tbuckley/cabot-search huggingface dataset:
Abstract A12: DNA methylation-based liquid biopsy detects primary and recurrent meningioma
Authors: Thais S. Sabedot, Tathiane M. Malta, James Snyder, Tobias Walbert, Ian Lee, Steven Kalkanis, Ana Valeria Castro, Houtan Noushmehr
Journal: Clinical Cancer Research (2020)

Abstract Meningiomas are mostly benign CNS tumors; however, a subset of these tumors may become atypical or malignant. The standard of care to monitor patients after diagnosis requires serial MRI assessments, which have limited value in distinguishing malignant tumors from benign disease. Therefore, the discovery of noninvasive methodologies that reflect meningioma tumor burden and its dynamic evolution in real-time is highly desirable. Liquid biopsy (LB) could be used to fine-tune surveillance and treatment with minimal risk to patients. Evidence of circulating tumor cells and cell-free (cf) tumor DNA in the blood has been shown in several tumor types; however, limited progress has been made for brain tumors with known biomarkers, possibly due to the unlikelihood of capturing point mutations in circulating DNA fragments. On the other hand, DNA methylation signatures are maintained even in small DNA fragments, which suggests that DNA methylation is an attractive marker to be studied in liquid biopsy of brain cancers. In order to identify DNA methylation-based biomarkers, we used archival serum and matching tissue specimens from primary (n=10) and recurrent (n=4) meningiomas. From isolated cfDNA from meningiomas and epileptic patients (n=5) as a control, we generated epigenetic data using Illumina Human EPIC array. cfDNA fragment size distribution revealed peaks with 150~200bp on average. We identified 482 CpGs (FDR&amp;lt;0.001) differentially methylated between primary meningiomas and controls, of which 294 (61%) show a DNA methylation profile similar to the epigenome of the matched tumor tissue. Overall, we observed that recurrent samples are hypermethylated (56%) compared to primary. From this pilot data, we were able to investigate the LB methylome of meningioma patients and identify potential markers to detect tumor cells in the serum of these patients, which could eventually allow clinicians to monitor impending disease progression and recurrence. Citation Format: Thais S. Sabedot, Tathiane M. Malta, James Snyder, Tobias Walbert, Ian Lee, Steven Kalkanis, Ana Valeria Castro, Houtan Noushmehr. DNA methylation-based liquid biopsy detects primary and recurrent meningioma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A12.
Fecal microbiota transplantation in alcohol related liver diseases
Authors: Saggere Muralikrishna Shasthry
Journal: Clinical and Molecular Hepatology (2020)

The current standard of care for severe alcoholic hepatitis (SAH) has several limitations in that only up to one-third of patients are eligible for steroid therapy. Additionally, steroids have their own issues: a portion of patients do not respond, while there is doubtful long-term benefit in those who do and a large proportion are ineligible to receive steroids entirely and hence have no definitive options for treatment. As such, there is a large gap between the problem and the available solutions. Alcohol causes dysbiosis and also disrupts gut barrier function, consequently promoting the translocation of microbial lipopolysaccharide into the portal circulation and liver. Therefore, probiotics, prebiotics, antibiotics, or transplantation of gut microbiota are likely to attenuate the dysbiosis-related liver insult. Fecal microbiota transplantation (FMT) is expected to have a role in managing alcoholic liver disease in general and SAH in particular by correcting dysbiosis, the primary insult. Results from mouse studies have suggested beyond doubt that alcohol-related liver injury is transferrable and also treatable by adopting FMT from suitable donors. Initial human trials from our center have affirmed benefits in human subjects with SAH as well, with both improvements in disease severity and as well as the rate of survival. Further studies addressing the head-to-head comparison of steroids and FMT are ongoing. Available preliminary data are promising and FMT and/or gut microbial modulation might become the standard of care in the near future for managing alcohol-related liver diseases, especially alcoholic hepatitis, with greater applicability, improved acceptability, and minimal side effects.
Chlorthalidone and Hydrochlorothiazide for Treatment of Patients With Hypertension
Authors: Franz H. Messerli, George C. Roush, Suzanne Oparil
Journal: JAMA Internal Medicine (2020)

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Upregulation of RIN3 induces endosomal dysfunction in Alzheimer’s disease
Authors: Ruinan Shen, Xiaobei Zhao, Lu He, Yongbo Ding, Wei Xu, Suzhen Lin, Savannah Fang, Wanlin Yang, Kijung Sung, Brian Spencer, Robert A. Rissman, Ming Lei, Jianqing Ding, Chengbiao Wu
Journal: Translational Neurodegeneration (2020)

Abstract Background In Alzheimer’s Disease (AD), about one-third of the risk genes identified by GWAS encode proteins that function predominantly in the endocytic pathways. Among them, the Ras and Rab Interactor 3(RIN3) is a guanine nucleotide exchange factor (GEF) for the Rab5 small GTPase family and has been implicated to be a risk factor for both late onset AD (LOAD) and sporadic early onset AD (sEOAD). However, how RIN3 is linked to AD pathogenesis is currently undefined. Methods Quantitative PCR and immunoblotting were used to measure the RIN3 expression level in mouse brain tissues and cultured basal forebrain cholinergic neuron (BFCNs). Immunostaining was used to define subcellular localization of RIN3 and to visualize endosomal changes in cultured primary BFCNs and PC12 cells. Recombinant flag-tagged RIN3 protein was purified from HEK293T cells and was used to define RIN3-interactomes by mass spectrometry. RIN3-interacting partners were validated by co-immunoprecipitation, immunofluorescence and yeast two hybrid assays. Live imaging of primary neurons was used to examine axonal transport of amyloid precursor protein (APP) and β-secretase 1 (BACE1). Immunoblotting was used to detect protein expression, processing of APP and phosphorylated forms of Tau. Results We have shown that RIN3 mRNA level was significantly increased in the hippocampus and cortex of APP/PS1 mouse brain. Basal forebrain cholinergic neurons (BFCNs) cultured from E18 APP/PS1 mouse embryos also showed increased RIN3 expression accompanied by early endosome enlargement. In addition, via its proline rich domain, RIN3 recruited BIN1(bridging integrator 1) and CD2AP (CD2 associated protein), two other AD risk factors, to early endosomes. Interestingly, overexpression of RIN3 or CD2AP promoted APP cleavage to increase its carboxyl terminal fragments (CTFs) in PC12 cells. Upregulation of RIN3 or the neuronal isoform of BIN1 increased phosphorylated Tau level. Therefore, upregulation of RIN3 expression promoted accumulation of APP CTFs and increased phosphorylated Tau. These effects by RIN3 was rescued by the expression of a dominant negative Rab5 (Rab5 S34N ) construct. Our study has thus pointed to that RIN3 acts through Rab5 to impact endosomal trafficking and signaling. Conclusion RIN3 is significantly upregulated and correlated with endosomal dysfunction in APP/PS1 mouse. Through interacting with BIN1 and CD2AP, increased RIN3 expression alters axonal trafficking and procession of APP. Together with our previous studies, our current work has thus provided important insights into the role of RIN3 in regulating endosomal signaling and trafficking.
COVID-19: can we learn from encephalitis lethargica?
Authors: Antonino Giordano, Ghil Schwarz, Laura Cacciaguerra, Federica Esposito, Massimo Filippi
Journal: The Lancet Neurology (2020)

In 1918, influenza caused one of the most severe pandemics in history. Encephalitis lethargica emerged at around the same time and affected more than one million individuals. It had a nonspecific prodromal phase, with influenza-like symptoms, and an acute phase, characterised by fever, sleepiness, ocular motility disturbances, and movement disorders. Months to years later, patients experienced subtle chronic neurological manifestations, mainly postencephalitic parkinsonism.1
Simulation across representation: The interplay of schemas and simulation-based inference on different levels of abstraction
Authors: Malte Schilling, Nancy Chang, Katharina J. Rohlfing, Michael Spranger
Journal: Behavioral and Brain Sciences (2020)

Abstract Language comprehension of action verbs recruits embodied representations in the brain that are assumed to invoke a mental simulation (e.g., “grasping a peanut”). This extends to abstract concepts, as well (“grasping an idea”). We, therefore, argue that mental simulation works across levels of abstractness and involves higher-level schematic structures that subsume a generic structure of actions and events.
Event-Free Survival, a Prostate-Specific Antigen–Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation
Authors: Wanling Xie, Meredith M. Regan, Marc Buyse, Susan Halabi, Philip W. Kantoff, Oliver Sartor, Howard Soule, Donald Berry, Noel Clarke, Laurence Collette, Anthony D’Amico, Richard De Abreu Lourenco, James Dignam, Mario Eisenberger, Nicholas James, Karim Fizazi, Silke Gillessen, Yohann Loriot, Nicolas Mottet, Wendy Parulekar, Howard Sandler, Daniel E. Spratt, Matthew R. Sydes, Bertrand Tombal, Scott Williams, Christopher J. Sweeney
Journal: Journal of Clinical Oncology (2020)

PURPOSE Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)–based composite end point, may further expedite trial completion. METHODS EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate–ICECaP–database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an R 2 ≥ 0.7. RESULTS Data for 10,350 patients were analyzed from 15 radiation therapy–based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall’s tau from a copula model. At the trial level, the R 2 was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS. CONCLUSION EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy–based trials.
AB0643 DRUG SURVIVAL OF SECUKINUMAB IN A SPONDYLOARTHRITIS COHORT. A 24 MONTHS MULTICENTRIC STUDY
Authors: P. Navarro Alonso, Á. García Martos, A. Castilla, L. González, M. D. C. Ortega, C. Arconada, A. Prada-Ojeda, L. Sala Icardo, L. Barrio Nogal, E. M. Andres, A. Diaz Oca
Journal: Annals of the Rheumatic Diseases (2020)

Background: Secukinumab inhibits the interaction between Interleukin 17A (IL-17A) and its receptor. Clinical trials have demonstrated good data in efficacy and safety in patients with spondyloarthritis (SpA) as first biological choice or inadecuate response to other biological in SpA. However there is few evidence in real clinical practice. Objectives: Evaluate the drug survival in a real clínical practice, as an indirect way to show the efficacy and security of Secukinumab at 24 months Methods: A multicentric observational, longitudinal, retrospective study of 24 months conducted in five Madrid hospitals (Spain). Patients older than 18 years treated with Secukinumab which fullfilled ASAS criteria for SpA and/or modified New York criteria for ankylosing spondylitis (AS) and/or CASPAR criteria for psoriatic arthritis (PsA) were included. For evaluation of the drug survival, dates from starting until closing date or definite withdrawal of the treatment were determined. Kaplan-Meier function was used to estimate the drug survival and Wilcoxon test for the comparison of the survival rate between the different diagnoses, because of the survival curves did not reach the median Results: A total of 71 patients were included. The mean age was 50.26 ys (SD 11.01), 57.75% women. 35 patients fullfilled classification criteria for PsA ant 36 fullfilled classification criteria for axSpA. 22 patients were naïve for biologic therapies and 49 patients had an inadecuate response to TNFi. 13 patients discontinued Secukinumab before the closing date, the main reason for the interruption was secondary failure (n= 6), and primary failure (n=2). Secukinumab survival rate was 81.95% up to 24 months in this cohort. The median of survival was 2.36 years (IC: 1.79-2.84). There were no significant differences about the drug survival related to diagnosis (p=0.976). The safety data were similar to those described in clinical trials. Conclusion: Secukinumab is an effective and safe treatment for the management of espondiloarthritis regardless of the subtypes, with a high survival rate. In this study naive patients show similar data obtained in clinical trials. In this cohort of patients, those who initiated secukinumab after failure to TNFi, showed a greater secukinumab survival than the data provided in clinical trials Disclosure of Interests: None declared
Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study
Authors: Lin Shen, Jun Guo, Qingyuan Zhang, Hongming Pan, Ying Yuan, Yuxian Bai, Tianshu Liu, Qing Zhou, Jun Zhao, Yongqian Shu, Xiaoming Huang, Siyang Wang, Jie Wang, Aiping Zhou, Dingwei Ye, Ting Sun, Yujuan Gao, Silu Yang, Zoubai Wang, Jian Li, Yi-Long Wu
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Tislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Methods The purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1. Results As of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types. Conclusions Tislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors. Trial registration number CTR20160872.
Abstract TMIM-077: MYXOMA VIRUS ENHANCES TREATMENT BENEFIT OF CHEMOTHERAPY AND DENDRITIC CELL IMMUNOTHERAPY IN OVARIAN CANCER PRECLINICAL MODEL
Authors: Steven J Conrad, Bernice Nounamo, Martin Cannon, Jia Liu
Journal: Clinical Cancer Research (2019)

Abstract Myxoma virus (MYXV) is a poxvirus with oncolytic and immunotherapeutic potential in many cancer models, including ovarian cancer (OC). Moreover, MYXV synergizes with chemotherapy including cisplatin for OC treatment. In this study, we used a p53-/- ID8 mouse model that closely portrays human high-grade serous OC to test MYXV virotherapy. We combined MYXV regime with cisplatin treatment and an innovative Th17-inducing dendritic cell (Th17-DC) vaccine currently being tested in clinical trials with OC patients. For DC immunotherapy, bone marrow-derived DC were pulsed with peptides from Sp17, a cancer testis antigen highly expressed in human OC and the ID8 mouse model. For MYXV virotherapy, we examined both wild-type and a replication-defective MYXV that is engineered without an essential viral immunomodulator called M062 (M062R-null MYXV). We found that inoculation with replication-competent MYXV improves survival when administered before cisplatin therapy. Interestingly, when the replication-defective M062R-null MYXV was used, improved survival was observed with virotherapy after the cisplatin treatment. We further found that M062R-null MYXV treatment provided long-lasting survival in combination with cisplatin and Th17-DC immunotherapy. Related studies showed that M062R-null MYXV infection in murine and primary human OC cells stimulated robust type I IFN expression and pro-inflammatory cytokines. Moreover, M062R-null MYXV activates type I IFN in macrophages and expression of inflammatory cytokines (e.g., CXCL-10 and IL-6). In conclusion, we propose that MYXV virotherapy provokes a type I interferon response and inflammatory cytokines that modulate the tumor microenvironment and enhance protective immune responses to Th17-DC vaccination for OC treatment. Citation Format: Steven J Conrad, Bernice Nounamo, Martin Cannon, Jia Liu. MYXOMA VIRUS ENHANCES TREATMENT BENEFIT OF CHEMOTHERAPY AND DENDRITIC CELL IMMUNOTHERAPY IN OVARIAN CANCER PRECLINICAL MODEL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-077.
Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers
Authors: Julia Remnestål, Linn Öijerstedt, Abbe Ullgren, Jennie Olofsson, Sofia Bergström, Kim Kultima, Martin Ingelsson, Lena Kilander, Mathias Uhlén, Anna Månberg, Caroline Graff, Peter Nilsson
Journal: Translational Neurodegeneration (2020)

Abstract Background The clinical presentations of frontotemporal dementia (FTD) are diverse and overlap with other neurological disorders. There are, as of today, no biomarkers in clinical practice for diagnosing the disorders. Here, we aimed to find protein markers in cerebrospinal fluid (CSF) from patients with FTD, presymptomatic mutation carriers and non-carriers. Methods Antibody suspension bead arrays were used to analyse 328 proteins in CSF from patients with behavioural variant FTD (bvFTD, n = 16) and progressive primary aphasia (PPA, n = 13), as well as presymptomatic mutation carriers (PMC, n = 16) and non-carriers (NC, n = 8). A total of 492 antibodies were used to measure protein levels by direct labelling of the CSF samples. The findings were further examined in an independent cohort including 13 FTD patients, 79 patients with Alzheimer’s disease and 18 healthy controls. Results We found significantly altered protein levels in CSF from FTD patients compared to unaffected individuals (PMC and NC) for 26 proteins. The analysis show patterns of separation between unaffected individuals and FTD patients, especially for those with a clinical diagnosis of bvFTD. The most statistically significant differences in protein levels were found for VGF, TN-R, NPTXR, TMEM132D, PDYN and NF-M. Patients with FTD were found to have higher levels of TN-R and NF-M, and lower levels of VGF, NPTXR, TMEM132D and PDYN, compared to unaffected individuals. The main findings were reproduced in the independent cohort. Conclusion In this pilot study, we show a separation of FTD patients from unaffected individuals based on protein levels in CSF. Further investigation is required to explore the CSF profiles in larger cohorts, but the results presented here has the potential to enable future clinical utilization of these potential biomarkers within FTD.
Extracellular-Regulated Protein Kinase 5-Mediated Control of p21 Expression Promotes Macrophage Proliferation Associated with Tumor Growth and Metastasis
Authors: Emanuele Giurisato, Silvia Lonardi, Brian Telfer, Sarah Lussoso, Blanca Risa-Ebrí, Jingwei Zhang, Ilaria Russo, Jinhua Wang, Annalisa Santucci, Katherine G. Finegan, Nathanael S. Gray, William Vermi, Cathy Tournier
Journal: Cancer Research (2020)

The presence of immunosuppressive macrophages that become activated in the tumor microenvironment constitutes a major factor responsible for tumor growth and malignancy. In line with this knowledge, we report here that macrophage proliferation is a significant feature of advanced stages of cancer. Moreover, we have found that a high proportion of proliferating macrophages in human tumors express ERK5. ERK5 was required for supporting the proliferation of macrophages in tumor grafts in mice. Furthermore, myeloid ERK5 deficiency negatively impacted the proliferation of both resident and infiltrated macrophages in metastatic lung nodules. ERK5 maintained the capacity of macrophages to proliferate by suppressing p21 expression to halt their differentiation program. Collectively, these data provide insight into the mechanism underpinning macrophage proliferation to support malignant tumor development, thereby strengthening the value of ERK5-targeted therapies to restore antitumor immunity through the blockade of protumorigenic macrophage activation. SIGNIFICANCE: These findings offer a new rationale for anti-ERK5 therapy to improve cancer patient outcomes by blocking the proliferative activity of tumor macrophages.