tbuckley/cabot-search huggingface dataset:
Abstract 4689: Subclone-specific evolution of tumor phenotypes – A framework to study subclone-specific gene expression from a combination of bulk DNA and single cell RNA sequencing data
Authors: Yi Qiao, Xiaomeng Huang, Samuel Brady, Andrea Bild, David Bowtell, William Johnson, Gabor Marth
Journal: Cancer Research (2019)

Abstract Several approaches are now available for subclonal reconstruction of heterogeneous tumor biopsies from somatic variant allele frequencies measured in bulk DNA sequencing datasets, including our own SubcloneSeeker program. However, to understand how chemoresistance, relapse, or metastasis evolves at a subclonal level, we also need to study the molecular phenotype corresponding to each subclone. Single-cell RNAseq technologies now allow one to study the transcriptomic characteristics and phenotypic behaviors of individual cells, but new algorithms are needed to link these cells to the genomically defined tumor subclones they represent. Here we present a computational approach to make such cell assignments, using a combination of bulk DNA sequencing data (WGS or WES), and single cell RNA sequencing (scRNAseq) collected from the same tissues. Subclones constructed from bulk DNA sequencing data are defined by specific combinations of somatic mutations (SNVs and CNVs). Our algorithm uses the scRNA-seq reads to assess which of these subclone-defining mutations are present in each individual cell, then utilizes a Bayesian probabilistic framework for making the cell-to-subclone assignment. This framework overcomes the challenges of sparse scRNA-seq read coverage, and maximizes the accuracy and efficiency of cell assignment. We have successfully applied this method to multiple longitudinal and metastatic cancer patient datasets, representing both WES and WGS bulk DNA sequencing, as well as datasets collected using the 10X Chromium and Fluidigm C1 technologies. Our algorithm uses both somatically acquired CNV and SNV events in the tumor for cell assignment. Using our approach, as many of 80% of tumor cells could be assigned to specific subclones, enabling comparative gene expression and pathway analysis across subclones. Citation Format: Yi Qiao, Xiaomeng Huang, Samuel Brady, Andrea Bild, David Bowtell, William Johnson, Gabor Marth. Subclone-specific evolution of tumor phenotypes – A framework to study subclone-specific gene expression from a combination of bulk DNA and single cell RNA sequencing 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 4689.
Abstract 288: Chest Wall Stiffness Varies During Cardiopulmonary Resuscitation
Authors: Sara Tisherman, Clifton W Callaway
Journal: Circulation (2012)

Introduction : Displacement of the sternum during cardiopulmonary resuscitation (CPR) is affected by the elastic properties of the chest wall but the dynamic properties of the chest wall have not been described. This study tested whether chest wall stiffness varies with depth of compression, and whether chest wall stiffness changes with repeated compressions. Methods : Acceleration and force applied to the chest wall during CPR were measured using an accelerometer and a force meter “puck” placed between the rescuer hand and the patient sternum (Philips MRX). Displacement of the sternum (double integrated acceleration) was used to calculate chest wall stiffness (force/displacement) using MATLAB and STATA. Changes in stiffness with compression depth and with compression number were analyzed using linear regression. Results : CPR data from 10 subjects with out-of-hospital cardiac arrest provided about 50 measurements per compression and 100-4739 compressions per subject. Chest wall stiffness decreased as depth of compression increased (p&lt;0.001), requiring varying force for any given displacement. Chest wall stiffness at a given depth (25 mm) decreased over consecutive compressions (p&lt;0.001) (Figure 1). Conclusions : Stiffness of the chest wall changes as the depth of compression increases. Over multiple compressions, the stiffness of the chest wall declines, perhaps reflecting loss of rib integrity. Future work should explore whether stiffness is related to optimal chest compression depth.
Abstract 2021: Role of MMP1-PAR-1 crosstalk in the pro-tumorigenic senescent fibroblasts in large cell carcinoma of the lung
Authors: Marta Gabasa, Rafael Ikemori, Evette Radisky, Noemí Reguart, Derek Radisky, Jordi Alcaraz
Journal: Cancer Research (2019)

Abstract Tumor associated fibroblasts (TAFs) are key effector cells of cancer progression. Intriguingly, senescent TAFs have been reported in a growing list of agressive cancer subtypes including large cell carcinoma (LCC) of the lung. We previously reported that LCC cells induce fibroblast senescence in indirect co-cultures with transwells, revealing that paracrine signaling must be involved. A follow-up study identified MMP1 as an important regulatory protein in fibroblast senescence, since knocking-down MMP1 in LCC cells was sufficient to abrogate the induction of fibroblast senescence in co-cultures as well as the growth and invasion enhancement elicited by the conditioned medium of fibroblasts in LCC cells. Here we examined the potential role of the protease activated protein 1 (PAR-1) in fibroblast senescence by MMP1, since PAR-1 can be activated by MMP1 and has been reported in the stroma of lung cancer patients. We found that PAR-1 expression was down-regulated in fibroblasts that become senescent upon co-culture with LCC cells. In addition, forcing a reduced PAR-1 expression in fibroblasts by siRNA increased their expression of markers of the senescence associated secretory phenotype (SASP) during co-culture with LCC cells, whereas the percentage of senescence-associated beta-galactosidase positive fibroblasts remained largely unaffected. These results suggest that fibroblast senescence elicited by MMP1 secreted by LCC cells is mediated by processes other than PAR-1 activation and/or overexpression in fibroblasts. Citation Format: Marta Gabasa, Rafael Ikemori, Evette Radisky, Noemí Reguart, Derek Radisky, Jordi Alcaraz. Role of MMP1-PAR-1 crosstalk in the pro-tumorigenic senescent fibroblasts in large cell carcinoma of the lung [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 2021.
Abstract 215: Generation of site-specific DARPin® drug conjugates using EGFR as a model system
Authors: Laura A. Laviolette, Cynthia J. Guidi, Christian Reichen, Qifeng Qiu, Luke Harris, Patricia Schildknecht, Stefanie Fischer, Zita Arany, Tanja Hospodarsch, Anna Skaletskaya, Megan Fuller, Stephen Abbott, Rebecca McCarthy, Jenny Lee, Katherine Francisco, Kerstin Sinkevicius, Sharlene Adams, Christopher Espelin, Emily Reid, Wei Li, Carla Marashio, Kerry Donahue, Stuart Hicks, Dan Snell
Journal: Cancer Research (2019)

Abstract DARPin® molecules are small engineered proteins, derived from natural ankyrin repeat proteins that are selected to bind to specific targets with high affinity. Individual DARPin® molecules can be linked together genetically in order to create multi-specific drug molecules. This versatility of DARPin® molecules makes them an attractive alternative to antibodies for the development of drug conjugates. We have developed DARPin® drug conjugates (DDCs) using a model EGFR multi-specific DARPin® molecule, consisting of four DARPin® domains linked together. DARPin® constructs were conjugated to the indolinobenzodiazepine mono-imine DGN549, a potent DNA alkylating payload. Biophysical characterization showed the DDCs to be well behaved in stability and solubility assays. The in vitro binding and cytotoxicity of these DDCs were evaluated. The DARPin® conjugates displayed in vitro potency in direct cytotoxicity assays across a panel of cell lines expressing EGFR. The impact of conjugation on PK parameters and in vivo efficacy is currently under evaluation. DARPin® drug conjugates combine the potency observed with antibody drug conjugates and the modular design of DARPin® molecules to create designer therapeutics. Citation Format: Laura A. Laviolette, Cynthia J. Guidi, Christian Reichen, Qifeng Qiu, Luke Harris, Patricia Schildknecht, Stefanie Fischer, Zita Arany, Tanja Hospodarsch, Anna Skaletskaya, Megan Fuller, Stephen Abbott, Rebecca McCarthy, Jenny Lee, Katherine Francisco, Kerstin Sinkevicius, Sharlene Adams, Christopher Espelin, Emily Reid, Wei Li, Carla Marashio, Kerry Donahue, Stuart Hicks, Dan Snell. Generation of site-specific DARPin® drug conjugates using EGFR as a model system [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 215.
Contemporary therapy efficacy for high-risk multiple myeloma: A systematic review.
Authors: Afia Ashraf, Udhayvir Singh Grewal, Prem Thirunagari, Ahsan Wahab, Ammara Majeed, Hamza Hassan, Midhat Lakhani, Atlantis Dawn Russ, Nadia C Nunes Cavalcante Parr, Faiz Anwer
Journal: Journal of Clinical Oncology (2019)

e19536 Background: Multiple Myeloma (MM) is a heterogeneous disease. High Risk (HR) MM is defined as the presence of abnormal cytogenetics i.e. t(4:14), t(14:16), t(14:20), del(17/17p), non hyperdiploidy and gain (1q). HR MM is a treatment challenge. We aim to explore efficacy of anti-myeloma therapy for newly diagnosed (ND) and relapsed/refractory (RR) HR MM. Methods: We used Pubmed, Ebsco and MBASE to select 18 trials with outcome data on ND (n = 598) and RR(n = 726) HR MM (n = 1321), after extensive review, treatment efficacy (CR, VGPR, ORR) and survival (mPFS, OS) data was extracted. Results: In HR MM the range of overall response rate (ORR) was 31%-100% (Standard Risk (SR): 56%-94.7%), complete response (CR) was 10%-58.3% (SR: 7%-38.1%) and very good partial response (VGPR) was 15%-88.3% (SR: 25%-63%). In ND HR patients, range of ORR was 71.2% - 86.2% (SR: 71.2% - 91.7%) and CR was 35% - 58.3% (SR: 22%-35%) and median progression free survival (mPFS) was 18 months (m) - 31.3m (SR: 31.3m – Not Reached). In RR HR patients, range of ORR was 31% – 85.2% (SR: 56%-94.7%) and CR was 10%-29.2% (SR: 7%-38.1%) and mPFS was 3.3m - 23.1m (SR: 4m - Not Reached). In RR HR MM, Daratumumab ( Dara) , lenalidomide (R) and dexamethasone (d) combination resulted in highest minimal residual disease (MRD) negativity 21.4%. In RR HR, Carfilzomib (Car)- R-d resulted in the longest mPFS of 23.1m (SR: 29.6m) followed by (Dara)-R-d of 22.6m (SR:NR) and Ixazomib (I)- R-d of 21.4m (SR:20.6). In ND HR, Bortezomib (V) with thalidomide (T)- d resulted in longest mPFS of 23.5m (SR: NR) and OS of 56.6m followed by Cyclophosphamide (Cy)-T-d of 20m (SR:34m) and (Dara)-V- Melphalan(M) and Prednisone of 18m (SR:NR). Quadruplet therapy in ND with Cy- V – d with pegylated liposomal doxorubicin resulted in the highest CR 58.3% and mPFS of 31.3m (~8m longer). Conclusions: Cytogenetically HR MM achieved high ORR, CR and VGPR similar to SR MM yet, the PFS and OS in HR (mPFS: 11.2m - 31.3m) was significantly shorter than SR (mPFS: 19m - Not Reached) representing poor prognosis. Promising strategies and targeted therapies that are currently evolving include antibody based combination therapy (3 or 4 drugs), various CAR-T cells constructs, targeted inhibitors, and antibody-drug conjugates.
Probiotics modulate the microbiota–gut–brain axis and improve memory deficits in aged SAMP8 mice
Authors: Xueqin Yang, Dongke Yu, Li Xue, Hui Li, Junrong Du
Journal: Acta Pharmaceutica Sinica B (2019)

ProBiotic-4 is a probiotic preparation composed of Bifidobacterium lactis, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus acidophilus. This study aims to investigate the effects of ProBiotic-4 on the microbiota-gut-brain axis and cognitive deficits, and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8 (SAMP8) mice. ProBiotic-4 was orally administered to 9-month-old SAMP8 mice for 12 weeks. We observed that ProBiotic-4 significantly improved the memory deficits, cerebral neuronal and synaptic injuries, glial activation, and microbiota composition in the feces and brains of aged SAMP8 mice. ProBiotic-4 substantially attenuated aging-related disruption of the intestinal barrier and blood-brain barrier, decreased interleukin-6 and tumor necrosis factor-α at both mRNA and protein levels, reduced plasma and cerebral lipopolysaccharide (LPS) concentration, toll-like receptor 4 (TLR4) expression, and nuclear factor-κB (NF-κB) nuclear translocation in the brain. In addition, not only did ProBiotic-4 significantly decreased the levels of γ-H2AX, 8-hydroxydesoxyguanosine, and retinoic-acid-inducible gene-I (RIG-I), it also abrogated RIG-I multimerization in the brain. These findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota-gut-brain axis and cognitive function in aging, and that its mechanism is associated with inhibition of both TLR4-and RIG-I-mediated NF-κB signaling pathway and inflammatory responses.
Abstract P129: Association Between Blood Pressure and DNA Methylation in Blood Pressure-related Genes in Adolescents
Authors: Fan He, Arthur Berg, Edward O Bixler, Julio Fernandez-Mendoza, Yuka Imamura Kawasawa, Anna C Salzberg, Alexandros N Vgontzas, Duanping Liao
Journal: Circulation (2018)

Introduction: Pediatric hypertension is a significant public health burden. Although the association between genetic variants and blood pressure (BP) has been extensively investigated, the relationship between DNA methylation and BP, especially in adolescents, has not been characterized. Hypothesis: DNA methylation of previously reported BP-related genes is associated with BP levels in adolescents. Methods: We examined this relationship in 263 adolescents from the Penn State Child Cohort follow-up exam. We extracted peripheral leukocytes DNA and subjected it to enhanced, reduced representation bisulfite sequencing. A high-throughput assay provided single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions. Bases with less than 10x coverage or available from less than 50% of the participants were excluded, resulting in a total of 165,297 analyzable sites. For each participant, 3 seated-BP measurements were taken and the average of 2 nd and 3 rd measurements was used to represent the participant’s BP. We used robust linear regression to associate site-specific methylation level with systolic BP (SBP) and diastolic BP (DBP). All regression models were adjusted for age, race, sex, and body mass index percentile. All intragenic sites were then mapped to the hg19 assembly and subjected to enrichment analyses. Significance of the enrichment analyses was assessed by hypergeometric and permutation tests. False discovery rate (FDR)-corrected p values were used to determine the significance between site-specific methylation and BP measures. Results: The mean (SD) age of the participants was 16.7 (2.2) years. It consisted of 55% male, 79% white and 16% obese. Among the 5,551 and 5,890 sites related to SBP and DBP at p&lt;0.05 level, 35 and 38 were intragenic to BP genes. BP genes were significantly enriched among intragenic sites for both SBP (P (hypergeometric)c =0.015; P (permutation) =0.019) and DBP (P (hypergeometric)c =0.008; P (permutation) =0.012). At individual site level, two sites within MECOM were significantly related to SBP (FDR-corrected P=0.02 and 0.03). Conclusion: Despite the need of external validation from other independent cohorts, data from this exploratory study suggests that DNA methylation of BP-related genes is associated with BP regulation in adolescents and, consequently, with the pathogenesis of hypertension in early developmental periods.
CA19-9 decrease and predictive value for response in patients with metastatic pancreatic cancer treated with FOLFIRINOX
Authors: J. Rodríguez Hernández, A. Gil Torralvo, M. Chaves, I. Beltrán Guerra, G. Lourenzo Aguilera, S. Garcia Rodríguez, A. López Ladrón, C. Robles Barraza, A. Sánchez Vegas, M. Rodríguez de la Borbolla, P. López Álvarez, J. Fuentes Pradera, E. Fernández-Parra
Journal: Annals of Oncology (2019)
ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor
Authors: Dong Li, Michael E. March, Alvaro Gutierrez-Uzquiza, Charlly Kao, Christoph Seiler, Erin Pinto, Leticia S. Matsuoka, Mark R. Battig, Elizabeth J. Bhoj, Tara L. Wenger, Lifeng Tian, Nora Robinson, Tiancheng Wang, Yichuan Liu, Brant M. Weinstein, Matthew Swift, Hyun Min Jung, Courtney N. Kaminski, Rosetta Chiavacci, Jonathan A. Perkins, Michael A. Levine, Patrick M. A. Sleiman, Patricia J. Hicks, Janet T. Strausbaugh, Jean B. Belasco, Yoav Dori, Hakon Hakonarson
Journal: Nature Medicine (2019)
DUSPs as markers of MEK/Erk activation in primary colorectal cancer
Authors: W. De Roock, M. Janssens, B. Biesmans, B. Jacobs, J. De Schutter, S. Fieuws, E. Van Cutsem, S. Tejpar
Journal: Journal of Clinical Oncology (2009)

4064 Background: DUSPs dephosphorylate P-MAPK and are activated as a negative feedback loop upon RTK signaling. Higher expression of DUSP 4 &amp; 6 is also found in cells with constitutive Erk activation like KRAS mutant (MUT) cells (Bild et al. Nature 2005). We correlated DUSP1, 4, 6 (isoforms a &amp; b) &amp; 8 mRNA expression level in FFPE primary colorectal cancer (CRC) of 186 chemorefractory patients treated with cetuximab (CTX) with KRAS MUT state and progression-free survival (PFS) and overall survival (OS). Methods: KRAS codon 12,13, 61&amp;146, BRAF V600E and NRAS codon 12&amp;13 MUT were analyzed with the Sequenom MALDI TOF MassArray system. The DUSPs and 3 housekeeping genes were quantified by qRT-PCR. TwoStep cluster analysis was performed. PFS and OS were estimated by the Kaplan-Meier method. Results: KRAS MUT was associated with increased DUSP4 (MWU;p=.0006) &amp; 6a (p=.0067). DUSP6a dephosphorylates P-Erk, DUSP4 also dephosphorylates P-JNK &amp; P-p38. DUSP1 &amp; 8 primarily dephosphorylate P-JNK &amp; P-p38 and were not associated with KRAS MUT. KRAS MUT clustered into 3 groups according to DUSP4 expression: 32 high, 38 median &amp; 13 low (t- test;p&lt;.0001). The low MUT expression was comparable to wild-type (WT) expression. KRAS WT clustered into 2 groups: 69 low &amp; 24 high DUSP4 (ANOVA;p&lt;.0001). 7/24 of high expressors were found to have a BRAF or NRAS MUT. The 32 MUT high expressors had a longer median PFS (log-rank;p=.015) and OS (p=.065) after CTX. The 17 KRAS/BRAF/NRAS WT high expressors had a shorter median OS (p=.026), but not PFS (p=.745). Conclusions: There is a significantly higher DUSP4 &amp; 6a mRNA expression in the KRAS MUT compared to WT primary CRC. However, this is not a black and white observation. In the KRAS MUT there are 3 distinct clusters of DUSP4 expression. The high expressors (= supposed attenuated Erk signaling) have a longer PFS and OS after CTX. Adaptation to constitutive KRAS signaling with differential levels of MEK/Erk activation needs to be further investigated and will be of help in selecting patients for therapy with MEK inhibitors. It suggests not all KRAS MUT will be good candidates for MEK inhibitors. In the cluster of high DUSP4 expressing KRAS WT 30% are BRAF or NRAS MUT. This suggests DUSP expression of FFPE samples could be a more sensitive marker of MEK/Erk activation and resistance to EGFR inhibitors than KRAS MUT analysis alone. [Table: see text]
BMA threatens legal action over “astronomical rises” in rent for premises
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The BMA has rejected a claim by the government’s spending watchdog that GPs regard paying for their premises “as optional,” after an inquiry found that almost £700m (€782m; $890m) owed to NHS Property Services (NHSPS) had been written off or was still unpaid.

In a report published on 26 June,1 the National Audit Office (NAO) said that NHSPS had incurred increasing levels of outstanding debt because it “lacks the powers it needs” to make its tenants sign lease agreements and pay the required share of rent.

But the BMA hit back as it announced that it had written to NHSPS threatening legal action over the “astronomical rises” to GPs’ service and maintenance fees, which the BMA argues have been imposed “with no agreement and no proper explanation.”

Richard Vautrey, chair of the BMA’s General Practitioners …
Abstract 989: The relationship between TP53 gene status and carboxylesterase 2 expression in human gastric cancer
Authors: Yoshinori Kohira, Hyeon-Cheol Lee, Momoko Ishimine, Hajime Orita, Toshiyuki Kobayashi, Koichi Sato, Takehiko Yokomizo, Tetsu Fukunaga
Journal: Cancer Research (2019)

Abstract Carboxylesterases are serine hydrolases that are involved in the metabolisms of various endogenous and exogenous compounds. They are also required for activation of many anti-cancer prodrugs. For example, irinotecan (CPT-11), an anti-cancer prodrug that has been approved for the treatment of many types of solid tumors including gastric cancer, is converted by the carboxylesterase CES2 to its active metabolite 7-ethyl-10-hydroxycamptothesin (SN-38), a very potent topoisomerase I inhibitor. Among carboxylesterase isozymes, CES2 is most highly expressed in the gastrointestinal tract. Thus, the expression of CES2 may play an important role in local (i.e., intratumoral) activation of anti-cancer prodrugs such as irinotecan in the gut. Recent studies with cultured cancer cell lines have shown that CES2 expression is regulated by the tumor suppressor protein p53. However, whether CES2 expression is affected by the presence of p53 mutation in clinical cancer samples still remains unclear. In this study, we focused on the regulatory mechanism of CES2 expression in gastric cancer. First, we examined the relationship between TP53 gene status and CES2 expression using gastric cancer cell lines. Several gastric cancer cell lines expressing wild-type p53 (AGS, NUGC4, MKN74, and HSC58) were treated with nutlin-3a, a drug that inhibits the interaction between p53 and the E3 ubiquitin ligase MDM2 and thereby directly activates p53 signaling without genotoxic side effects. The expression of p21, a downstream target of p53, was increased following nutlin-3a treatment in two p53 wild-type cell lines NUGC4 and HSC58. The expression of CES2 was also upregulated by nutlin-3a in three p53 wild-type cell lines AGS, NUGC4, and HSC58. As expected, the expression levels of p21 and CES2 were not largely affected by nutlin-3a in gastric cancer cell lines with TP53 mutations. These results indicate that CES2 expression is positively regulated by the p53 pathway in most gastric cancer cells. We also investigated the relationship between TP53 gene status and CES2 expression in human gastric cancer samples. Our results may provide useful information for predicting the efficacy of anti-cancer prodrugs that are activated by CES2 in gastric cancer. Note: This abstract was not presented at the meeting. Citation Format: Yoshinori Kohira, Hyeon-Cheol Lee, Momoko Ishimine, Hajime Orita, Toshiyuki Kobayashi, Koichi Sato, Takehiko Yokomizo, Tetsu Fukunaga. The relationship between TP53 gene status and carboxylesterase 2 expression in human gastric cancer [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 989.
Factors associated with the efficacy of aflibercept in patients with metastatic colorectal cancer: results of the multicenter observational study
Authors: M. Fedyanin, V. Chubenko, A. Belonogov, S. Beluhin, A. Belyaeva, L. Bolotina, L. Vladimirova, A. Zhabina, L. Zagorskaya, L. Khalikova, O. Fakhrudinova, F. Moiseenko, A. Khasanova, H. Musaeva, O. Novikova, I. Stradaeva, G. Mukhametshina, R. Orlova, A. Micshenko, I. Popova, L. Mukova, B. Kertiev
Journal: Annals of Oncology (2019)