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BRATT, JAMES D. "From Revivalism to Anti-Revivalism to Whig Politics: The Strange Career of Calvin Colton." Journal of Ecclesiastical History 52, no. 1 (January 2001): 63–82. http://dx.doi.org/10.1017/s0022046900005996.
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Calvin Colton (1789–1857) was an important publicist for both evangelical revivalism and the Whig party in antebellum America. Contrary to the standard historical interpretations, however, Colton did not move smoothly from the one to the other but took up political advocacy only after denouncing Yankee revivalism and its attendant social advocacy as threats to Church and State alike. At the same time his turn to episcopacy went together with a pronounced anglophobia. An analysis of Colton's rhetoric and career path reveals a consistent pattern beneath his unexpected changes and some under-explored dimensions of American religion before the Civil War.
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Persky, Joseph. "AMERICAN POLITICAL ECONOMY AND THE COMMON SCHOOL MOVEMENT: 1820–1850." Journal of the History of Economic Thought 37, no. 2 (June 2015): 247–62. http://dx.doi.org/10.1017/s1053837215000073.
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Classical political economy in Great Britain was broadly supportive of education, but limited government’s role to modest assistance for charitable schools. The early classical economists in the United States, men like Thomas Cooper and Francis Wayland, in addition to supporting free trade, took this classical position with respect to education. But a more aggressive democratic claim was being advanced by the American common school movement and its supporters among Whig protectionists. The early economic tracts of William Jennison, Willard Phillips, Calvin Colton, and Henry Carey envisioned a larger role for government and advocated support for publicly financed common schools. Most notably, the leader of the common school movement, Horace Mann, built a defense for public financing based on a radical theory of property, derived from distinctly Puritan economic doctrine. If his radical positions received little support from post-Civil War mainstream economists, Mann’s practical advocacy of public taxation for public schools very much carried the day.
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Lefebvre, Rémi. "IV. Les élections régionales en Nord-Pas-de-Calais-Picardie. Une non-campagne ?" Droit et gestion des collectivités territoriales 36, no. 1 (2016): 93–109. http://dx.doi.org/10.3406/coloc.2016.2958.
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Nicolas, Pascal. "II. Contribution à la sociologie des coalitions partisanes. L'union de la gauche à Calais (1971-2005)." Annuaire des collectivités locales 28, no. 1 (2008): 669–82. http://dx.doi.org/10.3406/coloc.2008.2008.
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FILATOV, А. V., A. V. YAKIMOV, and A. I. BAKHTEEVA. "INTESTINAL MICROBIOTA OF PIGLETS DURING THE GROWING PERIOD USING THE PROBIOTIC LIQUAFID." PIG-BREEDING, no. 1 (2023): 56–59. http://dx.doi.org/10.37925/0039-713x-2023-1-56-59.
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The article presents the results of a study of the effect of the LiquaFid probiotic on the colonic microbiome of pigs during the growing period. When using the real-time PCR method, it was found that the probiotic complex contributed to an increase in the total number of bacteria in the contents of the colon of the intestine relative to the group of control pigs. In experimental piglets, an increase in the proportion of normoflora representatives in the bacterial community is noted. In the structure of the normoflora of the colon calving in experimental animals, there is a quantitative increase in representatives of the genera Prevotella spp., Porphyromonas spp., Eubacterium spp., Lachnobacterium spp., Clostridium spp., Megasphaera spp., Veillonella spp., Dialister spp. and Lactobacillus spp. Against the background of the growth of representatives of the normoflora, a decrease in opportunistic and pathogenic microorganisms is observed.
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Fleige, S., W. Preißnger, H. H. D. Meyer, and M. W. Pfaffl. "Lactulose: effect on apoptotic- and immunological-markers in the gastro-intestinal tract of pre-ruminant calves." Veterinární Medicína 52, No. 10 (January 7, 2008): 437–44. http://dx.doi.org/10.17221/2046-vetmed.
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The study was conducted to elucidate the effects of orally administered lactulose in combination with <i>Enterococcus faecium</i> on immune response of the intestinal tract in pre-ruminant calves. The mRNA expression of pro- and anti-inflammatory cytokines and proliferation and apoptosis markers were investigated in jejunum, ileum, colon and caecum. Simmental calves were fed diets containing 1% (L1) or 3% (L3) lactulose and the probiotic strain of the genus <i>E. faecium</i>, and compared with a non treated control group. Primarily the high dose feeding with lactulose showed an effect on several mRNA gene expression parameters. In the jejunum a down-regulation of the anti-apoptotic marker Bcl-xl was determined and IL-10 mRNA gene expression was 2.6-fold up-regulated (<i>P</i> < 0.05). In the colon a 1.9-fold (<i>P</i> < 0.05) up-regulation of IL-10 and only in caecum an about 2-fold increase of TGF-β1 (<i>P</i> < 0.05) was found for both lactulose feedings. Caspase 3 was up-regulated in caecum only in the 3% lactulose treated group (<i>P</i> < 0.05). The enhanced apoptotic rate of caspase 3 seems to be associated with a decrease in crypth depth due to lactulose supplementation. The results indicated that mainly the high 3% lactulose dose in probiotic-fed calves has an affect on the intestinal immune function and on diverse apoptotic markers.
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Ramachandra, C., Pavan Sugoor, Uday Karjol, Ravi Arjunan, Syed Altaf, Vijay Patil, Harish Kumar, G. Beesanna, and M. Abhishek. "Robotic Complete Mesocolic Excision with Central Vascular Ligation for Right Colon Cancer: Surgical Technique and Short-term Outcomes." Indian Journal of Surgical Oncology 11, no. 4 (August 1, 2020): 674–83. http://dx.doi.org/10.1007/s13193-020-01181-9.
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Abstract Background Minimally invasive colorectal surgery has demonstrated to have the same oncological results as open surgery, with better clinical outcomes. Robotic assistance is an evolution of minimally invasive technique. Purpose The study aims to present technical details and short-term oncological outcomes of robotic-assisted complete mesocolic excision (CME) with central vascular ligation (CVL) for right colon cancer. Methodology Fifty-two consecutive patients affected by right colon cancer were operated between May 2016 and February 2020 with da Vinci Xi platform. Data regarding surgical and short-term oncological outcomes were systematically collected in a colorectal specific database for statistical analysis. Results Thirty-seven (71.15%) and 15 (28.85%) patients underwent right and extended right hemicoletomy with an extracorporeal anastomosis. Median age was 55 years. Mean operative time was 182 ± 36 min. Mean blood loss was 110 ± 90 ml. Conversion rate was 3.84% (two cases). 78.84% (41 cases) were pT3 and mean number of harvested lymph nodes was 28 ± 4. 1/52 (1.92%) had a documented anastomotic leak requiring exploratory laparotomy and diversion proximal ileostomy. Surgery-related grade IIIa–IIIb Calvien Dindo morbidity were noted in 9.61% and 1.92%, respectively. Conclusion Robotic assistance allows performance of oncological adequate dissection of the right colon with radical lymphadenectomy as in open surgery, confirming the safety and oncological adequacy of this technique, with acceptable results and short-term outcomes.
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Allen, Joshua E., and Wafik S. El-Deiry. "Calcein-effluxing human colon cancer cells are enriched for self-renewal capacity and depend on β-catenin." Oncotarget 4, no. 2 (February 18, 2013): 184–91. http://dx.doi.org/10.18632/oncotarget.883.
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Bęben, Dorota, Oliwia Siwiela, Anna Szyjka, Michał Graczyk, Daniel Rzepka, Ewa Barg, and Helena Moreira. "Phytocannabinoids CBD, CBG, and their Derivatives CBD-HQ and CBG-A Induced In Vitro Cytotoxicity in 2D and 3D Colon Cancer Cell Models." Current Issues in Molecular Biology 46, no. 4 (April 19, 2024): 3626–39. http://dx.doi.org/10.3390/cimb46040227.
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Phytocannabinoids, compounds found in Cannabis sativa L., are used in oncology and palliative care to reduce the adverse reactions of standard therapies. Cancer patients use formulations of Cannabis sativa L. to manage the anxiety, pain, and nausea associated with cancer treatment, and there is growing evidence that some of them may exhibit anticancer properties. In this study, we tested the anticancer potential of selected cannabinoids CBD (cannabidiol) and its quinone derivative CBD-HQ (cannabidiol hydroquinone), CBG (cannabigerol) and its acid derivative CBG-A (cannabigerolic acid), as well as a combination of CBD+CBG on the colon cancer cell line SW-620. The MTT assay was used to determine the cannabinoids’ ability to induce colon cancer cell death. All cannabinoids were cytotoxic at the lowest concentration (3 μg/mL). The half maximal inhibitory concentration (IC50) ranged from 3.90 to 8.24 μg/mL, depending on the substance. Cytotoxicity was confirmed in a 3D spheroidal cell culture with calcein and propidium iodide staining. The amount of intracellular reactive oxygen species (ROS) was examined using a DCF-DA assay. CBG showed the lowest antioxidant activity of all the cannabinoids tested. The level of intracellular ROS decreased only by 0.7–18%. However, CBG-A induced the strongest reduction in ROS level by 31–39%. Our results suggest that cannabinoids represent an interesting research direction with great implementation potential. These preliminary results represent the beginning of research into the potential of these substances for anticancer treatment and underscore the potential for further research.
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Litman, T., M. Brangi, E. Hudson, P. Fetsch, A. Abati, D. D. Ross, K. Miyake, J. H. Resau, and S. E. Bates. "The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2)." Journal of Cell Science 113, no. 11 (June 1, 2000): 2011–21. http://dx.doi.org/10.1242/jcs.113.11.2011.
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Mechanisms of drug resistance other than P-glycoprotein are of increasing interest as the list of newly identified members of the ABC transport family has grown. We sought to characterize the phenotype of the newly discovered ABC transporter encoded by the mitoxantrone resistance gene, MXR, also known as ABCP1 or BCRP. The pharmacodynamics of mitoxantrone and 12 other fluorescent drugs were evaluated by confocal microscopy in four multidrug-resistant human colon (S1) and breast (MCF-7) cancer cell lines. We utilized two sublines, MCF-7 AdVp3000 and S1-M1-80, and detected overexpression of MXR by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein- and MRP-mediated resistance. High levels of cross-resistance were observed for mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of mitoxantrone, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were observed in the two sublines with high MXR expression. Neither the P-glycoprotein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells. Thus, the multidrug-resistant phenotype due to MXR expression is overlapping with, but distinct from, that due to P-glycoprotein. Further, cells that overexpress the MXR protein seem to be more resistant to mitoxantrone and topotecan than cells with P-glycoprotein-mediated multidrug resistance. Our studies suggest that the ABC half-transporter, MXR, is a potent, new mechanism for conferring multiple drug resistance. Definition of its mechanism of transport and its role in clinical oncology is required.
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Zhou, Jun-Xian, and Michael Wink. "Reversal of Multidrug Resistance in Human Colon Cancer and Human Leukemia Cells by Three Plant Extracts and Their Major Secondary Metabolites." Medicines 5, no. 4 (November 13, 2018): 123. http://dx.doi.org/10.3390/medicines5040123.
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Background: We studied the effect of three plant extracts (Glycyrrhiza glabra, Paeonia lactiflora, Eriobotrya japonica) and six of their major secondary metabolites (glycyrrhizic acid, 18β glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, paeoniflorin, ursolic acid) on the multidrug resistant human colon cancer cell line Caco-2 and human leukemia cell line CEM/ADR 5000 as compared to the corresponding sensitive cell line CCRF-CEM, and human colon cancer cells HCT-116, which do not over-express ATP-binding cassette (ABC) transporters. Methods: The cytotoxicity of single substances in sensitive and resistant cells was investigated by MTT assay. We also applied combinations of extracts or single compounds with the chemotherapeutic agent doxorubicin or doxorubicin plus the saponin digitonin. The intracellular retention of the ABC transporter substrates rhodamine 123 and calcein was examined by flow cytometry to explore the effect of the substances on the activity of ABC transporters P-glycoprotein and MRP1. Real-time PCR was applied to analyse the gene expression changes of ABCB1, ABCC1, caspase 3, caspase 8, AhR, CYP1A1, and GSTP1 in resistant cells under the treatment of the substances. Results: All the substances moderately inhibited cell growth in sensitive and resistant cells to some degree. Whereas ursolic acid showed IC50 of 14 and 22 µM in CEM/ADR 5000 and Caco-2 cells, respectively, glycyrrhizic acid and paeoniflorin were inactive with IC50 values above 400 μM. Except for liquiritigenin and isoliquiritigenin, all the other substances reversed MDR in CEM/ADR 5000 and Caco-2 cells to doxorubicin. Ue, ga, 18ga, and urs were powerful reversal agents. In CEM/ADR 5000 cells, high concentrations of all the substances, except Paeonia lactiflora extract, increased calcein or rhodamine 123 retention in a dose-dependent manner. In Caco-2 cells, all the substances, except liquiritigenin, retained rhodamine 123 in a dose-dependent manner. We also examined the effect of the plant secondary metabolite (PSM) panel on the expression of ABCB1, ABCC1, caspase 3, caspase 8, AhR, CYP1A1, and GSTP1 genes in MDR cells. Conclusions: The extracts and individual PSM could reverse MDR in CEM/ADR 5000 and Caco-2 cells, which overexpress ABC transporters, in two- and three-drug combinations. Most of the PSM also inhibited the activity of ABC transporters to some degree, albeit at high concentrations. Ue, ga, 18ga, and urs were identified as potential multidrug resistance (MDR) modulator candidates, which need to be characterized and validated in further studies.
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Su, Tong, Bobby Kong, Calvin Huang, Jonathan Zhu, and Colleen McHugh. "Abstract 1533: Long non-coding RNA control of cancer cell growth." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1533. http://dx.doi.org/10.1158/1538-7445.am2022-1533.
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Abstract Long non-coding RNAs (lncRNAs) are involved in controlling regulatory networks critical for gene expression, cellular growth, and development. Altered expression of lncRNAs are associated with tumor progression in multiple types of human cancers, but the mechanisms by which lncRNAs may control growth and proliferation in cancer cells remain unknown in most cases. Development of interventions targeting non-coding RNA regulation of cell growth would open new avenues for cancer treatment. To identify growth regulatory pathways controlled by non-coding RNAs, we used proteomics and genomics tools to study the effect of changes in lncRNA expression levels in human cancer cell lines. First, we identified five growth regulator lncRNAs based on data mining of CRISPR/Cas9 screens and high throughput sequencing studies from patient tumor and normal cells. These lncRNAs have been associated with progression and metastasis in breast, lung and colon cancers. We hypothesized that growth regulator lncRNAs play a role in cancer development by recruiting effector proteins to regulate gene expression. Next, we evaluated the cellular growth phenotype for each lncRNA in overexpression and knockdown strains using multiple established cancer cell lines. We analyzed cellular transcriptome changes after lncRNA perturbation using high-throughput RNA sequencing. Finally, RNA-protein interactions for each growth regulator lncRNA were identified using an RNA hybridization capture method paired with mass spectrometry that enables purification of direct and specific endogenous RNA-binding proteins. Using this combination of transcriptomics and proteomics data, we discovered that perturbation of growth regulator lncRNAs results in dysregulation of growth signaling pathways and increased expression of p53. We are currently identifying the sequence and structure determinants of RNA-protein complex formation to uncover the mechanisms of action of lncRNAs in controlling cancer cell growth. Citation Format: Tong Su, Bobby Kong, Calvin Huang, Jonathan Zhu, Colleen McHugh. Long non-coding RNA control of cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1533.
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MacKay, Matthew, Joshua Drews, Bonnie V. Dougherty, Duane Hassane, Chris Mason, Gaurav Khullar, Calvin Chao, et al. "Abstract 62: Temporal concordance rates of pathogenic variants in liquid biopsies taken after solid tissue NGS profiling in a real-world pan-cancer cohort." Cancer Research 82, no. 12_Supplement (June 15, 2022): 62. http://dx.doi.org/10.1158/1538-7445.am2022-62.
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Abstract Background: Actionable genomic alterations can be identified through either a biopsy of solid tissue or the detection of circulating tumor DNA from plasma. Little is known about the concordance rates of pathogenic variants between cell free DNA (cfDNA) and solid biopsies, including how concordance varies over time, by cancer type, or by treatment. Here we examine the concordance of pathogenic variants identified in solid tissue biopsies to patient-matched cfDNA biopsies in one of the largest pan-cancer datasets. Methods: De-identified records of cfDNA (xF) and solid (xT) biopsies were analyzed in 2418 stage 4 patients across 5 cancer types: breast (N=459), colon (N= 564), non-small cell lung cancer (NSCLC) (N=750), pancreatic (N=353) and prostate (N=292). Patients were required to have ≥1 pathogenic variant detected in the solid biopsy and a cfDNA biopsy occurring on the same day or after the solid biopsy. Pathogenic SNVs and indels within overlapping probe regions of xF and xT meeting assay limits of detection were included for analysis. Only one cfDNA and solid biopsy were analyzed per patient. Results: Overall, the total number of pathogenic variants identified in solid tissue and cfDNA were highly similar within each cancer type (breast 881 vs 831; colon 1983 vs 1673; NSCLC 1672 vs 1470; pancreas 873 vs 703; prostate 480 vs 384; solid biopsy vs. cfDNA, respectively). Subsetting to patients with ≥1 pathogenic variant in both assays (77%), >40% of patients had additional pathogenic variants identified in their cfDNA which were not found in their solid tissue profiling. Of these subsetted patients which also had cfDNA collected >1 year after their solid biopsy, >25% of NSCLC and >20% of breast cancer patients had mutually exclusive variants (all solid tissue variants were undetectable while new pathogenic variants were found in cfDNA). When comparing samples taken between one week and over one year from each other, the percentage of solid tissue variants identified in cfDNA decreased in a time dependent manner (breast 73% vs. 48%; colon 76% vs. 55%; NSCLC 75% vs. 43%; pancreas 76% vs. 36%; prostate 72% vs. 42%; ≤1 week vs. >1 year, respectively). Conclusions: To our knowledge, this is the largest dataset of matched solid and cfDNA biopsies. >40% of patients with ≥1 pathogenic variants in both assays had additional pathogenic variants found only in their cfDNA. Further, cfDNA was capable of identifying the majority (>70%) of solid tissue variants when samples were taken within one week of each other, though this concordance decreased with time. This data strongly supports the use of matched solid and cfDNA testing, and further exploration of the clinical utility of cfDNA to identify pathogenic variants over the course of a patient’s disease. We will continue to acquire more data and results will be updated before presentation. Citation Format: Matthew MacKay, Joshua Drews, Bonnie V. Dougherty, Duane Hassane, Chris Mason, Gaurav Khullar, Calvin Chao, Joel Dudley, Kimberly L. Blackwell, Nike T. Beaubier, Justin Guinney. Temporal concordance rates of pathogenic variants in liquid biopsies taken after solid tissue NGS profiling in a real-world pan-cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 62.
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Suehnholz, Sarah P., Moriah Nissan, Hongxin Zhang, Ritika Kundra, Calvin Lu, Amanda Dhaneshwar, Nicole Fernandez, et al. "Abstract 3544: OncoKB™, MSK’s precision oncology knowledge base: 2023 updates." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3544. http://dx.doi.org/10.1158/1538-7445.am2024-3544.
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Abstract OncoKBTM is Memorial Sloan Kettering Cancer Center’s (MSK) FDA-recognized precision oncology knowledge base that contains detailed, evidence-based information about the oncogenic effect and therapeutic implications of individual somatic mutations and structural alterations present in patient tumors. Since its public release in 2016, OncoKBTM has expanded to include annotation for >7,500 alterations in ~820 cancer-associated genes. OncoKB supports variant interpretation by the cBioPortal for Cancer Genomics, is used to annotate >15,000 MSK patient sequencing reports annually and its data is publicly available through the website (www.oncokb.org). Programmatic access to OncoKBTM data via its web-based API is freely available to users in an academic setting while users from commercial and hospital settings require a fee-based license. OncoKBTM utilizes its Therapeutic Levels of Evidence system to classify variants based on their tumor type-specific sensitivity or resistance to matched standard care or investigational targeted therapies. To date, OncoKB includes 49 Level 1 genes as well as MSI-H and TMB-H (included in the FDA drug label), 24 Level 2 genes (included in professional guidelines), 35 Level 3A genes (predictive of drug response in well-powered clinical studies), 27 Level 4 genes (predictive of drug response based on compelling biological evidence), and 11 R1/R2 resistance genes. In 2023, OncoKBTM captured the following notable changes in precision oncology drug development: Level 1 annotation of ESR1 ligand-binding domain mutations in breast cancer and promotion from Level 2 to Level 1 of ERBB2 amplification in colorectal cancer following the FDA drug approvals of elacestrant and tucatinib + trastuzumab, respectively. Additionally, KRAS G12C became a Level 2 biomarker in pancreatic and colon cancers with the listing of adagrasib and sotorasib as systemic therapy options for KRAS G12C-mutant disease in the NCCN pancreatic and colon cancer guidelines. IDH1/2 mutations in low grade glioma were annotated as Level 3A based on compelling clinical evidence demonstrating response to the IDH-specific inhibitor vorasidenib. Lastly, noting emerging data with the KRAS G12X-specific inhibitor, RMC-6236, OncoKBTM included all alleles at KRAS position G12 as Level 4. In sum, six novel clinically actionable biomarkers (all Level 1) and 14 follow-on precision oncology therapies for existing leveled biomarkers were added to OncoKBTM in the past year. OncoKBTM’s current focus includes coverage of additional cancer-associated genes, annotation of germline alterations and incorporation of OncoKBTM data into an electronic health record system. Citation Format: Sarah P. Suehnholz, Moriah Nissan, Hongxin Zhang, Ritika Kundra, Calvin Lu, Amanda Dhaneshwar, Nicole Fernandez, Benjamin Preiser, Maria E. Arcila, Marc Ladanyi, Michael F. Berger, Aijazuddin Syed, A. Rose Brannon, Ross Levine, Ahmet Dogan, Alexander Drilon, David B. Solit, Nikolaus Schultz, Debyani Chakravarty. OncoKB™, MSK’s precision oncology knowledge base: 2023 updates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3544.
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Dean, Pamela M. Austin, Diana Canals Hernaez, Julyanne Brassard, Michael R. Hughes, Erin M. Bell, Kelly M. McNagny, and Calvin D. Roskelley. "Abstract 1134: Therapeutic potential of an antibody-drug conjugate directed against a tumor-specific epitope on podocalyxin." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1134. http://dx.doi.org/10.1158/1538-7445.am2023-1134.
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Abstract Podocalyxin (Podxl) is a cell surface sialomucin that is frequently upregulated in tumors with high metastatic potential and its expression is associated with poor outcome in several human cancers. As such, Podxl is emerging as an important prognostic and theragnostic marker. While Podxl is expressed on normal vascular endothelia and kidney podocytes, we sought to produce a novel anti-Podxl antibody that selectively recognizes a tumor-restricted glycoepitope on the extracellular mucin domain of Podxl. The antibody we have produced, PODO447, is specific to the tumor glycoform of Podxl, demonstrated by a lack of binding to normal tissues that are known to express Podxl. In contrast, we show binding of the antibody to tumor cell lines, patient-derived cell lines, and primary tumor tissues. We have previously shown that the majority of tumors in an ovarian carcinoma array (219 cases), including 65% of the high-grade serous histotype, are positive for PODO447. Here, we further show the presence of PODO447 in tumors of the breast, urothelium, pancreas, endometrium, colon, prostate, lung (both small cell and non-small cell), and glioblastoma. To assess the therapeutic potential of our antibody as an antibody drug conjugate (ADC), we coupled PODO447 to the microtubule disruptor monomethyl auristatin E (MMAE) with an enzyme cleavable linker carbamoyl p-aminobenzyl carbamate (PABC), resulting in the ADC PODO447-Vedotin. We demonstrate promising in vitro activity of the ADC to various human tumor cell lines as well as in vivo efficacy to xenografted ovarian and pancreatic tumor lines. Our data reveals PODO447-Vedotin as a tumor-specific and highly efficacious therapeutic agent for the targeting of human tumors and as such, PODO447 exhibits potential for further development as a targeted clinical immunotherapy. Citation Format: Pamela M. Austin Dean, Diana Canals Hernaez, Julyanne Brassard, Michael R. Hughes, Erin M. Bell, Kelly M. McNagny, Calvin D. Roskelley. Therapeutic potential of an antibody-drug conjugate directed against a tumor-specific epitope on podocalyxin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1134.
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Asbjornsdottir, Birna, Snaevar Sigurdsson, Alba Miranda-Ribera, Maria Fiorentino, Takumi Konno, Jinggang Lan, Larus S. Gudmundsson, et al. "Evaluating Prophylactic Effect of Bovine Colostrum on Intestinal Barrier Function in Zonulin Transgenic Mice: A Transcriptomic Study." International Journal of Molecular Sciences 24, no. 19 (September 29, 2023): 14730. http://dx.doi.org/10.3390/ijms241914730.
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The intestinal barrier comprises a single layer of epithelial cells tightly joined to form a physical barrier. Disruption or compromise of the intestinal barrier can lead to the inadvertent activation of immune cells, potentially causing an increased risk of chronic inflammation in various tissues. Recent research has suggested that specific dietary components may influence the function of the intestinal barrier, potentially offering a means to prevent or mitigate inflammatory disorders. However, the precise mechanism underlying these effects remains unclear. Bovine colostrum (BC), the first milk from cows after calving, is a natural source of nutrients with immunomodulatory, anti-inflammatory, and gut-barrier fortifying properties. This novel study sought to investigate the transcriptome in BC-treated Zonulin transgenic mice (Ztm), characterized by dysbiotic microbiota, intestinal hyperpermeability, and mild hyperactivity, applying RNA sequencing. Seventy-five tissue samples from the duodenum, colon, and brain of Ztm and wild-type (WT) mice were dissected, processed, and RNA sequenced. The expression profiles were analyzed and integrated to identify differentially expressed genes (DEGs) and differentially expressed transcripts (DETs). These were then further examined using bioinformatics tools. RNA-seq analysis identified 1298 DEGs and 20,952 DETs in the paired (Ztm treatment vs. Ztm control) and reference (WT controls) groups. Of these, 733 DEGs and 10,476 DETs were upregulated, while 565 DEGs and 6097 DETs were downregulated. BC-treated Ztm female mice showed significant upregulation of cingulin (Cgn) and claudin 12 (Cldn12) duodenum and protein interactions, as well as molecular pathways and interactions pertaining to tight junctions, while BC-treated Ztm males displayed an upregulation of transcripts like occludin (Ocln) and Rho/Rac guanine nucleotide exchange factor 2 (Arhgf2) and cellular structures and interfaces, protein–protein interactions, and organization and response mechanisms. This comprehensive analysis reveals the influence of BC treatment on tight junctions (TJs) and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway gene expressions. The present study is the first to analyze intestinal and brain samples from BC-treated Ztm mice applying high-throughput RNA sequencing. This study revealed molecular interaction in intestinal barrier function and identified hub genes and their functional pathways and biological processes in response to BC treatment in Ztm mice. Further research is needed to validate these findings and explore their implications for dietary interventions aimed at improving intestinal barrier integrity and function. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).
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Gujar, Ravindra, Chang Cui, Christine Lee, Maria Fumagalli, Nicole Martinez, Hannah Liu, Nicole Grigaitis, Sonia Feau, and Lev Becker. "Abstract 6578: N17465, a systemically deliverable elastase, attenuates tumorigenesis and stimulates anti-tumor immunity." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6578. http://dx.doi.org/10.1158/1538-7445.am2024-6578.
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Abstract Background. Neutrophil elastase (ELANE) - a neutrophil-derived serine protease - kills a wide range of cancer cells without harming non-cancer cells through a unique killing program involving histone H1 and the death domain of CD95. Although ELANE attenuates tumor growth and induces anti-tumor immunity following intratumoral delivery (Cui et al., Cell, 2021), systemic delivery is stymied by the presence of serine protease inhibitors in blood (eg. alpha-1-antitrypsin (A1AT) which rapidly inhibit its enzymatic activity essential for its anti-cancer function. To overcome this challenge, we developed N17465, an enzyme that resists serine protease inhibitors in blood, and tested its effects on tumor growth, both as a monotherapy and in combination with checkpoint inhibitors. Methods. Enzymatic properties: N17465 enzymatic activity was quantified in the +/- of A1AT or plasma in vitro, and in blood following intravenous (I.V) injection into tumor-bearing mice. Enzyme activity assays included a fluorogenic substrate AAPV-AMC and the C-terminal domain of CD95 (amino acids212-335). Anti-cancer properties: For in vitro studies, cells were treated with N17465 and viability was quantified by calcein-AM and immunogenic cell death (ICD) markers. Cancer/non-cancer cells included human/murine cell lines and primary cells from ovarian cancer (OvCa) patients. For in vivo studies, N17465 was injected I.V and effects on tumor growth, immunology and survival were assessed as monotherapy or in combination with a checkpoint inhibitor (anti-CTLA4) in pre-clinical models. Results. N17465 maintained enzymatic activity following incubation with A1AT or mouse/human plasma in vitro, and following I.V injection into CT26 tumor-bearing mice in vivo. Importantly, protecting N17465 from serine protease inhibitors did not interfere with its ability to cleave CD95 (therapeutic target) or selectively kill cancer cells in vitro. Indeed, N17465 induced ICD markers, killed a wide range of murine/human cancer cells and also well tolerated by non-cancer cells. Systemically delivered N17465 produced durable tumor regression in a murine CT26 colon cancer model resulting in ~50% tumor-free mice, induced a favorable immune profile, and synergized with anti-CTLA4. N17465 also exhibited efficacy across a range of xenograft models spanning human colon, prostate, and lung cancer, as well as OvCa patient-derived CDX models. Conclusions. Altogether, our data demonstrate that N17465 selectively kills cancer cells, produces durable responses in mice, induces favorable immunology and synergies with checkpoint inhibitors in pre-clinical models. Its ability to maintain enzymatic activity in blood following systemic delivery, selectively kill a wide range of cancer cells, and stimulate anti-tumor immunity warrants further investigation of this unique therapeutic modality across a wide range of solid tumors. Citation Format: Ravindra Gujar, Chang Cui, Christine Lee, Maria Fumagalli, Nicole Martinez, Hannah Liu, Nicole Grigaitis, Sonia Feau, Lev Becker. N17465, a systemically deliverable elastase, attenuates tumorigenesis and stimulates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6578.
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Otegbeye, Folashade, Evelyn Ojo, Nathan Mackowski, Stephen Moreton, and David N. Wald. "Inhibiting TGF-Beta Signaling in the Tumor Micro-Environment Enhances the Cytotoxic Function of Adoptive NK Cells." Blood 128, no. 22 (December 2, 2016): 2160. http://dx.doi.org/10.1182/blood.v128.22.2160.2160.
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Abstract Introduction: The tumor micro-environment poses a limitation to the efficacy of adoptive NK cell therapy due to several immunosuppressive cytokines. TGF-beta, produced in excess by tumor cells, regulatory T cells and stromal cells, facilitates epithelial to mesenchymal transformation thereby promoting metastasis and fibrosis. This high TGF-beta milieu in cancer patients also impairs innate natural killer (NK) cell mediated cancer immunity through various mechanisms. Adoptive transfer of healthy donor NK cells will have limited clinical efficacy when highly activated NK cells are introduced into the immunosuppressive TGF-beta rich tumor microenvironment of cancer patients. We are testing several small molecule inhibitors of the TGF-beta receptor in combination with healthy donor NK cells with a goal of enhancing adoptive NK cell therapy in various disease models. Methods: Human NK cells isolated from healthy donor peripheral blood were expanded over a 21-day period in co-culture with irradiated K562 cells genetically modified to express membrane-bound IL-21. (Somanchi et al. 2011 JoVE 48. doi: 10.3791/2540). Cell culture media was supplemented with IL-2 (50mU/mL). For in vitro assays, at the beginning of expansion week 3 the culture conditions for NK cells was continued unchanged, supplemented with TGF-beta 1 ligand (TGF-B1) at 5ng/mL or 10ng/mL either alone or in combination with EW7197 (a TGF-beta Type 1 receptor inhibitor) or with EW7197 alone. These NK cells were tested with Calcein-AM release cytotoxicity assays at various time points from addition of TGF-B1 (0h, 36h, 72h and 96h). Briefly, NK cells were co-cultured with OCI-AML cells labeled with Calcein-AM at a ratio of 5NK:1 OCI-AML. At the end of 4 hours co-incubation, cytotoxicity was measured by relative fluorescence of calcein release into the culture supernatant compared with Triton-X induced complete target cell lysis. In a murine liver metastases model using the colon cancer cell line HCT116, 105 HCT116 cells were surgically implanted into NSG mouse spleens (following hemi-splenectomy). Mice in 2 groups (3/group) subsequently received 5 x 106 NK cells each (tail vein), weekly for two weeks, starting 10 days post-op. Another control group received vehicle infusions alone while a fourth control group received the TGF-beta inhibitor LY2157299 by oral gavage twice daily at 75mg/kg for two weeks. One group of mice receiving NK cells also received twice daily LY2157299 for two weeks starting with the first NK cell infusion. Mice receiving NK cells also received IL2 (75,000U IP) three times a week for two weeks. Results: At TGF-beta levels similar to that found in AML patients (5ng/ml), NK cell killing of OCI cells was markedly impaired progressively from 36h to 96h exposure. This reduced cytotoxic activity correlated with a 3-4 fold decrease in expression of NKG2D most marked at 96h(Figure 1). CD16 expression was also significantly reduced by 2-3 fold on TGF-beta exposed NK cells after 96h. The TGF-beta inhibitor EW7197 maintained NK cell killing as well as NKG2D and CD16 expression in the presence of TGF-B1 (Figure 1). At 32 days post-splenic implantation, vehicle mice (those that received HCT116 either alone or in combination with LY2157299 alone) appeared moribund and had grossly distended abdomens with ascites. All mice were autopsied at this time point. All control mice had grossly enlarged livers with significant metastases and absence of viable liver tissue (Fig 2). In contrast, mice treated with two weekly infusions of NK cells and LY2157299 for 4 weeks had no ascites and predominantly healthy livers. All mice that received NK cells alone had some evidence of liver metastases with various degrees of disease burden. Composite H&E stains of liver sections from 3 mice/group showed <10% liver metastases microscopically in mice treated with a combination of NK cells and LY2157299. This was significantly reduced compared to 80-90% in the untreated or LY2157299 alone mice and 60-70% in the NK cell alone group (Fig 3). Discussion: Our preliminary results indicate that TGF-beta inhibition in combination with adoptive NK cell therapy can mitigate the immunosuppressive tumor microenvironment conferred by TGF-beta signaling. We are in the process of validating this approach in other preclinical models of both hematologic malignancies and solid tumors. Disclosures No relevant conflicts of interest to declare.
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DiRaimondo, Thomas R., Natalija Budimir, Lina Ma, Simon Shenhav, Vanessa Cicchini, Hu Wu, Renee Jocic, et al. "Abstract B04: Preclinical activity and safety profile or JANX008, a novel EGFR-targeting tumor-activated T cell engager for treatment of solid tumors." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): B04. http://dx.doi.org/10.1158/2326-6074.tumimm22-b04.
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Abstract Introduction: Epidermal growth receptor (EGFR) is the most expressed membrane oncogenic protein in human cancers. KRAS and BRAF mutations are significant drivers of resistance to EGFR-targeted therapies. Unlike other treatments, EGFR-targeting, CD3 bispecific T cell engagers (TCEs) can potentially retain activity against tumors bearing resistance mutations. However, cytokine release syndrome (CRS), on-target off-tumor toxicities, and poor pharmacokinetics (PK) properties present significant clinical limitations for these potent immunomodulators. To overcome these challenges, Janux has developed JANX008, an EGFR- and CD3-targeted tumor-activated T cell engager (TRACTr). JANX008 is a humanized tri-specific protein that contains EGFR- and CD3-binding domains, an albumin binding domain to extend circulating half-life, and two different peptide masks fused to the molecule through tumor protease cleavable linkers. One peptide mask inhibits EGFR engagement on target cells, and the other inhibits CD3 engagement on T cells. Once the cleavage sequences undergo proteolysis by tumor proteases, the EGFR and CD3 masks are released, and the resulting active molecule can bind EGFR and CD3 on target cells. Methods: Peptide masks against EGFR- and CD3-binding domains were identified via phage display. The efficiency of the masks was evaluated using human EGFR and CD3 ELISAs. JANX008-induced cleavage-dependent T cell killing was evaluated in human PBMC/tumor cell co-culture assays. Anti-tumor efficacy of JANX008 was tested in multiple preclinical models, including EGFR antibody-resistant KRAS- and PIK3CA-mutant mouse colon cancer model (HCT116) and a fully human primary colorectal cancer (CRC) tumoroid system. The pharmacokinetic and safety profile of JANX008 was evaluated in non-human primate studies. Results: JANX008 target engagement was cleavage-dependent where masking reduced EGFR and CD3 binding by >300x and >1,000x, respectively. JANX008 exhibited potent cleavage- and dose-dependent activity in multiple preclinical models, including EGFR antibody-resistant tumor and T cell co-culture assays, humanized mouse CRC model, and a human primary CRC tumoroids with an intact tumor microenvironment. JANX008 showed a significantly enhanced safety profile in NHPs compared to non-masked EGFR-TCE, including decreased CRS-associated cytokines and healthy tissue toxicities at high exposures. Clinical chemistry, hematology, and pathology measurements all supported No-Observed-Adverse-Effect-Level ≥ 0.6 mg/kg/dose. Finally, the cleavable albumin-binding domain extended the half-life of JANX008 to ~94h, relative to the ~1.3h half-life of non-masked TCE, supporting its weekly clinical dosing. Conclusions: Preclinical data demonstrate key characteristics of JANX008, including cleavage-dependent activity, half-life extended PK, the potential for superior safety, and manufacturability properties that could mitigate significant limitations of TCEs and support JANX008 clinical development. Citation Format: Thomas R DiRaimondo, Natalija Budimir, Lina Ma, Simon Shenhav, Vanessa Cicchini, Hu Wu, Renee Jocic, Fabrece Roup, Calvin Campbell, Carolina Caffaro, Hans Aerni, Ugur Eskiocak, Wayne Godfrey, Charles Winter, Marc Nasoff, Neil Gibson, David Campbell, shahram Salek-Ardakani. Preclinical activity and safety profile or JANX008, a novel EGFR-targeting tumor-activated T cell engager for treatment of solid tumors [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B04.
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Gujar, Ravindra, Chang Cui, Lilibet Valdovinos, Christine Lee, Arezoo Arjmand, Nicole Grigaitis, Asna Khalid, et al. "Abstract 6390: N17350 is an emerging therapeutic modality that selectively kills cancer cells and stimulates anti-tumor immunity." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6390. http://dx.doi.org/10.1158/1538-7445.am2023-6390.
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Abstract INTRODUCTION: Cancer is a disease driven by variable genetic mutations. Overcoming this variability while sparing normal cells has stymied broad-acting therapy development. Our innate immune system evolved to clear genetically diverse pathogens and limit host toxicity, raising the possibility that it can produce similar effects in cancer. Previous studies showed that neutrophil elastase (ELANE) - a neutrophil-derived serine protease - killed a wide range of cancer cells without harming non-cancer cells by cleaving CD95, the FAS receptor (Cui et al.,Cell, 2021). ELANE attenuated primary tumor growth and produced a CD8+T cell-mediated abscopal effect to attack metastases. Here we leveraged this ELANE-mediated pathway to produce an optimized N17350 biologic and tested its effects on tumor development, both as a monotherapy and in combination with checkpoint inhibitors. Our findings underscore the viability of N17350 as a new therapeutic modality leveraging innate immunity. METHODS: Anti-cancer effects of N17350 were examined in vitro and in vivo and compared with standard of care (SoC) agents. For in vitro studies, cells were treated with N17350 and viability was quantified by calcein-AM and immunogenic cell death (ICD) markers. Cancer/non-cancer cells included human/murine cell lines and primary cells isolated from healthy donors and ovarian cancer patients. We further tested the ability of cancer cells to develop resistance to N17350 and FAS-L. For in vivo studies, a single dose of N17350 was delivered intratumorally into CT26 (colon) and 4T1 (metastatic breast) tumors. Effects on primary and metastatic tumor growth, immunology, and survival were assessed in comparison to SoC agents (oxaliplatin, cyclophosphamide) or in combination with a checkpoint inhibitor (anti-CTLA4). RESULTS: N17350 killed and induced ICD markers in all cancer cell types tested without harming non-cancer cells, while SoC agents were similarly toxic to both cell types. Repeatedly killing E0771 cancer cells with N17350 did not produce resistance, which was observed with a FAS-L that targets CD95 via a distinct mechanism. A single intra-tumoral dose of N17350 produced durable effects in the 4T1 and CT26 models (CT26:75%-100% tumor-free). N17350 induced a robust innate/adaptive immune profile, abscopal effect to limit 4T1 lung metastasis, and synergized with anti-CTLA4 in cold (4T1) and hot (CT26) tumors. Finally, N17350 showed markedly improved efficacy over SoC agents in both models. CONCLUSIONS: Taken together, our data suggest that N17350 selectively kills cancer cells, produces complete responses in a subset of mice, induces favorable innate and adaptive immunology, and combines with checkpoint inhibitors in cold and hot tumors. Its ability to escape resistance, produce abscopal effects, and outperform SoC chemotherapies warrants further studies of this unique therapeutic modality in a clinical setting. Citation Format: Ravindra Gujar, Chang Cui, Lilibet Valdovinos, Christine Lee, Arezoo Arjmand, Nicole Grigaitis, Asna Khalid, Catherine A. Reardon, Kelly Q. Schoenfelt, Sonia Feau, Chris Twitty, Lev Becker. N17350 is an emerging therapeutic modality that selectively kills cancer cells and stimulates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6390.