tbuckley/cabot-search huggingface dataset:
Linked by Ancestral Bonds: Multiple Whole-Genome Duplications and Reticulate Evolution in a Brassicaceae Tribe
Authors: Xinyi Guo, Terezie Mandáková, Karolína Trachtová, Barış Özüdoğru, Jianquan Liu, Martin A Lysak
Journal: Molecular Biology and Evolution (2020)

Pervasive hybridization and whole-genome duplications (WGDs) influenced genome evolution in several eukaryotic lineages. Although frequent and recurrent hybridizations may result in reticulate phylogenies, the evolutionary events underlying these reticulations, including detailed structure of the ancestral diploid and polyploid genomes, were only rarely reconstructed. Here, we elucidate the complex genomic history of a monophyletic clade from the mustard family (Brassicaceae), showing contentious relationships to the early-diverging clades of this model plant family. Genome evolution in the crucifer tribe Biscutelleae (∼60 species, 5 genera) was dominated by pervasive hybridizations and subsequent genome duplications. Diversification of an ancestral diploid genome into several divergent but crossable genomes was followed by hybridizations between these genomes. Whereas a single genus (Megadenia) remained diploid, the four remaining genera originated by allopolyploidy (Biscutella, Lunaria, Ricotia) or autopolyploidy (Heldreichia). The contentious relationships among the Biscutelleae genera, and between the tribe and other early diverged crucifer lineages, are best explained by close genomic relatedness among the recurrently hybridizing ancestral genomes. By using complementary cytogenomics and phylogenomics approaches, we demonstrate that the origin of a monophyletic plant clade can be more complex than a parsimonious assumption of a single WGD spurring postpolyploid cladogenesis. Instead, recurrent hybridization among the same and/or closely related parental genomes may phylogenetically interlink diploid and polyploid genomes despite the incidence of multiple independent WGDs. Our results provide new insights into evolution of early-diverging Brassicaceae lineages and elucidate challenges in resolving the contentious relationships within and between land plant lineages with pervasive hybridization and WGDs.
EPID-13. A RETROSPECTIVE ANALYSIS TO STUDY THE SURVIVAL CHARACTERISTICS OF PATIENTS WITH FIRST PROGRESSION OF GLIOBLASTOMA AT THE CLEVELAND CLINIC
Authors: Yasmeen Rauf, Jimmy Yao, Addison Barnett, Yanwen Chen, Brian Hobbs, Glen Stevens, David Peereboom, Manmeet Ahluwalia
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive primary central nervous system malignancy. The median overall survival is 15 to 18 months with treatment and decreases to nine months after first progression. METHODS This is a retrospective study. Data was collected from all patients with first progression of GBM treated at CCF between Jan 2012 to Jan 2020. Eight cohorts of patients were evaluated: Group 1 received cytotoxic chemotherapy, Group 2 received bevacizumab alone, Group 3 received surgical or reirradiation alone, Group 4 were enrolled in clinical trials. Each group was divided into methylated and unmethylated cohorts. RESULTS Median overall survival was 12.4 months for patients with first progression of GBM (n= 248). Among the methlylated patients, the median overall survival was 16.5 months for group 1, 13.4 for group 2, 23.7 for group 3, and 17.3 for group 4. Among the unmethylated patients, the Median overall survival was 8.6 months for group 1, 7.7 months for group 2, 11.7 months for group 3 and 10.7 months for group 4. (p= 0.00016). Progression free survival (PFS) was 4.3 months for all patients with first progression of GBM. Among the unmethlylated patients, the PFS was 3.6 months for group 1, 15.3 months for group 2, 4.8 months for group 3, and 6.1 months for group 4. Among the unmethylated patients, the PFS was 2.3 months for group 1, 3.9 months for group 2, 3.8 months for group 3, and 4.4 months for group 4. (p &amp;lt; 0.0001). CONCLUSION Patients with first progression of GBM had the best overall survival in the cohort that underwent a surgical or reirradiation. The best progression free survival was for patients who were treated with Bevacizumab if they were methylated and those enrolled in clinical trials if they were unmethylated. The study was statistically significant.
RARE-15. EARLY PSEUDOPROGRESSION POST-RADIATION IN PAEDIATRIC HIGH-GRADE GLIOMA PATIENTS WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY: TWO CASE REPORTS FROM A SINGLE CENTRE
Authors: Ay-Jiuan Teng, Breege Gilmartin, Marty Campbell, Kanika Bhatia, Greg Wheeler, Michael Sullivan, Jordan Hansford, Dong-Anh Khuong-Quang
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition syndrome caused by biallelic mutations in the mismatch repair pathway, and high-grade glioma (HGG) constitute the most prevalent brain tumours. Pseudoprogression alludes to radiological changes that mimic tumour progression, but are in fact due to other causes such as therapy related inflammation. It can occur as early as three months post treatment. To our knowledge, its characteristics in CMMRD patients has not been reported. METHODS We retrospectively identified seven patients with CMMRD and history of HGG at The Royal Children’s Hospital, Melbourne from 2005 to 2019. Our objective was to review the characteristics of pseudoprogression in this cohort. RESULTS Out of the seven patients, two with constitutional loss of PMS2 demonstrated evidence of pseudoprogression. Patient 1 presented at 16 years old with a cerebellar anaplastic astrocytoma. She developed clinical and radiological progression within two weeks of starting radiotherapy, persisting up to four months after completion. However, six months post radiation she improved without intervention and the tumour remains stable five years post therapy. Patient 2 presented at 17 years old with a midbrain anaplastic astrocytoma, and showed signs of progression four weeks after completion of radiotherapy. She was then treated with Bevacizumab, an anti-VEGFA antibody with remarkable response. She subsequently received Nivolumab, a checkpoint inhibitor with ongoing stable disease for four months. CONCLUSION Our findings showed that pseudoprogression can occur early in the treatment course in CMMRD patients. Identification of this entity is important for appropriate clinical management.
Systemic and intravesical adoptive cell therapy of tumor-reactive T cells can decrease bladder tumor growth in vivo
Authors: Brittany L Bunch, Jennifer Morse, Sarah Asby, Jamie Blauvelt, Ahmet M Aydin, Patrick Innamarato, Ali Hajiran, Matthew Beatty, Michael Poch, Shari Pilon-Thomas
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The therapeutic armamentarium of bladder cancer has been recently enriched with the introduction of new therapies including immune checkpoint inhibitors, receptor tyrosine kinase inhibitors and antibody drug conjugates, however treatment responses and duration of responses are still less than expected. Adoptive cellular therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has potential to treat bladder cancer, as previously demonstrated by successful expansion of tumor reactive T cells from human bladder tumors. Methods A model system using OT-I T cells and an ovalbumin expressing MB49 tumor cell line (MB49OVA) was developed to study ACT in bladder cancer. Systemic ACT-treated mice were given T cells intravenously after lymphodepleting chemotherapy and followed by interleukin (IL)-2 administration. Intravesical ACT treated mice were given T cells directly into the bladder, without chemotherapy or IL-2. TILs were isolated from MB49 orthotopic tumors and expanded ex vivo in IL-2. Immune cell infiltrates were analyzed by flow cytometry. T cell infiltration was studied using a CXCR3 blocking antibody. Results Systemic ACT-treated mice had a decrease in tumor growth, increase in T cell infiltration and long-term immune protection compared with control-treated mice. OT-I T cells delivered intravesically were able to control tumor growth without lymphodepleting chemotherapy or IL-2 in MB49OVA orthotopic tumors. Intravesical delivery of TIL expanded from MB49 tumors was also able to decrease tumor growth in mice with MB49 orthotopic tumors. Blocking CXCR3 on OT-I T cells prior to intravesical delivery decreased T cell infiltration into the tumor and prevented the control of tumor growth. Conclusions This study demonstrates how TIL therapy can be used in treating different stages of bladder cancer.
EPCO-28. SPHEROID STUDY OF A GLIOBLASTOMA TUMOR IDENTIFIED A SUBCLONAL MUTATION OF EGFR T790M
Authors: Shai Rosenberg, Eliana Steinberg, Adar Yaacov, Ranel Lutati, Anat Mordechai, Eduard Linetsky, Alexander Lossos, ido Paldor, Ofra Benny
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) is the most common and the most devastating primary brain cancer in adults. Precision genetic medicine approach does not provide benefit to majority of GBM patients. A major reason for this is tumor heterogeneity harboring potential resistance mechanisms. Here, we describe an approach to grow spheroids of GBM, containing tumor, stroma and vascular tissues. We show that this approach can identify undetected subclonal driver mutations that can potentially cause drug resistance later in the disease course. METHODS We grew spheroids of a GBM patient in a multi-well array and monitored them visually. Exome sequencing of the parental tumor (coverage of 557X) and of spheroids after 10 days (n=3) and 20 days (n=5) of growth was performed. In addition, we sequenced six spheroids that were grown for 10 days and treated by Temozolomide for the next 10 days. RESULTS 70 somatic mutations were detected in the parental tumor. 42/70 of the tumor’s somatic mutations were also detected in the spheroids. 192 somatic mutations were detected in the spheroids only and not in the parental tumor despite high coverage sequencing of the parental tumor. In cancer genes: six somatic mutations were identified in the parental tumor, 5/6 were also detected in the spheroids and 13 mutations were detected only in the spheroids. EGFR V774M mutation was detected in both tumor and spheroids. However – EGFR T790M was independently detected in 7/11 of the spheroids sequenced after 20 days or growth but not in the parental tumor. CONCLUSION Analysis of GBM spheroids enables detection of rare subclonal mutations not detected in parental tumor. We hypothesize that this is due to positive selection of the ex vivo growth conditions. This analysis enabled detection of EGFR T790M – an important targetable resistance mutation in lung cancer not previously described in primary GBM.
DIPG-52. PHASE I CLINICAL TRIAL OF ONC201 IN PEDIATRIC H3 K27M-MUTANT GLIOMA OR NEWLY DIAGNOSED DIPG
Authors: Sharon Gardner, Rohinton Tarapore, Jeffrey Allen, Wafik Zaky, Yazmin Odia, Matthew Hall, Doured Daghistani, Ziad Khatib, Carl Koschmann, Dolly Aguilera, Tobey MacDonald, Maryam Fouladi, Susan McGovern, Cassie Kline, Nicholas Vitanza, Guangrong Lu, Krystal Merdinger, Wolfgang Oster, Joshua Allen, Soumen Khatua
Journal: Neuro-Oncology (2020)

Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.
Characteristics and Work Life Quality of Nursing Home Care Aides in Canada
Authors: Yuting Song, Ala Iaconi, Stephanie A. Chamberlain, Greta Cummings, Matthias Hoben, Peter Norton, Carole Estabrooks
Journal: JAMA Network Open (2020)

This cross-sectional study describes care aides’ characteristics and quality of work life in Western Canadian nursing homes.
LGG-56. INFANTILE HEMISPHERIC BRAIN TUMOR WITH A GOPC-ROS1 FUSION GENE: A CASE REPORT
Authors: Rieko Taniguchi, Atsushi Natsume, Nozomu Kawashima, Shinji Tanioka, Hideki Muramatsu, Motoharu Hamada, Daisuke Ichikawa, Masayuki Imaya, Kotaro Narita, Michihiro Kurimoto, Yoshiki Shiba, Kosuke Aoki, Fumiharu Ohka, Junko Hirato, Toshihiko Wakabayashi, Yoshiyuki Takahashi
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Infantile hemispheric gliomas with ROS1 fusion genes have been reported to have a relatively poor prognosis. Treatment using a ROS1 inhibitor is expected to generate less toxicity and effective for brain tumors with ROS1 fusion genes. CASE PRESENTATION: A one-month-old female presented with a seizure, and a large hypervascular mass in the right hemisphere was found on MRI. The tumor was not biopsied over concerns of an increased risk for bleeding. The mass was clinically diagnosed as an atypical teratoid rhabdoid tumor. She received neoadjuvant chemotherapy using the modified EU-RHAB protocol. The tumor gradually decreased to 70% of its original size with a reduction of vascularity. A near-total resection (&amp;gt; 95%) was performed at eight months of age. Pathological examination revealed the unusual histology with immunostaining positive for INI-1, GFAP, synaptophysin, neurofilament, and slightly positive for NeuN. MIB-1 labeling index was 6%. The pathological diagnosis was a glioneuronal tumor with desmoplastic infantile ganglioglioma-like features, suggestive of low grade. She received adjuvant chemotherapy with carboplatin and vincristine, which is the standard treatment for low-grade gliomas, and achieved a partial response. The GOPC-ROS1 fusion gene was detected in the tumor by FoundationOneⓇ CDx. CONCLUSION Chemotherapy may effectively reduce the size of an infant’s brain tumor which is initially considered to be inoperable. A gene profile should be performed as soon as possible in order to direct appropriate management.
Trends in the Surgical Treatment of Pseudotumor Cerebri Syndrome in the United States
Authors: Ali G. Hamedani, Dylan P. Thibault, Karen E. Revere, John Y. K. Lee, M. Sean Grady, Allison W. Willis, Grant T. Liu
Journal: JAMA Network Open (2020)

Optic nerve sheath fenestration (ONSF) and cerebrospinal fluid shunting are sometimes used to treat pseudotumor cerebri syndrome (PTCS), but their use patterns are unknown.To investigate the frequency of surgical PTCS treatment in the United States and to compare patients undergoing ONSF with those treated with shunting.This was a retrospective longitudinal cross-sectional study. Inpatient data were obtained from the National Inpatient Sample (NIS), and outpatient surgical center data were obtained from the National Survey of Ambulatory Surgery (NSAS) and National Hospital Ambulatory Medical Care Survey (NHAMCS). Included in the analysis were 10 720 patients aged 18 to 65 years with a diagnosis code for PTCS, excluding venous thrombosis and other causes of intracranial hypertension. Time trends were explored and logistic regression was used to measure differences according to age, race/ethnicity, sex, Elixhauser comorbidity index, and other patient and hospital characteristics. Data analysis was performed from March 31 to October 7, 2020.Treatment for PTCS, excluding venous thrombosis and other causes of intracranial hypertension.Annual number of PTCS-related admissions, ONSFs, and shunt procedures from 2002-2016. Patient and hospital-level characteristics of patients with PTCS undergoing ONSF or shunting were compared.Between 2010 and 2016, 297 ONSFs were performed and 10 423 shunts were placed as treatment for PTCS. The procedures were most commonly performed in individuals aged 26 to 35 years (39.4%), and 9920 (92.4%) of the surgically treated patients were women. ONSF was more common among younger patients (eg, adjusted odds ratio [AOR] for patients ≥46 years vs those 18-25 years, 0.22; 95% CI, 0.08-0.61) and in Black, Hispanic, or other minority populations (AOR, 2.37; 95% CI, 1.31-4.30) and less common in the South (AOR, 0.34; 95% CI, 0.13-0.88) and West (AOR, 0.15; 95% CI, 0.04-0.58) compared with the Northeast. Total PTCS-related hospitalizations increased from 6081 (95% CI, 5137-7025) in 2002 to 18 020 (95% CI, 16 607-19 433) in 2016. Shunting increased from 2002 to 2011 and subsequently plateaued and declined. ONSF was used much less frequently, and use has not increased. No instances of outpatient ONSF or shunting for PTCS were recorded in the NSAS or NHAMCS databases.This study's findings suggest that shunting is more common than ONSF and that the use gap has widened as shunting has increased. However, because overall PTCS-related hospitalizations have increased even more rapidly, the percentage of inpatients with PTCS undergoing surgery has decreased. These trends may reflect changes in medical treatment practices and outcomes or growing limitations in access to ophthalmic surgical expertise.
IMMU-03. UPDATES ON BRAINCHILD-01, -02, AND -03: PHASE 1 LOCOREGIONAL CAR T CELL TRIALS TARGETING HER2, EGFR, AND B7-H3 FOR CHILDREN WITH RECURRENT CNS TUMORS AND DIPG
Authors: Nicholas Vitanza, Juliane Gust, Ashley Wilson, Wenjun Huang, Francisco Perez, Jason Wright, Sarah Leary, Bonnie Cole, Catherine Albert, Navin Pinto, Rimas Orentas, Michael Jensen, Julie Park
Journal: Neuro-Oncology (2020)

Abstract We report preliminary results of three Phase 1 trials of repetitively dosed locoregional CAR T cells for children with recurrent/refractory CNS tumors, targeting HER2 (BrainChild-01), EGFR (BrainChild-02), and B7-H3 (BrainChild-03). Cells are delivered into the tumor cavity (Arm A) or ventricular system (Arm B and BrainChild-03’s DIPG-specific Arm C). Primary endpoints are feasibility and safety. Successful CAR T cell manufacture occurred in 2/2 subjects (BrainChild-01) and 2/3 (BrainChild-02). All subjects tolerated intra-patient dose escalation from 1x107 to 2.5x107 cells/dose without DLTs. Two subjects were evaluable on BrainChild-01 (S-001: glioblastoma, Arm A, survival 173 days post-first infusion, received 6 infusions; S-002: ependymoma, Arm B, survival 111 days, 9 infusions). One subject was evaluable on BrainChild-02 (glioblastoma, Arm A, withdrew from trial at 49 days, 5 infusions). One enrolled patient on BrainChild-03 has not begun treatment. None of the subjects developed new neurologic toxicities, although transient worsening of baseline tumor-related signs and symptoms were seen. Secondary endpoints are efficacy and disease response. No objective radiographic responses have been observed. Both BrainChild-01 subjects had transient systemic CRP elevations following infusions (S-001: peak of 3.9 post Course 1 Week 1; S-002: peak of 2.3 post Course 2 Week 1), possibly indicating an inflammatory response. Both subjects had post-infusion CSF cytokine elevations (CXCL10, GCSF, GM-CSF, IFNa2, IFNg, IL-10, IL12-p40, IL12-p70, IL-15, IL-1a, IL-3, IL-6, IL-7, TNFa, VEGF) without concurrent systemic changes. In summary, we provide preliminary evidence of safety and feasibility of intracranial delivery of CAR T cells for pediatric CNS tumors.
Abstract 13314: Extended Thromboprophylaxis in Hospitalized Patients With Heart Failure: A Retrospective Analysis of the Magellan Study
Authors: Alex C Spyropoulos, Gary Raskob, Theodore Spiro, Jianfeng Xu, Yoriko De Sanctis, John Albanese, Alexandre Mebazaa, Elliot S Barnathan
Journal: Circulation (2019)

Introduction: Patient with heart failure (HF) are at risk for post-discharge venous thromboembolism (VTE) but the role of extended thromboprophylaxis (ET) is not well defined. The MAGELLAN trial de...
Letter to the Editor: Liver Cell Models for Premature Termination Codon Readthrough Analyses
Authors: Lavinija Matakovic, Qinghong Li, Sven C.D. van Ijzendoorn
Journal: Hepatology (2020)

Potential conflict of interest: Nothing to report. TO THE EDITOR: Amzal et al.(1) reported about the prospect of pharmacological premature termination codon (PMT) readthrough of ATP‐binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11) mRNA in bile salt export pump deficiency, the latter causing progressive familial intrahepatic cholestasis (PFIC)‐type 2. The investigators demonstrate that aminoglycoside antibiotics can stimulate readthrough of nonsense mutation‐induced PMT in ABCB11 mRNA, thereby rescuing full‐length ABCB11 protein synthesis. The study provides proof of principle for a potential therapy for nonsense mutation‐associated PFIC2. The investigators acknowledge that their cell‐line–based model does not take nonsense‐mediated mRNA decay (NMD) into account, which, however, determines whether PFIC2 patients may actually benefit from PMT readthrough therapy. Importantly, other cell models exist that do take NMD into account, and we believe these should be discussed as part of the path to bring their exciting findings closer to the clinic. NMD is a cellular surveillance pathway that safeguards the quality of mRNA transcripts and eliminates most PMT‐containing mRNA. NMD efficiency is variable and depends, among others, on the precise nonsense mutation. Because a sufficient amount of target mRNA is a prerequisite for effective PMT readthrough and the synthesis of a sufficient amount of the encoded protein, NMD poses a significant hurdle in the application of PMT readthrough‐stimulating drugs in the clinic.(2) Measurements of patients' baseline ABCB11 mRNA may provide a prognostic indicator of response to PMT readthrough‐stimulating drugs, but because ABCB11 is exclusively expressed in hepatocytes, this would require a liver biopsy. Patient‐derived somatic cells from blood, skin, or urine are easier to obtain. These can be reprogrammed to induced pluripotent stem cells (iPSCs) and subsequently differentiated to hepatocytes. Human iPSC‐derived hepatocytes that form bile canaliculi and express ABCB11 were recently reported,(3) as well as a PFIC2 patient iPSC‐derived hepatocyte model for ABCB11 deficiency.(4) The big advantage of patient iPSC‐derived hepatocytes is that these express the endogenously expressed—and NMD‐responsive—gene variant(s) and reflect individual NMD levels. With the exciting results from Amzal et al. at hand, confirmatory studies using iPSC‐derived hepatocytes promise a better and patient‐tailored prediction of PMT readthrough‐stimulating drug efficacy, as such or in combination with NMD inhibitors, for the treatment of nonsense mutation‐associated PFIC and other hereditary liver diseases. Author Contributions Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: L.M., Q.L., S.C.D.v.I.; drafting the article or revising it critically for important intellectual content: L.M., Q.L., S.C.D.v.I.; final approval of the version to be published: L.M., Q.L., S.C.D.v.I.