tbuckley/cabot-search huggingface dataset:
Tumor Microenvironment Responsive Biodegradable Fe‐Doped MoO<i><sub>x</sub></i> Nanowires for Magnetic Resonance Imaging Guided Photothermal‐Enhanced Chemodynamic Synergistic Antitumor Therapy
Authors: Yusheng Chen, Mengluan Gao, Lingjian Zhang, Enna Ha, Xin Hu, Rujia Zou, Li Yan, Junqing Hu
Journal: Advanced Healthcare Materials (2020)

Rational design of nanosystems that target tumor microenvironment have attracted widespread attention. However, it is still a great challenge to make a multifunctional nanoplatform that actively and selectively interacts with tumor microenvironment, without causing toxicity to surrounding normal tissues. Herein, the biodegradable Fe-doped MoOx (FMO) nanowires are designed as an anti-tumor nanoreagent that possesses great photothermal conversion ability (48.5%) and magnetic properties for T1 weighted magnetic resonance imaging (MRI). Also, FMO can be used as a chemodynamic therapy (CDT) reagent to effectively catalyze the decomposition of H2 O2 and produce hydroxyl radical (·OH). At the same time, the consumption of glutathione will also enhance the CDT effect. More importantly, FMO presents pH-dependent degradation behavior: rapid degradation at physiological pH, but relatively stable at acidic pH. In vivo anti-tumor experiment demonstrates that the FMO is able to effectively inhibit the tumor growth with minimal side effects. Generally speaking, these results indicate that the FMO has huge potential for MRI image-guided cancer therapy and promotes the clinical translation of nanodrugs.
Abstract 10764: Defining Cardiogenic Shock and Pre-shock in the Cardiac Intensive Care Unit
Authors: Jacob C Jentzer, Sean Van Diepen, Barry Burstein, Gregory W Barsness, Timothy Henry, Venu Menon, Srihari S Naidu, David A Baran
Journal: Circulation (2019)

Background: Cardiogenic shock is defined as hypotension (HT) with end-organ hypoperfusion (HP); normotensive patients with HP are classified as pre-shock. We sought to describe the incremental prog...
QOL-46. LATE EFFECTS CARE FOR CHILDHOOD BRAIN TUMOUR SURVIVORS: A QUALITY IMPROVEMENT PROJECT
Authors: Chantel Cacciotti, Adam Fleming, JoAnn Duckworth, Hanna Tseitlin, Loretta Anderson, Stacey Marjerrison
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Childhood and adolescent brain tumor survivors are at risk for considerable late morbidity and mortality from their disease and the treatment they receive. Surgery, chemotherapy, radiation therapy and tumor location all have the potential to impact the physical, psychological, functional and social health of these survivors. Comprehensive late effects care may mitigate these risks, but the necessary elements of this care model is unclear. We describe a quality-improvement initiative to improve the long-term follow-up (LTFU) care provided to brain tumour survivors at the McMaster Children’s Hospital. METHODS An anonymous needs assessment circulated to health providers was used to evaluate the LTFU practices. Utilizing this feedback as well as the LTFU guidelines from the Children’s Oncology Group a care plan was made for these survivors. RESULTS 17 of 33 (52%) health care staff responded to the survey, this included 70% physicians or nurse practitioners, and 30% nurses and allied health staff. Improvements suggested included consistent inclusion of additional care providers (i.e. social work, dietitians, endocrinology) reported by 76%, as well as a need for improved patient education and surveillance for late effects of therapy. CONCLUSION Treatment summaries with surveillance care plans and LTFU resources were created for all survivors of childhood brain tumours at risk of treatment-related complications. Late effects counselling with distribution of these materials is ongoing as part of this quality improvement initiative. To provide comprehensive management, a neuro-oncology specific late effects programs with multi-disciplinary support is essential for the care of brain tumour survivors.
Trajectories of anxiety and depressive symptoms during enforced isolation due to COVID-19 in England: a longitudinal observational study
Authors: Daisy Fancourt, Andrew Steptoe, Feifei Bu
Journal: The Lancet Psychiatry (2020)

SummaryBackgroundThere is major concern about the impact of the global COVID-19 outbreak on mental health. Several studies suggest that mental health deteriorated in many countries before and during enforced isolation (ie, lockdown), but it remains unknown how mental health has changed week by week over the course of the COVID-19 pandemic. This study aimed to explore the trajectories of anxiety and depression over the 20 weeks after lockdown was announced in England, and compare the growth trajectories by individual characteristics.MethodsIn this prospective longitudinal observational study, we analysed data from the UCL COVID-19 Social Study, a panel study weighted to population proportions, which collects information on anxiety (using the Generalised Anxiety Disorder assessment) and depressive symptoms (using the Patient Health Questionnaire) weekly in the UK since March 21, 2020. We included data from adults living in England who had at least three repeated measures between March 23 and Aug 9, 2020. Analyses were done using latent growth models, which were fitted to account for sociodemographic and health covariates.FindingsBetween March 23, and Aug 9, data from over 70 000 adults were collected in the UCL COVID-19 Social Study. When including participants living in England with three follow-up measures and no missing values, our analytic sample consisted of 36 520 participants. The average depression score was 6·6 (SD=6·0, range 0–27) and the average anxiety score 5·7 (SD=5·6, range 0–21) in week 1. Anxiety and depression levels both declined across the first 20 weeks following the introduction of lockdown in England (b=–1·93, SE=0·26, p<0·0001 for anxiety; b=–2·52, SE=0·28, p<0·0001 for depressive symptoms). The fastest decreases were seen across the strict lockdown period (between weeks 2 and 5), with symptoms plateauing as further lockdown easing measures were introduced (between weeks 16 and 20). Being a woman or younger, having lower educational attainment, lower income, or pre-existing mental health conditions, and living alone or with children were all risk factors for higher levels of anxiety and depression at the start of lockdown. Many of these inequalities in experiences were reduced as lockdown continued, but differences were still evident 20 weeks after the start of lockdown.InterpretationThese data suggest that the highest levels of depression and anxiety occurred in the early stages of lockdown but declined fairly rapidly, possibly because individuals adapted to circumstances. Our findings emphasise the importance of supporting individuals in the lead-up to future lockdowns to try to reduce distress, and highlight that groups already at risk for poor mental health before the pandemic have remained at risk throughout lockdown and its aftermath.FundingNuffield Foundation, UK Research and Innovation, Wellcome Trust.
Abstract 15545: Incidence and Costs Associated With 30-Day Unplanned Readmission in Relation to MI Presentation With NSTEMI versus STEMI in the United States: A Population-Based Cohort Study
Authors: Karthik Seetharam, Annapoorna Kini, Roxana Mehran, Jacqueline E Tamis-Holland, Matthew Tomey, Nitin Barman, Jeffrey Bander, Joseph Sweeny, George Dangas, Samin K Sharma, Usman Baber
Journal: Circulation (2019)

Background: Population-based estimates quantifying readmission rates and costs in patients hospitalized with acute myocardial infarction (AMI) in relation to AMI type (NSTEMI versus STEMI) are lack...
A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD
Authors: Robert Toto, Jeffrey Petersen, Jeffrey S. Berns, Eldrin Foster Lewis, Qui Tran, Matthew R. Weir
Journal: Journal of the American Society of Nephrology (2020)

Background Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure—while reducing the need for red blood cell transfusions—is unknown. Methods In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µ g/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician. Results There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µ g) compared with the titration-dose group (53. 6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µ g and 53.6 (31.1, 89.9) µ g, respectively; the median of the difference between treatment groups was −22.1 (95% CI, −26.1 to −18.1) µ g. Conclusions These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.
RADT-40. TRENDS IN THE USE OF RADIATION FOR MENINGIOMA ACROSS THE UNITED STATES
Authors: Hirsch Matani, Stephen Abel, Linda Xu, Alexander Yu, Tulika Ranjan, Stephen Karlovits, Rodney Wegner
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Meningiomas are tumors originating from arachnoid cap cells on the surface of the brain or spinal cord. Treatment differs by grade but can consist of surgery, radiation therapy or both. We utilized the national cancer database (NCDB) to compare trends in the use stereotactic radiosurgery (SRS) and external beam radiation therapy (EBRT) in the management of meningioma. METHODS We queried the NCDB from 2004-15 for meningioma patients (Grade 1-3) treated with radiation therapy, either SRS or EBRT. Multivariable logistic regression was used to identify predictors of each treatment and to generate a propensity score. Propensity adjusted Kaplan-Meier survival curve analysis and multivariable cox hazards ratios were used to identify predictors of survival. RESULTS We identified 5406 patients with meningioma meeting above criteria. Median follow up was 43 months. 45%, 44%, and 11% were Grade 1, 2, and 3, respectively. Predictors for SRS were distance from treatment facility and histology. Predictors of EBRT were tumor size and WHO grade 2 or 3 disease. Tumor size, treatment year, and receipt of chemotherapy were associated with improved survival. Five and ten year survival rates were 89.2% vs. 72.6% (p &amp;lt; 0.0001) and 80.3% vs. 61.4% (p = 0.29) for SRS and EBRT respectively. After propensity matching 226 pairs were generated. For SRS, 5 year survival was not significantly improved at 88.2% (p = 0.056) CONCLUSIONS In the present analysis, predictors of SRS utilization in management of meningioma include distance from treatment facility and histology whereas conventional EBRT utilization was associated with tumor size and grade 2 or 3 disease. Despite a possible survival benefit with SRS, inherent selection bias may confound interpretation of the apparent survival benefit reflected in our study.
Combined ERCP and transhepatic endoscopic ultrasound-guided stent placement for biliary drainage in malignant hilar obstruction: not too good to be true
Authors: Manuel Perez-Miranda
Journal: Endoscopy (2020)

Palliative biliary drainage is the mainstay of treatment for malignant hilar biliary obstruction (MHBO). Unresectable MHBO includes varying degrees of anatomical complexity, defined by the Bismuth classification. Higher Bismuth grades correspond to greater involvement of main and segmental hepatic bile ducts bilaterally. Complete drainage of complex MHBO improves patient outcomes; however, complete drainage in high-grade MHBO is not only difficult to achieve but also difficult to maintain, as clogging and ingrowth result in limited stent patency. Given the technical challenges in draining multiple intrahepatic ducts, endoscopic retrograde cholangiopancreatography (ERCP) is often combined with percutaneous transhepatic biliary drainage (PTBD) in complex MHBO or avoided altogether in favor of PTBD as the primary drainage method. PTBD generally achieves more effective biliary drainage than ERCP in complex MHBO, but incurs the expense of patient discomfort and decreased quality of life. In addition to the difficulties attributed to achieving initial biliary drainage in MHBO, subsequent stent dysfunction is common and challenging to manage.
DIPG-07. HIGH THROUGHPUT DRUG SCREENING IDENTIFIES POTENTIAL NEW THERAPIES FOR DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGs)
Authors: Dannielle Upton, Santosh Valvi, Jie Liu, Nicole Yeung, Sandra George, Caitlin Ung, Aaminah Khan, Laura Franshaw, Anahid Ehteda, Han Shen, Isabella Orienti, Giovanna Farruggia, Christa Nath, Patrick Reynolds, Maria Tsoli, David Ziegler
Journal: Neuro-Oncology (2020)

Abstract DIPGs are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12 months. There is an urgent need for novel effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,500 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds- auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine- that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in-vitro. To determine whether the in-vitro efficacy could be replicated in-vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different Fenretinide formulations (LYM-X-Sorb and NanoMicelle) which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG.
DDRE-06. CELLULAR STRESS RESPONSE IN DIPG THERAPY
Authors: Sreepradha Sridharan, Arif Harmanci, Robert Siddaway, Tara Dobson, Jyothishmathi Swaminathan, Ajay Sharma, Rohinton S Tarapore, Joshua Allen, Cynthia Hawkins, Soumen Khatua, Wafik Zaky, Vidya Gopalakrishnan
Journal: Neuro-Oncology (2020)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor of the pons and brainstem. Therefore, there is a desperate need for new therapeutics. Genomic profiling of tumors identified a highly prevalent dominant negative somatic mutation at lysine (K)-27 in histone genes HIST1H3B and H3F3A. Clonal evolution modeling suggests these mutations are truncal, and studies have demonstrated their contribution to tumorigenesis. ONC201, a first-in-class DRD2 antagonist and ClpP agonist is an anticancer drug developed by Oncoceutics, which targets the unfolded protein response (UPR) and integrated stress response (ISR) signaling and is actively being investigated in patients with recurrent H3 K27M-mutant gliomas. In adults with recurrent glioma, single agent studies showed benign-safety, no dose-limiting toxicities and a durable objective response when administered orally. In addition, intra-tumoral drug levels exceeded therapeutic thresholds, and induced tumor cell apoptosis. Based on this and response seen in a pediatric patient with DIPG for whom compassionate use of ONC201 was approved, a multi-arm, non-randomized multi-institutional Phase I clinical trial (NCT03416530) is actively accruing patients. However, the strength of UPR and ISR in DIPGs and their effect on DIPG response to ONC201 is not known. Our group employed bulk/single cell transcriptomic and single cell proteomic approaches to demonstrate substantial heterogeneity in UPR and ISR signaling in human DIPG samples. Consistent with this, DIPG cell lines exhibited considerable variability in sensitivity to ONC201. Single cell profiling identified tumor sub-populations with significant proliferative capacity even after ONC201 exposure. Incomplete response promotes recurrence. To target these cells, we performed a synthetic lethality screen with a library of 360 FDA-approved CNS penetrant compounds, which identified HDAC inhibitors and DNA damage-inducing chemotherapy as having synergy with ONC201. Thus, we suggest that tumor heterogeneity impacts sensitivity to ONC201 and that this can be reduced by combination treatments.
Degree of Functional Divergence in Duplicates Is Associated with Distinct Roles in Plant Evolution
Authors: Akihiro Ezoe, Kazumasa Shirai, Kousuke Hanada
Journal: Molecular Biology and Evolution (2020)

Abstract Gene duplication is a major mechanism to create new genes. After gene duplication, some duplicated genes undergo functionalization, whereas others largely maintain redundant functions. Duplicated genes comprise various degrees of functional diversification in plants. However, the evolutionary fate of high and low diversified duplicates is unclear at genomic scale. To infer high and low diversified duplicates in Arabidopsis thaliana genome, we generated a prediction method for predicting whether a pair of duplicate genes was subjected to high or low diversification based on the phenotypes of knock-out mutants. Among 4,017 pairs of recently duplicated A. thaliana genes, 1,052 and 600 are high and low diversified duplicate pairs, respectively. The predictions were validated based on the phenotypes of generated knock-down transgenic plants. We determined that the high diversified duplicates resulting from tandem duplications tend to have lineage-specific functions, whereas the low diversified duplicates produced by whole-genome duplications are related to essential signaling pathways. To assess the evolutionary impact of high and low diversified duplicates in closely related species, we compared the retention rates and selection pressures on the orthologs of A. thaliana duplicates in two closely related species. Interestingly, high diversified duplicates resulting from tandem duplications tend to be retained in multiple lineages under positive selection. Low diversified duplicates by whole-genome duplications tend to be retained in multiple lineages under purifying selection. Taken together, the functional diversities determined by different duplication mechanisms had distinct effects on plant evolution.
NIMG-13. GENETIC, CELLULAR, AND CONNECTOMIC CHARACTERIZATION OF THE ADULT HUMAN BRAIN REGIONS COMMONLY PLAGUED BY GLIOMA
Authors: Ayan Mandal, Rafael Romero-Garcia, Michael Hart, John Suckling
Journal: Neuro-Oncology (2020)

Abstract For decades, it has been known that gliomas follow a nonrandom spatial distribution, appearing more often in some brain regions (e.g. the insula) compared to others (e.g. the occipital lobe). A better understanding of the glioma localization patterns could lend clues to the origins of these types of tumors, and consequently inform treatment targets. Following hypotheses derived from prior research into neuropsychiatric disease and cancer, gliomas may be expected to localize to brain regions characterized by functional hubness, stem-like cells, and transcription of genetic drivers of gliomagenesis. We combined neuroimaging data from 335 adult patients with high- and low-grade glioma to form a replicable tumor frequency map. Using this map, we demonstrate that glioma frequency is elevated in association cortex and correlated with multiple graph-theoretical metrics of high functional connectedness. Brain regions populated with putative cells-of-origin for glioma, neural stem cells and oligodendrocyte precursor cells, exhibited a high glioma frequency. Leveraging a human brain atlas of post-mortem gene expression, we found that gliomas were localized to brain regions enriched with expression of genes associated with chromatin organization and synaptic signaling. A set of glioma proto-oncogenes was enriched among the transcriptomic correlates of glioma distribution. Finally, a regression model incorporating connectomic, cellular, and genetic factors explained 58% of the variance in glioma frequency. These results add to previous literature reporting the vulnerability of hub regions to neurological disease, as well as provide support for cancer stem cell theories of glioma. Our findings illustrate how factors of diverse scale, from genetic to connectomic, can independently influence the anatomic localization of brain dysfunction.
Targeted delivery of extracellular vesicles in heart injury
Authors: Peier Chen, Ling Wang, Xianglin Fan, Xiaodong Ning, Bin Yu, Caiwen Ou, Minsheng Chen
Journal: Theranostics (2020)

Extracellular vesicles (EVs) are nanoscale extracellular vesicles derived from endocytosis that are crucial to intercellular communication.EVs possess natural biocompatibility and stability that allow them to cross biological membranes and that protect them from degradation.Recent studies have shown that EVs-mediated crosstalk between different cell types in the heart could play important roles in the maintenance of cardiac homeostasis and the pathogenesis of heart diseases.In particular, EVs secreted by different types of stem cells exhibit cardioprotective effects.However, numerous studies have shown that intravenously injected EVs are quickly cleared by macrophages of the mononuclear phagocyte system (MPS) and preferentially accumulate in MPS organs such as the liver, spleen, and lung.In this review, we discuss exosome biogenesis, the role of EVs in heart diseases, and challenges in delivering EVs to the heart.Furthermore, we extensively discuss the targeted delivery of EVs for treating ischemic heart disease.These understandings will aid in the development of effective treatment strategies for heart diseases.