tbuckley/cabot-search huggingface dataset:
Abstract B031: A brain penetrant Nicotinamide-adenine dinucleotide mimetic impedes <i>de novo</i> guanylate synthesis and glioblastoma growth
Authors: Yu-Jung Chen, Swathi V. Iyer, Chun-Cheng David Hsieh, Tao Wang, Jing Li, Michelle C. Lien, Mungunsarnai Ganbold, Xuanhua P. Xie, Chenura Jayewickreme, Sean F Brady, Kyun Lim, Luis F Parada
Journal: Cancer Research (2024)

Abstract Glioblastoma is a malignant disease with dire prognosis and in urgent need of improved therapeutics. We identify a small compound, Gliocidin, that kills glioblastoma cells while sparing replicative mouse embryonic fibroblasts. Gliocidin activity reveals a de novo purine synthesis pathway metabolic vulnerability in glioblastoma caused by indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). Gliocidin mediated IMPDH2 blockade reduces intracellular guanine nucleotide levels causing nucleotide imbalance, replication stress, and tumor cell death. Gliocidin is a prodrug anabolized into its tumoricidal metabolite by the enzyme nicotinamide nucleotide adenylyltransferase (NMNAT1) of the NAD+ salvage pathway. In vivo, Gliocidin penetrates the blood brain barrier and extends orthotopic murine GBM mouse survival. The DNA alkylating agent, Temozolomide (TMZ), induces Nmnat1 expression causing a synergistic tumor killing effect and additional survival benefit in patient-derived xenograft (PDX) orthotopic mouse models. This study brings Gliocidin to light as a prodrug that can improve the survival of GBM patients. Citation Format: Yu-Jung Chen, Swathi V. Iyer, Chun-Cheng David Hsieh, Tao Wang, Jing Li, Michelle C. Lien, Mungunsarnai Ganbold, Xuanhua P. Xie, Chenura Jayewickreme, Sean F Brady, Kyun Lim, Luis F Parada. A brain penetrant Nicotinamide-adenine dinucleotide mimetic impedes de novo guanylate synthesis and glioblastoma growth [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B031.
Abstract B038: Accurate quantitative profiling of rna modifications and their associations with glioblastoma
Authors: Frank A Morales Shnaider, Coston Eddings, Jennifer Simpson, Bakhos A. Tannous, Norman Chiu
Journal: Cancer Research (2024)

Abstract Every chemical group that is added to one of the canonical ribonucleotides, i.e., RNA modification, in a specific transcript can potentially alter the RNA folding as well as the RNA-protein interactions. Hence, RNA modifications are considered as post-transcriptional regulators for RNA splicing, RNA stability, and translation, just to name a few. Today, 170+ different RNA modifications have been identified, but only half a dozen of them are linked to glioblastoma (GBM). On the other hand, other RNA biology studies indicated the interplays between RNA modifications within a specific epitranscriptome could play a regulatory role in cellular activities. Although suitable methods for profiling RNA modifications in a specific epitranscriptome are available, the lack of ribonucleoside standards has prohibited the accurate quantification of each detectable RNA modification. To address this analytical challenge, our group has recently developed a mass spectrometric method that can achieve accurate quantitative profiling of untargeted RNA modifications without using any standards. Using the developed method, all the RNA modifications in patient-derived GBM cell lines could be profiled with high accuracy. In total, 31 different RNA modifications were detected in the GBM epitranscriptomes. By comparing with the profile detected in healthy human brain tissues, a unique set of upregulated RNA modifications is associated with the development of GBM. These findings are supported by the upregulated gene expression data obtained from GBM patients that are available in The Cancer Genome Atlas program. Citation Format: Frank A Morales Shnaider, Coston Eddings, Jennifer Simpson, Bakhos A. Tannous, Norman Chiu. Accurate quantitative profiling of rna modifications and their associations with glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B038.
Abstract B032: Designing arrays for the mouse head to facilitate <i>in vivo</i> studies of Tumor Treating Fields (TTFields) treatment of glioblastoma
Authors: Sewar Zbidat, Roni Blatt, Mariell Sellevoll, Martin Gabay, Inbar Schlachet, Shay Cahal, Shiri Davidi, Itai Tzchori, Amal El-Mabhouh, Adi Haber, Moshe Giladi, Yoram Palti
Journal: Cancer Research (2024)

Abstract Background: Tumor Treating Fields (TTFields) therapy is a noninvasive, anticancer treatment delivered by two pairs of arrays placed on the skin surrounding the tumor location. Based on efficacy and safety data from phase 3 global clinical studies, TTFields therapy is FDA-approved and CE marked for treatment of glioblastoma (GBM), the most common malignant brain tumor. In vivo studies of TTFields in GBM models, which are mostly based on mice, are complicated by the relatively small size of the mouse head and corresponding limited surface area to apply the arrays. This challenge has thus far limited in vivo research on TTFields treatment in GBM. Materials and Methods: To identify a method for efficient delivery of TTFields to the mouse brain, we examined the ability of different array layouts to accommodate the geometries of the mouse head while minimally impacting head movement, taking into account that it may not be feasible to place two pairs of arrays on the head. The properties of different adhesive tapes, specifically their ability to attach to the skin, was also investigated. Finally, the ability of array layouts to deliver therapeutic intensities to the desired region was validated using simulations and direct electric field measurements. Results: Assessments showed an optimal layout consisted of arrays such that one of the pair was on the mouse head, and the other on the mouse torso; and the arrays for placement on the head divided into two smaller disks, A thin, transparent adhesive tape was identified that allowed the arrays to be securely attached to the skin, but was easily removed without leaving residues. Validation studies using simulations demonstrated that the array layout met the minimum treatment requirements (field intensity ≥1 V/cm RMS; current ≥50 mA), and facilitated TTFields usage for ≥75% of each day. Conclusions: These data show that TTFields treatment can be effectively delivered to the heads of mice by utilizing carefully designed arrays. Our newly developed mouse head arrays are a flexible construct, that adheres strongly to the skin, and enables efficient electric field delivery to the mouse brain. These improvements in the delivery of TTFields treatment to mice will facilitate research of TTFields as a therapy for GBM. Citation Format: Sewar Zbidat, Roni Blatt, Mariell Sellevoll, Martin Gabay, Inbar Schlachet, Shay Cahal, Shiri Davidi, Itai Tzchori, Amal El-Mabhouh, Adi Haber, Moshe Giladi, Yoram Palti. Designing arrays for the mouse head to facilitate in vivo studies of Tumor Treating Fields (TTFields) treatment of glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B032.
Early-life ruminal microbiome-derived indole-3-carboxaldehyde and prostaglandin D2 are effective promoters of rumen development
Authors: Daming Sun, Gaorui Bian, Kai Zhang, Ning Liu, Yuyang Yin, Yuanlong Hou, Fei Xie, Weiyun Zhu, Shengyong Mao, Junhua Liu
Journal: Genome biology (2024)

Abstract Background The function of diverse ruminal microbes is tightly linked to rumen development and host physiology. The system of ruminal microbes is an excellent model to clarify the fundamental ecological relationships among complex nutrient–microbiome–host interactions. Here, neonatal lambs are introduced to different dietary regimes to investigate the influences of early-life crosstalk between nutrients and microbiome on rumen development. Results We find starchy corn-soybean starter-fed lambs exhibit the thickest ruminal epithelia and fiber-rich alfalfa hay-fed lambs have the thickest rumen muscle. Metabolome and metagenome data reveal that indole-3-carboxaldehyde (3-IAld) and prostaglandin D2 (PGD2) are the top characteristic ruminal metabolites associated with ruminal epithelial and muscular development, which depend on the enhanced ruminal microbial synthesis potential of 3-IAld and PGD2. Moreover, microbial culture experiment first demonstrates that Bifidobacterium pseudolongum is able to convert tryptophan into 3-IAld and Candida albicans is a key producer for PGD2. Transcriptome sequencing of the ruminal epithelia and smooth muscle shows that ruminal epithelial and muscular development is accompanied by Wnt and Ca 2+ signaling pathway activation. Primary cell cultures further confirm that 3-IAld promotes ruminal epithelial cell proliferation depending on AhR-wnt/β-catenin signaling pathway and PGD2 accelerates ruminal smooth muscle cell proliferation via Ca 2+ signaling pathway. Furthermore, we find that 3-IAld and PGD2 infusion promote ruminal epithelial and musculature development in lambs. Conclusions This study demonstrates that early-life ruminal microbiome-derived 3-IAld and PGD2 are effective promoters of rumen development, which enhances our understanding of nutrient–microbiome–host interactions in early life.
Factors associated with successful liberation from continuous renal replacement therapy in children and young adults: analysis of the worldwide exploration of renal replacement outcomes collaborative in Kidney Disease Registry
Authors: Erin K. Stenson, Issa Alhamoud, Rashid Alobaidi, Gabriella Bottari, Sarah Fernandez, Dana Y. Fuhrman, Francesco Guzzi, Taiki Haga, Ahmad Kaddourah, Eleonora Marinari, Tahagod Mohamed, Catherine Morgan, Theresa Mottes, Tara Neumayr, Nicholas J. Ollberding, Valeria Raggi, Zaccaria Ricci, Emily See, Natalja L. Stanski, Huaiyu Zang, Emily Zangla, Katja M. Gist, Andrea Cappoli, Eileen A Ciccia, Michaela Collins, Denise Colosimo, Gerard Cortina, Mihaela A Damian, Sara De la Mata Navazo, Gabrielle DeAbreu, Akash Deep, Kathy L Ding, Kristin J Dolan, Sarah N Lafever Fernandez, Dana Y Fuhrman, Ben Gelbart, Katja M Gist, Stephen M Gorga, Francesco Guzzi, Isabella Guzzo, Elizabeth Harvey, Denise C Hasson, Taylor Hill-Horowitz, Haleigh Inthavong, Catherine Joseph, Ahmad Kaddourah, Aadil Kakajiwala, Aaron D Kessel, Sarah Korn, Kelli A Krallman, David M Kwiatkowski, Jasmine Lee, Laurance Lequier, Tina Madani Kia, Kenneth E Mah, Eleonora Marinari, Susan D Martin, Shina Menon, Tahagod H Mohamed, Catherine Morgan, Theresa A Mottes, Melissa A Muff-Luett, Siva Namachivayam, Tara M Neumayr, Jennifer Nhan, Abigail O’Rourke, Nicholas J Ollberding, Matthew G Pinto, Dua Qutob, Valeria Raggi, Stephanie Reynaud, Zaccaria Ricci, Zachary A Rumlow, María J Lozano Santiago, Emily See, David T Selewski, Carmela Serpe, Alyssa Serratore, Ananya Shah, Weiwen V Shih, H Shin Stella, Cara L Slagle, Sonia Solomon, Danielle E Soranno, Rachana Srivastava, Natalja L Stanski, Michelle C Starr, Erin K Stenson, Amy E Strong, Susan A Taylor, Sameer V Thadani, Amanda M Uber, Brynna Wyk, Tennille N Webb, Huaiyu Zang, Emily E Zangla, Michael Zappitelli
Journal: Intensive Care Medicine (2024)
Gut microbiota-palmitoleic acid-interleukin-5 axis orchestrates benzene-induced hematopoietic toxicity
Authors: Lei Zhang, Ziyan Liu, Wei Zhang, Jingyu Wang, Huiwen Kang, Jiaru Jing, Lin Han, Ai Gao
Journal: Gut Microbes (2024)

Due to the annual increase in its production and consumption in occupational environments, the adverse blood outcomes caused by benzene are of concern. However, the mechanism of benzene-induced hematopoietic damage remains elusive. Here, we report that benzene exposure causes hematopoietic damage in a dose-dependent manner and is associated with disturbances in gut microbiota-long chain fatty acids (LCFAs)-inflammation axis. C57BL/6J mice exposed to benzene for 45 days were found to have a significant reduction in whole blood cells and the suppression of hematopoiesis, an increase in Bacteroides acidifaciens and a decrease in Lactobacillus murinus. Recipient mice transplanted with fecal microbiota from benzene-exposed mice showed potential for hematopoietic disruption, LCFAs, and interleukin-5 (IL-5) elevation. Abnormally elevated plasma LCFAs, especially palmitoleic acid (POA) exacerbated benzene-induced immune-inflammation and hematopoietic damage via carnitine palmitoyltransferase 2 (CPT2)-mediated disorder of fatty acid oxidation. Notably, oral administration of probiotics protects the mice against benzene-induced hematopoietic toxicity. In summary, our data reveal that the gut microbiota-POA-IL-5 axis is engaged in benzene-induced hematopoietic damage. Probiotics might be a promising candidate to prevent hematopoietic abnormalities from benzene exposure.
Maternal smoking during pregnancy increases the risk of gut microbiome-associated childhood overweight and obesity
Authors: Ye Peng, Hein M Tun, Siew C Ng, Hogan Kok-Fung Wai, Xi Zhang, Jaclyn Parks, Catherine J Field, Piush Mandhane, Theo J Moraes, Elinor Simons, Stuart E Turvey, Padmaja Subbarao, Jeffrey R Brook, Tim K Takaro, James A Scott, Francis KL Chan, Anita L Kozyrskyj
Journal: Gut Microbes (2024)

Childhood obesity is linked to maternal smoking during pregnancy. Gut microbiota may partially mediate this association and could be potential targets for intervention; however, its role is understudied. We included 1,592 infants from the Canadian Healthy Infants Longitudinal Development Cohort. Data on environmental exposure and lifestyle factors were collected prenatally and throughout the first three years. Weight outcomes were measured at one and three years of age. Stool samples collected at 3 and 12 months were analyzed by sequencing the V4 region of 16S rRNA to profile microbial compositions and magnetic resonance spectroscopy to quantify the metabolites. We showed that quitting smoking during pregnancy did not lower the risk of offspring being overweight. However, exclusive breastfeeding until the third month of age may alleviate these risks. We also reported that maternal smoking during pregnancy significantly increased Firmicutes abundance and diversity. We further revealed that Firmicutes diversity mediates the elevated risk of childhood overweight and obesity linked to maternal prenatal smoking. This effect possibly occurs through excessive microbial butyrate production. These findings add to the evidence that women should quit smoking before their pregnancies to prevent microbiome-mediated childhood overweight and obesity risk, and indicate the potential obesogenic role of excessive butyrate production in early life.
Abstract B029: A novel lupus-associated antibody that inhibits the growth of aggressive high-grade glioma orthotopic xenografts and enhances radiotherapy via a unique mechanism
Authors: Terrance G. Johns, Mani Kuchibhotla, Kim O'Sullivan, Zi Ying Ng, Ranjith Palanisamy, James Campbell, Valentina Dubljevic, Raelene Endersby
Journal: Cancer Research (2024)

Abstract A major immune dysregulation in lupus patients is the generation of autoantibodies targeting a range of self-molecules. Some of these lupus antibodies may have anti-tumor activity in high-grade glioma (HGG). An autoantibody, 3E10, was isolated from a mouse model of lupus that has high affinity for DNA. Two different humanized forms of 3E10 were generated, PAT-DX1 (a di-scFV) and PAT-DX3 (a humanized IgG1). Neither DX1 nor DX3 inhibited the in vitro growth of HGG patient-derived cell lines, either alone or in combination with radiotherapy (RT). In contrast, both antibody constructs inhibited the growth of GBM6 orthotopic xenografts in mice as single agents, consistent with our data showing uptake of labelled DX1 in HGG xenografts. Interestingly, despite its larger molecular weight, DX3 displayed greater anti-tumor activity than DX1, possibly due to improved tumor localization. DX1 showed at least additive anti-tumor activity in combination with RT against GBM6 xenografts, significantly extending survival. Neutrophils produce NETs, a proinflammatory form of cell death that generates web-like structures composed of various injurious enzymes and DNA. NET release promotes a favorable tumor environment through induction of cellular proliferation and angiogenesis. NETs cause resistance to therapeutics in a variety of cancers and their inhibition improves response to these therapeutics. Our published data shows that DX1 inhibits the formation of NETs in neutrophils, suggesting this could be its mechanism of action and is consistent with the lack of DX1 in vitro activity. Large scale production of DX1 has been optimized and toxicology and safety studies in rats and non-human primates have not identified any concerns. A first in human Phase 1 clinical trial of DX1 is planned in 2024 and will include HGG patients. Citation Format: Terrance G. Johns, Mani Kuchibhotla, Kim O'Sullivan, Zi Ying Ng, Ranjith Palanisamy, James Campbell, Valentina Dubljevic, Raelene Endersby. A novel lupus-associated antibody that inhibits the growth of aggressive high-grade glioma orthotopic xenografts and enhances radiotherapy via a unique mechanism [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B029.
Abstract A028: Investigating the role of SOX2 in promoting anchorage-independent survival of ovarian cancer cells
Authors: Shriya Kamlapurkar, Coryn Stump, Mythreye Karthikeyan, Nadine Hempel
Journal: Cancer Research (2024)

Abstract Ovarian cancer (OVCA) is the most lethal gynecologic malignancy, often detected at an advanced stage. OVCA progression involves transcoelomic metastasis, where tumor cells disseminate into the peritoneal ascites. Malignant cells in the ascites adapt to survive under Anchorage-Independent (A-I) conditions by altering the expression of genes escalating anoikis (A-I cell death) resistance and metastasis. Our lab has shown that OVCA cells manipulate their transcriptomic profile to promote the expression of anoikis resistance genes in A-I. Expression profiling of genes upregulated in A-I revealed the transcription factor SRY-Box Transcription Factor 2 (SOX2) to be highly upregulated in response to OVCA cell detachment. While we have previously demonstrated that SOX2 is necessary for the A-I survival of OVCA cells, the specific mechanism underlying SOX2-dependent A-I survival remains unknown. RNA-sequencing studies performed in the high-grade serous ovarian cancer cell line, OVCAR3, revealed that the Leucine-rich repeat-containing G-protein coupled receptor 5, LGR5, is the most significantly upregulated gene in A-I compared to attached conditions. Importantly, amongst those genes that are upregulated in A-I, LGR5 is significantly downregulated following SOX2 knockdown in A-I. LGR5 is an ‘orphan’ G-protein coupled receptor known to modulate canonical Wnt signaling upon interacting with its ligand R-spondin1 (RSPO1). Time-course experiments in OVCAR3 cells revealed a striking increase in LGR5 expression that peaked after 24 hours in A-I. Furthermore, siRNA mediated knockdown of SOX2 downregulated LGR5 expression only in A-I, suggesting that LGR5 is a potential SOX2 target under A-I conditions. Interestingly, bioinformatics analysis of the existing OVCA datasets from the Cancer Genome Atlas showed increased expression of RSPO1, which correlated with a significant decrease in the overall survival of OVCA patients. Interaction of LGR5 with its ligand RSPO1 is crucial for the receptor to signal through the Wnt pathway to promote cell survival and cancer stemness. Although SOX2 and LGR5 are established markers of cancer stemness in various tumor types, their direct relationship in promoting tumor progression and regulation of OVCA A-I cell survival remains unknown. Our data suggests that increased SOX2 and LGR5 expression could drive OVCA cell survival under A-I conditions. Our current studies focus on understanding the molecular mechanisms behind SOX2-driven regulation of LGR5 and the role of LGR5 in driving OVCA A-I cell survival. Citation Format: Shriya Kamlapurkar, Coryn Stump, Mythreye Karthikeyan, Nadine Hempel. Investigating the role of SOX2 in promoting anchorage-independent survival of ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A028.
Abstract A019: Development of adaptive anoikis resistance promotes ovarian cancer metastasis that can be prevented by CDK8/19 Mediator kinase inhibition
Authors: Mehri Monavarian, Resha Rajkarnikar, Emily Faith Page, Asha Kumari, Liz Macias Quintero, Lara Ianov, sarthak Sahoo, Mohit Kumar Jolly, Elizabeth Worthey, Nadine Hempel, Abhyudai Singh, Eugenia Broude, Karthikeyan Mythreye
Journal: Cancer Research (2024)

Abstract Anoikis resistance or evasion of cell death triggered by cell detachment is a hallmark of cancer that is concurrent with cell survival and metastasis. Phenotypes of intrinsically anoikis resistant cancer cells have been extensively investigated but the mechanism of how exposure to suspension stress may lead to the acquisition of an anoikis resistance phenotype has not been previously described. Here we show that cycles of suspension stress followed by attached growth, mimicking an in vivo scenario, lead to adaptation to anoikis and acquisition of resistance to cell death, concomitant with increased chemoresistance and metastasis in vivo. Based on mutational and clonal population behavior analysis and modeling using a modified Luria-Delbrück’s fluctuation analysis we find that such acquired anoikis resistance is not genetic. Transcriptional reprogramming is, however,essential for the acquisition of adaptive anoikis resistance in vitro and in vivo, since these processes are exquisitely sensitive to selective inhibition of the CDK8/19 Mediator kinase, a broad-spectrum regulator of transcriptional reprogramming. Longitudinal analysis of the acquisition of anoikis resistance indicates strong repression programs along with a hybrid epithelial/mesenchymal phenotype and an enhanced need for oxidative phosphorylation, resulting in the emergence of anoikis-adapted cells that also efficiently evade T cell-mediated immune surveillance. Our data demonstrate that recovery from the brink of anoikis is a direct contributor to metastasis in ovarian cancer and can be therapeutically prevented using inhibitors of CDK8/19 Mediator kinase Citation Format: Mehri Monavarian, Resha Rajkarnikar, Emily Faith Page, Asha Kumari, Liz Macias Quintero, Lara Ianov, sarthak Sahoo, Mohit Kumar Jolly, Elizabeth Worthey, Nadine Hempel, Abhyudai Singh, Eugenia Broude, Karthikeyan Mythreye. Development of adaptive anoikis resistance promotes ovarian cancer metastasis that can be prevented by CDK8/19 Mediator kinase inhibition [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A019.