- modifications on their nucleotide sequence, were used as the criteria for the selection and characterization of the best aptamer candidates to target p-AXL. Two of the best candidates, GLB-G25 and GLB-A04 thus chosen with the highest bioavailability and stability, when tested in ovarian cancer cell lines, decreased the migration and invasion of cells in vitro. Treatment of ovarian cancer orthotopic murine model animals with modified DNA aptamer candidates chosen above significantly reduced tumor growth and the number of metastases. The candidates, GLB-G25 and GLB-A04 show highest potential to be developed into therapeutics to target p-AXL that is elevated in several cancers including ovarian cancer. Note: This abstract was not presented at the meeting. Citation Format: Paola AMERO, Cristian Rodriguez-Aguayo, Rajan R. Chaudhari, Shuxing Zhang, Anil K. Sood, Gabriel Lopez-Berestein. Next generation DNA aptamers with prolonged stability and antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 368.
How oncologists adhere to evidence-based G-CSF-guidelines to prevent febrile neutropenia: A sample survey in hospitals and practices in Germany.
Authors: Hartmut Link, Josef Nietsch, Markus Kerkmann, Petra Angelika Ortner
Journal: Journal of Clinical Oncology (2013)

6591 Background: Primary G-CSF prophylaxis after chemotherapy is recommended in evidence based guidelines (GL), if the risk of febrile neutropenia (FN) is high (≥20%), or intermediate (≥ 10% - 20%) in case of risk factors. The aim was to evaluate, if G-CSF is used as proposed by GL, to identify determinants of GL implementation and adherence. Methods: The sample size was calculated at 2% of the incidence of malignant lymphoma, breast and lung cancer in Germany. Pts who had received 3-9 cycles of chemotherapy with a FN risk ≥10% between 5/2011 to 4/2012 were documented retrospectively. Results: 286 lymphoma, 666 lung cancer and 976 breast cancer pts were collected from 87 hospitals and 59 oncology practices with 195 physicians participating. Adherence to GL was higher in physicians up to 10 than over 10 years of experience. Conclusions: The adherence to and acceptance of GL for G-CSF may not be sufficient. Patient risk factors are underestimated therefore resulting in a possible underuse of G-CSF. Physicians may underestimate FN risk in pts who have an intermediate risk of FN and they overestimate their adherence to the GL. [Table: see text]
Human CD4 <sup>+</sup> CD103 <sup>+</sup> cutaneous resident memory T cells are found in the circulation of healthy individuals
Authors: Maria M. Klicznik, Peter A. Morawski, Barbara Höllbacher, Suraj R. Varkhande, Samantha J. Motley, Leticia Kuri-Cervantes, Eileen Goodwin, Michael D. Rosenblum, S. Alice Long, Gabriele Brachtl, Thomas Duhen, Michael R. Betts, Daniel J. Campbell, Iris K. Gratz
Journal: Science Immunology (2019)

Human blood and lymph contain circulating CD4 + CD103 + cutaneous resident memory T cells that can seed distant skin sites. See the related Focus by Carbone and Gebhardt .
Abstract 17518: Risk Assessment to Recommend Best Supportive Care in Patients With Critical Limb Ischemia
Authors: Ryuma Ishihara, Atsushi Tosaka, Kousuke Katano, Kimihiro Osada, Nozomi Fuse, Akira Miyabe, Yuriko Sato, Taisuke Mizumura, Youichi Sugimura
Journal: Circulation (2017)

Background: Although revascularization is the optimal treatment to avoid major amputation for critical limb ischemia (CLI) patients, mortality of CLI patients is extremity high. Therefore, despite ...
Faster and sustained improvement in health-related quality of life (HRQoL) for newly diagnosed multiple myeloma (NDMM) patients ineligible for transplant treated with daratumumab, lenalidomide, and dexamethasone (D-Rd) versus Rd alone: MAIA.
Authors: Aurore Perrot, Thierry Facon, Torben Plesner, Saad Zafar Usmani, Shaji Kumar, Nizar J. Bahlis, Karthik Ramasamy, Murielle Roussel, Carla Araujo, Arnaud Jaccard, Michel Delforge, Caroline McKay, Katharine Gries, Jeremiah Trudeau, Cyrille Hulin, Katja Weisel
Journal: Journal of Clinical Oncology (2019)

8016 Background: MAIA, an ongoing phase 3 trial of transplant-ineligible patients (pts) with NDMM, demonstrated significant improvement in progression-free survival with D-Rd vs Rd alone. Assessment of pt-reported outcomes alongside efficacy endpoints provides pt perspective on their quality of survival and overall value of HRQoL while on treatments (tx). Methods: The EORTC QLQ-C30 and EQ-5D-5L questionnaires were completed by pts using an electronic device at baseline and every 3 mo during tx; interim results are presented for first 12 mo. Tx effects were assessed using repeated measures, mixed effects models and thresholds for clinically meaningful benefit were based on established criterion from the literature. Results: Compliance rates were high and comparable at baseline ( &gt; 90%) and through month 12 ( &gt; 80%) for both groups (D-Rd [n = 368]; Rd [n = 369]). Improvement in Global Health Status (GHS) occurred in both groups; however, for D-Rd, significantly greater improvement was observed at cycle 3 (LS mean change; D-Rd: 4.5 [95% CI: 2.4, 6.6], Rd: 1.5 [95% CI: -0.7, 3.7]; [p = 0.0454]) and increasing improvement occurred across all time points. Significant improvement and clinically meaningful benefit in HRQoL for D-Rd was also observed in EQ-5D-5L Visual Analog Scale (VAS) scores (LS mean change; D-Rd: 10.1 [95% CI: 8.1, 12.1], Rd: 4.9 [95% CI: 2.8, 7.0]; [p = 0.0002]). The VAS median time to worsening was 10 mo longer for D-Rd. Of note, meaningful differences were observed between the tx groups in two subscale scores, pain symptoms and cognitive functioning. Statistically significant less pain was reported early with D-Rd (LS mean change at cycle 3; D-Rd: -17.9 [95% CI: -20.7, -15.0], Rd: -11.0 [95% CI: -14.0, -8.1]; [p = 0.0007]); clinically meaningful reduction in pain symptoms was sustained with D-Rd. There was a decline in cognitive functioning at cycle 12 in both tx arms, with no statistically significant differences between groups. Conclusions: Faster and sustained improvement in HRQoL was observed in pts treated with D-Rd vs Rd with similar findings reflected across pain subscale. Clinical trial information: NCT02252172.
Abstract 838: Epigenetic reprogramming of different cancer-related pathways at the single cell level after low-dose DNA demethylation therapy
Authors: Hideyuki Takeshima, Yukie Yoda, Naoko Watanabe, Mika Wakabayashi, Toshikazu Ushijima
Journal: Cancer Research (2019)

Abstract The efficacy of DNA demethylation therapy is highly dependent on the dosing regimen. Administration of a drug at a dose much lower than the maximum tolerated dose (MTD) for a prolonged period shows a high therapeutic efficacy, despite its small demethylating effect. However, the mechanisms underlying the high therapeutic efficacy of low-dose treatment are still unclear. In this study, we aimed to reveal the mechanisms by analyzing decitabine (DAC)-treated individual cancer cells. To reveal the epigenetic reprogramming at the single cell level and its functional consequences, individual DAC-treated HCT116 cells (H3 clones) were cloned from DAC-treated bulk HCT116 cells. Genome-wide DNA methylation was analyzed using InfiniumHuman450 beadChip. In bulk cells, only partial reduction of DNA methylation levels was observed, and no genes were completely demethylated. In contrast, in cloned cells, a much larger reduction of DNA methylation levels was observed, depending upon genes. Promoter CpG islands of 233-470 genes of 1,188 hypermethylated genes in HCT116 were completely demethylated (Δβ ≥ 0.6) in some of the clones analyzed. Demethylated genes were highly variable among individual clones, and different cancer-related genes, such as those involved in the p53 pathway, WNT pathway, and cell cycle regulation, were completely demethylated, depending upon clones. For example, CDKN2A (p16) was completely demethylated only in a H3-32 clone, and this clone showed slower cell growth rate (14.6% of untreated cells), and aneuploid cells were detected possibly due to cellular senescence. These results showed that epigenetic reprogramming at the single cell level involves diverse cancer-related pathways, and this mechanism is likely to underlie the high efficacy of low-dose DNA demethylation therapy. Citation Format: Hideyuki Takeshima, Yukie Yoda, Naoko Watanabe, Mika Wakabayashi, Toshikazu Ushijima. Epigenetic reprogramming of different cancer-related pathways at the single cell level after low-dose DNA demethylation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 838.
Unsound Evaluations of Medical Machine Translation Risk Patient Health and Confidentiality
Authors: Jonathan Downie, Angela Dickson
Journal: JAMA Internal Medicine (2019)

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Histological patterns and clinical characteristics of metastatic gastric adenocarcinoma, single institutional experience in the eastern province of Saudi Arabia
Authors: N. Bukhari, W. Taha, A. Zahralliyali, S. Shahrani, W. AlSelwi, A. AlSowayigh, D. AlAbdulhadi, F. Ibnshamsah, M. Rahal, H. Halawani, O. Al-Saif, M. Mashhour, H. Al-Hashmi, M. Latif, F. Azam
Journal: Annals of Oncology (2019)
Medical devices: new EU regulations won’t guarantee safe design, doctors warn
Authors: Jane Feinmann
Journal: BMJ (2019)

Doctors have been urged to inform their trusts when medical devices are difficult to use or have confusing instructions, amid concerns that new European regulations will fail to guarantee safe design of the devices that doctors are asked to use.

Tom Clutton-Brock, clinical director of the Medical Devices Testing and Evaluation Centre, told a Clinical Human Factors Group (CHFG) meeting in London on 12 June that new EU medical devices regulation that will come in force in May 2020 forms “an excellent basis for much safer design but it remains to be seen how these new rules are interpreted and enforced.”

Under the new regulation, manufacturers will be required to provide in-depth clinical data underpinning safety and performance claims, along with …
Abstract 2511: Analysis of circulating tumor DNA by targeted ultra-deep sequencing across various non-Hodgkin lymphoma subtypes
Authors: Yeon Jeong Kim, Seung-Ho Shin, Danbi Lee, Woong-Yang Park, Seok Jin Kim, Won Seog Kim, Donghyun Park
Journal: Cancer Research (2019)

Abstract Although targeted deep sequencing of cell-free DNA (cfDNA) was recently used to investigate tumor somatic mutations in particular subtypes of non-Hodgkin lymphomas (NHLs), the immense genetic heterogeneity across subtypes poses a hurdle to design a universal gene panel applicable for diverse subtypes of NHLs. We designed a panel targeting 66 genes associated with NHLs and performed targeted deep sequencing to analyze plasma cfDNA from patients with various subtypes of NHLs. Genetic profiling in plasma cfDNA using the method resulted in 88.0% sensitivity and &amp;gt;99% specificity in detecting mutations present at a frequency greater than 20% in the tumor biopsies. Furthermore, the level of ctDNA significantly decreased and increased depending on designated clinical responses to therapy and disease progression. These results demonstrated that ctDNA sensitively indicated the presence of cancer and reliably correlated with tumor burden, suggesting potential utility of the method for patients with various subtypes of NHLs. Citation Format: Yeon Jeong Kim, Seung-Ho Shin, Danbi Lee, Woong-Yang Park, Seok Jin Kim, Won Seog Kim, Donghyun Park. Analysis of circulating tumor DNA by targeted ultra-deep sequencing across various non-Hodgkin lymphoma subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2511.