tbuckley/cabot-search huggingface dataset:
Retrospective analysis of risk factors for fatigue in clinical trial patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Martin Eric Gore, Viktor Gruenwald, Robert John Motzer, David I. Quinn, Brian I. Rini, Xun Lin, Julia Jane Perkins, Ronit Simantov, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2013)

e15624 Background: Fatigue is a common toxicity in pts with mRCC, often associated with therapy, particularly with tyrosine kinase inhibitors (TKI). We performed a pooled retrospective analysis of pts with mRCC treated in clinical studies in order to explore predictors for fatigue. Methods: Data from pts treated in Pfizer mRCC trials (2003-2011) from phase III (NCT00083899, NCT00065468, NCT00678392) and phase II trials (NCT00054886, NCT00077974, NCT00083889, NCT00338884, NCT00137423) were included. Adverse event (CTCAE v3.0) terms of “fatigue” and “asthenia” were used. Hypothyroidism was defined as TSH&gt;ULN or T4&lt;LLN. A multivariate logistic regression analysis was performed to identify significant risk factors for grade (G) 2 (moderate or causing difficulty performing some ADL) or higher fatigue. Results: 2749 pts (71% male) with a median age 60 (33% ≥65) were treated (median 162 days) with axitinib (n=359), sunitinib (n=1059), temsirolimus (TEM) (n=208), interferon-alfa (IFN) (n=560), sorafenib (n=335), or TEM + IFN (n=208). Most pts had baseline ECOG PS of 0 (47%) or 1 (51%), clear cell histology (91%), and nephrectomy (84%). 553 (20%) pts reported fatigue prior to starting study therapy. During study, fatigue was reported in 1794 (65%) pts (21% G1, 26% G2, 17% G3, 1% G4); in 61% pts worst grade was reported within the first 2 months of therapy. Fatigue led to discontinuation in 2%, and dose interruption or adjustment in 8%. Of 1773 pts treated with TKIs, 42% had ≥G2 fatigue. Of pts treated with TEM, IFN or both, 39%, 50% and 50%, respectively, had ≥G2 fatigue. Baseline factors [Odds Ratio] associated (p &lt; 0.05) with ≥G2 fatigue were pretreatment fatigue [1.7] or hypothyroidism [1.6], age ≥65 [1.6], time from diagnosis ≥1 yr [1.4], female gender [1.3], ECOG PS 0 [0.7], and Asian vs Caucasian race [0.5]. Baseline LDH, calcium, and anemia were not significant. Conclusions: Pt attributes and comorbidities at baseline, independent of therapy, are associated with increased risk of clinically significant fatigue in pts treated for mRCC, and can be used to generate a predictive model. Appropriate counseling and control of co-morbid conditions may be important in managing fatigue in pts on TKI therapy.
Abstract 1593: Genetic interactions in lung cancer using machine-learning approaches in genome-wide association studies
Authors: Jinyoung Byun, Younghun Han, Christopher I. Amos
Journal: Cancer Research (2019)

Abstract Genome-wide association studies (GWAS) consisting of hundreds of thousands or millions of single nucleotide polymorphisms (SNPs) have presented the complex inheritance patterns of disease/trait. Although GWAS have identified thousands of SNPS associated with diseases, few studies have explored interactions among these SNPs that may influence disease risks. Machine learning applications can identify SNPs that influence disease risk through interactions and define how these SNPs jointly influence disease risks. Tree-based machine-learning applications; classification and regression trees (CART) and random forest (RF) methods, have become increasingly popular and convenient tools for understanding interactions influencing disease development. Here we apply these methods to understand the genetic architecture of lung cancer. To elucidate the SNP-SNP interactions that influence lung cancer risk, we applied supervised tree-based approaches using 18,444 cases and 14,027 controls from lung cancer OncoArray GWAS data that is the largest lung cancer GWAS so far. To reduce the space of SNPs to consider in modeling, we first selected the SNPs very significantly (p&amp;lt;0.00001) associated with lung cancer risk. Random Forests, which consists of systematically fitting classification trees, was run 1,000 times to identify the most influential SNPs that jointly influence lung cancer risk. Subsequently we applied a classification tree approach to summarize interactions that predict risk. The final parsimonious tree included effects from genetic variants in rs55781567(CHRNA5): rs452384(CLPTM1L): rs9258608(LOC105375010): rs6154144(DNAJC5): rs116506680(HLA-G): rs9271365(near HLADQA1): rs421629(CLPTM1L). The nodes of this tree had Odds ratios for lung cancer ranging from 0.87 to 1.63. Machine-learning approaches in genomics can provide an important genetic mechanism in lung cancer development. Citation Format: Jinyoung Byun, Younghun Han, Christopher I. Amos. Genetic interactions in lung cancer using machine-learning approaches in genome-wide association studies [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 1593.
Ancient Hybridization and Adaptive Introgression of an Invadolysin Gene in Schistosome Parasites
Authors: Roy N Platt, Marina McDew-White, Winka Le Clec’h, Frédéric D Chevalier, Fiona Allan, Aidan M Emery, Amadou Garba, Amina A Hamidou, Shaali M Ame, Joanne P Webster, David Rollinson, Bonnie L Webster, Timothy J C Anderson
Journal: Molecular Biology and Evolution (2019)

Abstract Introgression among parasite species has the potential to transfer traits of biomedical importance across species boundaries. The parasitic blood fluke Schistosoma haematobium causes urogenital schistosomiasis in humans across sub-Saharan Africa. Hybridization with other schistosome species is assumed to occur commonly, because genetic crosses between S. haematobium and livestock schistosomes, including S. bovis, can be staged in the laboratory, and sequencing of mtDNA and rDNA amplified from microscopic miracidia larvae frequently reveals markers from different species. However, the frequency, direction, age, and genomic consequences of hybridization are unknown. We hatched miracidia from eggs and sequenced the exomes from 96 individual S. haematobium miracidia from infected patients from Niger and the Zanzibar archipelago. These data revealed no evidence for contemporary hybridization between S. bovis and S. haematobium in our samples. However, all Nigerien S. haematobium genomes sampled show hybrid ancestry, with 3.3–8.2% of their nuclear genomes derived from S. bovis, providing evidence of an ancient introgression event that occurred at least 108–613 generations ago. Some S. bovis-derived alleles have spread to high frequency or reached fixation and show strong signatures of directional selection; the strongest signal spans a single gene in the invadolysin gene family (Chr. 4). Our results suggest that S. bovis/S. haematobium hybridization occurs rarely but demonstrate profound consequences of ancient introgression from a livestock parasite into the genome of S. haematobium, the most prevalent schistosome species infecting humans.
Abstract 3763: Effect of cancer-associated fibroblasts on lymphatic vessel formation in malignant melanoma
Authors: Shusaku Maeda, Masakazu Yashiro, Hisashi Motomura, Takaharu Hatano, Heishiro Fujikawa
Journal: Cancer Research (2019)

Abstract Introduction: It has been reported that cancer-associated fibroblasts (CAFs) in tumor microenvironment may play an important role for the progression and metastasis of cancer cells. Some reports suggested that CAFs may promote tumor lymphangiogenesis. In malignant melanoma, lymph node metastasis is one of important prognostic factors. Tumor lymphangiogenesis may be controlled not only by tumor cells but also tumor microenvironment such as CAFs, however no study about the interaction between CAFs and human lymphatic endothelial cells (HLECs) was found. Then, we evaluated the effect of CAFs on lymphatic vessel formation in malignant melanoma. Materials and methods: We used CAFs, normal tissue associated fibroblasts (NAFs) established from a patient of malignant melanoma, and HLECs. Serum-free conditioned medium was obtained from NAFs (NAF-CM) or CAFs (CAFs-CM). CAFs and NAFs were cultured with or without supernatant from malignant melanoma cells. HLECs were cultured by EBM with 50% of NAF-CM or CAFs-CM. Control group was cultured with 50% EBM and 50% of serum-free medium. The effect of each CM on the proliferation of HLECs was examined by CCK assay and tube formation assay. Tube formation was assessed at 12 hours of incubation by fluorescence microscope. Result: CAFs-CM significantly decreased the proliferation of HLECs in comparison with NAFs-CM after 48, 72 and 96 hours of incubation by CCK assay. In tube formation assay, tube length and number of tubes and junctions were also significantly shorter and smaller in CAFs group, in compared with the control and NAFs group. Conclusion: CAFs might have a suppressive effect on HLECs, resulting in inhibition of lymphangiogenesis. Citation Format: Shusaku Maeda, Masakazu Yashiro, Hisashi Motomura, Takaharu Hatano, Heishiro Fujikawa. Effect of cancer-associated fibroblasts on lymphatic vessel formation in malignant melanoma [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 3763.
Abstract 1829: HSF1 suppresses AMPK to promote lipogenesis, cholesterol biosynthesis and protein lipidation
Authors: Kuo-Hui Su, Chengkai Dai
Journal: Cancer Research (2019)

Abstract AMP-activated protein kinase (AMPK), a key cellular metabolic sensor, suppresses anabolic pathways, including lipogenesis and cholesterol biosynthesis, thereby maintaining energy homeostasis. Heat shock factor 1 (HSF1) is the master regulator of the evolutionarily conserved proteotoxic stress response (PSR), thereby preserving proteostasis in the face of environmental insults. In contrast to its beneficial role in enhancing survival under proteotoxic stress, it has been demonstrated that HSF1 acts as a potent pro-oncogenic factor. Our previous study has shown that metabolic stressors, via AMPK activation, inactivate HSF1 and disrupt proteostasis to suppress tumor growth. Interestingly, our new study now reveals that HSF1, in reciprocal, also suppresses AMPK activation. HSF1 does so independently of its canonical transcriptional action. Furthermore, Hsf1 deficiency promotes the interactions between AMPK and LKB1, a key upstream kinase activating AMPK. Congruent with the suppression of lipogenesis by AMPK, Hsf1 deficiency depletes cellular lipid content and reduces body fat mass in mice. Importantly, these defects can be largely rescued by either pharmacological or genetic inhibition of AMPK. At the molecular level, Hsf1 deficiency leads to inactivation of acetyl-CoA Carboxylase (ACC) and sterol regulatory element-binding transcription factor 1c (SREBP1c), both of which are key players in de novo lipogenesis. In addition to impaired lipogenesis, Hsf1-deficient cells and mice display reduced cholesterol levels. Of particular interest, this defect leads to impaired cholesteroylation of sonic hedgehog (SHH), the best known signaling molecule undergoing this covalent modification. In consequence, SHH secreted by HSF1-deficient cells are less potent in activating its downstream signaling cascade, indicated by reduced DNA binding of GLI1, a transcription factor responding to activation of SHH signaling. Conversely, HSF1 overexpression increases the lipid content, cholesterol levels and the amount of cholesteroylated SHH proteins in xenografted melanomas. Taken together, our results reveal that HSF1, through AMPK suppression, promotes lipogenesis, cholesterol biosynthesis and protein lipidation, thereby supporting malignant growth. Citation Format: Kuo-Hui Su, Chengkai Dai. HSF1 suppresses AMPK to promote lipogenesis, cholesterol biosynthesis and protein lipidation [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 1829.
Abstract 2396: Development of a new generation of dimeric, highly cytotoxic fusion proteins containing active GrB and VEGF targeting tumor neovasculature: Incorporating IgG heavy chain Fc fragments improves cytotoxicity, stability and pharmacokinetics
Authors: Khalid A. Mohamedali, Lawrence H. Cheung, Ana Alvarez-Cienfuegos, Michael G. Rosenblum
Journal: Cancer Research (2019)

Abstract VEGF121 is a naturally-occurring splice variant that binds to VEGF receptors R-1 and R-2, which are over-expressed on the endothelium of tumor vasculature but not normal vasculature. The serine protease granzyme B (GrB) is capable of inducing intense cellular apoptosis through both caspase-dependent and caspase-independent multiple-cascade mechanisms. We have previously reported the expression of a fusion protein composed of Granzyme B and VEGF121 (GrB/VEGF121) and its subsequent in vitro and in vivo characterization. Here we report on the development and characterization of GrB-Fc-VEGF, which fuses the two domains via an IgG heavy chain Fc-fragment. We hypothesized that this modification, resulting in a relatively high molecular weight (133 kDa vs 80 kDa) would result in improved in vivo circulation and efficacy. VEGF inter-chain dimerization domains were modified such that dimerization occurred only through the Fc domain. GrB-Fc-VEGF121was expressed in HEK-293E cells under serum-free conditions and purified from the media by immobilized metal affinity chromatography (25 mg/L). Western blotting confirmed incorporation of both VEGF121 and GrB moieties into the construct. Comparison of GrB-Fc-VEGF121 with its expected molecular weight suggests significant glycosylation when produced in HEK293E cells. The enzymatic activity of GrB in GrB-Fc-VEGF121 was comparable to that of human GrB. In vitro studies of GrB-Fc-VEGF121 suggests improved cytotoxicity against cell lines expressing high levels of VEGFR-1 or VEGFR-2, unlike GrB/VEGF121, which targeted VEGFR-2+ cells more efficiently. Thus, the GrB-Fc-VEGF121 produced in HEK293E cells is active and has significant potential as a targeted therapeutic. In vitro cytotoxicity against an expanded panel of cells, internalization, and in vivo pharmacokinetics and efficacy against various tumor models are currently ongoing and will be presented. Research conducted, in part, by the Clayton Foundation for Research. Citation Format: Khalid A. Mohamedali, Lawrence H. Cheung, Ana Alvarez-Cienfuegos, Michael G. Rosenblum. Development of a new generation of dimeric, highly cytotoxic fusion proteins containing active GrB and VEGF targeting tumor neovasculature: Incorporating IgG heavy chain Fc fragments improves cytotoxicity, stability and pharmacokinetics [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 2396.
Новый эпигенетический путь канцерогенеза, ассоциированного с helicobacter pylori
Authors: S.I. Klymniuk, E.M. Kovanova, M.S. Tvorko
Journal: GASTROENTEROLOGY (2020)

Новый эпигенетический путь канцерогенеза Helicobacter pylori инициируется триггерами-онкогенами бактерии. Главный механизм канцерогенеза — тирозинкиназное фосфорилирование с избыточной активацией тирозинкиназ и активированием ЕRK MARK сигнальных путей нормальной пролиферации клетки, что нарушает нормальную пролиферацию и приводит к неконтролируемому росту клеток, трансформации и, как результат, к туморогенезу.
Once-weekly (70 mg/m<sup>2</sup>) versus twice-weekly (56 mg/m<sup>2</sup>) dosing of carfilzomib (CFZ) for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM).
Authors: Philippe Moreau, A. Keith Stewart, Meletios A. Dimopoulos, David Samuel DiCapua Siegel, Thierry Facon, James R. Berenson, Noopur S. Raje, Jesus G. Berdeja, Robert Z. Orlowski, Hui Yang, Haijun Ma, Zandra Karina Klippel, Anita Zahlten-Kumeli, Khalid Mezzi, Karim Iskander, Maria-Victoria Mateos
Journal: Journal of Clinical Oncology (2019)

e19505 Background: CFZ combined with dexamethasone is approved to treat pts with RRMM, with CFZ given once-weekly at 70 mg/m 2 (Kd70 QW) or twice-weekly at 56 mg/m 2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW. We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION-1 trials. Methods: Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION-1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION-1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW. Results: Among BTZ non-refractory pts with 2–3 lines of prior therapy, median progression-free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well-tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69). Conclusions: This post hoc analysis suggests that once-weekly Kd70 has a comparable benefit-risk profile to twice-weekly Kd56. Clinical trial information: NCT02412878, NCT01677858, NCT01568866.
Abstract 1554: Uncoupling tumor-cell cytotoxicity from cytokine release with novel T-cell engaging bispecific antibodies
Authors: Kyle Lorentsen, Preethi Sankaran, Nathan D. Trinklein, Duy Pham, Ute Schellenberger, Ben Buelow, Andrew Boudreau, Priya Choudhry, Starlynn C. Clarke, Kevin Dang, Katherine E. Harris, Suhasini Iyer, Brett Jorgensen, Payal Pratap, Udaya S. Rangaswamy, Harshad S. Ugamraj, Omid Vafa, Arun P. Wiita, Wim van Schooten, Roland Buelow, Shelley Force Aldred
Journal: Cancer Research (2019)

Abstract T-cell recruiting bispecific antibody (T-BsAb) treatment is an emerging cancer immunotherapy notable for its highly-specific tumor killing activity in humans. However, the success of T-BsAbs in the clinic has been limited due to cytokine-release related toxicities. In order for this technology to reach its potential, the next generation of T-BsAbs must avoid this unintended toxicity by uncoupling cytokine-release from tumor-cell killing. To this end, we used a sequence-based discovery method on CD3-immunized OmniFlic rats, which express human fixed light-chain antibodies, to identify several novel anti-CD3 antibodies. These antibodies bind to multiple CD3 epitopes, each with varying affinities and degrees of T-cell activation. Furthermore, when placed in the context of a T-BsAb, these novel anti-CD3 antibodies achieve similar levels of T-cell mediated tumor-specific lysis, but with a thousand-fold range in potency. Among these antibodies, we identified one lead with particularly favorable properties, in that it stimulates very low levels of cytokine production without sacrificing its potent antigen-specific tumor lysis in vitro, in mouse xenograft assays, as well as ex vivo patient sample studies. This unique behavior gives our novel anti-CD3 antibody the potential to widen the therapeutic window when treating patients and ultimately usher in the next generation of T-BsAbs. Citation Format: Kyle Lorentsen, Preethi Sankaran, Nathan D. Trinklein, Duy Pham, Ute Schellenberger, Ben Buelow, Andrew Boudreau, Priya Choudhry, Starlynn C. Clarke, Kevin Dang, Katherine E. Harris, Suhasini Iyer, Brett Jorgensen, Payal Pratap, Udaya S. Rangaswamy, Harshad S. Ugamraj, Omid Vafa, Arun P. Wiita, Wim van Schooten, Roland Buelow, Shelley Force Aldred. Uncoupling tumor-cell cytotoxicity from cytokine release with novel T-cell engaging bispecific antibodies [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 1554.
Medium-Dose VP-16 Intensified Conditioning Regimen Is Effective in Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia
Authors: Feifei Sun, Xiaosheng Fang, Jiang Yujie, Xiaohui Sui, Xin Liu, Xianghua Wang, Ying Li, Na Wang, Changqing Zhen, Huiting Qu, Juan Fan, Hongzhi Xu, Xin Wang
Journal: Blood (2018)
Effects of short-term prednisolone treatment on indices of lipolysis and lipase signaling in abdominal adipose tissue in healthy humans
Authors: Nilani Ramshanker, Niels Jessen, Thomas Schmidt Voss, Steen Bønløkke Pedersen, Jens Otto Lunde Jørgensen, Thomas Svava Nielsen, Jan Frystyk, Niels Møller
Journal: Metabolism (2019)
Abstract 833: Integrative analysis of TCGA pancreatic ductal adenocarcinoma data
Authors: Nitish K. Mishra, Siddesh Southekal, Chittibabu Guda
Journal: Cancer Research (2019)

Abstract Pancreatic cancer is a heterogeneous type of cancer that exhibits different histopathological, molecular and genomic phenomena. Pancreatic ductal adenocarcinoma (PDAC) is the deadliest type of pancreatic cancer with a five-year survival of only 8%. Prognostic biomarkers for early detection of PDAC are not available. In this study, we used clinical, DNA methylation, and gene expression profiles of 146 TCGA PDAC patients. We analyzed the global patterns of DNA methylation and correlated the promoter DNA methylation with corresponding gene expression. CpG sites with a difference of 0.2 in the mean β value of the primary tumor and normal samples were considered as differentially methylated. We observed differential methylation of about 12-thousand CpG sites between tumor and normal samples, the majority of which are hypermethylated. Chromosome 1, 20, 18 and 19 are predominately hypermethylated and chromosome 9 is hypomethylated. CpG islands and regions that are in close proximity to CpG islands (shores) have more hypermethylated sites compared to the far away regions (shelf). Pathway enrichment analysis of differentially methylated genes enabled us to understand how changes in methylation affect biological pathways involved in the progression of PDAC. Our analysis reveals enrichment of MAPK signaling, Rap1 signaling, calcium signaling pathway, etc. Promoter DNA methylation is highly associated with its corresponding gene expression. A significant correlation between methylated CpG sites within 1.5kb from TSS and corresponding gene expression was observed between 4,971 CpGs and 1,744 corresponding genes, out of these about 92% of the genes showed a negative correlation. Survival analysis showed a statistically significant correlation between the expression levels of genes, NEK2, and ASPM with overall survival of the patients. In the future, we will further analyze the long non-coding RNA (lncRNA) promoter methylation, and role of lncRNA and miRNA in PDAC patients’ survival. Citation Format: Nitish K. Mishra, Siddesh Southekal, Chittibabu Guda. Integrative analysis of TCGA pancreatic ductal adenocarcinoma 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 833.