tbuckley/cabot-search huggingface dataset:
Abstract 5296: DNAJA1 promotes cancer progression by stabilizing mutant p53
Authors: Tomoo Iwakuma
Journal: Cancer Research (2019)

Abstract The tumor suppressor p53 is mutated in approximately 50% of human cancers. Majority of them are missense mutations, which results in accumulation of dysfunctional p53 proteins in tumors. Increasing evidence suggests that accumulation of mutant p53 is crucial for its oncogenic gain-of-function activities, such as proliferation, metastasis, and chemotherapy resistance. Previous work from our lab has revealed that DNAJA1, a HSP40 family member, specifically binds to and stabilizes conformational/misfolded mutant p53. DNAJA1 downregulation induces ubiquitination and proteasomal degradation of conformational p53 mutants, but does not affect the levels of wild-type p53 or DNA contact mutants. Based on these observations, we hypothesize that DNAJA1 promotes cancer progression in a manner dependent on conformational/misfolded mutant p53. To test this hypothesis, we examined the effects of DNAJA1 deletion/knockdown on malignant properties of head and neck squamous cell carcinoma (HNSCC) cells. Genetic deletion/knockdown of DNAJA1 resulted in reduced proliferation, colony formation, migration, and orthotopic tumor growth of HNSCC cells expressing conformational mutant p53, but not DNA contact mutant p53. These cellular phenotypes induced by DNAJA1 knockdown/knockout were substantially rescued by overexpression of DNAJA1 or mutant p53. We also conducted RNA sequencing analyses using HN31 cells (control, DNAJA1 knockdown or mutant p53 knockdown). Notably, 77.2% of downregulated genes by p53 knockdown were overlapped with genes downregulated by DNAJA1 knockdown. Moreover, genes involved in cancer-related pathways, including adhesion and actin cytoskeleton organization, were commonly downregulated. These results strongly suggest that DNAJA1 promotes HNSCC progression mostly dependent on conformational mutant p53. Our results may also suggest that DNAJA1 could be a novel therapeutic target for cancers carrying conformational/misfolded mutant p53. Citation Format: Tomoo Iwakuma. DNAJA1 promotes cancer progression by stabilizing mutant p53 [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 5296.
Final Analysis of the Phase 1a/b Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with Relapsed or Refractory AL Amyloidosis
Authors: Camille Vanessa Edwards, Julia Gould, Arielle L Langer, Markus Y Mapara, Jai Radhakrishnan, Mathew S. Maurer, Shahzad Raza, John G. Mears, Siyang Leng, Jonathan S. Wall, Andrew Eisenberger, Alan Solomon, Suzanne Lentzsch
Journal: Blood (2017)
Abstract 4706: Temperature-dependent transcription artifacts and cell population biases in scRNAseq data are minimized by tissue dissociation at low temperatures
Authors: Ciara H. O'Flanagan, Kieran R. Campbell, Farhia Kabeer, Allen Zhang, Jamie Lim, Sohrab P. Shah, Samuel Aparicio
Journal: Cancer Research (2019)

Abstract Single cell RNA sequencing (scRNAseq) is a powerful tool, particularly for studying complex biological systems, such as tumor heterogeneity and the tumor microenvironment, which may not be resolved by sequencing of bulk material. Nonetheless, it is not without limitations, which include the technical challenges of generating a high quality single cell suspension. Dissociation of tissue to single cell suspension requires mechanical and enzymatic disruption, and the effect of these methods on gene expression or cellular population bias has not been established. In this study, we examined the effects of enzymatic dissociation on cell population capture and transcriptional changes at single cell resolution in breast and ovarian cancer patient samples, patient-derived breast cancer xenografts and cultured cell lines. scRNAseq data showed that enzymatic dissociation of tissues at 37oC with collagenase resulted in significant induction of heat shock, stress and immediate response genes, which was conserved across all tissues. This gene expression induction was not observed when tissues were dissociated at 6oC with a protease derived from a Himalayan glacier soil bacterium. Moreover, dissociation of patient tumors at low temperature enhanced the abundance of rare cell populations, including B-cells, T-Cells and cytotoxic T-cells, which were significantly depleted following dissociation at 37oC. These biases resulting from standard sample preparation methods could significantly affect biological interpretation of scRNAseq data, and can be minimized by dissociation of tissues at low temperature. Note: This abstract was not presented at the meeting. Citation Format: Ciara H. O'Flanagan, Kieran R. Campbell, Farhia Kabeer, Allen Zhang, Jamie Lim, Sohrab P. Shah, Samuel Aparicio. Temperature-dependent transcription artifacts and cell population biases in scRNAseq data are minimized by tissue dissociation at low temperatures [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 4706.
Abstract 5059: Early life risk factors and childhood cancer risk
Authors: Shaina L. Stacy, Jeanine M. Buchanich, Zhen-qiang Ma, Christina Mair, Linda Robertson, Ravi K. Sharma, Evelyn O. Talbott, Jian-Min Yuan
Journal: Cancer Research (2019)

Abstract Prenatal exposures, including maternal, delivery, and newborn characteristics, may affect childhood cancer risk. Our objective was to examine whether such birth certificate-derived factors are associated with increased risk of subsequent cancer development, including leukemia and central nervous system (CNS) tumors, in children ages zero to 13. Pennsylvania state birth and cancer registry files obtained from the PA Department of Health were linked to create a cohort of children born from 2003 to 2015 who developed cancer from 2003 to 2016. After exclusions, 1,834,796 infants were included with a total of 13,785,309 person-years of observation. Among these, there were 2,355 children diagnosed with any cancer, 748 with leukemia, and 545 with CNS tumors. Older maternal age increased the hazard of developing any childhood cancer, leukemia, and CNS tumors. Children born to severely obese mothers (body mass index ≥40 kg/m2) were at over 50% higher hazard of leukemia (P=0.01) after adjustment for age and other significant risk factors; however, maternal obesity did not significantly increase the risk of childhood CNS tumors. Among the infant characteristics, having a fetal growth ratio 30% higher than expected was significantly associated with increased hazard of any childhood cancer, leukemia, or CNS tumors (hazard ratios 2.19, 1.79, and 1.77, respectively). Other fetal and newborn factors associated with higher risk of total childhood cancer included fetal intolerance of labor, lower gestational age, and having a low Apgar score at birth. This analysis demonstrated significant and independent impacts of maternal obesity and fetal growth rate on childhood cancer development, particularly leukemia, after accounting for multiple risk factors. If confirmed, weight control during pregnancy would be an effective means of childhood cancer prevention. Citation Format: Shaina L. Stacy, Jeanine M. Buchanich, Zhen-qiang Ma, Christina Mair, Linda Robertson, Ravi K. Sharma, Evelyn O. Talbott, Jian-Min Yuan. Early life risk factors and childhood cancer risk [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 5059.
Abstract 18564: The Interaction of Age and Exercise Capacity in the Prediction of All-Cause Mortality: Data From the FIT Project
Authors: Michael J Blaha, Yichen Zhong, Seamus Whelton, Khurram Nasir, Roger S Blumenthal, John R Schairer, Steve J Keteyian, Mouaz Al-Mallah
Journal: Circulation (2013)

Background: Cardiorespiratory fitness, measured clinically as exercise capacity, is a strong predictor of survival. We investigated whether this favorable prognosis is consistent across age groups, particularly in the young and the elderly. Methods: This retrospective cohort study included 56,592 patients without known CAD or CHF (median age 53 years old, 51% men, 64% Caucasian) who underwent clinical treadmill stress testing at Henry Ford Hospital between 1991 and 2009. Patients were followed 11.1 ± 4.6 years for the occurrence of all-cause mortality assessed via search of the Death Master File. We first calculated median METS attained on the treadmill by age decile. Then in multivariable models within each age decile, we assessed the prognostic value of: 1) METS above/below median for age; 2) METS by category; and 3) METS as a continuous variable. Models were adjusted for age (continuous), sex, race, SBP/DBP, hypertension, hyperlipidemia, smoking, diabetes, family history of CAD, obesity, COPD and cardiovascular medication use, and indication for stress test. Results: Median METS decreased with age, from 13 for patients 80 (p&lt;0.001). Older patients were less likely to achieve target heart rate (p&lt;0.001). There were 6,105 deaths during follow-up. By any measure, increasing exercise capacity was a powerful predictor of survival across all age deciles, although there was an interaction with age (Figure). The relative reduction with increasing fitness was greatest in younger patients and decreased with age. The absolute risk reduction was greatest in older patients. Conclusion: Improved cardiorespiratory fitness - as assess clinically by improved exercise capacity - is a powerful predictor of survival across all age groups, although an interaction exists with age. Younger patients have a greater relative reduction in mortality with increasing fitness, while older patients have a greater absolute reduction in mortality.
Validation of broad panel clinical sequencing-based genomic risk stratification in patients with advanced lung adenocarcinomas.
Authors: Sam Whipple, Axel Martin, Michael Martinec, Kathryn Cecilia Arbour, Venkatraman E. Seshan, Gregory J. Riely, Gracy Crane, Ronglai Shen
Journal: Journal of Clinical Oncology (2019)

9113 Background: We recently established the ability of broad-panel clinical sequencing data to stratify overall survival of patients with advanced lung adenocarcinomas in a single institutional experience (Shen, Riely et al., JCO Precision Oncology 2019). Here we sought to assess its generalizability to a broader range of patients (including patients from multiple community and academic sites) using a different sequencing panel, with an integrated electronic health record and genomic database. Methods: We identified 2,779 next-generation sequencing-tested patients with advanced lung adenocarcinomas from the Flatiron-Foundation Medicine Clinico-Genomic database. A genomic risk model developed from the initial discovery cohort (n=1,054) was used to calculate a risk score for each patient in the validation cohort, scaled between 0 and 10, indicating the risk of cancer specific mortality. Results: Patients in the validation cohort were classified into four risk categories with median survival ranging from 37.6 months (95% CI: 32.9-43.8) in the low risk group (n=534) to 10.9 months (95% CI: 8.0-16.5) in the highest risk group (n=75), representing a hazard ratio of 3.0 (95% CI: 2.2-4.1) and closely matching the discovery cohort observations. A smaller proportion of patients were deemed high risk in the validation cohort (2.7% vs 10% in the discovery cohort). There were some differences in the frequencies of the most common genomic alterations between the validation and discovery cohorts, including TP53 (57.3% vs 55.1%) , KRAS (32.8% vs 30%), EGFR (18.6% vs 29.4%) as well as overlapping STK11 and KEAP1 co-mutations (2.4% vs 10%). Conclusions: We demonstrate that a clinical tumor sequencing-based genomic risk stratification strategy can be applied broadly across cohorts and different sequencing panels and platforms, to improve the understanding of heterogeneity in clinical outcome for patients with metastatic lung adenocarcinomas and the mutation and co-mutational patterns that underlie such heterogeneity.
Efficacy and mechanism of action of NKTR-255, a polymer-conjugated IL-15 receptor agonist in hematological tumors.
Authors: Loui Madakamutil
Journal: Journal of Clinical Oncology (2019)

e19512 Background: NKTR-255 is a polymer-conjugated IL-15 receptor agonist that accesses the IL-15 signaling pathway, and enhances the function and numbers of natural killer (NK) cells and CD8 memory T cell populations. Many hematological malignancies are treated with targeted antibodies that utilize effector mechanisms to recruit NK cells and macrophages. Most patients with hematological malignancies experience a progressive decline of NK cell immunity, a phenomenon termed as an “immunological desert”. We evaluated the hypothesis that a combination of NKTR-255 with a targeted antibody such as an anti-CD38 monoclonal antibody (mAb) or an anti-CD20 mAb, when evaluated in a preclinical hematological tumor model, would provide enhanced efficacy. Methods: Human PBMCs were stimulated with NKTR-255 and/or daratumumab for in vitro NK cell characterization. Using a B cell lymphoma model, SCID mice were inoculated i.v. with 10 7 Daudi cells and treated with a single dose of daratumumab or rituximab two weeks after tumor cell injection. NKTR-255 was administered s.c. concurrently on a q7dx3 dosing schedule. Survival of treated animals was measured using hind limb paralysis and morbidity as surrogate endpoints. Tumor cell depletion and phenotyping of immune cells in bone marrow were conducted by flow cytometry. Results: NKTR-255, when combined with daratumumab, enhanced NK cell degranulation and decreased NK cell death, leading to enhanced antibody-dependent cellular cytotoxicity (ADCC) activity for the daratumumab - NKTR-255 combination over the single agents. NKTR-255 demonstrated synergistic activity and provided a long-term survival benefit when combined with daratumumab or rituximab in the CD38 and CD20-expressing lymphoma mouse models. Mechanistic studies conducted in tumor-bearing mice treated with a combination of NKTR-255 and daratumumab showed effective clearance of lymphoma cells from the bone marrow and increased expansion of effector NK cells and other immune cells. Depletion experiments confirmed the role of NK, CD8 and other monocyte lineage immune cells in the observed anti-myeloma activity. Conclusions: These studies indicate that administration of NKTR-255, when combined with a monoclonal antibody such as daratumumab and rituximab, significantly increases NK cell numbers and activates their tumor killing capacity by virtue of an enhanced ADCC effect. Combinatorial approaches of NKTR-255 with these targeting agents could lead to novel and effective clinical applications in hematology.
Clinical responses and pharmacokinetics of fully human BCMA targeting CAR T-cell therapy in relapsed/refractory multiple myeloma.
Authors: chunrui li, Jianfeng Zhou, Jue Wang, Guang Hu, Aihua Du, Xiaoxi Zhou, Li Meng, Zhenya Hong, Liting Chen, Xia Mao
Journal: Journal of Clinical Oncology (2019)

8013 Background: Previous studies indicate patients with relapsed/refractory multiple myeloma (RRMM) who receive high-dose BCMA-targeting CAR-T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM. The primary objectives are to characterize the safety and tolerability in patients with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, cytokines, CAR-T cell persistence, and pharmacokinetics. Between September 21, 2018, and January 21, 2019, nine patients (including 3 patients having relapsed after being given a murine BCMA CAR-T) received CT103A in 3+3 dose-escalation trial (three doses at 1, 3, 6 ×10 6 /kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. All Patients had received a median of 4 prior lines (range 3 - 5) of MM therapy. Results: At the time of the February 4, 2019 data analysis, the overall response rate was 100% (Table), and all patients had a rapid response within 14 days, with 67% (2/3) reaching CR/sCR at the lowest dose. The pharmacokinetics of CT103A were assessed by a digital polymerase chain reaction. Robust expansions were seen even at the lowest dosage level. In addition, Cmax and AUC0-28 reached levels comparable to reported CD19 CAR-T. In the first two dose groups, the grade of cytokine release syndrome (CRS) was 0 - 2. In the 6 ×10 6 /kg dose group, DLT had been observed in one patient. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A. Major AEs were transient, manageable, and reversible. three patients who relapsed the murine BCMA CAR-T were treated with CT103A, two patients achieved CR, and one patient achieved VGPR. 100% ORR and a rapid response within 2 weeks, suggests CT103A could be developed as a competitive therapeutic to treat patients with RRMM. Treatment Response (Case 1,5 and 7 are patients who relapsed the murine BCMA CAR-T). Clinical trial information: ChiCTR1800018137. [Table: see text]
Enhanced local production of IL-26 in uncontrolled compared with controlled adult asthma
Authors: Ellen Tufvesson, Prajakta Jogdand, Karlhans Fru Che, Bettina Levänen, Jonas S. Erjefält, Leif Bjermer, Anders Lindén
Journal: Journal of Allergy and Clinical Immunology (2019)

Current pharmacotherapy is insufficient for patients with poorly controlled asthma.1,2 To facilitate the development of novel and effective therapy, we need to improve the mechanistic understanding of this phenotype.3
Abstract 2837: Fusobacterium nucleatum and T cells in colorectal cancer liver metastasis
Authors: Yuki Sakamoto, Kosuke Mima, Nobuya Daitoku, Yukiharu Hiyoshi, Katsunori Imai, Masaaki Iwatsuki, Takatsugu Ishimoto, Yoshifumi Baba, Shiro Iwagami, Yuji Miyamoto, Yoichi Yamashita, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2019)

Abstract Background: Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum has been shown to promote colorectal tumor growth and inhibit antitumor immune responses. Emerging evidence demonstrates an enrichment of Fusobacterium species in colorectal cancer live metastasis (CRLM). Aim: To test the hypothesis that higher amount of Fusobacterium nucleatum is associated with lower density of CD8+ T-cells in CRLM. Method: Genomic DNA was extracted from CRLM and adjacent normal liver tissues. We measured the amount of Fusobacterium nucleatum DNA in 164 CRLM tissues using a quantitative polymerase chain reaction assay. The density of CD8+ T-cells in CRLM was determined by immunohistochemical staining. Result: Fusobacterium nucleatum was detected in 8 (4.9%) of 164 CRLM cases. A higher density of CD8+ T-cells in CRLM was significantly associated with better relapse-free survival (P =0.036). Fusobacterium nucleatum-negative cases, Fusobacterium nucleatum-positive cases were inversely associated with the density of CD8+T-cells (P =0.020). Conclusions: The presence of Fusobacterium nucleatum is inversely associated with CD8+ T-cells density in CRLM. Upon validation, our data may have implications for preventing the formation of liver metastases in colorectal cancer through targeting intestinal microflora. Citation Format: Yuki Sakamoto, Kosuke Mima, Nobuya Daitoku, Yukiharu Hiyoshi, Katsunori Imai, Masaaki Iwatsuki, Takatsugu Ishimoto, Yoshifumi Baba, Shiro Iwagami, Yuji Miyamoto, Yoichi Yamashita, Naoya Yoshida, Hideo Baba. Fusobacterium nucleatum and T cells in colorectal cancer liver metastasis [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 2837.
A mixed method analysis of toxicities of anti-CD19-CAR T cell therapy in hematological malignancies.
Authors: Vishal Jindal, Padmastuti Akella, Paramarajan Piranavan, Ahmad Daniyal Siddiqui
Journal: Journal of Clinical Oncology (2019)

e19068 Background: CAR (Chimeric Antigen Receptor) T cell therapy is a promising therapy with significant benefits. But cytokine release syndrome (CRS) and neurological toxicities (NT) are major obstacles in its success. In this study we did mixed method analysis of literature to explore side effect profile of Anti CD19-CAR T cell therapy in hematological malignancies. Methods: A review of literature was done to find appropriate studies on Medline database. Total 11 studies were selected on the basis of 1) Anti CD19-CAR T cell therapy 2) Lymphodepletion 3) Sample size equal to or more than 15, 4) Hematological Malignancies 5) Detailed toxicities mentioned. Data was extremely heterogenous for metanalysis therefore results were descriptively formatted using summary texts and tables. Results: Total patient count was 452, out of them 59% had ALL, 35.61% had NHL and 5.30% had CLL. Majority of studies used second generation CAR T cells (n = 10, 90.1). CAR T cell dosage protocol was variable among studies and it range from 1 X 10 5 to 1 X 10 7 cells. CRS occurred in 82.7%, with grade 1-2 CRS in 58.4% and grade 3-4 CRS in 24.3%. CRS presented early (range of median = 2.5 – 4 days) and recovers completely generally with in 1 st week (range of median = 4.8 - 8 days). NT are seen in 45.6%, with grade 1-2 NT in 20.6% and grade 3-4 NT in 25.0%. NT have variable presentations, encephalopathy was seen in 22.65% of patients and 3.22% had seizures. For management of side effects 28.6% patients required ICU level of care and 21.86% required pressor support. Tocilizumab was used in 30.7%. Total 10 patients (2.2%) died due to side effects and out of them 6 (1.32%) due to CRS and 4 (0.88%) due to NT. Clinically significant associations were shown between tumor grade and CRS (n = 6, 54.5%), IL-6 and CRS (n = 8, 72.7%), CRP (C reactive Protein) and CRS (n =6, 54.5%), and CRS and NT (n = 7, 63.6%) (Table). Conclusions: This study concludes that CRS and NT are most common side effects of CAR T cell therapy. Most of the time they are completely reversible and manageable with tocilizumab and steroid therapy. Levels of IL6, Interferon gamma, CRP and ferritin are elevated in CRS patients. Therefore, can be used as biomarkers. NT and CRS are also associated with each other and likely share the pathological pathway. [Table: see text]