tbuckley/cabot-search huggingface dataset:
NIMG-03. DEEP LEARNING SURVIVAL ANALYSIS FOR MULTIPLE BRAIN METASTASES
Authors: Enoch Chang, Marina Joel, Hannah Chang, Justin Du, James Yu, Yi An, James Hansen, Antonio Omuro, Veronica Chiang, Sanjay Aneja
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Deep learning survival models show promise for outcome prediction by leveraging the ability to model non-linear relationships between pixel-level imaging predictors and survival data. We hypothesized that a deep learning survival model derived from quantitative imaging predictors would be more effective than traditional models of survival in patients with brain metastases. METHODS We analyzed 831 patients with 3596 total brain metastases treated with primary stereotactic radiosurgery at our institution between 2000-2018. The primary outcome of interest was overall survival following treatment. 851 3D radiomic features were extracted from T1 post contrast MRI images of each brain metastasis and aggregated per patient. Minimum redundancy maximum relevance was used for dimensionality reduction. Relevant features were trained on DeepSurv (Cox proportional hazard neural network architecture) to model overall survival. The disease-specific Graded Prognostic Assessment which uses age, Karnofsky performance status, presence of extracranial metastases, number of brain metastases, and disease-specific molecular characteristics was used as our traditional model. Discriminatory ability between models was assessed with concordance indices (c-index) using 100 bootstrapped samples of 415 patients and evaluated for statistical significance in difference with the 2-sample t-test. RESULTS Median overall survival was 13 months, median age was 63 years, and the most common primary sites were NSCLC (38.5%), melanoma (18.9%), breast (14.9%), SCLC (7.2%), renal (5.3%), and GI (4.7%). The deep learning model using radiomic imaging features (c-index: 0.848, 95% CI [0.811, 0.877]) had superior discriminatory ability compared to the GPA (c-index: 0.380, 95% CI [0.356, 0.403]). Performance was significantly improved with p&amp;lt; 0.001 on the 2-sample t-test. CONCLUSIONS A deep learning model using quantitative radiomic imaging features performed better than a traditional linear model using clinical predictors at modeling survival in patients with multiple brain metastases. This represents a promising method to improve prognostication for patients diagnosed with brain metastases.
Gastroparesis – too complicated for a simplistic therapeutic approach
Authors: Thomas Frieling
Journal: Endoscopy (2020)

See also:Gastric peroral endoscopic pyloromyotomy versus gastric electrical stimulation in the treatment of refractory gastroparesis: a propensity score-matched analysis of long term outcomesEndoscopy 2020; 52(05): 349-358DOI: 10.1055/a-1111-8566See also:Response to Dr. FrielingEndoscopy 2021; 53(01): 99-99DOI: 10.1055/a-1214-6170
IMMU-08. reMATCH PROTOCOL: PHASE II STUDY OF EX-VIVO EXPANDED AUTOLOGOUS TUMOR SPECIFIC LYMPHOCYTE TRANSFER (X-ALT) + TOTAL TUMOR RNA DC VACCINE (TT-RNA DC) DURING RECOVERY FROM MYELOABLATIVE CHEMOTHERAPY (MAC) AND PERIPHERAL BLOOD STEM CELL (PBSC) RESCUE OR NON-MYELOABLATIVE CHEMOTHERAPY (NMAC) AND PBSC IN PATIENTS (PTS) WITH RECURRENT PNET (R-PNET)
Authors: Sridharan Gururangan, Eugene Hwang, Girish Dhall, Oleg Yegorov, Lance Governale, Jason Blatt, Biljana Horn, Duane Mitchell
Journal: Neuro-Oncology (2020)

Abstract A phase II study was performed to assess vaccine-related toxicities and efficacy of x-ALT+tt-RNA DC following MAC +PBSC (group A) or NMAC +PBSC (group B) in pts with r-PNET. METHODS: Eligible pts underwent biopsy to confirm r-PNET and obtain tumor for vaccine preparation. Pts with local (group A) or metastatic (group B) disease received cytoreductive induction chemotherapy prior to either MAC (carboplatin+ thiotepa+ etoposide) or NMAC (cyclophosphamide + fludarabine) respectively and then received one dose of x-ALT (3 x 107cells/kg), PBSC, and 3 doses of bi-weekly intradermal tt-RNA DCs (107cells each). Patients were followed for survival and vaccine-related toxicities. Correlative studies included TCR RNA sequencing and measurement of serum cytokines. RESULTS: 20 evaluable pts (75% males) [Medulloblastoma 17, PNET 3; unifocal 40%] were treated on protocol (group A 7, group B 13). There were no significant vaccine-related toxicities. At a median follow-up of 8.5 months, 5 patients (all with medulloblastoma) are alive following vaccine therapy; 2 pts with SD (3.5+ and 6.5+ months) and 3 pts with PD that stabilized with salvage therapies (26+, 31+, and 46+ months respectively). One patient with medulloblastoma and bone marrow involvement who had PD despite MAC, had an almost complete response one month following x-ALT + tt-RNA DCs and TCR RNA sequencing demonstrated massive clonal expansion of T cells. Correlative studies are ongoing. CONCLUSIONS: x-ALT+tt-RNA DC following either MAC or NMAC is safe and shows signs of biologic and possible clinical activity in some pts with r-PNET.
TAMI-53. THE ONCOMETABOLITE D-2HG INDUCE INFLAMMATORY ASTROGLIOSIS CAUSING NEUROTOXICITY AND SEIZURES IN IDH MUTATED GLIOMA
Authors: Simon Behringer, Vidhya Ravi, Kevin Joseph, Juergen Beck, Oliver Schnell, Dieter Heiland
Journal: Neuro-Oncology (2020)

Abstract The role of tumor-associated astrocytes in the microenvironment of glioma has long been underestimated but is moving into the focus of current research. We explored the role of reactive astrocytes in IDH-mutated glioma using RNA-sequencing of purified astrocytes and microglia and single-nucleus RNA-sequencing of infiltrating tumor regions. Mapping of the transcriptional phenotype of astrocytes along developmental and reactive trajectories revealed an inflammatory transformation of IDH-mutated associated astrocytes. The major proportion of astrocytes is marked by complement-activation similar to findings in neuroinflammatory diseases. A human neocortical slices model with injected IDH-mutated patient-derived cells or D-2HG treatment (+/- microglia depletion) was used to map shared and unique transcriptional adaptation in astrocytes promoted by either tumor cells or metabolic alteration. High-dimensional electrophysiological profiling was used to investigate alterations in neural response to tumor-induced microenvironmental transformation. We showed that 2HG alone promote the inflammatory pattern of astrocytes, which causes neurotoxicity and seizures in our neocortical slice model. Depletion of microglia rescued the neurotoxicity suggesting that microglia predominantly drive inflammatory astrogliosis as a response to metabolic alteration the tumor environment. We showed that neurotoxic astrogliosis induced by the oncometabolite D-2HG via distinct microglia activation promote the evolution of frequently observed seizures in IDH-mutated glioma patients.
Challenges and strategies for in situ endothelialization and long-term lumen patency of vascular grafts
Authors: Yu Zhuang, Chenglong Zhang, Mengjia Cheng, Jinyang Huang, Qingcheng Liu, Guangyin Yuan, Kaili Lin, Hongbo Yu
Journal: Bioactive Materials (2020)

Vascular diseases are the most prevalent cause of ischemic necrosis of tissue and organ, which even result in dysfunction and death. Vascular regeneration or artificial vascular graft, as the conventional treatment modality, has received keen attentions. However, small-diameter (diameter < 4 mm) vascular grafts have a high risk of thrombosis and intimal hyperplasia (IH), which makes long-term lumen patency challengeable. Endothelial cells (ECs) form the inner endothelium layer, and are crucial for anti-coagulation and thrombogenesis. Thus, promoting in situ endothelialization in vascular graft remodeling takes top priority, which requires recruitment of endothelia progenitor cells (EPCs), migration, adhesion, proliferation and activation of EPCs and ECs. Chemotaxis aimed at ligands on EPC surface can be utilized for EPC homing, while nanofibrous structure, biocompatible surface and cell-capturing molecules on graft surface can be applied for cell adhesion. Moreover, cell orientation can be regulated by topography of scaffold, and cell bioactivity can be modulated by growth factors and therapeutic genes. Additionally, surface modification can also reduce thrombogenesis, and some drug release can inhibit IH. Considering the influence of macrophages on ECs and smooth muscle cells (SMCs), scaffolds loaded with drugs that can promote M2 polarization are alternative strategies. In conclusion, the advanced strategies for enhanced long-term lumen patency of vascular grafts are summarized in this review. Strategies for recruitment of EPCs, adhesion, proliferation and activation of EPCs and ECs, anti-thrombogenesis, anti-IH, and immunomodulation are discussed. Ideal vascular grafts with appropriate surface modification, loading and fabrication strategies are required in further studies.
59P Real-world data of immunotherapy in patients over 65 years old with lung cancer
Authors: B. Nuñez-Garcia, Y. Garitaonaindía Díaz, M. Martinez-Cutillas, M. Blanco, R. Aguado, A.M. Morito Aguilar, C. Traseira, G. Visedo, V. Calvo, F. Franco, M. Provencio Pulla
Journal: Annals of Oncology (2020)
Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms
Authors: Antonio Inserra, Danilo De Gregorio, Gabriella Gobbi
Journal: Pharmacological Reviews (2020)

Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT<sub>2A</sub> and 5-HT<sub>1A</sub> receptors) and glutamatergic [via <i>N</i>-methyl-d-aspartate (NMDA) and <i>α</i>-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin–, brain-derived neurotrophic factor–, and early growth response–related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-<i>α</i> and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds. <h3>Significance Statement</h3> Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.
SARS-CoV-2 infection and adverse outcomes in users of ACE inhibitors and angiotensin-receptor blockers: a nationwide case-control and cohort analysis
Authors: Christian Fynbo Christiansen, Anton Pottegård, Uffe Heide-Jørgensen, Jacob Bodilsen, Ole Schmeltz Søgaard, Michael Maeng, Simon Tilma Vistisen, Morten Schmidt, Lars Christian Lund, Mette Reilev, Jesper Hallas, Marianne Voldstedlund, Anders Husby, Marianne Kragh Thomsen, Nanna Borup Johansen, Nikolai Constantin Brun, Reimar Wernich Thomsen, Hans Erik Bøtker, Henrik Toft Sørensen
Journal: Thorax (2020)

To examine the impact of ACE inhibitor (ACE-I)/angiotensin receptor blocker (ARB) use on rate of SARS-CoV-2 infection and adverse outcomes. This nationwide case-control and cohort study included all individuals in Denmark tested for SARS-CoV-2 RNA with PCR from 27 February 2020 to 26 July 2020. We estimated confounder-adjusted ORs for a positive test among all SARS-CoV-2 tested, and inverse probability of treatment weighted 30-day risk and risk ratios (RRs) of hospitalisation, intensive care unit (ICU) admission and mortality comparing current ACE-I/ARB use with calcium channel blocker (CCB) use and with non-use. The study included 13 501 SARS-CoV-2 PCR-positive and 1 088 695 PCR-negative individuals. Users of ACE-I/ARB had a marginally increased rate of a positive PCR when compared with CCB users (aOR 1.17, 95% CI 1.00 to 1.37), but not when compared with non-users (aOR 1.00 95% CI 0.92 to 1.09).Among PCR-positive individuals, 1466 (11%) were ACE-I/ARB users. The weighted risk of hospitalisation was 36.5% in ACE-I/ARB users and 43.3% in CCB users (RR 0.84, 95% CI 0.70 to 1.02). The risk of ICU admission was 6.3% in ACE-I/ARB users and 5.4% in CCB users (RR 1.17, 95% CI 0.64 to 2.16), while the 30-day mortality was 12.3% in ACE-I/ARB users and 13.9% in CCB users (RR 0.89, 95% CI 0.61 to 1.30). The associations were similar when ACE-I/ARB users were compared with non-users. ACE-I/ARB use was associated neither with a consistently increased rate nor with adverse outcomes of SARS-CoV-2 infection. Our findings support the current recommendation of continuing use of ACE-Is/ARBs during the SARS-CoV-2 pandemic. EUPAS34887.
Greetings from the editor 2021
Authors: Josef S Smolen
Journal: Annals of the Rheumatic Diseases (2020)

The year just past, 2020, will be remembered as the year COVID-19, elicited by SARS-CoV-2, was recognised as a pandemic, with about 120 000 reported cases and 4000 deaths globally around the ides of March.1 Since then, a huge burden of morbidity and especially mortality has accrued, soon to exceed 65 million infected persons and 1.5 million deaths worldwide.2 Numerous challenges have arisen, including inconsistent, frequently unpredictable and often indifferent, even frivolous approaches of politicians to the problem and varying attitudes espoused by leading experts in epidemiology and/or infectious diseases (eg, ‘masks don’t help’ vs ‘masks are very important’; or ‘aim for herd immunity’ vs ‘herd immunity will not occur without a vaccine’; or ‘lockdown is a must’ vs ‘no lockdown needed’). Together this has been confusing, distressing and worrisome in light of overflowing intensive care units and mass funerals in many regions of the world.

As these greetings were being written, the first vaccine, an mRNA vaccine currently named BNT162b2, has been announced effective and safe, developed by a German company, BioNtech, tested in a trial performed by a US company, Pfizer,3 and using lipid nanoparticles for vaccine delivery provided by an Austrian company, Polymun4—a great success of European and transcontinental collaboration. The efficacy and safety of more vaccines have been or are soon to be revealed.

European and global collaboration was indeed also wonderful to see among rheumatologists during these first months of the COVID-19 pandemic. International databases to register patients with COVID-19 with rheumatic and musculoskeletal diseases (RMDs) were established and first analyses presented rapidly to assist clinical practice,5 as were preliminary recommendations regarding the management of patients with RMDs during the pandemic.6–9 

Just like many other journals, the Annals of the Rheumatic Diseases ( ARD ) was overwhelmed with submissions since March 2020, when …
A trifunctional contraceptive gel enhances the safety and quality of sexual intercourse
Authors: Mengjie Xie, Junlang Li, Sichen Zhang, Dashuai Zhu, Xuan Mei, Zhenzhen Wang, Xiao Cheng, Zhenhua Li, Shaowei Wang, Ke Cheng
Journal: Bioactive Materials (2020)

Current contraceptive methods come with a number of drawbacks, including low efficacy, in the case of commercial contraceptive gels, and a reduction in the quality of sexual intercourse, in the case of condoms. Adding pharmacologically-active agents to contraceptive gels holds the potential to improve sexual experience, and hardbor safety and hygiene. In this study, we fabricated a carbomer-based contraceptive gel consisting of three agents: tenofovir, gossypol acetate, and nitroglycerin (TGN), with pH adjusted to 4.5 (to be compatible with the vagina). In vitro, the gossypol component of the contraceptive gel proved to be an effective spermicide. When the concentration of gossypol acetate was 10 mg/ml, the spermicidal ability reached 100% after 30 s. In addition, tenofovir in the gel significantly inhibited lentiviral transfection efficiency in cell-containing media. In 6 pairs of rats, the gel successfully prevented all females from conceiving after successful mating. Moreover, increased sexual frequency and enhanced erection, which were promoted by the nitroglycerin in the components, were observed in male rats that had the gel applied to their penises. This novel TGN contraceptive gel yielded a higher contraceptive success rate than that of the commercial contraceptive gel (Contragel®). In addition, it has the added benefits to prevent sexually transmitted diseases and improve male libido and erectile function during sexual intercourse. Combining three FDA-approved and marketed agents together, our trifunctional TGN gel has a great potential for further translation and commercialization.
Efficient Gene Suppression by DNA/DNA Double-Stranded Oligonucleotide In Vivo
Authors: Yutaro Asami, Tetsuya Nagata, Kotaro Yoshioka, Taiki Kunieda, Kie Yoshida-Tanaka, C. Frank Bennett, Punit P. Seth, Takanori Yokota
Journal: Molecular Therapy (2020)

We recently reported the antisense properties of a DNA/RNA heteroduplex oligonucleotide consisting of a phosphorothioate DNA-gapmer antisense oligonucleotide (ASO) strand and its complementary phosphodiester RNA/phosphorothioate 2′-O-methyl RNA strand. When α-tocopherol was conjugated with the complementary strand, the heteroduplex oligonucleotide silenced the target RNA more efficiently in vivo than did the parent single-stranded ASO. In this study, we designed a new type of the heteroduplex oligonucleotide, in which the RNA portion of the complementary strand was replaced with phosphodiester DNA, yielding an ASO/DNA double-stranded structure. The ASO/DNA heteroduplex oligonucleotide showed similar activity and liver accumulation as did the original ASO/RNA design. Structure-activity relationship studies of the complementary DNA showed that optimal increases in the potency and the accumulation were seen when the flanks of the phosphodiester DNA complement were protected using 2′-O-methyl RNA and phosphorothioate modifications. Furthermore, evaluation of the degradation kinetics of the complementary strands revealed that the DNA-complementary strand as well as the RNA strand were completely cleaved in vivo. Our results expand the repertoire of chemical modifications that can be used with the heteroduplex oligonucleotide technology, providing greater design flexibility for future therapeutic applications. We recently reported the antisense properties of a DNA/RNA heteroduplex oligonucleotide consisting of a phosphorothioate DNA-gapmer antisense oligonucleotide (ASO) strand and its complementary phosphodiester RNA/phosphorothioate 2′-O-methyl RNA strand. When α-tocopherol was conjugated with the complementary strand, the heteroduplex oligonucleotide silenced the target RNA more efficiently in vivo than did the parent single-stranded ASO. In this study, we designed a new type of the heteroduplex oligonucleotide, in which the RNA portion of the complementary strand was replaced with phosphodiester DNA, yielding an ASO/DNA double-stranded structure. The ASO/DNA heteroduplex oligonucleotide showed similar activity and liver accumulation as did the original ASO/RNA design. Structure-activity relationship studies of the complementary DNA showed that optimal increases in the potency and the accumulation were seen when the flanks of the phosphodiester DNA complement were protected using 2′-O-methyl RNA and phosphorothioate modifications. Furthermore, evaluation of the degradation kinetics of the complementary strands revealed that the DNA-complementary strand as well as the RNA strand were completely cleaved in vivo. Our results expand the repertoire of chemical modifications that can be used with the heteroduplex oligonucleotide technology, providing greater design flexibility for future therapeutic applications.
EPEN-44. EXTRACELLULAR VESICLES OF SUPRATENTORIAL EPENDYMOMA RELA MEDIATE INTERACTIONS WITH CELLS OF THE TUMOR MICROENVIRONMENT
Authors: Kendra K Maass, Mieke Roosen, Julia Benzel, Tatjana Wedig, Britta Statz, Torsten Mueller, Mathias Kalxdorf, Jeroen Krijgsveld, Stefan M Pfister, Kristian W Pajtler
Journal: Neuro-Oncology (2020)

Abstract Ependymal tumors (EPNs) account for ~10% of all pediatric brain tumors. Supratentorial EPN characterized by RELA fusions (ST-EPN-RELA) and posterior fossa EPN group A (PF-EPN-A) form the two most frequent molecular groups, both of which are associated with poor prognosis and for which only limited therapeutic options are available. Since pediatric EPNs have a relatively low mutational burden, identification and characterization of tumor-associated pathways and molecular processes is of critical importance to inform potential therapeutic targets. Previous transcriptional studies implicated aberrant vesicular pathways in ST-EPN-RELA, prompting further investigation into their putative role in EPN pathogenesis. To this aim, we isolated extracellular vesicles (EVs) of ST-EPN-RELA patient derived cell lines and performed protein mass spectrometry. The specific ST-EPN-RELA EV protein content resembles the parental cells as well as primary tumors. Promising candidates to be transferred by ST-EPN-RELA EVs but not control EVs were associated with unfolded protein response and endoplasmic reticulum stress. When uptaken by recipient cells of the tumor microenvironment, brain endothelial cells or microglia, ST-EPN-RELA EVs induced proliferation and had a chemoattractant effect towards the tumor. ST-EPN-RELA EVs stimulated angiogenesis of brain endothelial cells potentially by the transfer of ER stress proteins. Uptake of ST-EPN-RELA EVs by microglia changed their activation status indicating a tumor promoting function through EV transfer. Therefore, we hypothesize that vesicular pathways play an important role in the pathogenesis of pediatric ST-EPN-RELAs and that an improved understanding may promote new therapeutic opportunities.
The effect of cognitive behavioural therapy for insomnia on sedative-hypnotic use: A narrative review
Authors: Alexander Sweetman, Stacey Putland, Leon Lack, R.Doug McEvoy, Robert Adams, Ron Grunstein, Nigel Stocks, Billingsley Kaambwa, Emer Van Ryswyk, Christopher Gordon, Andrew Vakulin, Nicole Lovato
Journal: Sleep Medicine Reviews (2020)
Adenosine Signaling Regulates Erythroid Commitment Via Modulation of Metabolic Reprogramming in Stress Erythropoiesis
Authors: Liu Hong, Travis Nemkov, Rongrong Liu, Jacob Couturier, Ye Youqiong, Angelo D'Alessandro, Anren Song, Shushan Zhao, Kaiqi Sun, Adebiyi Morayo, Yuan Edward Wen, Alexander Wen, C Hansen Kirk, Leng Han, Dorothy E. Lewis, Xian Wa, Holger K. Eltzschig, Michael Blackburn, Rodney Kellems, Yang Xia
Journal: Blood (2017)