tbuckley/cabot-search huggingface dataset:
Abstract 7: Modeling cell-cell crosstalk in TNBC brain metastasis
Authors: Hong Zhao, Xin Wang, Nikola Liu, Jianting Sheng, Stephen Wong
Journal: Cancer Research (2021)

Abstract Brain metastasis (BrM) is a difficult clinical problem in triple-negative breast cancer (TNBC) patients: it occurs in 25% to 40% of metastatic patients while two-year survival rate stubbornly remains a single digit. TNBC usually spreads to the brain rapidly at earlier stages or before the diagnosis of primary cancer. The shorter development time of BrM in TNBC and shorter survival time after BrM diagnosis may indicate a unique innate ability of TNBC tumor cells in adapting to the brain. Indeed, emerging data including ours indicates that TNBC tumor cells have intrinsic brain-like traits resulting in brain-tropism metastasis. Our preliminary studies identified enriched and diverse expressions of receptors and transporters of various neuro-active substances in brain metastatic TNBC cells, including neurotransmitters, gliotransmitters, neurotrophic factors and neural cytokines. By immunopanning astrocytes and microglia/macrophages from mouse brains bearing TNBC brain metastatic tumors at day 3 post tumor cell injection through left cardiac ventricle, and use the CCCExplorer software in modeling the interactions among tumor cells, astrocytes, and microglia/macrophage with cell-type specific RNAseq data, we identified several novel crosstalk signaling, including tumor autocrine TPH1-HTR2, astrocyte→tumor PCDH7-EGFR, IL6-IL6R, CCL5-CCR5 and VGF-C3AR1, and microglia/macrophage→tumor ARTN-GFAR3. Functional experiments demonstrated that cell type-specific depletion of the secreted neuro-active substances deactivated the activities of corresponding receptor and downstream signaling in co-cultured BrM tumor cells. Given that more complex paracrine/autocrine signaling network may dynamically evolve during BrM development, we are characterizing the spatiotemporal cell-cell crosstalk in the BrM metastatic niche that will have important implications for novel therapeutics development. Citation Format: Hong Zhao, Xin Wang, Nikola Liu, Jianting Sheng, Stephen Wong. Modeling cell-cell crosstalk in TNBC brain metastasis [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 7.
マクロファージ媒介腫瘍標的化診断と治療のための重合と配位相乗的に構築した光熱剤【JST・京大機械翻訳】
Authors: Zhang Xue, Si Zhenjun, Wang Yanbing, Li Yanhui, Xu Caina, Tian Huayu
Journal: Biomaterials (2021)
Medical algorithm: <i>Aspergillus fumigatus</i> components in the diagnosis of allergic bronchopulmonary aspergillosis
Authors: Raphael Lukaszewicz, Guillaume Mahay, Olivier Boyer, Jérémie Martinet
Journal: Allergy (2021)

Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease involving hypersensitivity to Aspergillus fumigatus (Af) antigens caused by repeated inhalation of spores in susceptible hosts. Its identification is sometimes difficult, and delayed diagnosis, or lack of treatment, leads to worsening lung function and major complications like pulmonary fibrosis or bronchiectasis.
マウス脳におけるニューロンとCREB活性間の結合のin vivoイメージング【JST・京大機械翻訳】
Authors: Laviv Tal, Scholl Benjamin, Parra-Bueno Paula, Foote Beth, Zhang Chuqiu, Yan Long, Hayano Yuki, Chu Jun, Yasuda Ryohei
Journal: Neuron (2020)
Abstract 1731: EXS21546, a non-CNS penetrant A2AR-selective antagonist for anti-cancer immunotherapy
Authors: Andrew Payne, Pierre Fons, Isabella Alt, Joost van Ham, Christina Taubert, Andy Bell, Stephanie Versluys, Florie Bertrand, Virgile Visentin, Emilie Mirey, Emilie Pelissier, Michael Paillasse, Sabrina Pagliarusco, Gregory Vladimer, Mark Whittaker
Journal: Cancer Research (2021)

Abstract Elevated levels of adenosine found in the tumor microenvironment have been highlighted as a potential mechanism contributing to the restricted efficacy of immune checkpoint inhibitors. While the advent of these inhibitors has brought significant benefit to patients with cancer, there is still significant unmet need even in disease indications for which these agents are approved. Adenosine has an immune-suppressive effect in tumors, and pre-clinical and early clinical evidence indicates that antagonists of the GPCR family of adenosine receptors are able to relieve that suppression and restore anti-tumor immune cell activity. EXS21546 is a non-furan, selective antagonist of the A2A receptor with low brain penetration. Using EXS21546, we show that activity at the A2A receptor is sufficient for complete restoration of T-cell function in the presence of high concentrations of adenosine analogue. Translational studies with EXS21546 have been undertaken using patient samples to better understand its activity in signaling and disease-relevant endpoints. We will present data characterizing the activity of EXS21546 ex vivo in patient-derived whole blood samples. Interrogation of primary cancer cells from pancreatic and lung cancer patients treated with EXS21546 ex vivo by phenotypic image-based screening, demonstrated that EXS21546 reduces the relative fraction of viable cancer cells while inducing an expansion of the viable CD8+ T cell fraction in the presence of high concentrations of an adenosine analogue. Together, these data indicate the potential for EXS21546 may have a role in cancer therapy. EXS21546 has completed pre-IND studies in preparation for initiation of first-in-human clinical studies. Citation Format: Andrew Payne, Pierre Fons, Isabella Alt, Joost van Ham, Christina Taubert, Andy Bell, Stephanie Versluys, Florie Bertrand, Virgile Visentin, Emilie Mirey, Emilie Pelissier, Michael Paillasse, Sabrina Pagliarusco, Gregory Vladimer, Mark Whittaker. EXS21546, a non-CNS penetrant A2AR-selective antagonist for anti-cancer immunotherapy [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 1731.
Secretory otitis media: the Cantekin affair
Authors: I. Tessman
Journal: JAMA (1992)

To the Editor.  —It was reassuring to see in Dr Rennie's long review of The Cantekin Affair 1 the statement that editors make great efforts to judge manuscripts on the quality of research rather than the status of the researcher. It is surely a fundamental principle that authority is irrelevant; the science must always speak for itself.  But are you consistent? Why do medical journals publish the academic degrees of its authors, a policy that practically no other type of scientific journal would tolerate? Rennie presents us with a telling quote from Cantekin's disapproving bosses: Indeed, Dr Cantekin is not a physician. I wonder if it is that type of pathetic snobbery that motivates the listing of academic degrees.
Abstract 2664: Mutation characteristics of histone modification related genes in cholangiocarcinoma
Authors: Yunfeng Li, Huanwei Chen, Zanmei Xu, Libo Yao, Junying Li, Chengzhi Cai, Dong You
Journal: Cancer Research (2021)

Abstract Background and objective: Histone modification, as an important part of epigenetics researches, can cause tumorigenesis and development by changing chromatin status and regulating gene expression. Histone deacetylase (HDAC) inhibitors have made great progress as new drugs, and its mechanism is related to the mutation of HDAC family genes. However, mutations of other related genes lacked reports. Here, we analyzed the mutation characteristics of 13 histone related genes in patients with cholangiocarcinom. Methods: 380 cholangiocarcinom patients were enrolled. Next generation sequencing targeting 450 cancer genes was performed in OrigiMed. Disease-free survival (DFS) curve after operation was drawn with Kaplan-Meier and compared with Log-rank. Fisher's exact test was adapted to perform other statistical analysis. Results: 153 mutations were occurred in 13 histone modification related genes (HDAC1, HDAC7, HDAC9, KMT2A, KMT2B, KMT2C, KMT2D, KMT2E, KMT5A, KMT5B, EZH2, EP300 and CREBBP), and 66.7% (102/153) was substitution/indel, 31.4% (48/153) truncation and 2.0% (3/153) rearrangement. According to the mutation, patients were divided into histone gene wild type (WT) group and histone gene mutation type (MUT) group, patients with at least one mutation in 13 genes. Co-mutation analysis of 450 genes revealed that KTM2D and KTM6A tended to co-mutate with other genes, including FAT4, ATM, BRAF and ERBB3. KTM2C and KRAS mutation were mutually exclusive (P&amp;lt;0.01). 98 patients (25.8%) had at least one histone modification related mutation; Among them, KTM2C was the highest (10.5%, 40/380), followed by KTM2D (7.9%, 30/380), CREBBP (3.9%, 15/380), EP300 (3.4%, 13/380) , KTM2A (3.4%, 13/380) and HDAC9 (2.6%, 10/380). Furthermore, compared with WT group, patients in MUT group had a short DFS time after operation (mDFS: 7 vs 11.15 months, P=0.0139). Besides, the TMB had no significant difference between two groups, as well as the PD-L1 expression and microsatellite status. Conclusion: We firstly exhibited 13 histone related mutations in Chinese patients with cholangiocarcinoma. Mutations of histone modification related genes suggested poor outcomes of cholangiocarcinom. Citation Format: Yunfeng Li, Huanwei Chen, Zanmei Xu, Libo Yao, Junying Li, Chengzhi Cai, Dong You. Mutation characteristics of histone modification related genes in cholangiocarcinoma [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 2664.
Hepatic Nervous System in Development, Regeneration, and Disease
Authors: Bess M. Miller, Isaac M. Oderberg, Wolfram Goessling
Journal: Hepatology (2021)

The liver is innervated by autonomic and sensory fibers of the sympathetic and parasympathetic nervous systems that regulate liver function, regeneration, and disease. Although the importance of the hepatic nervous system in maintaining and restoring liver homeostasis is increasingly appreciated, much remains unknown about the specific mechanisms by which hepatic nerves both influence and are influenced by liver diseases. While recent work has begun to illuminate the developmental mechanisms underlying recruitment of nerves to the liver, evolutionary differences contributing to species-specific patterns of hepatic innervation remain elusive. In this review, we summarize current knowledge on the development of the hepatic nervous system and its role in liver regeneration and disease. We also highlight areas in which further investigation would greatly enhance our understanding of the evolution and function of liver innervation.
Over-the-counter alkali agents to raise urine ph and citrate excretion: A randomized crossover study in healthy adults
Authors: G.M. Kamphuis, N.E. Canvasser, M. Rivera, S.K. Bechis, J. Ingimarsson, J. Knoedler, K. Stern, C. Stoughton, D. Wollin, M. Borofsky, N. Bhojani, M. El Tayeb, D. Leavitt, R.S. Hsi, K.B. Scotland
Journal: European Urology (2021)
Abstract 1085: PD-L1-mediated resistance to chemotherapy is overcome by an irreversible JNK inhibitor in colorectal cancer cells
Authors: Frank A. Sinicrope, Lei Sun, Arpad Patai, Tara L. Hogenson, Martin E. Fernandez-Zapico, Bo Qin
Journal: Cancer Research (2021)

Abstract Background Colorectal cancers (CRCs) are intrinsically drug resistant tumors with frequent low or absent tumor cell PD-L1 expression. Previously, we reported that PD-L1 depletion in CRC cells can confer chemoresistance. Given that JNK signaling has been implicated in cell survival and drug resistance in CRC cells, we examined the role of JNK and its regulation in chemoresistance in CRC cells with loss of PD-L1. Materials &amp; MethodsHuman CRC cell lines (RKO, DLD1 and HCT15) were utilized and parental and PD-L1 knockout/knockdown cells were generated. Cells were treated with a JNK1-3 inhibitor (JNK-IN-8) alone or combined with a MEK1/2 inhibitor (cobimetinib), CPT-11 or oxaliplatin. Protein/protein interaction was analyzed by immunoprecipitation (IP); protein/RNA interaction was analyzed by RNA IP assay. RNA level and half life were measured by QRT-PCR. Apoptosis was measured by cleaved caspase-3 and quantified by Annexin V labeling using FACS. Colony formation assay was performed. ResultsPD-L1 depletion in CRC cells was shown to enhance JNK activity that was due to reduced mRNA stability of the upstream CYLD deubiquitinase. Since PD-L1 competes with the ribonuclease EXOSC10 for binding to CYLD mRNA, loss of PD-L1 increases the interaction of EXOSC10 and CYLD mRNA resulting in its ribonuclease-mediated degradation and activation of JNK signaling. JNK activation increased BIM phosphorylation at Thr116 that promotes its sequestration by MCL-1 and BCL-2. Notably, a selective and irreversible JNK1-3 inhibitor (JNK-IN-8) reduces BIMThr116 phosphorylation and can release BIM from its sequestration by MCL-1 and BCL-2 to promote apoptosis. Furthermore, use of JNK-IN-8, an MCL-1 antagonist (AZD5991), or their combination in tumor cells lacking PD-L1 is shown to promote apoptosis and reduce long-term clonogenic survival induced by multiple anti-cancer drugs. As confirmation, knockdown of PD-L1 can confer drug resistance in a human colon cancer-derived organoid model that can be reversed by JNK-IN-8. Conclusion Tumor cells with low or absent PD-L1 expression show increased JNK activity that promotes BIM sequestration by MCL-1/BCL-2 to confer multiple drug resistance that can be reversed by a JNK inhibitor. Citation Format: Frank A. Sinicrope, Lei Sun, Arpad Patai, Tara L. Hogenson, Martin E. Fernandez-Zapico, Bo Qin. PD-L1-mediated resistance to chemotherapy is overcome by an irreversible JNK inhibitor in colorectal cancer cells [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 1085.
Endoscopic esophagogastric anastomosis using a lumen-apposing metal stent to manage an anastomotic leakage after esophagectomy
Authors: Thomas Lambin, Marion Schaefer, Pierre Lafeuille, Florian Rostain, Jérôme Rivory, Mathieu Pioche, Thierry Ponchon
Journal: Endoscopy (2021)

Ivor-Lewis esophagectomy (ILE) for esophageal cancer is associated with a significant risk of anastomotic leakage [1]. Recently, a lumen-apposing metal stent (LAMS) has been used to create an anastomosis between the lumen of two digestive structures [2]. An animal study showed technical feasibility of endoscopic esophagogastric anastomosis with LAMS following ILE [3]. To our knowledge, no case of anastomotic leakage managed endoscopically with LAMS has been described to date.
Abstract 268: DNA-launched HPV E7 nanoparticle vaccine induces potent anti-tumor cytolytic T-cell responses
Authors: Kevin Liaw, Ziyang Xu, Nicholas Tursi, Neethu Chokkalingam, Daniel Kulp, David Weiner
Journal: Cancer Research (2021)

Abstract Nanotechnology-based approaches have provided promising tools for development of novel cancer immunotherapeutic immunogens through the decoration of multiple antigens on nanoparticle scaffolds. However, challenges with inducing robust cytolytic T cell responses critical to anti-tumor immunity, as well as purification and scalability, have hampered their clinical translation. To address these challenges, here we present the design and characterization of a DNA-launched nanoparticle vaccine displaying the HPV E7 epitope for inducing anti-tumor immune responses. We designed a nanovaccine construct by scaffolding the HPV E7 epitope with bacterial enzyme lumazine synthase. We demonstrate that through electroporation-facilitated DNA vaccination encoding the antigen-scaffold construct, this nanovaccine self-assembles in vivo into nanoparticles displaying 60 copies of the antigen on its surface. Compared to vaccination with CpG-adjuvanted HPV E7 peptide, the DNA-launched nanovaccine induced significantly greater antigen-specific CD8+ T cell responses upon stimulation with the HPV E7 peptide as well as with the epitope natively expressed on the target tumor cells. In a flank model of TC-1 lung cancer, the DNA-launched nanovaccine achieved complete tumor protection in 70% of mice when administered prophylactically. With therapeutic treatment, the nanovaccine achieved complete tumor regression in 60% of mice. In addition, anti-tumor immunity was retained upon rechallenge over 100 days after initial tumor challenge, supporting the induction of immune memory. These promising results, along with its facile characterization and scalability, support that DNA-launched nanovaccines that self-assemble in vivo can induce significant anti-tumor cellular immunity and are ideally positioned for study in clinical translation. Citation Format: Kevin Liaw, Ziyang Xu, Nicholas Tursi, Neethu Chokkalingam, Daniel Kulp, David Weiner. DNA-launched HPV E7 nanoparticle vaccine induces potent anti-tumor cytolytic T-cell responses [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 268.
Sacral neuromodulation with the InterStim™ system for lower urinary tract dysfunctions (SOUNDS): 3-Year results of clinical effectiveness, quality of life, patient-reported outcomes and safety in a French multicenter observational study
Authors: E. Chartier-Kastler, A. Ruffion, L. Le Normand, J-N. Cornu, A. Abouihia, A. Melotti, D.U.J. Keller
Journal: European Urology (2021)
Drug importation: limitations of current proposals and opportunities for improvement
Authors: Caleb J. Scheckel, S. Vincent Rajkumar
Journal: Blood Cancer Journal (2021)

Drug importation is a policy proposal to help alleviate rising pharmaceutical prices. Restrictions on drug importation stem from the Federal Food, Drug, and Cosmetic Act but authorization of importation can be made by the Health and Human Services (HHS) Secretary. During the Trump administration a number of states passed laws to develop a drug importation programs, however, none have been authorized by HHS. Limitations of these importation programs include sole reliance on Canada, exclusion of high-cost drugs like biologics, and persistent legal hazard of the Personal Importation Program. Potential revisions to current law include expansion of countries approved for importation, inclusion of biologics, and codifying protection for personal importation. Drug importation policies are not a panacea to address rising pharmaceutical prices but may blunt prices while more permanent solutions are pursued.
Abstract 1986: p53/FBXL20 axis negatively regulates the protein stability of PR55α, a PP2A regulatory subunit
Authors: Ying Yan, Lepakshe Madduri, Nichole Brandquist, Chitra Palanivel, Sumin Zhou, Charles Enke, Michel Ouellette
Journal: Cancer Research (2021)

Abstract PP2A holoenzymes are the majority of Ser/Thr phosphatases in human cells and each PP2A complex contains one scaffold subunit, one catalytic subunit, and one regulatory subunit. PP2A regulatory subunits, existing in four sub-families encoded by 15 genes, determine the substrate specificities and intracellular localizations of PP2A. We previously reported an essential role for PR55α, a PP2A regulatory subunit, in the support of malignant potential of pancreatic cancer cells, which includes promoting YAP-activation that supports anchorage-independent growth and metastasis. Furthermore, our data showed that PR55α level is elevated in pancreatic cancer relative to normal tissues and high PR55α levels correlate with poor patient survival. The studies in this report reveal a novel mechanism by which the p53 tumor suppressor negatively regulates PR55α protein stability. The results show that p53 inactivation by siRNA-knockdown, gene-deletion, HPV-E6 promoted degradation, or p53R175H mutant expression all results in the increase of PR55α expression. Subsequent studies demonstrate that this p53 function is mediated through its target gene FBXL20, a substrate recognition component of the SCF (Skp_Cullin_F-box) ubiquitin ligase complex that facilitates proteasomal degradation. As a result, the expression of mutant p53R175H in human pancreatic ductal cells mimics the PR55α effect, increasing c-Myc protein stability, and promoting anchorage-independent proliferation. Additionally, FBXL20 mRNA levels are significantly reduced in pancreatic cancers relative to normal control, and low FBXL20 levels correlate with poor patient survival, both of which inversely resemble the pathological effects of PR55α in pancreatic cancer. Collectively, these results define a novel p53 function in the suppression of PR55α expression. Citation Format: Ying Yan, Lepakshe Madduri, Nichole Brandquist, Chitra Palanivel, Sumin Zhou, Charles Enke, Michel Ouellette. p53/FBXL20 axis negatively regulates the protein stability of PR55α, a PP2A regulatory subunit [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 1986.
High Intensity Focused Ultrasound (HIFU) vs. Radical Prostatectomy (RP) in the curative treatment of ISUP 1-2 localized prostate cancer: Safety results of the HIFI study
Authors: P. Rischmann, D. Kassab, T. Chevallier, X. Rebillard, A. Villers, N. Houede, P. Coloby
Journal: European Urology (2021)
Abstract 627: Molecular validation of the 8th edition AJCC cancer staging system for resectable pancreatic cancer: Proposal of integrative translational staging system
Authors: Sung Hwan Lee, Sunyoung Lee, Ju-Seog Lee
Journal: Cancer Research (2021)

Abstract Introduction: Even though the 8th edition AJCC cancer staging system for pancreatic cancer has validated major clinicopathologic factors in multiple clinical cohorts, there is still an unmet need for integrative consideration using multi-omics data to stratify the patients with pancreatic cancer elaborately. Methods: We performed a comprehensive analysis and profiling using genomic, transcriptomic, and proteomic data from TCGA-PAAD and other translational cohorts (4 cohorts, n=340). Molecular features and major subtypes were analyzed mutually with clinical and pathologic factors, especially the 8th AJCC staging system. Results: Aggressive molecular subtypes, basal-like and squamous subtype, were significantly associated with a higher nodal stage, but tumor size didn't show a clear association with molecular features. The activated stroma of the pancreatic cancer microenvironment was significantly correlated with poor differentiation and large tumor size. The mutational pattern of KRAS and several transcriptomic pathways, such as epithelial-mesenchymal transition and DNA repair, were differently presented in each clinical stage from the 8th AJCC TNM staging system. The optimal algorithm was identified to show significantly higher performance for the prediction for cancer relapse and cancer-specific survival in discovery and validation cohorts. The in-silico prediction for molecular target agents and immunotherapy was performed for final clusters from the optimal stratification system revealed from the integrative analysis. Conclusions: Our comprehensive multi-omics analysis reveals clear needs for the combination of clinical staging and molecular profiling and provides crucial evidence for precision strategy in patients with resectable pancreatic cancer. Citation Format: Sung Hwan Lee, Sunyoung Lee, Ju-Seog Lee. Molecular validation of the 8th edition AJCC cancer staging system for resectable pancreatic cancer: Proposal of integrative translational staging system [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 627.
An efficiency decision-tree for treating urolithiasis up to 3 cm based on a cost-effective analysis
Authors: A. Bernal Gomez, F. Gómez Palomo, G. Romeu Magraner, J. Pérez Ardavín, P. Bahílo Mateu, M. Trassierra Villa, D. López Acón, D.G. Ordaz Jurado, I. Sáez Moreno, O. Dagà Matrínez, J. Bolón Marset, J. Ortiz Salvador, J.O. Colet Guitert, A. Budía Alba
Journal: European Urology (2021)