tbuckley/cabot-search huggingface dataset:
Progression of diabetic kidney disease and trajectory of kidney function decline in Chinese patients with Type 2 diabetes
Authors: Guozhi Jiang, Andrea On Yan Luk, Claudia Ha Ting Tam, Fangying Xie, Bendix Carstensen, Eric Siu Him Lau, Cadmon King Poo Lim, Heung Man Lee, Alex Chi Wai Ng, Maggie Chor Yin Ng, Risa Ozaki, Alice Pik Shan Kong, Chun Chung Chow, Xilin Yang, Hui-yao Lan, Stephen Kwok Wing Tsui, Xiaodan Fan, Cheuk Chun Szeto, Wing Yee So, Juliana Chung Ngor Chan, Ronald Ching Wan Ma, Ronald C.W. Ma, Juliana C.N. Chan, Yu Huang, Hui-yao Lan, Si Lok, Brian Tomlinson, Stephen K.W. Tsui, Weichuan Yu, Kevin Y.L. Yip, Ting Fung Chan, Xiaodan Fan, Wing Yee So, Cheuk Chun Szeto, Nelson L.S. Tang, Andrea O. Luk, Xiaoyu Tian, Guozhi Jiang, Claudia H.T. Tam, Heung Man Lee, Cadmon K.P. Lim, Katie K.H. Chan, Fangying Xie, Alex C.W. Ng, Grace P.Y. Cheung, Ming-wai Yeung, Shi Mai, Fei Xie, Sen Zhang, Pu Yu, Meng Weng
Journal: Kidney International (2018)
The role of DNA methylation in epigenetics of aging
Authors: Archana Unnikrishnan, Willard M. Freeman, Jordan Jackson, Jonathan D. Wren, Hunter Porter, Arlan Richardson
Journal: Pharmacology & Therapeutics (2018)

Recent research suggests that epigenetics, especially DNA methylation, plays a mechanistic role in aging. Epigenetic clocks, which measure changes in a few hundred specific CpG sites, can accurately predict chronological age in a variety of species, including humans. These clocks are currently the best biomarkers for predicting mortality in humans. Additionally, several studies have characterized the effects of aging across the methylome in a wide variety of tissues from humans and mice. A small fraction (~2%) of the CpG sites show age-related changes, either hypermethylation or hypomethylation with aging. Evaluation of non-CpG site methylation has only been examined in a few studies, with about ~0.5% of these sites showing a change with age. Therefore, while only a small fraction of cytosines in the genome show changes in DNA methylation with age, this represents 2 to 3 million cytosines in the genome. Importantly, the only study to compare the effect of aging on DNA methylation in male and female mice and humans found that >95% of the age-related changes in DNA methylation in the hippocampus were sexually divergent, i.e., the methylation did not differ between males and females at young age but age-related changes occurred in one sex but not the other. The age-related changes in DNA methylation tend to be enriched and under-represented in specific genomic contexts, with some commonalities between tissues and species that require further investigation. The strongest evidence that the age-related changes in DNA methylation play a role in aging comes from studies of anti-aging interventions (e.g., caloric restriction, dwarfism, and rapamycin treatment) in mice. These anti-aging interventions deaccelerate the epigenetic clocks and reverse/prevent 20 to 40% of the age-related changes in DNA methylation. It will be important in the future to demonstrate that at least some of the age-related changes in DNA methylation directly lead to alterations in the transcriptome of cells/tissues that could potentially contribute to aging.
Abstract 18835: Chromatin Gene Cohorts, Not Individual Cardiac Genes, Modulate Cardiac Phenotype in a Genetically Diverse Population
Authors: Elaheh Karbassi, Emma Monte, Rachel Lopez, Joseph Kim, Doug Chapski, Christoph Rau, Jessica Wang, James N Weiss, Yibin Wang, Aldons J Lusis, Thomas M Vondriska
Journal: Circulation (2015)

Re-expression of fetal genes is a hallmark of transcriptome change in models of cardiac hypertrophy, but how this remodeling is affected by the common genetic variation present in populations is unknown. We examined gene expression in 86 strains of control and isoproterenol (ISO)-treated mice, which exhibited varying degrees of disease. Correlations between individual fetal genes (Anf, Serca2a, alpha-MHC, beta-MHC) and hypertrophic phenotypes were not significant. Expanded analysis of 37 fetal genes showed sparse correlation (at p&lt;0.05) between expression of individual genes with one or more of 52 systemic phenotypes. We next tested the hypothesis that groups of genes exhibit emergent association with phenotype not observed with individual transcripts. Examining the fetal genes as a group unmasked a correlation with left atrial mass (enriched 3.04-fold vs transcriptome, p&lt;0.001). Grouping cardiac transcription factors (n=31 genes) or genes shown by gain/loss of function studies to contribute to hypertrophic signaling (n=142) revealed no correlation to cardiac phenotypes, whereas chromatin regulators (n=124) were associated with right ventricular mass (1.55-fold, p&lt;0.01), fractional shortening (1.52-fold, p&lt;0.05) and ejection fraction (1.50-fold, p&lt;0.05). We next analyzed histone genes. HOPACH clustering generated 39 clusters of strains based on the basal transcriptome that collapsed to 13 clusters after ISO, suggesting that adrenergic stress entrains gene expression. We observed transcriptional co-regulation of H2A with H2B, and H3 with H4 (the other pairings did not show correlation), mirroring the protein level assembly, which proceeds via pairs of dimers according to the same logic. Comparison of strain grouping based on partitioning clustering using histone stoichiometry or phenotype revealed that hypertrophic mice were enriched in histone cluster 4, marked by minimal change to histone variant expression (enriched 2.27-fold, p&lt;0.01). The two novel conclusions are: fetal gene regulation is buffered within populations by common genetic variation and is not a good predictor of disease; and cardiac phenotype is influenced in the basal and disease states through global changes in chromatin.
NIMG-51. THE IMPACT OF FUNCTIONAL MAGNETIC RESONANCE IMAGING ON CLINICAL OUTCOMES IN A PROPENSITY-MATCHED LOW GRADE GLIOMA COHORT
Authors: Joseph Megyesi, Jonathan Lau, Suzanne Kosteniuk
Journal: Neuro-Oncology (2018)

This study aims to evaluate the impact of preoperative functional magnetic resonance imaging (fMRI) on clinical outcomes in low grade glioma (LGG) patients. In a retrospective propensity-matched cohort study, we compared LGG patients based on whether they underwent fMRI as part of preoperative assessment. Twelve LGG patients who underwent preoperative fMRI were selected, and a contemporaneous group of twelve control LGG patients who did not undergo fMRI were matched to the fMRI group based on age, sex and 1p/19q status. Functional MRI group subjects tended to have more aggressive surgeries (67% resection, 33% biopsy) than the control group (33% resection, 67% biopsy). There were no significant differences in outcomes between the groups. Time between clinical assessment and surgery tended to be longer in the fMRI group (6.3 +/- 4.2 weeks) than in the control group (2.7 +/- 2.2 weeks). Extent of resection was similar between the cohorts. Functional MRI groups subjects had lower preoperative functional status, and tended to have a greater postoperative functional status improvement than control group subjects. Mean survival was not significantly different (fMRI group five year survival 88.9%, control group five year survival 61.1%). CONCLUSIONS: We evaluated the impact of preoperative fMRI in patients with LGG in this propensity-matched cohort study. This study has not demonstrated any significant difference in outcomes between the fMRI and control groups, although there were non-significant trends for patients who underwent fMRI to undergo more aggressive surgical interventions, and have greater postoperative functional status improvement.
INNV-47. TREATMENT ALLOCATION AMONG PATIENTS EVALUATED IN A MULTIDISCIPLINARY RADIATION ONCOLOGY AND NEUROSURGERY CENTRAL NERVOUS SYSTEM CLINIC
Authors: Shearwood McClelland, Timur Mitin, Jerry Jaboin, Jeremy Ciporen
Journal: Neuro-Oncology (2018)

Treatment allocation for central nervous system disease has rarely been examined in a collaborative fashion. We describe our experience with RADIANS (RADIation oncology And NeuroSurgery), a novel multidisciplinary clinic model featuring radiation oncology in tandem with neurosurgery in a community hospital setting. RADIANS patients were assessed to determine treatment allocation: surgery alone, radiation therapy (RT) alone, surgery with RT, or observation. Patient satisfaction was assessed via survey questionnaire. Forty-two patients have been seen since RADIANS inception. Median age was 65; median patient distance from RADIANS was 42.7 miles (mean=62.6; range 0.7–285); half of patients travelled more than 50 miles to receive care. Patients were most commonly treated with surgery and RT (33.3%), followed by RT alone (28.6%), observation (26.2%), and least commonly surgery alone (11.9%). More than three-fourths of patients were seen for metastatic disease of the brain and/or spine; 75% of patients delineated to RT received stereotactic body RT (SBRT). Lesions were nearly equally distributed between the brain (22 patients) and spine (20 patients). A majority of survey responders felt comfortable receiving two separate bills rather than a single bill for their RADIANS visit; all responders would recommend RADIANS for a friend/relative with a newly diagnosed spine or brain tumor. The average overall satisfaction on a 0 (not satisfied) to 5 (very satisfied) scale was 4.8. The RADIANS clinic model has proved viable in a community setting; half of patients travel a great distance to receive care. The most common treatment modality has involved SBRT with or without surgery. A large majority of patients are referred with metastatic disease. Thorough study will be needed to optimally evaluate the long-term impact of RADIANS on patient education and quality of care.
IMMU-46. GLIOBLASTOMA PATIENT DIAGNOSES AND IMMUNOSUPPRESSION ARE MAXIMAL DURING OLD AGE: A RANDOM COINCIDENCE, OR CAUSE AND EFFECT?
Authors: Erik Ladomersky, Sebastian Otto-Meyer, Lijie Zhai, Rohan Savoor, Kristen Lauing, Alicia Lenzen, Rimas Lukas, Derek Wainwright
Journal: Neuro-Oncology (2018)

Immunotherapy fails to improve overall survival (OS) of adults with glioblastoma (GBM) according to recent Phase III clinical trial outcomes. Though immune checkpoint blockade improves OS among patients diagnosed with other, end-stage, non-CNS cancers (ie. melanoma, renal, etc.), there now exists a question of whether immune-based therapies hold promise for GBM. Somewhat under-appreciated is that, de novo GBM is a disease that primarily affects the elderly, with a median age of diagnosis at 64 years old. Strikingly, we recently discovered a higher mortality rate in elderly C57BL/6 mice with syngeneic, intracranial GL261, as compared to young, 6-8-week-old counterparts, after simultaneous treatment with radiotherapy and PD-1/IDO1 inhibitors (Ladomersky et al., 2018; CCR). To follow-up the striking age-dependent decrease of immunotherapeutic efficacy, preclinically, we investigated the: (i) Surveillance, Epidemiology, and End Results (SEER) database; (ii) Broad Institute’s GTex portal; and (iii) 10k Immunomes repository, to understand the relationship(s) between human GBM, human immunology and aging. GBM patient incidence is 3.4× higher among individuals ≥65 years old, as compared to those <65 (n=7155; P<0.0001). Unexpectedly, the rate of mortality among GBM patients ≥65 years old, is 7× higher, as compared to GBM patients <65 (n=9761; P<0.0001). Strikingly, immunosuppressive IDO1 levels increase in the normal human brain with advanced age, and is maximal among individuals aged 60–69 years old (n=1152; P<0.05). There is also a maximal incidence of circulating immunosuppressive Tregs among normal individuals aged 65–74 years old (n=578; P<0.05). The elderly population has a cumulative peak for indicators of immunosuppression, at the same age range as the maximal incidence of GBM patient diagnoses. We are currently pursuing how old age enhances immunosuppression, is associated with the maximal incidence of GBM diagnoses, and detracts from immunotherapy for malignant glioma, which is a clinically-relevant priority.
Lenalidomide plus R-CHOP21 in newly diagnosed diffuse large B-cell lymphoma (DLBCL): long-term follow-up results from a combined analysis from two phase 2 trials
Authors: A. Castellino, A. Chiappella, B. R. LaPlant, L. D. Pederson, G. Gaidano, W. R. Macon, G. Inghirami, C. B. Reeder, A. Tucci, R. L. King, A. Congiu, J. M. Foran, V. Pavone, C. E. Rivera, M. Spina, S. M. Ansell, F. Cavallo, A. L. Molinari, Giovannino Ciccone, T. M. Habermann, T. E. Witzig, U. Vitolo, G. S. Nowakowski
Journal: Blood Cancer Journal (2018)

Abstract Lenalidomide-RCHOP (R2-CHOP21) has been shown to be safe and effective in patients with untreated diffuse large B-cell lymphoma (DLBCL). The aim of this analysis is to report long-term outcome and toxicities in newly diagnosed DLBCL patients who received R2-CHOP21 in two independent phase 2 trials, conducted by Mayo Clinic (MC) and Fondazione Italiana Linfomi (FIL). All patients received R-CHOP21 plus lenalidomide. Long-term progression-free survival (PFS), time to progression (TTP), overall survival (OS) and late toxicities and second tumors were analyzed. Hundred and twelve patients (63 MC, 49 FIL) were included. Median age was 69 years, 88% were stage III–IV. At a median follow-up of 5.1 years, 5y-PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%; according to cell of origin (COO): 5y-PFS 52.8% vs 64.5%, 5y-TTP 61.6% vs 69.6% and 5y-OS 68.6% vs 74.1% in germinal center (GCB) vs non-GCB respectively. Four patients experienced grade 4–5 late toxicities. Grade ≤ 3 toxicities were infections ( N = 4), thrombosis ( N = 1) and neuropathy ( N = 3). Seven seconds tumors were observed. Long-term follow-up demonstrates that R2-CHOP21 efficacy was maintained with high rates of PFS, TTP, and OS. Lenalidomide appears to mitigate the negative prognosis of non-GCB phenotype. Incidence of therapy-related secondary malignancies and late toxicities were low.
Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis
Authors: Irene Zubiri, Vittoria Lombardi, Michael Bremang, Vikram Mitra, Giovanni Nardo, Rocco Adiutori, Ching-Hua Lu, Emanuela Leoni, Ping Yip, Ozlem Yildiz, Malcolm Ward, Linda Greensmith, Caterina Bendotti, Ian Pike, Andrea Malaspina
Journal: Molecular Neurodegeneration (2018)

It is unclear to what extent pre-clinical studies in genetically homogeneous animal models of amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disorder, can be informative of human pathology. The disease modifying effects in animal models of most therapeutic compounds have not been reproduced in patients. To advance therapeutics in ALS, we need easily accessible disease biomarkers which can discriminate across the phenotypic variants observed in ALS patients and can bridge animal and human pathology. Peripheral blood mononuclear cells alterations reflect the rate of progression of the disease representing an ideal biological substrate for biomarkers discovery. We have applied TMTcalibrator™, a novel tissue-enhanced bio fluid mass spectrometry technique, to study the plasma proteome in ALS, using peripheral blood mononuclear cells as tissue calibrator. We have tested slow and fast progressing SOD1G93A mouse models of ALS at a pre-symptomatic and symptomatic stage in parallel with fast and slow progressing ALS patients at an early and late stage of the disease. Immunoassays were used to retest the expression of relevant protein candidates. The biological features differentiating fast from slow progressing mouse model plasma proteomes were different from those identified in human pathology, with only processes encompassing membrane trafficking with translocation of GLUT4, innate immunity, acute phase response and cytoskeleton organization showing enrichment in both species. Biological processes associated with senescence, RNA processing, cell stress and metabolism, major histocompatibility complex-II linked immune-reactivity and apoptosis (early stage) were enriched specifically in fast progressing ALS patients. Immunodetection confirmed regulation of the immunosenescence markers Galectin-3, Integrin beta 3 and Transforming growth factor beta-1 in plasma from pre-symptomatic and symptomatic transgenic animals while Apolipoprotein E differential plasma expression provided a good separation between fast and slow progressing ALS patients. These findings implicate immunosenescence and metabolism as novel targets for biomarkers and therapeutic discovery and suggest immunomodulation as an early intervention. The variance observed in the plasma proteomes may depend on different biological patterns of disease progression in human and animal model.
DDIS-21. KIF11 INHIBITORS FILANESIB AND ISPINESIB AS NOVEL AGENTS FOR MENINGIOMA THERAPY
Authors: Gerhard Jungwirth, Christine Jungk, Rolf Warta, Andreas Unterberg, Christel Herold-Mende
Journal: Neuro-Oncology (2018)

KIF11 is a highly conserved motor protein, which plays an important role in cell division by separating the spindle poles. KIF11 have been reported to be involved in multiple cancer types including melanoma, retinoblastoma, and glioma. In our previous studies, we found grade-specific expression levels of KIF11 in meningioma. Higher expression of KIF11 was associated with shorter progression-free survival and siRNA mediated knockdown inhibited the proliferation of two different meningioma cell lines in vitro. KIF11 inhibitors like Filanesib and Ispinesib are available and currently tested in phase II clinical trials for treatment of multiple myeloma. We investigated their potential benefit for treating meningiomas. To evaluate the potential of Filanesib and Ispinesib on meningioma cell lines, crystal violett assay was performed. Dose-curve analysis revealed IC50 values of less than 1 nM in the benign meningioma cell line Ben-Men-1 and the anaplastic cell line NCH93. Proliferation assay showed that single shot inhibitor dosage of 10 nM and higher led to an average inhibition of Ben-Men-1 cells by 58% and 66% on day 1 and 2 for Filanesib and by 63% and 60% for Ispinesib. NCH93 cells decreased their proliferation by 63% and 84% for Filanesib and by 67% and 89% for Ispinesib (p<.001). To explore the mechanism of diminished proliferation, we performed a FACS analysis. It revealed a G2/M block after treatment with Filanesib or Ispinesib compared to control in both cell lines (p<.001). Since KIF11 inhibition in other tumors have shown reduced cell migration, we performed a scratch assay. Treatment with KIF11 inhibitors resulted in reduced migration only in NCH93 cells compared to control after 8 and 12 hours by 20% and 85% (p<.05). Currently, we are testing KIF11 inhibitors in a xenograft mouse model. Taken together, KIF11 inhibitors Filanesib and Ispinesib could play a potential role in future meningioma therapy.
Abstract 17543: Endothelial Hif-1a,Inflammation,Hypertesion and Chronic Kidney Disease
Authors: Renna Luo, Chen Liu, Wei Wang, Hongli Lin, Lijian Tao, Rodney E. Kellems, Yang Xia
Journal: Circulation (2017)

Introduction: Hypertension and chronic kidney disease (CKD) drive each other and they are one of the most prevalent medical conditions with high morbidity and mortality in the United States and worldwide. Emerging evidence indicates that increased inflammatory response is involved in both hypertension and CKD. We and others have recently showed that persistently elevated HIF-1a in particular in endothelial cells contributes to hypertensive models induced by angiotension II, a potent vasoconstrictor. However, the role of endothelial HIF-1α in hypertension and CKD remains unidentified. Hypothesis: To determine the general significance of persistently elevated endothelial HIF-1 in hypertension and CKD, we used LIGHT, a new family member of TNF-α super family-infused hypertensive CKD mouse model. Methods: Six to twelve VE-cadherin cre+ mice and Hif-1αf/fVE-cadherin cre+ mice for each group were infused with LIGHT by minipump (4ng/day) and PBS as controls.. We collected urine for proteinuria analysis and measu...
ATIM-38. PHASE 2 STUDY TO EVALUATE THE CLINICAL EFFICACY AND SAFETY OF MEDI4736 (DURVALUMAB, DURVA) + BEVACIZUMAB (BEV) IN BEV-NAÏVE PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)
Authors: David Reardon, Thomas Kaley, Jorg Dietrich, Jennifer Clarke, Gavin Dunn, Michael Lim, Tim Cloughesy, Hui Gan, Andrew Park, Paul Schwarzenberger, Toni Ricciardi, Mary Macri, Aileen Ryan, Ralph Venhaus
Journal: Neuro-Oncology (2018)

Durva is a human IgG1 mAb against PD-L1. Blockade of PD-1/PD-L1 has shown benefit among solid tumors; data implicate PD-1/PD-L1 signaling as a significant contributor to immunosuppression in GBM. BEV is an approved angiogenesis inhibitor for recurrent GBM; angiogenesis inhibition may promote antitumor benefit of immunotherapies. A review showed that lower dose BEV resulted in longer PFS/OS than the standard. Ongoing Phase 2 open-label study (NCT02336165) evaluates safety and efficacy of durva (10mg/kg Q2W) in 5 GBM cohorts. Results are presented for Cohorts B2 (durva + BEV 10mg/kg Q2W) and B3 (durva +BEV 3mg/kg Q2W) in BEV-naïve recurrent GBM. Primary efficacy endpoint for Cohorts B2/B3 is 6-month progression-free survival (PFS6), by modified RANO per investigator assessment; secondary endpoints include safety/tolerability. Comparative benchmark for BEV in recurrent GBM is PFS6 of 42%. The null hypothesis (PFS6 ≤42%) was tested in Intent-to-Treat (ITT) population against the alternative hypothesis (PFS6 ≥62%). ITT includes patients receiving any dose of durva and having at least baseline and 1 post-baseline tumor assessment. Durva alone in Cohort B of this study demonstrated PFS6 of 20% (90% CI: 9.7, 33.0). As of 02Apr2018, 33 patients were treated in each cohort (B2, male: 54.5%, median age: 57.0 [40–74] years; B3, male: 60.6%, median age: 54.0 [23–73] years). Most common treatment-related adverse events (TRAEs, in ≥4 [12.1%] patients in either cohort): fatigue, dysphonia, increased ALT, AST, amylase, or lipase, diarrhea, hypertension, arthralgia, headache, and proteinuria. Incidences of TRAEs by maximum CTCAE grade (Gr) ≥3 for Cohorts B2/B3 were Gr3: 24.2/6.1%; Gr4: 0/6.1%; and Gr5: 0/0%. Kaplan-Meier estimate for PFS6 (n=33 each): B2, 15.2% (80% CI: 8.2, 24.0); B3, 21.1% (80% CI: 12.4, 31.4); 3 patients in each cohort showed partial response. The addition of durva to BEV did not improve on the outcome of durva alone.