tbuckley/cabot-search huggingface dataset:
Survival rates in re-transplantation. Are 3rd and 4th grafts a good option?
Authors: M. Fiol Riera, B. Etcheverry Giadrosich, L. Riera Canals, A. Alabat Roca, E. Magret Descamps, E. Melilli, F. Vigués Julià
Journal: European Urology (2021)
Distinct nuclear compartment-associated genome architecture in the developing mammalian brain
Authors: Sajad Hamid Ahanger, Ryan N. Delgado, Eugene Gil, Mitchel A. Cole, Jingjing Zhao, Sung Jun Hong, Arnold R. Kriegstein, Tomasz J. Nowakowski, Alex A. Pollen, Daniel A. Lim
Journal: Nature Neuroscience (2021)
East or West—Manual Therapy As a Viable Nonpharmacologic Option for Chronic Neck Pain
Authors: Julie M. Fritz
Journal: JAMA Network Open (2021)

Jinho Lee, KMD, PhD; Jae-Heung Cho, KMD, PhD; Koh-Woon Kim, KMD, PhD; Jun-Hwan Lee, KMD, PhD; Me-riong Kim, KMD, PhD; Joowon Kim, KMD, MSc; Min-Young Kim, KMD, MSc; Hyun-Woo Cho, KMD, MSc; Yoon Jae Lee, KMD, PhD; Sook-Hyun Lee, PhD; Joon-Shik Shin, KMD, PhD; Lawrence L. Prokop, DO; Byung-Cheul Shin, KMD, PhD; In-Hyuk Ha, KMD, PhD
Simulation in urological training and Education (SIMULATE): A randomised controlled clinical and educational trial to determine the effect of simulation-based surgical training
Authors: A. Aydin, K. Ahmed, T. Abe, N. Raison, M. Van Hemelrijck, H.U. Ahmed, A. Al-Jabir, O. Brunckhorst, N. Shinohara, W. Zhu, G.. Zeng, J.P. Sfakianos, A. Tewari, A.S. Gözen, J. Rassweiler, A. Skolarikos, T. Kunit, T. Knoll, F. Moltzahn, G. Thalmann, A.G. Lantz Powers, B.H. Chew, K. Sarica, M.S. Khan, P. Dasgupta
Journal: European Urology (2021)
Abstract 1225: LNS8801: A novel, enantiomerically pure, small molecule agonist of the G protein-coupled estrogen receptor (GPER) for the treatment of cancer
Authors: Chris Natale, Tina Garyantes, Todd Ridky
Journal: Cancer Research (2021)

Abstract Women have a lower incidence of and improved clinical outcomes for most cancer types, but the mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despite the fact that many cancer types lack classic nuclear estrogen receptors. The GPER agonist G-1, a racemate, has been demonstrated to have anticancer activities by many independent laboratories, though there are some contradictory findings in the literature. We resolved the enantiomers that compose G-1 and determined that LNS8801 is the sole enantiomer responsible for G-1's anticancer effects. Using CRISPR to deplete GPER, we determined that the anticancer activity of LNS8801 is dependent upon GPER expression within the tumor cells. Previously, we determined that the anticancer mechanism of GPER activation is through a rapid proteasomal degradation of c-Myc. The PRISM screen was performed on LNS8801 at the Broad Institute, and it was determined that this compound has universal anticancer activity across multiple cancer types, consistent with our inhouse data. Sensitivity to LNS8801 was highly correlated with expression of c-Myc target genes, which is consistent with the known mechanism of action. Lineage analysis identified two specific cancer types that were uniformly more sensitive to LNS8801 than other cancer types: diffuse large B-cell lymphoma (DLBCL) and anaplastic large cell lymphoma (ALCL). DLBCL has historically been considered to be highly dependent on c-Myc, which is consistent with the known mechanism of action of LNS8801; however, the identification of ALCL was unexpected. Deeper analysis determined that high expression of anaplastic lymphoma kinase (ALK) fusion genes tightly correlated with sensitivity to LNS8801 in ALCL and other ALK+ cancer types. Using non-small cell lung cancer cell lines engineered to express EML4-ALK, we validated that ALK fusion expression results in increased sensitivity to LNS8801 relative to isogenic controls. This work has identified an enantiomerically pure GPER agonist that has potent activity across many cancer types, with c-Myc-dependent and ALK+ cancer types being enriched for heightened sensitivity. Citation Format: Chris Natale, Tina Garyantes, Todd Ridky. LNS8801: A novel, enantiomerically pure, small molecule agonist of the G protein-coupled estrogen receptor (GPER) for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1225.
Abstract 1600: Cancer driver screens identifyregulators of immune checkpoint blockade therapy response
Authors: Wenrong Zhou, Zhengang Peng, Dawei Huang, Min Long, Tianyu Song, Siyuan Ni, Yong Cang
Journal: Cancer Research (2021)

Abstract Cancer mutations play essential roles in tumor development by promote cell proliferation or immune evasion. However, some recent researches indicate that cancer cells with these mutation burden also expose their vulnerability to immune-based therapies such as checkpoint blockade. Here we performed comprehensive CRISPR knockout library screens in syngeneic mouse models on cancer driver mutation genes. We identified a set of genes including Kmt2d, Arid2, Rhob, Eloc, Ptpn11 and Xpo1, which have high frequency mutation in several human cancer types and their deficiency made tumor cells better respond to anti-PD-1 treatment. Furthermore, some of these deletions were validated to sensitize the tumor cells to cytotoxic T cells by in vitro co-culture with CD8+ T cells. The findings of Kmt2d was in accordance with a recent report for its role as a sensitizing modulator of immune checkpoint blockade from mouse model and patient prediction. These findings provide a new insight for understanding the interaction between the tumor heterogeneity and microenvironment. These results revealed CRISPR in vivo screen as a robust tool for both context and target discovery for tumor immunotherapy. Citation Format: Wenrong Zhou, Zhengang Peng, Dawei Huang, Min Long, Tianyu Song, Siyuan Ni, Yong Cang. Cancer driver screens identifyregulators of immune checkpoint blockade therapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1600.
Glucocorticoid induced adrenal insufficiency
Authors: Alessandro Prete, Irina Bancos
Journal: BMJ (2021)

ABSTRACT Synthetic glucocorticoids are widely used for their anti-inflammatory and immunosuppressive actions. A possible unwanted effect of glucocorticoid treatment is suppression of the hypothalamic-pituitary-adrenal axis, which can lead to adrenal insufficiency. Factors affecting the risk of glucocorticoid induced adrenal insufficiency (GI-AI) include the duration of glucocorticoid therapy, mode of administration, glucocorticoid dose and potency, concomitant drugs that interfere with glucocorticoid metabolism, and individual susceptibility. Patients with exogenous glucocorticoid use may develop features of Cushing’s syndrome and, subsequently, glucocorticoid withdrawal syndrome when the treatment is tapered down. Symptoms of glucocorticoid withdrawal can overlap with those of the underlying disorder, as well as of GI-AI. A careful approach to the glucocorticoid taper and appropriate patient counseling are needed to assure a successful taper. Glucocorticoid therapy should not be completely stopped until recovery of adrenal function is achieved. In this review, we discuss the factors affecting the risk of GI-AI, propose a regimen for the glucocorticoid taper, and make suggestions for assessment of adrenal function recovery. We also describe current gaps in the management of patients with GI-AI and make suggestions for an approach to the glucocorticoid withdrawal syndrome, chronic management of glucocorticoid therapy, and education on GI-AI for patients and providers.
PP16. ANGIOTENSIN SIGNALLING IN GBM: AT2R AS A NOVEL THERAPEUTIC TARGET
Authors: Mr Alexander Renziehausen, Dr Jennifer Eschbacher, Dr Andreas Tzakos, Dr Kevin O’Neill, Dr Tim Crook, Dr Nelofer Syed
Journal: Neuro-Oncology (2017)

INTRODUCTION: Locally expressed components (angiotensin II type 1 and type 2 receptors, AT1R and AT2R respectively) of the renin-angiotensin system have been implicated in non-cardiovascular functions including cancer progression. Drugs targeting angiotensin signalling to manage blood pressure therefore have the potential to be repurposed to treat cancer. Moreover, a recent retrospective study highlighted improvements in clinical outcomes of GBM patients treated with Ang-II inhibitors in combination with RT and TMZ. While the involvement of AT1R in cancer has been well studied, the role of AT2R is largely unknown. The aim of this study is to investigate the influence of angiotensin signalling on the growth, migration and induction of angiogenesis in GBM and determine its therapeutic potential. METHODS: GBM cell lines, both primary and established were profiled for expression of AT1R and AT2R by qPCR and pyrosequencing. The antihypertensive drug Losartan and the AT2R antagonist PD123319 were used alone or in combination with the ligand angiotensin II in various assays. Colorimetric proliferation assays were used to assess the impact on growth and wound healing assays to assess migration, a determinant of GBM invasiveness. In addition, the induction of angiogenesis was also examined using conditioned media from GBM cells and analysing the effect on proliferation, migration and tube formation of the brain microvascular endothelial cell line hCMEC/D3. RESULTS: Inhibition of AT1R signalling via Losartan had no effect on the growth of GBM whereas inhibition of AT2R with PD123319 significantly reduces GBM cell proliferation, migration and the induction of angiogenesis. CONCLUSION: Our data suggest that AT2R rather than AT1R is the main receptor promoting GBM cell growth, migration and the induction of angiogenesis. Therefore, inhibition of AT2R signalling could have potential in the treatment of GBM.
Youtube clips to select low-grade low-stage recurrent Non-Muscle-Invasive Bladder Cancers (NMIBC) for office fulguration, a multinational multi institutional study
Authors: T. Minvielle-Moncla, P. Emmanuel, S. Pericart, M. Babjuk, P. Black, A. Brisuda, M. Burger, M. Colombel, J.L. Dominguez Escrig, D. Eenikev, L. Ilaria, J. Jensen, E. Liatsikos, L. Lusuardi, H. Mostafid, N. Mottet, J. Rassler, I. Ouzaid, J. Teoh, U. Ukimura, E. Xylinas, M. Roumiguie, B. Malavaud
Journal: European Urology (2021)
Abstract 2073: Co-Targeting PARP and ATR in biliary tract cancer
Authors: Ah Rong Nam, Mei Hua Jin, Kyoung-Seok Oh, Hye Rim Seo, Jae-Min Kim, Ju-Hee Bang, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
Journal: Cancer Research (2021)

Abstract Background: Targeting DNA damage response (DDR) has potential anti-tumor effects in diverse cancer types. Homologous-recombination DDR gene mutations are found in 28.9% of biliary tract cancer (BTC). We aimed to evaluate the anti-tumor effects of olaparib (PARP inhibitor) with or without ceralasertib (ATR inhibitor) in BTC.Methods: Ten BTC cell lines (SNU245, SNU308, SNU478, SNU869, SNU1079, SNU1196, HuCCT-1, TFK-1, SNU2670, and SNU2773) were tested to evaluate the anti-tumor effects of olaparib alone and in combination with ceralasertib. MTT assay, colony formation assay, cell cycle analysis, western blot, comet assay and co-culture with human PBMC were used as experimental methods. Tumor xenograft model was established to test olaparib with or without ceralasertib in vivo.Results: Olaparib alone showed moderate anti-proliferative effects in all BTC cells and increased p-ATR and PD-L1 expression. Olaparib plus ceralasertib showed synergistic anti-proliferative effects and led to DNA damage breaks in vitro. Ceralasertib also downregulated PD-L1 level through p-STAT3 and YAP pathway with or without human PBMC conditions. In SNU478-xenograft models, Olaparib plus ceralasertib combination significantly suppressed tumor growth and downregulated PD-L1 and YAP, compared with monotherapy. It also effectively reduced CXCR2 and CXCR4 expression. Conclusion: Combination of olaparib plus ceralasertib showed potent anti-tumor effects in BTC cells. This study could provide the preclinical evidence of development of PARP and ATR dual inhibition in BTC patients. Clinical trial using olaparib and ceralasertib combination in advanced BTC is ongoing (ClinicalTrials.gov Identifier: NCT04298021). Citation Format: Ah Rong Nam, Mei Hua Jin, Kyoung-Seok Oh, Hye Rim Seo, Jae-Min Kim, Ju-Hee Bang, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh. Co-Targeting PARP and ATR in biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2073.
Abstract 1268: A novel treatment approach for melanoma by dually targeting MCT1 and MCT4 lactate transporters
Authors: Sambad Sharma, Gregory Goreczny, Satish Kumar Noonepalle, Erica Palmer, Maria Garcia-Hernandez, Daliya Banerjee, Jaime Escobedo, Alejandro Villagra, Vincent Sandanayaka
Journal: Cancer Research (2021)

Abstract Cancer cells are metabolically rewired to activate glycolysis, which results in the generation and excretion of lactate as a byproduct. Although lactate was previously thought to be a waste product of anaerobic respiration, increasing evidence has revealed that distinct cell populations within tumors use lactate as a source of energy through TCA cycle. This metabolic symbiosis between distinct cell populations, hypoxic lactate consumers, and oxidative glycolytic lactate exporters within the tumor is regulated by differential expression of lactate transporters, mainly MCT1 and MCT4. Therefore, dual targeting of MCT1 and MCT4 is a novel approach to treat cancer. We have developed a compound, NGY-B, which binds and inhibits both MCT1 and MCT4 transporters. This compound has shown to significantly increase intracellular lactate levels in melanoma models and thereby decreasing in vitro cell proliferation. When cultured in the media with exogenous lactate to mimic the tumor microenvironment, NGY-B greatly reduced lactate uptake by cancer cells. Mechanistically, NGY-B deactivated glycolytic pathway by reducing hexokinase 2 (HK2), phosphoglycerate dehydrogenase (PHGDH), and pyruvate dehydrogenase kinase 1 (PDK1) expression. Additionally, NGY-B treatment strongly decreased STAT3 and mTOR signaling pathways. Furthermore, the in vivo therapeutic efficacy of NGY-B was validated in xenograft and syngeneic mouse models of melanoma. While a significant reduction in tumor size was observed in A375 xenograft model treated with NGY-B, a robust tumor growth reduction was evident in SM1 immunocompetent syngeneic melanoma mouse model, suggesting the involvement of immune cells for higher response in this model. Supporting this premise, we also found that NGY-B treated cells showed a decrease in PD-L1, B7-H3, and B7-H4 expression. Overall, our results indicate that NGY-B inhibits melanoma by targeting metabolic symbiosis and activating antitumor immune response mechanisms. Citation Format: Sambad Sharma, Gregory Goreczny, Satish Kumar Noonepalle, Erica Palmer, Maria Garcia-Hernandez, Daliya Banerjee, Jaime Escobedo, Alejandro Villagra, Vincent Sandanayaka. A novel treatment approach for melanoma by dually targeting MCT1 and MCT4 lactate transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1268.
Unraveling heterogeneity in pediatric atopic dermatitis: Identification of serum biomarker based patient clusters
Authors: Daphne S. Bakker, Marlies de Graaf, Stefan Nierkens, Eveline M. Delemarre, Edward Knol, Femke van Wijk, Marjolein S. de Bruin-Weller, Julia Drylewicz, Judith L. Thijs
Journal: Journal of Allergy and Clinical Immunology (2021)
Abstract 2027: SETD2 loss in renal carcinoma cells induces the unfolded protein response
Authors: Alexander Metz, Robert Uzzo, Philip Abbosh
Journal: Cancer Research (2021)

Abstract Introduction: SETD2 encodes a histone H3-K36 methyltransferase which is frequently inactivated in clear cell renal carcinomas (ccRCCs) and papillary RCCs via 3p deletion/LOH and deleterious mutations. Histone H3-K36 trimethylation is facilitated by SETD2, which is necessary for proper pre-mRNA intron splicing. Improperly spliced mature-mRNA may lead to aberrant translation of retained introns (ATaRI), which represents potential therapeutic vulnerabilities. We explored this hypothesis using real world data and RCC models. Methods and Results: Gene set enrichment analysis comparing SETD2-mutant to WT tumors using samples from the TCGA KIRC data set revealed that the untranslated protein response (UPR) was strongly enriched, as well as several immunotherapy-relevant pathways. This suggested that peptides arising from ATaRI may be present, since they would not be expected to fold properly and thus need to be addressed by the UPR pathway to maintain homeostasis. To investigate this further, we generated Setd2-isogenic RENCA cells using CRISPR. Knockout was confirmed by sequencing and immunoblot. H3K36 trimethylation was decreased or eliminated in monoclonal knockout cell lines, confirming a functional effect. Markers of UPR activation, including cleaved Atf6 and Atf4, were found to be upregulated in Setd2-mutant RENCA cells compared to controls as measured by immunoblot. Cleaved ATF6 is known to translocate to the nucleus to take part in a UPR transcriptional program. Consistent with this, ATF6 was found to localize to the nucleus in Setd2-knockout cells using immunofluorescence. Interestingly, CHOP, another downstream effector of the UPR pathway which predominantly regulates cell death, did not become upregulated in Setd2-knockout cells, suggesting activation of a compensatory cell survival pathway. Conclusions: We identify activation of the UPR upon Setd2 loss and suggest that activation of part of the UPR pathway may represent a new therapeutic vulnerability for exploitation as a rationale for personalized medicine. We continue to evaluate the generation of peptides arising from ATaRI in Setd2-mutant contexts. Citation Format: Alexander Metz, Robert Uzzo, Philip Abbosh. SETD2 loss in renal carcinoma cells induces the unfolded protein response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2027.
Abstract 2565: Detection of ETV1 expression in human prostate tissue specimens using a novel and highly specific rabbit monoclonal antibody
Authors: Shyh-Han Tan, Denise Young, Sally Elsamanoudi, Jacob Kagan, Sudhir Srivastava, Albert Dobi, Gyorgy Petrovics, Isabell A. Sesterhenn, Gregory T. Chesnut
Journal: Cancer Research (2021)

Abstract Introduction: ETV1 is frequently involved in genomic fusions and translocation events that lead to its overexpression in multiple cancers. These events occur in approximately 5% of prostate cancers, which are mutually exclusive from tumors harboring TMPRSS2-ERG fusion or PTEN deletion. Studies suggest a correlation between strong ETV1 protein expression and poor outcome in prostate cancer. ETV1 has been reported to synergistically cooperate with KIT as a lineage survival factor in gastrointestinal stromal tumors. The expression of ETV1 in a subset of sarcomas that harbor CICrearrangements or CIC-DUX4 gene fusions presents a reliable molecular signature for the diagnosis of this cancer. Our understanding of the role that ETV1 plays in the activation of prostate cancer has been limited by the lack of ETV1 specific antibodies. Methods: A novel ETV1 monoclonal antibody (MAb) was raised by immunization of ETV1 peptides in rabbit followed by screening of hybridomas by ELISA and immunoblot assays. Further screening using exogenously expressed ETV1, ETV4, ETV5, ERG, SPDEF, and FLI1 proteins identified the clone with the most reactive MAb. Purified MAb was used to evaluate ETV1 expression on a tissue micro-array (TMA) constructed from radical prostatectomies of 50 African American (AA) and 50 Caucasian American (CA) patients by immunohistochemistry (IHC). Key residues required for Mab binding were mapped by ELISA using overlapping peptides and alanine scanning. Results: IHC evaluation using the ETV1 specific rabbit Mab on a prostate cancer TMA derived from 100 patients identified five ETV1 positive cases, of whom four were CA. The index tumors for these five ETV1 cases were ERG negative. One patient harbored both ERG positive and ERG negative tumor foci, and as expected, the ETV1 positive tumor focus was ERG negative, and vice versa. Conclusions: We developed a novel rabbit monoclonal ETV1 antibody that is suitable for IHC assay in human prostate tissue. An evaluation of prostate cancer specimens confirmed the reported frequency of ETV1 alteration. Further evaluation using tissue specimens from larger cohorts to establish the sensitivity and specificity of this antibody and validate the utility of ETV1 detection in improving the diagnosis and stratification of prostate and other cancers are in progress. Citation Format: Shyh-Han Tan, Denise Young, Sally Elsamanoudi, Jacob Kagan, Sudhir Srivastava, Albert Dobi, Gyorgy Petrovics, Isabell A. Sesterhenn, Gregory T. Chesnut. Detection of ETV1 expression in human prostate tissue specimens using a novel and highly specific rabbit monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2565.
miR-424 loaded circulating small extracellular vesicles: Novel biomarkers associated with aggressive prostate cancer
Authors: D. Albino, G. Sandrini, R. Valzelli, R.P. Mestre, A. Cacciatore, D. Shinde, V. Uboldi, D.O. Temilola, M. Wium, L. Barile, R. Geiger, M. Pecoraro, R.M. Henrique, C. Jeronimo, L.F. Zerbini, C.V. Catapano, G.M. Carbone
Journal: European Urology (2021)
Beyond Visual Acuity—A Comprehensive Assessment of Vision and Cognition in Older Adults With Visual Impairment
Authors: Preeti Gupta, Tai Anh Vu, Ecosse L. Lamoureux
Journal: JAMA Network Open (2021)

Varshini Varadaraj, MD, MPH; Beatriz Munoz, MS; Jennifer A. Deal, PhD; Yang An, MS; Marilyn S. Albert, PhD; Susan M. Resnick, PhD; Luigi Ferrucci, MD, PhD; Bonnielin K. Swenor, PhD, MPH