tbuckley/cabot-search huggingface dataset:
Glomerular Volume and Glomerulosclerosis at Different Depths within the Human Kidney
Authors: Aleksandar Denic, Luisa Ricaurte, Camden L. Lopez, Ramya Narasimhan, Lilach O. Lerman, John C. Lieske, R. Houston Thompson, Walter K. Kremers, Andrew D. Rule
Journal: Journal of the American Society of Nephrology (2019)

Age, CKD risk factors, and kidney function are associated with larger glomerular volume and a higher percentage of globally sclerotic glomeruli. Knowledge of how these associations may differ by cortical depth is limited.To investigate glomerular volume and glomerulosclerosis across different depths of cortex, we studied wedge sections of the renal parenchyma from 812 patients who underwent a radical nephrectomy (for a tumor), separately characterizing glomeruli in the superficial (subcapsular), middle, and deep (juxtamedullary) regions. We compared the association of mean nonsclerotic glomerular volume and of glomerulosclerosis (measured as the percentage of globally sclerotic glomeruli) with age, obesity, diabetes, smoking, kidney function, and structural pathology in the superficial, middle, and deep regions.The superficial, middle, and deep regions showed significant differences in glomerular volume (0.0025, 0.0031, and 0.0028 µm3, respectively) and in glomerulosclerosis (18%, 7%, and 11%, respectively). There was a marked increase in glomerulosclerosis with age in the superficial region, but larger glomerular volume was not associated with age at any cortical depth. Glomerulosclerosis associated more strongly with arteriosclerosis and ischemic-appearing glomeruli in the superficial region. Hypertension, lower eGFR, and interstitial fibrosis associated with glomerulosclerosis and glomerular volume to a similar extent at any depth. Diabetes and proteinuria more strongly associated with glomerulosclerosis in the deep and middle regions, respectively, but neither associated with glomerular volume differently by depth. Obesity associated more strongly with glomerular volume in the superficial cortex.Most clinical characteristic show similar associations with glomerulosclerosis and glomerulomegaly at different cortical depths. Exceptions include age-related glomerulosclerosis, which appears to be an ischemic process and is more predominant in the superficial region.
Abstract 4631: Modeling the vascular sarcoma spectrum with genetically engineered mice
Authors: Jason A. Hanna, Casey G. Langdon, Matthew R. Garcia, David Finkelstein, Jerold E. Rehg, Mark E. Hatley
Journal: Cancer Research (2019)

Abstract Angiosarcomas are highly aggressive vascular sarcomas with an extremely poor prognosis. Angiosarcomas can develop spontaneously or are associated with prior radiation, chronic lymphedema, or exposure to toxic chemicals such as vinyl chloride. Sequencing efforts have identified a number of genetic alterations in angiosarcoma, however the genetic drivers and actionable targets remain unclear. Despite the poor outcome for patients, there are limited resources for studying angiosarcoma, highlighting the need for genetic, in vivo models to better elucidate the underlying biology of the disease. In studying the role of DICER1 and microRNAs in mouse models of tumorigenesis, we found that Dicer1 deletion with aP2-Cre leads to aggressive and metastatic angiosarcoma development with 100% penetrance. ERK and S6 hyperphosphorylation in the aP2-Cre;Dicer1cKO (AD) tumors suggest Dicer1 loss results in activation of the RAS-MEK-ERK and mTOR pathways. To determine if direct activation of the these pathways could similarly transform aP2-Cre expressing cells we first interrogated the combination of oncogenic KrasG12D with Cdkn2a inactivation. We found that aP2-Cre;LSL-KrasG12D;Cdkn2acKO (AKC) mice rapidly develop angiosarcomas providing an accelerated model for assessing cooperating alleles and therapies. To activate the mTOR pathway we tested conditional Tsc1 deletion with aP2-Cre and found that all aP2-Cre;Tsc1cKO (AT) animals develop vascular tumors in the paws. In contrast to the AD and AKC tumors, AT tumors express markers of lymphatic endothelial cells such as PROX1. In addition, the tumors display a distinct nodular spindle cell-like morphology that is consistent with a low grade angiosarcoma resembling human kaposiform hemangioendotheliomas, a vascular tumor occurring predominantly in the extremities of infants. The distinct onset, growth kinetics, anatomic locations, and histologic presentation of the tumors from AD, AT, and AKC mice provide a mechanism to interrogate the drivers of angiosarcoma in less aggressive AT paw tumors and more aggressive AD and AKC tumors. Furthermore, the aP2-Cre driven mouse models provide a platform to study angiosarcoma initiation, progression, and metastasis for the identification of novel therapeutics to improve outcomes for this understudied and devastating disease. Citation Format: Jason A. Hanna, Casey G. Langdon, Matthew R. Garcia, David Finkelstein, Jerold E. Rehg, Mark E. Hatley. Modeling the vascular sarcoma spectrum with genetically engineered mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4631.
Abstract 4679: NRF2/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma
Authors: Hoi Wing Leung, Eunice Yuen Ting Lau, Kin Wah Lee
Journal: Cancer Research (2019)

Abstract Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. The long-term prognosis of HCC remains unsatisfactory due to high recurrence rates and chemoresistance. Solid evidence shows that tumor-initiating cells (T-ICs) are the root of tumor relapse and drug resistance, which led to poor prognosis of patients with hepatocellular carcinoma (HCC). Therefore, identification of crucial transcriptional regulator in liver T-IC may improve the prognosis of these patients. Through in vitro liver T-IC enrichment approach, we identified Nuclear Factor (Erythroid-Derived 2)-Like 2 (NRF2) as transcriptions regulator be significantly upregulated in enriched liver T-IC populations. NRF2 regulated liver T-IC properties including self-renewal, tumorigenicity, and liver T-IC marker expression and significantly affected patients’ clinical outcome. Furthermore, NRF2 repression led to sensitization to doxorubicin and 5-FU treatment. Furthermore, we found that ROS-induced NRF2 activation regulates sorafenib resistance of HCC cells. Mechanistically, NRF2 was found to physically bind to promoter SHH, which triggers activation of sonic hedgehog pathway. NRF2 was significantly correlated with SHH expression, which was associated with poor patient’s survival. The effect of NRF2 knockdown was eliminated upon administration of recombinant SHH, demonstrating that NRF2 mediated the TIC function via upregulation of SHH expression. Our study suggested a novel regulatory mechanism for the canonical sonic hedgehog pathway that may function through NRF2/SHH/GLI signaling axis, thus mediating T-IC phenotypes. Targeting NRF2 mediated signaling cascade alone or in combination with other treatment modalities may be a new a potential therapeutic approach for treatment of HCC. Citation Format: Hoi Wing Leung, Eunice Yuen Ting Lau, Kin Wah Lee. NRF2/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4679.
Abstract 3588: Identification of a potent, orally bioavailable and selective MCT4 Inhibitor for the treatment of solid Warburg tumors
Authors: Nina Hambruch, Barbara Herkert, Christian Gege, Aurelie Mallinger, Johannes Fabian, Olaf Kinzel, Yansong Wang, Gero Fink, Michael Albers, Anette Funk, Annika Bittman-Waetzig, Tilly Fleckenstein, Floriane Braun, Claus Kremoser
Journal: Cancer Research (2019)

Abstract A key metabolic alteration in tumor cells is an elevated glycolysis rate, resulting in the production of increased amounts of protons and lactate leading to lactic acidosis within the tumor microenvironment. The tumor-promoting effects of lactic acidosis are versatile, ranging from stimulation of proliferation, angiogenesis and metastasis to the reshaping of the tumor immune environment to a tumor-permissive phenotype. In tumors lactate is transported across the plasma membrane by the monocarboxylate transporters 1 and 4 (MCT 1/4) in symport with a proton. While MCT1 is expressed almost ubiquitously at low levels, MCT4 expression is regulated by hypoxia-inducible factor 1α (Hif1α), the central player in the cellular response to hypoxia. Thus, MCT4 is present in hypoxic, highly glycolytic cells. Given their central role in prevention of intracellular acidification and lactate transport, MCTs appear to be indispensable for glycolytic tumor growth. Since MCT4 has the strongest implication on the development and aggressiveness of diverse cancer types it has emerged as a new target for the treatment of solid tumors. We have identified MCT4 specific inhibitors structurally based on an internal compound library using cell-based lactate export assays. A subsequent extensive medicinal chemistry program was able to significantly improve activity and selectivity of the primary structures. Cellular target engagement was verified by cell-based assays like cellular thermal shift assay (CETSA). These efforts resulted in the identification of highly potent, orally bioavailable and selective MCT4 inhibitors (MCT4 IC50 &amp;lt; 20nM; MCT1 IC50 &amp;gt; 100µM) with good physicochemical properties and beneficial pharmacokinetics in mouse. In vivo efficacy and tumor lactate modulation were evaluated in NCI-H358 xenograft and MC38 syngeneic mouse models. Thereby we explore the potential of our MCT4 inhibitor to act as a single anti-cancer agent or to synergize with other established therapies like angiogenesis inhibitors or cancer immunotherapeutics. Citation Format: Nina Hambruch, Barbara Herkert, Christian Gege, Aurelie Mallinger, Johannes Fabian, Olaf Kinzel, Yansong Wang, Gero Fink, Michael Albers, Anette Funk, Annika Bittman-Waetzig, Tilly Fleckenstein, Floriane Braun, Claus Kremoser. Identification of a potent, orally bioavailable and selective MCT4 Inhibitor for the treatment of solid Warburg tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3588.
The role of combined treatment of metastatic colorectal cancer in patients with liver metastases
Authors: D. Gridnev, M. Trandofilov, A. Zhevelyuk, D. Islamova, V. Makarov, A. Popov, E. Vozny, A. Kudryavtseva, S. Kostyrev, M. Rudakova, K. Ryabov, A. Sizova
Journal: Annals of Oncology (2019)
Abstract 3642: Combination nanotherapy using the PARP inhibitor talazoparib and cyclin dependent kinase inhibitor dinaciclib
Authors: Paige Baldwin, Adrienne Orriols, Srinivas Sridhar
Journal: Cancer Research (2019)

Abstract Introduction: PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells. As such, Talazoparib (TLZ), a potent PARP inhibitor, offers a way to target the biology of a number of cancers with DNA repair defects until these tumors develop resistance. PARP inhibitors must be used in combination with other inhibitors or chemotherapeutics to reverse resistance and sensitize non-responsive tumors. Dinaciclib, a potent cyclin dependent kinase (CDK) inhibitor, has been shown to sensitize both BRCA wild-type tumors and PARP inhibitor resistant tumors to PARP inhibition through disruption of homologous recombination. In clinical trials, Talazoparib and Dinaciclib have both demonstrated hematologic toxicities, suggesting a combination of these drugs would result in compounded toxicity, leading to dose reduction and an ineffective combination. Nanoparticle delivery systems offer a means to modify the toxicity profiles of these drugs and enhance the therapeutic window, therefore allowing for effective combination treatment. Methods: Separate nanoformulations of Talazoparib (NanoTLZ) and Dinaciclib (NanoDCB) were optimized, and pharmacokinetics and pharmacodynamics assessed. Nanoformulations were tested alone and in combination in vitro to ensure NanoDCB could sensitize a model with no known DNA repair defects to NanoTLZ. The combination of the two nanoformulations was then assessed for efficacy and toxicity in orthotopic MDA-MB-231 xenografts. Results: Robust formulations of NanoTLZ and NanoDCB were developed. Each nanoformulation extended the half-life of the drug it encapsulates. A constant low dose of Dinaciclib sensitized MDA-MB-231 cells to Talazoparib, significantly lowering the IC50 value. As a single agent NanoDCB was more effective in vitro than free Dinaciclib. In vivo, the combination of the two nanoformulations was more effective than either single nanoformulation or the combination of the two free drugs. Assessments of hematologic toxicities are underway, but thus far, there were no signs of gross toxicity in the combination therapy group. Conclusions: The combination of NanoDCB and NanoTLZ has provided an effective method for sensitizing tumors to PARP inhibition that are otherwise nonresponsive to this therapy. The development of two separate nanoformulations has allowed for tailored dosing. These long-circulating nanoformulations have proven more effective than the free drugs in stabilizing tumor growth and were well tolerated. This work was supported by ARMY/W81XWH-16-1-0731. Citation Format: Paige Baldwin, Adrienne Orriols, Srinivas Sridhar. Combination nanotherapy using the PARP inhibitor talazoparib and cyclin dependent kinase inhibitor dinaciclib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3642.
Abstract 17405: Phosphodiesterase-based Vasodilation Improves Oxygen Delivery and Clinical Outcomes Following Stage 1 Palliation
Authors: Kimberly I Mills, Brian K Walsh, Aditya K Kaza, Hilary Bond, David Wypij, James A DiNardo, Ravi R Thiagarajan, John N Kheir
Journal: Circulation (2015)

Introduction: The use of systemic vasodilators is known to decrease the incidence of postoperative cardiac arrest in infants with hypoplastic left heart syndrome (HLHS) following stage 1 palliation (S1P) with Blalock-Taussig shunt. Their impact on measured oxygen delivery (DO2) are uncharacterized. Methods: In 2013, we implemented a treatment algorithm at our institution to standardize care and lower systemic vascular resistance (SVR) in the postoperative period (A). We measured standard hemodynamic variables in consecutive neonates prior to (n=32) and following (n=24) its implementation. 92% of these infants received a Sano modification. We continuously measured oxygen consumption (E-COVX module™, GE Healthcare) and venous oxyhemoglobin saturation (SvO2, PediaSat, Edwards) for Fick-based calculation of DO2 and SVR in a subset (n=21) of patients. Variables were compared pre and post-implementation using linear mixed effects models. Results: Demographic, anatomic and echocardiographic risk factors were similar between groups, although aortic cross-clamp (ACC) time was significantly shorter following protocol implementation (120.9 vs 91.9 mins, P&lt;0.001). When corrected for ACC time, serum lactate (p&lt;0.001, B) and incidence of postoperative cardiac arrest (P=0.04, C) were lower (B), and SvO2 (P&lt;0.001) was higher following protocol implementation. Systemic cardiac output (β[SE], 0.52 [0.32] L/min/m2; P=0.10) and systemic DO2 (β[SE], 86.7 [55.4] mL/min/m2; P=0.12, D) were higher post-implementation. DO2 was most closely correlated with SVR (r2=0.87), and commonly utilized surrogate variables such as arterial saturation (r2=0.01), SvO2 (r2=0.1), and arterial-venous saturation difference (r2=0.35) correlated poorly. Conclusions: The implementation of a phosphodiesterase-based treatment algorithm decreased SVR, lactate accumulation and the incidence of cardiac arrest in infants with HLHS following S1P with Sano modification.
Whole-exome sequencing in tumor samples from sequenom-wild-type, ALK negative stage IV lung adenocarcinoma (ADC) patients (p).
Authors: Enriqueta Felip, Ginevra Caratu, Daniel Silberschmidt, Pablo Martinez, Alex Martinez Marti, Susana Cedres, Nuria Murtra-Garrell, Alejandro Navarro-Mendivil, Ludmila Prudkin, Jose Jimenez, Pilar de la Morena, Mercedes Canela, Paolo Nuciforo, Hector G. Palmer, Ana Vivancos
Journal: Journal of Clinical Oncology (2013)

8070 Background: The majority of lung ADC tumors are characterized by specific genetic features with KRAS mutations (mut) seen in 20-30%, EGFR mut in 15%, EML4-ALK translocations in 5%, and ERBB2 mut in 2%, among others. Some of these genetic alterations are already being used for selecting targeted therapies. However, identification of additional genomic alterations is required. Methods: In the present ongoing study we perform whole-exome sequencing in paraffin-embedded tumor samples from OncoCarta v1.0 panel wild-type (no mut in hotspots of KRAS, EGFR, ERBB2, AKT1, BRAF, PIK3CA genes) and ALK negative (by FISH) stage IV ADC lung cancer p, and in their matched normal tissue samples. Results: To date, a total of 7 tumors and matched normal tissues have been successfully analyzed. We have detected mut in previously identified ADC genes, such as ERBB2, CTNNB1, TP53, SMAD4 or APC. Interestingly, mut were found in genes belonging to the proposed new cancer hallmark ‘epigenetic and RNA regulation’, such as BRD3, EPC1, PHF1 in almost every p included in our study. Regarding alterations that could be considered relevant for lung tumor pathogenesis/growth or as potential targets for treatment therapies, we were able to identify candidates in 4 of the 7 p. In one p, a case of a transmembrane domain ERBB2mut in exon 20 (p.E770delinsEAYVM) not previously detected by the OncoCarta v1.0 panel (that interrogates L755P, G776S/L/V/C, A775_G776insYVMA, P780_Y781insGSP, S779_P780insVGS mut) was found. In another p, three somatic mut in the BRCA1/2 genes were detected. Additionally, one p had an ALK point mut (p.P336K), for which no functional information is available, together with an APC mutation. In the remaining p, a non-hotspot mutation (although previously detected in a colorectal tumor) was found in CTNNB1. Conclusions: In this limited experience of whole-exome sequencing of a subgroup of stage IV lung ADC p, potentially targetable alterations not formerly detected by other techniques were found. We believe that genomic approaches to detecting alterations may be useful in clinical practice and will hopefully provide assistance in making treatment decisions.
New Alternatives for the Evaluation of Minimal Residual Disease (MRD) Detection By Next Generation Sequencing in Multiple Myeloma
Authors: Alejandro Medina, Cristina Jiménez, Noemi Puig, Beatriz Sanchez-Vega, Juan Flores-Montero, Marcos González, Maria Jose Calasanz, Rosa M. Ayala, Maria E Sarasquete, Bruno Paiva, Maria Teresa Cedena, Marta Fernández-Mercado, Inmaculada Rapado, Laura Rosinol, Enrique M. Ocio, Albert Oriol, Miguel Alcoceba, Miguel T Hernández, Rafael Martinez Martinez, Maria-Victoria Mateos, Juan-José Lahuerta, Joan Bladé, Alberto Orfao, Jesus F. San Miguel, Joaquin Martínez-López, Ramón García-Sanz
Journal: Blood (2017)
Noninvasive Tests Accurately Identify Advanced Fibrosis due to NASH: Baseline Data From the STELLAR Trials
Authors: Quentin M. Anstee, Eric J. Lawitz, Naim Alkhouri, Vincent Wai‐Sun Wong, Manuel Romero‐Gomez, Takeshi Okanoue, Michael Trauner, Kathryn Kersey, Georgia Li, Ling Han, Catherine Jia, Lulu Wang, Guang Chen, G. Mani Subramanian, Robert P. Myers, C. Stephen Djedjos, Anita Kohli, Natalie Bzowej, Ziad Younes, Shiv Sarin, Mitchell L. Shiffman, Stephen A. Harrison, Nezam H. Afdhal, Zachary Goodman, Zobair M. Younossi
Journal: Hepatology (2019)

Accurate noninvasive tests (NITs) are needed to replace liver biopsy for identifying advanced fibrosis caused by nonalcoholic steatohepatitis (NASH). We analyzed screening data from two phase 3 trials of selonsertib to assess the ability of NITs to discriminate advanced fibrosis. Centrally read biopsies from the STELLAR studies, which enrolled patients with bridging fibrosis and compensated cirrhosis, were staged according to the NASH Clinical Research Network classification. We explored associations between fibrosis stage and NITs, including the nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis‐4 (FIB‐4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by vibration‐controlled transient elastography (LS by VCTE). The performance of these tests to discriminate advanced fibrosis, either alone or in combinations, was evaluated using areas under the receiver operating characteristic curve (AUROCs) with 5‐fold cross‐validation repeated 100 times. Of the 4,404 patients screened for these trials, 3,202 had evaluable biopsy data: 940 with F0‐F2 fibrosis and 2,262 with F3‐F4 fibrosis. Significant differences between median values of NITs for patients with F0‐F2 versus F3‐F4 fibrosis were observed: −0.972 versus 0.318 for NFS, 1.18 versus 2.20 for FIB‐4, 9.22 versus 10.39 for ELF, and 8.8 versus 16.5 kPa for LS by VCTE (all P &lt; 0.001). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis. FIB‐4 followed by an LS by VCTE or ELF test in those with indeterminate values (FIB‐4 between 1.3 and 2.67) maintained an acceptable performance while reducing the rate of indeterminate results. Conclusion: Among patients being considered for enrollment into clinical trials, NITs alone or in combination can reduce the need for liver biopsy to discriminate advanced fibrosis caused by NASH. The predictive value of these tests for general screening will require confirmation in a real‐world population.