tbuckley/cabot-search huggingface dataset:
Abstract 269: Duo-impairment of the Ubiquitin-Proteasome System and Autophagy by Ablation of COP9 Signalosome Subunit 8 Activates a Programmed Necrosis Pathway Mediated by RIP1-RIP3 Kinases but not Cyclophilin D-regulated Mitochondrial Membrane Permeability
Authors: Changhua Wang, Andrea Jahn, Huabo Su, Xuejun Wang
Journal: Circulation Research (2014)

Programmed cell death includes apoptosis and programmed necrosis (AKA, necroptosis). A well-recognized feature of necrosis is the loss of membrane integrity of the dying cell. Cells undergoing apoptosis, however, maintain their membrane integrity. We previously reported massive cardiomyocyte (CM) necrosis, before increased apoptosis is discernible, in mouse hearts with cardiomyocyte-restricted knockout of the COP9 signalosome subunit 8 (CR-Csn8KO). This is associated with defective autophagosome maturation and ubiquitin-proteasome system (UPS) dysfunction. Consequently, mice with perinatal CR-Csn8KO develop rapidly dilated cardiomyopathy (DCM) and die prematurely. The present study sought to search for the mechanisms underlying the CM necrosis. Here our immunoprecipitation revealed significant increases of RIP1-interacted RIP3 in CR-Csn8KO myocardium, indicative of activation of the RIP1-RIP3 pathway. The RIP1-RIP3 pathway is known to mediate necroptosis. To further test whether RIP1 activation plays an essential role in CM necrosis in CR-Csn8KO mice, we treated the mice with a RIP1 kinase specific inhibitor necrostatin-1 (Nec-1) or vehicle control via osmotic mini-pump implanted in the peritoneal cavity at 2 weeks of age. Nec-1 significantly suppressed CM necrosis as measured by the positivity of Evan’s blue dye (EBD) uptake (p&lt;0.00001), prevented left ventricle dilatation (p&lt;0.05) at 3 weeks, and delayed premature death of the CR-Csn8KO mice (p=0.0072). These results demonstrate that CM necrosis in CR-Csn8KO mice is necroptosis in which the RIP1-RIP3 kinases-mediated pathway plays a major pathogenic role, and that CM necroptosis is the primary cause of DCM and mouse premature death. Increased mitochondrial membrane permeability, which can be suppressed by inhibition of cyclophilin D, has been shown to play a critical mediating role in myocytes necrosis. Hence, we cross-bred CR-Csn8KO mice with cyclophilin D knockout mice and obtained the Kaplan-Meier survival curve. Unexpectedly, cyclophilin D deficiency exacerbated the premature death of CR-Csn8KO mice (p=0.007), indicating that cyclophilin D regulated mitochondrial membrane permeability does not play an important role in CM necrosis in CR-Csn8KO mouse hearts.
Phosphorylation of mTOR and S6RP predicts the efficacy of everolimus in patients with metastatic renal cell carcinoma.
Authors: Si Ming Li, Yan Kong, Lu Si, Xi Nan Sheng, Jun Guo
Journal: Journal of Clinical Oncology (2014)

e15556 Background: Everolimus (RAD001), as a new inhibitor for mammalian target of rapamycin (mTOR) provides clinical benefit to patients with anti-VEGF-refractory metastatic renal cell carcinoma (mRCC). However, factors for selection of patients who will benefit from Everolimus remain uncovered. Here we aimed to explore the potential molecular indicators for mRCC patients who may benefit from everolimus treatment. Methods: Paraffin-embedded tumor tissue specimens derived from 18 mRCC patients, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC, were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥6 months) and progression-free survival time (PFS) were correlated with expression levels of these mTOR-associated molecules. Results: Tumor tissue samples were obtained before treatment for the 18 patients. Of them, there were 1 PR, 15 SDs (including 9 SDs ≥6 months), and 2 progressive diseases (PD) responded to treatment with everolimus. The clinical benefit rate (CBR) was 55.6% (10/18), and the median PFS time was 8.4 months. Patients with positive expression of phospho-mTOR had a better CBR (71.4% versus 0%, P=0.023) and PFS time (11.3 versus 3.7 months, P=0.001) than patients with negative expression. A trend toward a positive association between positive phospho-S6RP expression and CBR was noted (63.3% vs. 0%, P = 0.069). The median PFS of patients with positive phospho-S6RP was longer (11.3 versus 3.7 months, P=0.002) than that of patients with negative expression. Expression levels of phospho-4EBP1 and phospho-AKT were unassociated to efficacy of everolimus with respect to CBR and PFS. Conclusions: The expression levels of phospho-mTOR and phospho-S6RP may be potential predictive biomarkers for efficacy of everolimus in patients with metastatic RCC, which is worthy to be investigated with larger sample size. Clinical trial information: NCT01152801.
Serum Markers for early diagnosis of hepatocellular carcinoma in hepatitis C cirrhotic patients with sustained virological response to direct-acting antivirals treatment
Authors: A. Sangiovanni, R. D’Ambrosio, G. Lunghi, M. Bruccoleri, E. Alimenti, M. Borghi, R. Perbellini, A. Aghemo, M. Iavarone, M. Colombo, P. Lampertico
Journal: Journal of Hepatology (2017)
Intravital Microscopy Reveals Fundamental Differences in the Interaction of Stem Cells and T Acute Lymphoblastic Leukaemia with the Bone Marrow Microenvironment
Authors: Cristina Lo Celso, Edwin D Hawkins, Delfim Duarte, Olufolake Akinduro, Reema A Khorshed, Diana Passaro, Malgorzata Nowicka, Lenny Straszkowski, Mark K Scott, Steve Rothery, Nicola Ruivo, Katie Foster, Michaela Waibel, Ricky W Johnstone, Simon J. Harrison, David A Westerman, Hang Quach, John Gribben, Mark D Robinson, Louise E Purton, Dominique Bonnet
Journal: Blood (2016)
Early function modulation and reprogramming of Kupffer cells promote establishment and maintenance of HBV infection
Authors: S. Faure-Dupuy, L. Aillot, N. Isorce, L. Dimier, B. Testoni, A. Lam, K. Klumpp, C. Zanetti, N. Bendriss-Vermare, U. Hasan, F. Zoulim, J. Lucifora, D. Durantel
Journal: Journal of Hepatology (2017)
Operability of perihilar cholangiocellular carcinoma can be reliably predicted by combination of endoscopic retrograde cholangiography, endoscopic ultrasound and computer tomography as variables in the European staging system
Authors: B. Schlevogt, S. Kammerer, M. Lessing, D. Domagk, A. Hüsing-Kabar, I. Kabar, H.H.-J. Schmidt, H. Wolters, T. Meister, H.S. Heinzow
Journal: Journal of Hepatology (2017)
Abstract PR06: PTEN-mTOR pathway serves as a guardian of ribosomal DNA
Authors: Baoshan Xu, Hua Li, John Perry, Bethany Harris, Brian Slaughter, Jay Unruh, Vijay Pratap Singh, Musinu Zakari, William McDowell, Linheng Li, Jennifer L. Gerton
Journal: Cancer Research (2017)

Abstract Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number, yet we know virtually nothing about what governs its copy number, stability, and sequence. Ribosomal DNA is present in many tandem repeats that are incredibly important because 1) they encode the template for the RNA component of ribosomes, 2) they organize large parts of nearly every human chromosome and 3) they can titrate factors involved in chromosomal processes, with profound impact on DNA replication, repair, and gene expression. We applied computational and droplet digital PCR approaches to explore rDNA copy number in normal and cancer states in human and mouse genomes. We find that the copy number is similar between tissues from the same mouse, and is similar within inbred mouse strains, but can vary widely between individuals in an outbred strain. PTEN is a tumor suppressor and negative regulator of mTOR activity that is critical for genome stability. We find that hematopoietic stem cells from a PTEN-/- mouse model for leukemia have lower rDNA copy number than normal tissue, associated with hypersensitivity to DNA damage. Remarkably, analysis of three human cancer genome projects reveals low rDNA copy number relative to matched normal tissue. Our analysis reveals a genomic signature associated with hyperactive mTOR in osteosarcoma that includes loss of rDNA copies accompanied by an increase in sequence heterogeneity, as well as additional genes that co-vary in copy number. PTEN-mTOR may normally contribute to maintenance of ribosomal DNA. This abstract is also being presented as Poster A38. Citation Format: Baoshan Xu, Hua Li, John Perry, Bethany Harris, Brian Slaughter, Jay Unruh, Vijay Pratap Singh, Musinu Zakari, William McDowell, Linheng Li, Jennifer L. Gerton. PTEN-mTOR pathway serves as a guardian of ribosomal DNA. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr PR06.
Correlation between clinical outcomes of patients treated within the tailor trial and next-generation sequencing (NGS) results: Analysis of genes associated to KRAS mutations
Authors: M. Ganzinelli, M. Broggini, G. Sozzi, M. Moro, M. Marabese, E. Caiola, A. Busico, E. Bria, E. Rulli, M.C. Garassino
Journal: Annals of Oncology (2017)
Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones
Authors: Mark Ping Chao, Gentles Andrew, Chatterjee Susmita, Andreas Reinisch, M. Ryan Corces, Jinfeng Shen, Morganti Rachel, Rahul Singha, Daniel Haag, Marius Wernig, Joseph Wu, Ravi Majeti
Journal: Blood (2016)
Simple non-invasive fibrosis scores identify patients with non-alcoholic fatty liver disease who progress to advanced fibrosis/cirrhosis:evidence from a large cohort of patients with sequential liver biopsies
Authors: S. Mcpherson, R. Pais, L. Valenti, J.M. Schattenberg, J.-F. Dufour, E. Tsochatzis, S. Francque, T. Hardy, M. Boyle, D. Tiniakos, V. Ratziu, Q. Anstee
Journal: Journal of Hepatology (2017)
Identifying residual risk of hepatocellular carcinoma following hepatitis C virus eradication in compensated cirrhosis: decision-tree and random forest models developed in the French multicenter prospective ANRS CO12 CirVir cohort
Authors: E. Audureau, V. Bourcier, R. Layese, C. Cagnot, P. Marcellin, D. Guyader, S. Pol, D. Larrey, F. Roudot-Thoraval, P. Nahon
Journal: Journal of Hepatology (2017)
Serum hepatocyte growth factor (HGF) is a potential marker for baseline liver function and its early deterioration in patients treated with sorafenib
Authors: Y. Yasui, M. Kurosaki, K. Tsuchiya, W. Wang, M. Okada, Y. Kubota, T. Goto, Y. Komiyama, M. Higuchi, K. Takaura, T. Hayashi, H. Takada, N. Tamaki, H. Nakanishi, J. Itakura, N. Izumi
Journal: Journal of Hepatology (2017)
EFFECTS OF BACTERIAL ENDOTOXINS ON METABOLISM
Authors: L. Joe Berry, Dorothy S. Smythe
Journal: The Journal of Experimental Medicine (1963)

Cortisone is known to protect mice against the lethal effects of endotoxin. It also elevates liver tryptophan pyrrolase (TP) activity, an enzyme that converts tryptophan into an intermediate which, in turn, is transformed in a series of reactions into nicotinamide, a component of the pyridine nucleotides. In the present report, results of experiments attempting to link the prophylactic action of cortisone in endointoxication to metabolism of tryptophan are described. It was shown first that both nicotinamide and diphosphopyridine nucleotide (DPN), compounds along the pathway initiated by TP, are each as effective as cortisone in protecting mice against lethality of different amounts of endotoxin. L-Tryptophan, which alone results in an increase in liver TP, fails to protect against endotoxin when it is given either 4 hours before or concurrently with the toxin while it potentiates the toxin when administered 4 hours later. Cortisone, nicotinamide, and DPN all fail to protect mice against lethality when given 4 hours after endotoxin but they do not potentiate it as does tryptophan. Additional evidence linking tryptophan metabolism to endotoxin poisoning was derived from assays for TP. Activity of the enzyme in livers of mice 17 hours after injecting an LD50 of endotoxin is less than one-half the control value. It remains below normal for 48 hours. In adrenalectomized mice, TP activity is about the same as in mice 17 hours after endotoxin. Animals protected against lethality of endotoxin by cortisone have normal levels of TP but if the cortisone is given 4 hours after the toxin, TP activity is the same as in mice given endotoxin alone. Tryptophan is unable to maintain a normal level of TP when it is given concurrently with endotoxin. TP activity is not depressed when mice made tolerant to endotoxin are given an injection of endotoxin at the LD50 level for normal animals. Normal activity of the enzyme was always observed in livers of mice protected against endotoxin but not in those where protection failed. The total amount of oxidized pyridine nucleotides (PN+) in livers of mice 17 hours after an LD60 of endotoxin is about two-thirds the normal level. Animals injected with either cortisone or nicotinamide at the same time as endotoxin maintain the PN+ level in liver. Mice exposed to 5°C during the postinjection period can be protected with cortisone or nicotinamide against lethality of endotoxin but not with DPN. Changes in TP activity do not parallel those found in mice kept at 25°C. The toxic manifestations of endotoxin appear to be different, therefore, in animals stressed by cold.
Non-invasive detection of patients with nonalcoholic steatohepatitis at risk of adverse liver outcomes
Authors: R. Mohammadi, M. Dhyani, S. Kamarathi, A.K. Bhan, Z. Chen, J.R. Grajo, K.E. Corey, R. Chung, A. Samir, J. Chhatwal
Journal: Journal of Hepatology (2017)
Clinical significance of post-liver transplant hepatitis E seropositivity in high prevalence area of genotype 3: interim result of 8-month prospective follow-up study
Authors: P. Komolmit, V. Oranrap, K. Thanapirom, S. Suksawatamnuay, N. Srisoonthorn, N. Posuwan, T. Thongmee, S. Treeprasertsuk, Y. Poovorawan
Journal: Journal of Hepatology (2017)
Phase I/II study of investigational agent MLN8237 (alisertib) plus rituximab with or without vincristine in patients (pts) with relapsed/refractory (rel/ref) aggressive diffuse large B-cell lymphoma (DLBCL)/transformed follicular lymphoma (TFL).
Authors: Daniel Oscar Persky, Kevin R. Kelly, Peter Lee, Steven I. Park, Bin Zhang, E. Jane Leonard, Ely Benaim, Jonathan W. Friedberg
Journal: Journal of Clinical Oncology (2012)

TPS8109 Background: DLBCL and TFL are aggressive subtypes of non-Hodgkin lymphoma (NHL), with poor prognosis in the rel/ref setting. Alternatives to standard rituximab-based treatments are needed. MLN8237 is an oral, selective inhibitor of Aurora A kinase – a key mitotic regulator overexpressed/amplified in various human cancers, including lymphomas (Hamada et al, 2003; Yakushijin et al, 2004; Qi et al, 2011). Emerging data from a phase 2 study suggest that MLN8237 has single agent activity in aggressive NHL (Friedberg et al, ASH 2011). MLN8237 + rituximab (MR) ± vincristine (MRV) has also shown activity in preclinical B-cell NHL models (Mahadevan et al, ASH 2011). Further clinical evaluation of these regimens in rel/ref B-cell NHL is warranted. Methods: This single-arm phase 1/2 study (ClinicalTrials.gov #NCT01397825) aims to assess the safety, efficacy, and pharmacokinetics of, and determine a recommended phase 2 dose (RP2D) and schedule for, MR and MRV in adults with CD20+ rel/ref DLBCL/TFL after 1–4 prior regimens (including ASCT) and ECOG PS 0–2. Pts with other aggressive B-cell lymphomas may also enroll in phase 1. ~100 pts will be recruited at 22 sites in the US, UK, Italy, and Spain, and study duration will be ~2 years. In part 1, a safety lead-in cohort will receive MR (table), with the RP2D determined as when &lt;2 dose limiting toxicities (DLT) occur in 6 pts in cycle 1. MRV dose escalation (part 2) will then follow a 3+3 design. Phase 2 enrollment (part 3) will follow a Simon optimal 2-stage design, with pts receiving MRV at the RP2D determined in part 2. The primary phase 2 objective is overall response rate by IWG criteria. Responders may continue MLN8237 if clinical benefit is seen and if the regimen is tolerable. Enrollment as of 20 Jan 2012 is 6 evaluable pts. [Table: see text]
The microcirculation: a key player in obesity-associated cardiovascular disease
Authors: Oana Sorop, T. Dylan Olver, Jens van de Wouw, Ilkka Heinonen, Richard W. van Duin, Dirk J. Duncker, Daphne Merkus
Journal: Cardiovascular Research (2017)

It is increasingly recognized that obesity is a risk factor for microvascular disease, involving both structural and functional changes in the microvasculature. This review aims to describe how obesity impacts the microvasculature of a variety of tissues, including visceral adipose tissue, skeletal muscle, heart, brain, kidneys, and lungs. These changes involve endothelial dysfunction, which in turn (i) impacts control of vascular tone, (ii) contributes to development of microvascular insulin resistance, (iii) alters secretion of paracrine factors like nitric oxide and endothelin, but (iv) also influences vascular structure and perivascular inflammation. In concert, these changes impair organ perfusion and organ function thereby contributing to altered release and clearance of neurohumoral factors, such as adipokines and inflammatory cytokines. Global microvascular dysfunction in obese subjects is therefore a common pathway that not only explains exercise-intolerance but also predisposes to development of chronic kidney disease, microvascular dementia, coronary microvascular angina, heart failure with preserved ejection fraction, chronic obstructive pulmonary disease, and pulmonary hypertension.
DNA methylation profile of 1501 loci in bladder cancer shows evidence of a field defect
Authors: Gangning Liang, Erika Wolff, Yoshitomo Chihara, Fei Pan, Daniel Weisenberger, Peter Laird, Peter Jones
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2625 

Transitional cell carcinoma (TCC) is the most common form of bladder cancer in the United States. The disease is characterized by a high rate of recurrence and necessitates frequent and invasive monitoring. The biological basis for the high rate of recurrence remains unknown, although the presence of a field defect has been postulated. DNA methylation has been shown to be involved in field defects in other cancers. Therefore, we decided to profile the DNA methylation changes that occur during bladder cancer on a large scale. We sought to identify new markers to be used in the detection of bladder cancer recurrence and determine whether a field defect exists in the bladders of patients with bladder cancer. Using the Illumina GoldenGate methylation assay we measured DNA methylation at 1,505 different loci in 92 bladder urothelium samples from three different sources: 12 age-matched bladder cancer-free patients, 34 adjacent normal tissue samples from bladder cancer patients, and 46 malignant tissue samples from bladder cancer patients. A comparison of methylation in TCC tissue versus bladder urothelium from bladder cancer-free patients yielded 346 hypermethylated loci and 77 hypomethylated loci in TCC. Interestingly, we also found 39 loci that were hypermethylated not only in tumors but also in adjacent normal appearing tissue when compared to normal urothelium from bladder cancer-free patients, indicating the presence of an epigenetic field defect in bladder cancer patients. In conclusion, we have conducted large scale profiling of DNA methylation changes in bladder cancer. The loci that we found to be hypermethylated specifically in bladder tumors may provide markers for the detection of bladder cancer and its recurrence. We also found evidence of an epigenetic field defect, as 39 loci were hypermethylated not just in tumor tissue but also in normal appearing adjacent tissue. These loci may provide markers for the identification of individuals at risk for developing bladder cancer, as they are only methylated in bladders with cancer.
Mohs Micrographic Surgery Use in the United States Based on Medicare Data—Reply
Authors: Adewole S. Adamson, Stacie B. Dusetzina
Journal: JAMA Dermatology (2017)

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Elevated hepatic and adipose hepcidin expression in patients with advanced NAFLD fibrosis
Authors: J.D. Ryan, M. Watson, T. Cargill, L. Rickers, C. Fletcher, A. Foliaki, G. Kalogeropoulos, J.W. Tomlinson, R. Gillies, B. Sgromo, J.F. Cobbold
Journal: Journal of Hepatology (2017)
Just Ask Us LGBTQI Patient and Provider Experiences.
Authors: Gwendolyn P. Quinn, Julian Sanchez, Gina Shetty, Matthew B. Schabath, B Lee Green, Steve Sutton
Journal: Journal of Clinical Oncology (2015)

e17595 Background: The lesbian, gay, bisexual, transgender, queer/questioning, Intersex (LGBTQI) community represents a growing and underserved population in the US. LGBTQI healthcare experiences and provider practices in the oncology setting are less known. This goal of this study was to assess and compare the knowledge, attitudes, and practice behaviors of providers regarding LGBTQI health, as well as the LGBTQI population’s perceptions and experiences. Methods: A 33-item web-based survey was emailed to providers at a single institution. The survey included: demographics, knowledge of cancer risk, attitudes, practice behaviors, and open-ended comments. In addition, members of Equality Florida (EF) participate in a 60-item web survey assessing knowledge of cancer risk and experiences with providers. Results: 113 providers completed the survey. Less than 50% reported accurate knowledge of LGBTQI cancer health risks and concerns; 74% of providers do not ask patients about sexual orientation or gender identity and 72% did not feel well-informed on LGBTQI healthcare needs. 632 EF members (41% gay men, 29% lesbian) completed the survey. 67% reported always or often disclosing their sexual orientation/identity to providers and < 10% experienced negative reactions in the healthcare setting. Settings were perceived as safe when equality signs and gender-neutral language in documents was present. 85% of LGBTQI respondents regarded it “highly important” that their provider knew their sexual orientation/gender identity. Conclusions: Recent American Medical Association policies uphold the need for providers to inquire about sexual orientation/identity to prevent failures in screening and diagnosis. Knowledge gaps and practice behaviors among providers indicate a need for additional training and education. Results from the LGBTQI population highlight the need for examination of hospital policies and improved cultural competency