tbuckley/cabot-search huggingface dataset:
Tissue-Specific Gene Expression Changes are Associated with Aging in Mice
Authors: Akash Srivastava, Emanuel Barth, Maria A. Ermolaeva, Madlen Guenther, Christiane Frahm, Manja Marz, Otto W. Witte
Journal: Genomics Proteomics & Bioinformatics (2020)

Aging is a complex process that can be characterized by functional and cognitive decline in an individual. Aging can be assessed based on the functional capacity of vital organs and their intricate interactions with one another. Thus, the nature of aging can be described by focusing on a specific organ and an individual itself. However, to fully understand the complexity of aging, one must investigate not only a single tissue or biological process but also its complex interplay and interdependencies with other biological processes. Here, using RNA-seq, we monitored changes in the transcriptome during aging in four tissues (including brain, blood, skin and liver) in mice at 9 months, 15 months, and 24 months, with a final evaluation at the very old age of 30 months. We identified several genes and processes that were differentially regulated during aging in both tissue-dependent and tissue-independent manners. Most importantly, we found that the electron transport chain (ETC) of mitochondria was similarly affected at the transcriptome level in the four tissues during the aging process. We also identified the liver as the tissue showing the largest variety of differentially expressed genes (DEGs) over time. Lcn2 (Lipocalin-2) was found to be similarly regulated among all tissues, and its effect on longevity and survival was validated using its orthologue in Caenorhabditis elegans. Our study demonstrated that the molecular processes of aging are relatively subtle in their progress, and the aging process of every tissue depends on the tissue's specialized function and environment. Hence, individual gene or process alone cannot be described as the key of aging in the whole organism.
NIMG-43. IMAGING FINDINGS FOLLOWING REGORAFENIB IN PATIENTS WITH MALIGNANT GLIOMA: FET PET ADDS VALUABLE INFORMATION TO ANATOMICAL MRI
Authors: Jan-Michael Werner, Caroline Tscherpel, Gabriele Stoffels, Philipp Lohmann, Gereon R Fink, Karl-Josef Langen, Norbert Galldiks
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Recent phase 2 data showed that the small molecule regorafenib with antiangiogenic properties has promising effectivity in glioblastoma patients at first progression. Following antiangiogenic therapy with bevacizumab, amino acid PET provides valuable additional diagnostic information regarding bevacizumab-related effects on MRI (e.g., pseudoresponse). In contrast, only a little is known about regorafenib. Thus, we evaluated prospectively the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the assessment of regorafenib-related treatment effects. METHODS Twenty-two patients with progressive malignant glioma (median number of relapses, 2; range, 1-4) were included. Up to now, 10 of 22 patients were eligible for data evaluation and underwent regorafenib therapy (median number of cycles, 2; range, 1-5 cycles). FET PET and MRI were performed at baseline and after the second cycle. After the second cycle, MRI was performed every 8 weeks. In case of a suspicious MRI after the second cycle, a FET PET scan was added. MRI changes were evaluated according to the RANO criteria. Maximum tumor-to-brain ratios (TBRmax) were calculated. Pseudoresponse was considered if (i) the follow-up MRI showed an improvement (i.e., at least “partial response” according to RANO criteria) despite subsequent clinical progression, and (ii) an increase of TBRmax&amp;gt;25% occurred. Pseudoresponse was confirmed if (i) the subsequent MRI follow-up showed progression, and/or (ii) the clinical status worsened, or the patient died. RESULTS In 4 of 10 patients, FET PET provided clinically relevant additional information. In two patients, pseudoresponse could be confirmed. Furthermore, in one patient with stable disease according to MRI, increasing TBRmax (+138%) enabled earlier diagnosis of tumor progression (time benefit, 5 weeks). In another patient without signs of MRI response after 2 cycles, decreasing TBRmax (-23%) indicated metabolic response and was associated with a significant clinical improvement. CONCLUSIONS FET PET seems to add valuable diagnostic information for regorafenib therapy monitoring.
Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients
Authors: Xixiang Ma, Chuhuai Guan, Rong Chen, Yunyun Wang, Shenglei Feng, Rongshuai Wang, Guoqiang Qu, Sijia Zhao, Fengli Wang, Xiaoli Wang, Dingyu Zhang, Liang Liu, Aihua Liao, Shuiqiao Yuan
Journal: Cellular and Molecular Immunology (2020)

In late December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), was identified in Wuhan, China, and the ensuing pandemic has led to more than 50 million infected individuals and more than one million deaths by November 10, 2020 (https://covid19.who.int/).Pathologic investigations of autopsy tissue have focused primarily on the lung, heart, and kidney, whereas morphologic data on testis injury and the effects of SARS-CoV-2 infection on spermatogenesis are limited.Although two groups did not detect SARS-CoV-2 in the semen or testes of recovered COVID-19 patients, 1,2 another group confirmed SARS-CoV-2 in the semen of patients. 3Therefore, it is currently unknown whether SARS-CoV-2 infection impacts spermatogenesis and male fertility.In the present study, we evaluated the effects of SARS-CoV-2 infection on spermatogenesis by examining the pathophysiology and molecular features of testes obtained from five male COVID-19 patients at autopsy.First, the histological morphology of the testes from five COVID-19 patients and three uninfected controls was examined by periodic acid-Schiff (PAS) staining.The COVID-19 patients were aged 51, 62, 70, 78, and 83 years, and the control patients were aged 71, 78, and 80 years (Supplementary Table S1).In all five COVID-19 patients, numerous degenerated germ cells (GCs) had sloughed into the lumen of seminiferous tubules (Fig. 1a).In contrast, in the age-matched control tissues, GCs at various stages were well aligned around the whole seminiferous tubules (Fig. 1a).Strikingly, in four of the five cases, GC loss was massive, with only a few GCs left attached to the seminiferous tubules.In particular, many seminiferous tubules in the testes of patients 4 and 5 showed almost no intact GCs, similar to Sertoli cell-only syndrome.Consistent with this morphological observation, the number of DDX4 (a germ cell marker)-positive cells was dramatically reduced in all testicular specimens from the COVID-19 group (Supplementary Fig. S1a,b).Interestingly, the number of Sertoli cells in the testes of SARS-CoV-2-infected patients and uninfected controls was comparable (Supplementary Fig. S1c,d), suggesting that SARS-CoV-2 infection may not impair Sertoli cells.These morphological changes in the testes of COVID-19 patients
Active bacterial modification of the host environment through RNA polymerase II inhibition
Authors: Inès Ambite, Nina A. Filenko, Elisabed Zaldastanishvili, Daniel S.C. Butler, Thi Hien Tran, Arunima Chaudhuri, Parisa Esmaeili, Shahram Ahmadi, Sanchari Paul, Björn Wullt, Johannes Putze, Swaine L. Chen, Ulrich Dobrindt, Catharina Svanborg
Journal: Journal of Clinical Investigation (2020)

Unlike pathogens, which attack the host, commensal bacteria create a state of friendly coexistence. Here, we identified a mechanism of bacterial adaptation to the host niche, where they reside. Asymptomatic carrier strains were shown to inhibit RNA polymerase II (Pol II) in host cells by targeting Ser2 phosphorylation, a step required for productive mRNA elongation. Assisted by a rare, spontaneous loss-of-function mutant from a human carrier, the bacterial NlpD protein was identified as a Pol II inhibitor. After internalization by host cells, NlpD was shown to target constituents of the Pol II phosphorylation complex (RPB1 and PAF1C), attenuating host gene expression. Therapeutic efficacy of a recombinant NlpD protein was demonstrated in a urinary tract infection model, by reduced tissue pathology, accelerated bacterial clearance, and attenuated Pol II-dependent gene expression. The findings suggest an intriguing, evolutionarily conserved mechanism for bacterial modulation of host gene expression, with a remarkable therapeutic potential.
Evaluation of the rapid antigen test Panbio COVID-19 in saliva and nasal swabs in a population-based point-of-care study
Authors: Vanesa Agulló, Marta Fernández-González, Victoria Ortiz de la Tabla, Nieves Gonzalo-Jiménez, José A. García, Mar Masiá, Félix Gutiérrez
Journal: Journal of Infection (2020)
CSIG-17. PRMT5 INHIBITION SENSITIZES GLIOBLASTOMA MODELS TO TRAMETINIB TREATMENT
Authors: Yoshihiro Otani, Sriya Namagiri, Shilpa Thammegowda, Hannah Sur, Ashis Chowdhury, Cole Lewis, Toshihiko Shimizu, Tae Jin Lee, Dragan Maric, Ji Young Yoo, John Heiss, Balveen Kaur, Yeshavanth Kumar Banasavadi-Siddegowda
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioblastoma (GBM) is the most common malignant primary brain tumor. With limited effective therapeutic strategies, prognosis for GBM is very poor. Our previous study shows that the expression of Protein Arginine Methyltransferase 5 (PRMT5) is upregulated in GBM; its inhibition promotes anti-GBM effect through apoptosis and senescence of mature and immature tumor cells, respectively. In GBM, RAS-RAF- MEK-ERK signaling is aberrantly activated and promotes tumor growth. Therefore, MEK inhibitors, including trametinib are currently under investigation for GBM therapy. In this study, we tested whether inhibition of PRMT5 can enhance the anti-tumor efficacy of trametinib in GBM. METHODS Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, and western blot analysis were conducted. In vivo, PRMT5-intact and -depleted GBMNS were intracranially implanted in NSG mice and treated with trametinib by daily oral gavage, and tumor progression and mice survival rate were analyzed by MRI and Kaplan-Meier survival curve, respectively. RESULTS Trametinib treatment upregulated the expression of PRMT5 in GBMNS. Depletion of PRMT5 increased the cytotoxic effect of trametinib in GBMNS. In concurrence with the trametinib-induced PRMT5 upregulation, trametinib treatment increased the activity of AKT that was blocked with PRMT5 knockdown. In vivo, PRMT5-depletion extended the survival of the tumor bearing mice that further increased in combination with trametinib treatment. Interestingly, trametinib treatment alone had no survival benefit. CONCLUSION Trametinib treatment induces PRMT5 expression. Depletion of trametinib-induced PRMT5 expression sensitizes GBMNS for trametinib by inhibiting AKT activity.
EPEN-05. MUTATIONAL ANALYSIS OF THE C11ORF95 DOMAIN AND SINGLE-CELL RNA-SEQ PROFILE OF A MOUSE MODEL OF SUPRATENTORIAL EPENDYMOMA
Authors: Kevin Truong, James He, Gavin Birdsall, Ericka Randazzo, Jesse Dunnack, Joseph LoTurco
Journal: Neuro-Oncology (2021)

Abstract We used a recently developed mouse model to better understand the cellular and molecular determinants of tumors driven by the oncogenic fusion protein C11orf95-RELA. Our approach makes use of in utero electroporation and a binary transposase system to introduce human C11orf95-RELA sequence, wild type and mutant forms, into neural progenitors. We used single cell RNA-seq to profile the cellular constituents within the resulting tumors in mice. We find that approximately 70% of the cells in the tumors do not express the oncogene C11orf95-RELA and these non-oncogene expressing cells are a combination of different non-tumor cell cell-types, including significant numbers of T-cells, and macrophages. The C11orf95-RELA expressing tumor cells have a unique transcriptomic profile that includes both astrocytic and neural progenitor marker genes, and is distinct from glioblastoma transcriptomic profiles. Since C11orf95-RELA is believed to function through a combination of both activation of NF-κB response genes by constitutive activation of RELA, and genes not activated by NF-κB, we assessed the expression of NF-κB response genes across the populations of cells in the tumor. Interestingly, when tumor cells highly expressing C11orf95-RELA were analyzed further, the subclusters identified were distinguished by upregulation of non-NF-kB pathways involved in cell proliferation, cell fate determination, and immune activation. We hypothesized that the C11orf95 domain may function to bring RELA transcriptional activation to inappropriate non-NF-κB targets, and we therefore performed a point mutation analysis of the C11orf95 domain. We found that mutations in either of the cysteines or histidines that make up a possible zinc finger domain in C11orf95 eliminate the ability of the fusion to induce tumors. In cell lines, these loss-of-function point mutants still trafficked to nuclei, and activated NF-κB pathways. We are currently using RNAseq and CRISPR loss-of function to identify genes downstream of C11orf95-RELA that are required for tumorigenesis.
Use of graphene-based materials as carriers of bioactive agents
Authors: Wing-Fu Lai, Wing-Tak Wong
Journal: Asian Journal of Pharmaceutical Sciences (2020)

Graphene possesses a large specific surface area, a high Young's modulus, high fracture strength, high electrical conductivity, and excellent optical performance. It has been widely studied for biomedical use since its first appearance in the literature. This article offers an overview of the latest advances in the design of graphene-based materials for delivery of bioactive agents. To enhance the translation of these carriers into practical use, the toxicity involved is needed to be examined in future research in more detail. In addition, guidelines for standardizing experimental conditions during the evaluation of the performance of graphene-based materials are required to be established so that candidates showing higher practical potential can be more effectively identified for further development. This can streamline the optimization and use of graphene-based materials in delivery applications.
3P Association between inflammation index and nutritional status and the effectiveness of immunotherapy in NSCLC treatment
Authors: S. Tolu, F. Balconi, N. Liscia, D. Spanu, M. Persano, G. Pinna, M. Dubois, G. Saba, V. Impera, S. Mariani, C. Donisi, A. Pretta, A. Pireddu, F. Musio, M. Migliari, R. Piredda, M. Scartozzi, C. Madeddu
Journal: Annals of Oncology (2020)
Frequency and Evolution of TP53 Mutant Clones in Shwachman Diamond Syndrome. a Cohort Study from the French Severe Chronic Neutropenia (SCN) Registry
Authors: Jean Donadieu, Jean-Alain Martignoles, Blandine Beaupain, Pascale Flandrin-Gresta, Hannah Moatti, Pierre Hirsch, Despina Moshous, Stephane Blanche, Dalila Adjaoud, Etienne Merlin, Fanny Fouyssac, Ouahiba Nachit, Yves Bertrand, Virginie Gandemer, Nathalie Aladjidi, Marlène Pasquet, Thierry Leblanc, Vincent Barlogis, Isabelle Meitz, Vahid Asnafi, Guy Leverger, Hélène Lapillonne, Christine bellanne Chantelot, Francois Delhommeau
Journal: Blood (2017)
CTIM-21. PEPTIDE VACCINE DIRECTED TO CMV pp65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL
Authors: Eric Thompson, Daniel Landi, Eric Thompson, Eric Lipp, Bea Balajonda, James Herndon, Evan Buckley, Charlene Flahiff, Denise Jaggers, Kristin Schroeder, Dina Randazzo, Annick Desjardins, Maggie Johnson, Katherine Peters, Mustafa Khasraw, Michael Malinzak, Duane Mitchell, David Ashley, John Sampson
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION The cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma. METHODS Vaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly. RESULTS To date, 17 patients have been enrolled. Diagnoses include medulloblastoma (n=1), glioblastoma (n=9), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=2), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 41% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 0.8, not estimable) and median OS is 6.5 months (95% CI 1.8, not estimable). Interim analysis of immune monitoring bloodwork and perfusion MRI to quantify responses to PEP-CMV has been delayed due to COVID-19. However, adults with GBM who received PEP-CMV (NCT02864368) had significant (p≤0.05) increases in GCSF, GM-CSF, IFN-γ, IL-10, IL-2, IL-8, MIP1-α, and TNF-α levels. CONCLUSIONS Preliminary results demonstrate that PEP-CMV is feasible and well-tolerated in heavily pretreated, multiply recurrent patients.
Demonstration of Double Bladder Diverticula on Bone Scan
Authors: Qianyu Bian, Lingling Luo, Xiaomao Jin, Xiaobo Yao
Journal: Clinical Nuclear Medicine (2020)

A 75-year-old man with suspected prostate cancer underwent a 99mTc-MDP bone scan to exclude the possibility of bone metastasis. Scans revealed areas of increased tracer uptake in a symmetric distribution on both sides of the pelvis. Further SPECT/CT imaging showed focal 99mTc-MDP accumulation within 2 cystic lesions on both sides of the bladder. Subsequent x-ray cystography showed contrast agent filling within both cystic lesions, which suggested double bladder diverticula. Eventually, these 2 cystic lesions were confirmed by surgery and pathology as double congenital bladder diverticula.
LGG-01. CLINICAL MANAGEMENT AND GENOMIC PROFILING OF PEDIATRIC LOW-GRADE GLIOMAS IN SAUDI ARABIA
Authors: Nahla A Mobark, Musa Alharbi, Ali Abdullah O Balbaid, Lamees Al-Habeeb, Latifa AlMubarak, Rasha Alaljelaify, Mariam AlSaeed, Amal Almutairi, Fatmah A Alanazi, Yara Bashawri, Maqsood Ahmad, Ayman Al-Banyan, Fahad E Alotabi, Duna Barakeh, Malak AlZahrani, Hisham Al-Khalidi, Abdulrazag Ajlan, Lori A Ramkissoon, Shakti H Ramkissoon, Malak Abedalthagafi
Journal: Neuro-Oncology (2020)

Abstract Pediatric Low Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes. The treatment modality dictates the outcome and optimizing patient management can be challenging. In this study, we profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. We detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1 3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). BRAF V600E mutations were observed in only 2/37 patients, while H3F3A (K27M) histone mutations were not detected. Interestingly, we identified a GOPC-ROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low grade glioma. The patient underwent gross total resection (GTR) currently he is disease free. To our knowledge this is the first report of GOPC-ROS1 fusion in PLGG which may represent a genomically-distinct subgroup of pLGGs that could be targeted with oral target therapy crizotinib. Taken together, we reveal the genetic characteristics of pLGG Saudi patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG. Our study proves the possibility of using genetic profiling to guide optimal treatment strategies for pLGG in Saudi population
RADT-37. THE IMPACT OF POSTOPERATIVE RADIATION THERAPY (PORT) AND EXTENT OF SURGERY ON CLINICAL OUTCOMES OF ATYPICAL MENINGIOMA (AM): A META-ANALYSIS
Authors: Philip Haddad, Furqan Akhtar, Kevin Gallagher
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Although meningiomas are among the most prevalent types of brain tumors, AMs account for around 4% of all meningiomas. AMs tend to be more aggressive with relatively higher rates of recurrence and mortality. Gross total resection (GTR) has been the standard of care when possible. However, GTR itself is not always enough to prevent the recurrence of AMs. The role of PORT remains controversial in AM as the comparative studies to support its use have provided conflicting RESULTS: The purpose of this meta-analysis is to evaluate the impact of PORT on clinical outcomes according to the extent of resection in AMs. METHODS A review of the medical literature was conducted using online databases. Inclusion criteria consisted of AM diagnosis, English language, Simpson graded resections, and comparative studies reporting recurrence rates (RcR), Progression-Free Survival (PFS), and Overall Survival (OS) with hazard ratios (HR) or Kaplan-Meier curves. A meta-analysis was conducted using an inverse variance method with a random-effects model. RESULTS Twenty-two comparative studies with a total of 5,129 patients were included and analyzed. When GTR was attained, PORT was associated with improved RcR (HR =0.72, 95%CI:0.59-0.86) and PFS (HR=0.77, 95%CI:0.65-0.90), but not OS (HR=0.93, 95%CI:0.83-1.04). When subtotal resection (STR) was attained, PORT was associated with improved PFS (HR=0.35, 95%CI:0.26-0.48) as well as OS (HR=0.70, 95%CI:0.54-0.89). The extent of surgery also impacted AM outcomes as GTR demonstrated superior PFS (HR=0.45, 95%CI:0.31-0.65) and OS (HR=0.30, 95%CI:0.13-0.72). CONCLUSIONS This is the first meta-analysis to show that PORT is associated with PFS benefit in AMs with GTR and STR. Moreover, PORT significantly improved OS of AMs that underwent STR but had no impact on OS when GTR was achieved. In the absence of randomized clinical trials, this meta-analysis represents the most compelling data supporting the use of PORT in this patient population.