tbuckley/cabot-search huggingface dataset:
Abstract PO-037: Leveraging polyamine metabolic stress to enhance sensitivity to epigenetic therapy for prostate cancer
Authors: Aryn M. Rowsam, Hayley C. Affronti, Spencer R. Rosario, Mark D. Long
Journal: Cancer Research (2020)

Abstract While polyamines are required for proliferation in all cells, the prostate synthesizes and secretes high levels into its lumen, resulting in depletion of intracellular polyamines. To meet polyamine biosynthetic demands, which is enhanced in Prostate Cancer (CaP), there is high flux through one carbon metabolism to provide S’-Adenosylmethionine (SAM), which donates its aminopropyl group to polyamine synthesis. This flux is driven by Spermidine/ Spermine N1-Acetyltransferase (SSAT) which adds acetyl groups to spermidine and spermine, leading to their secretion. To deal with the stress, the methionine salvage pathway (MSP) recycles one carbon units lost during polyamine synthesis back to the methionine cycle for SAM replenishment, by methylthioadenine phosphorylase (MTAP). We have shown increased polyamine catabolism by SSAT stabilization and MTAP inhibition results in cell death in in vitro, in vivo, and ex vivo CaP models. We expect the CaP epigenome to be impacted by stressed acetyl-CoA and SAM pools, which are used by chromatin modifying enzymes, and that this stress will alter CaP sensitivity to epigenetic based drugs. While epigenetic therapies are currently being investigated in the clinic for targeting CaP, their success has been limited due to toxicity and non-specificity. We hypothesize that increased flux through polyamine metabolism and one carbon metabolism disrupts SAM and acetyl-CoA pool maintenance, making CaP cells sensitized to therapy targeting their utilization. Our findings suggest that certain histone modifications are affected by treatment with BENSpm in vitro. Additionally, we have found treatment of CaP cells with BENSpm and MTDIA induces significant broad DNA methylation changes. Furthermore, our preliminary data shows that the addition of metabolic therapies, BENSpm and MTDIA, to an epigenetic targeting drug, JQ1, further suppresses CaP growth in vitro. We expect that future studies combining our metabolic therapies with epigenetic drugs targeting acetyl-CoA and SAM usage will maintain anti-tumor efficacy with reduced systemic toxicity. Citation Format: Aryn M. Rowsam, Hayley C. Affronti, Spencer R. Rosario, Mark D. Long. Leveraging polyamine metabolic stress to enhance sensitivity to epigenetic therapy for prostate cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-037.
Trends in Cancer Incidence in US Adolescents and Young Adults, 1973-2015
Authors: Alyssa R. Scott, Kelsey C. Stoltzfus, Leila T. Tchelebi, Daniel M. Trifiletti, Eric J. Lehrer, Pooja Rao, Archie Bleyer, Nicholas G. Zaorsky
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Previous studies have demonstrated that adolescents and young adults (AYAs) with cancer are a distinct cancer population; however, research on long-term epidemiological trends and characteristics of cancers in AYAs is lacking. <h3>Objective</h3> To characterize the epidemiology of cancer in AYAs aged 15 to 39 years with respect to (1) patient demographic characteristics, (2) frequencies of cancer types, and (3) cancer incidence trends over time. <h3>Design, Setting, and Participants</h3> This retrospective, serial cross-sectional, population-based study used registry data from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 1973, to December 31, 2015 (SEER 9 and SEER 18). The study population was from geographically distinct US regions, chosen to represent the racial and ethnic heterogeneity of the country. Initial analyses were performed from January 1 to August 31, 2019. <h3>Main Outcomes and Measures</h3> Incidence rates and descriptive epidemiological statistics for patients aged 15 to 39 years with invasive cancer. <h3>Results</h3> A total of 497 452 AYAs diagnosed from 1973 to 2015 were included in this study, with 293 848 (59.1%) female and 397 295 (79.9%) White participants. As AYAs aged, an increase in the relative incidence of carcinomas and decrease in the relative incidence of leukemias, lymphomas, germ cell and trophoblastic neoplasms, and neoplasms of the central nervous system occurred. Among the female AYAs, 72 564 (24.7%) were diagnosed with breast carcinoma; 48 865 (16.6%), thyroid carcinoma; and 33 828 (11.5%), cervix and uterus carcinoma. Among the male AYAs, 37 597 (18.5%) were diagnosed with testicular cancer; 20 850 (10.2%), melanoma; and 19 532 (9.6%), non-Hodgkin lymphoma. The rate of cancer in AYAs increased by 29.6% from 1973 to 2015, with a mean annual percentage change (APC) per 100 000 persons of 0.537 (95% CI, 0.426-0.648;<i>P</i> &lt; .001). Kidney carcinoma increased at the greatest rate for both male (APC, 3.572; 95% CI, 3.049-4.097;<i>P</i> &lt; .001) and female (APC, 3.632; 95% CI, 3.105-4.162;<i>P</i> &lt; .001) AYAs. <h3>Conclusions and Relevance</h3> In this cross-sectional, US population-based study, cancer in AYAs was shown to have a unique epidemiological pattern and is a growing health concern, with many cancer subtypes having increased in incidence from 1973 to 2015. Continued research on AYA cancers is important to understanding and addressing the distinct health concerns of this population.
Abstract IA02: Regulating amino acid metabolism can improve response to immunotherapy
Authors: Ayelet Erez, Eytan Ruppin
Journal: Cancer Research (2020)

Abstract Aberrant expression of urea cycle enzymes occurs in multiple types of cancer. We have previously demonstrated that the urea cycle enzyme ASS1 is downregulated in different tumor types to increase the availability of its substrate aspartate for pyrimidine synthesis, supporting cell proliferation. Therapeutically, we demonstrated that high pyrimidine to purine ratio improves response to immunotherapy. Interestingly, in several prevalent types of cancer ASS1 expression is upregulated for a yet unknown metabolic benefit that associates with poor patients’ prognosis. We now find that ASS1 expression in cancer provides a survival advantage in nutrient deficiency states by generating NO that activates gluconeogenesis. The increase in gluconeogenic flux increases serine levels and leads to a nucleotide imbalance promoting pyrimidine to purine transversion mutations. Consequently, cancers with high ASS1 expression are less immunogenic. Reversing the nucleotide imbalance to favor pyrimidines leads to better response to immunotherapy. Our data establish ASS1 expression as a metabolic survival mechanism under nutrient deprivation that may also serve as a strong determinant of the immune response. Importantly, our findings suggest that we can metabolically regulate tumor mutations to improve patients’ responsiveness to immunotherapy. Citation Format: Ayelet Erez, Eytan Ruppin. Regulating amino acid metabolism can improve response to immunotherapy [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr IA02.
A New Catalog of Structural Variants in 1,301 <i>A. thaliana</i> Lines from Africa, Eurasia, and North America Reveals a Signature of Balancing Selection at Defense Response Genes
Authors: Mehmet Göktay, Andrea Fulgione, Angela M Hancock
Journal: Molecular Biology and Evolution (2020)

Abstract Genomic variation in the model plant Arabidopsis thaliana has been extensively used to understand evolutionary processes in natural populations, mainly focusing on single-nucleotide polymorphisms. Conversely, structural variation has been largely ignored in spite of its potential to dramatically affect phenotype. Here, we identify 155,440 indels and structural variants ranging in size from 1 bp to 10 kb, including presence/absence variants (PAVs), inversions, and tandem duplications in 1,301 A. thaliana natural accessions from Morocco, Madeira, Europe, Asia, and North America. We show evidence for strong purifying selection on PAVs in genes, in particular for housekeeping genes and homeobox genes, and we find that PAVs are concentrated in defense-related genes (R-genes, secondary metabolites) and F-box genes. This implies the presence of a “core” genome underlying basic cellular processes and a “flexible” genome that includes genes that may be important in spatially or temporally varying selection. Further, we find an excess of intermediate frequency PAVs in defense response genes in nearly all populations studied, consistent with a history of balancing selection on this class of genes. Finally, we find that PAVs in genes involved in the cold requirement for flowering (vernalization) and drought response are strongly associated with temperature at the sites of origin.
Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model
Authors: Amélie M. Borie, Yann Dromard, Gilles Guillon, Aleksandra Olma, Maurice Manning, Françoise Muscatelli, Michel G. Desarménien, Freddy Jeanneteau
Journal: Journal of Clinical Investigation (2020)

Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes.
Medical treatment was used as cover for sexual abuse of children, inquiry concludes
Authors: Clare Dyer
Journal: BMJ (2020)

The sexual abuse of children in healthcare settings has typically been carried out under the guise of medical procedures, the independent inquiry into child sexual abuse in England and Wales has concluded.

Perpetrators were commonly male GPs or other healthcare practitioners with clinical access to children, who were in positions of trust and whose actions were not questioned by parents, children, or other staff, a research report for the inquiry found.1

The report, based on victims’ experiences from the 1960s to the early 2000s as told to the inquiry’s Truth Project, is the fifth report from the inquiry. Set up in 2015 to look at how institutions …
Venetoclax with decitabine vs intensive chemotherapy in acute myeloid leukemia: A propensity score matched analysis stratified by risk of treatment‐related mortality
Authors: Abhishek Maiti, Wei Qiao, Koji Sasaki, Farhad Ravandi, Tapan M. Kadia, Elias J. Jabbour, Naval G. Daver, Gautam Borthakur, Guillermo Garcia‐Manero, Sherry A. Pierce, Kathryn S. Montalbano, Naveen Pemmaraju, Kiran Naqvi, Maro Ohanian, Nicholas J. Short, Yesid Alvarado, Koichi Takahashi, Musa Yilmaz, Nitin Jain, Steven M. Kornblau, Michael Andreeff, Prithviraj Bose, Alessandra Ferrajoli, Ghayas C. Issa, Lucia Masarova, Philip A. Thompson, Caitlin R. Rausch, Jing Ning, Hagop M. Kantarjian, Courtney D. DiNardo, Marina Y. Konopleva
Journal: American Journal of Hematology (2020)

Abstract Hypomethylating agents (HMA) with venetoclax is a new standard for older/unfit patients with acute myeloid leukemia (AML). However, it is unknown how HMA with venetoclax compare to intensive chemotherapy (IC) in patients who are “fit” or “unfit” for IC. We compared outcomes of older patients with newly diagnosed AML receiving 10‐day decitabine with venetoclax (DEC10‐VEN) vs IC. DEC10‐VEN consisted of daily venetoclax with decitabine 20 mg/m 2 for 10 days for induction and decitabine for 5 days as consolidation. The IC cohort received regimens containing cytarabine ≥1 g/m 2 /d. A validated treatment‐related mortality score (TRMS) was used to classify patients at high‐risk or low‐risk for TRM with IC. Propensity scores were used to match patients to minimize bias. Median age of the DEC10‐VEN cohort (n = 85) was 72 years (range 63‐89) and 28% patients were at high‐risk of TRM with IC. The comparator IC group (n = 85) matched closely in terms of baseline characteristics. DEC10‐VEN was associated with significantly higher CR/CRi compared to IC (81% vs 52%, P &lt; .001), and lower rate of relapse (34% vs 56%, P = .01), 30‐day mortality (1% vs 24%, P &lt; .01), and longer overall survival (OS; 12.4 vs 4.5 months, HR = 0.48, 95%CI 0.29‐0.79, P &lt; .01). In patients at both at high‐risk and low‐risk of TRM, DEC10‐VEN showed significantly higher CR/CRi, lower 30‐day mortality, and longer OS compared to IC. Patients at both high‐risk and low‐risk of TRM had comparable outcomes with DEC10‐VEN. In conclusion, DEC10‐VEN offers better outcomes compared to intensive chemotherapy in older patients with newly diagnosed AML, particularly in those at high‐risk of TRM.
Filgotinib: First Approval
Authors: Sohita Dhillon, Susan J. Keam
Journal: Drugs (2020)

Filgotinib (Jyseleca®) is an oral, ATP-competitive, reversible JAK1 preferential inhibitor that is being developed by Galapagos NV and Gilead Sciences for the treatment of inflammatory autoimmune diseases, including inflammatory arthritis and inflammatory bowel disease. The JAK-STAT signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases, and filgotinib modulates this pathway by preventing the phosphorylation and activation of STATs. In September 2020, filgotinib received its first approvals in the EU and Japan. In the EU, filgotinib is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults who have responded inadequately to, or who are intolerant to, one or more disease-modifying anti-rheumatic drugs (DMARDs). In Japan, filgotinib is indicated for the treatment of RA in patients who had an inadequate response to conventional therapies (including prevention of structural damage to joints). Clinical studies of filgotinib for the treatment of inflammatory autoimmune diseases are ongoing worldwide. This article summarizes the milestones in the development of filgotinib leading to this first approval.
165P Prognostic factors in sorafenib-treated hepatocellular carcinoma: Multicentre analysis of a European population sample
Authors: J. Gramaça, J. Liz Pimenta, G. Nogueira Da Costa, S.A. Duarte, P.C. Liu, I.C. Gomes Fernandes, R. Gameiro Dos Santos, C.F.P. Trabulo, E. Cadavez, R.M. Gomes, M. Castelo Branco, A. Lojo Teira, T. Malheiro Sarmento, A. Baptista, I.M. Matos Pina, M. Sousa
Journal: Annals of Oncology (2020)
Cardiac Toxicity of Thoracic Radiotherapy: Existing Evidence and Future Directions
Authors: Kathryn Banfill, Meredith Giuliani, Marianne Aznar, Kevin Franks, Alan McWilliam, Matthias Schmitt, Fei Sun, Marie Catherine Vozenin, Corinne Faivre Finn
Journal: Journal of Thoracic Oncology (2020)

The impact of radiotherapy on the heart has become an area of interest in recent years. Many different cardiac dose-volume constraints have been associated with cardiac toxicity and survival; however, no consistent constraint has been found. Many patients undergoing treatment for lung cancer have risk factors for cardiovascular disease or known cardiac comorbidities; however, there is little evidence on the effects of radiotherapy on the heart in these patients. We aim to provide a summary of the existing literature on cardiac toxicity of lung cancer radiotherapy, propose strategies to avoid and manage cardiac toxicity, and suggest avenues for future research.
The vascular landscape of human cancer
Authors: Benjamin M. Kahn, Alfredo Lucas, Rohan G. Alur, Maximillian D. Wengyn, Gregory W. Schwartz, Jinyang Li, Kathryn Sun, H. Carlo Maurer, Kenneth P. Olive, Robert B. Faryabi, Ben Z. Stanger
Journal: Journal of Clinical Investigation (2020)

Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anticancer target. However, only a fraction of patients with cancer benefit from angiogenesis inhibitors. Whether antiangiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric - the endothelial index (EI) - to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypovascular tumors, enabling the classification of human tumors into 6 vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular "hub" genes. The EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Thus, we believe our studies provide an unbiased picture of human tumor vasculature that may enable more precise deployment of antiangiogenesis therapy.
Clinicopathological characteristics and management of colitis with anti-PD1 immunotherapy alone or in combination with ipilimumab
Authors: Kazi J Nahar, Robert V Rawson, Tasnia Ahmed, Stephen Tattersall, Neomal Sandanayake, Christopher J Kiely, Serigne Lo, Matteo Carlino, Umaimainthan Palendira, Richard A Scolyer, Georgina V Long, Alexander M Menzies
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Colitis is one of the common immune-related adverse events that leads to morbidity and treatment discontinuation of immunotherapy. The clinical presentation, endoscopic and histopathological features and best management of this toxicity are not well defined. Patients and methods Patients with metastatic melanoma who received immunotherapy (programmed cell death protein 1 (PD1) antibodies, alone or in combination with a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody (PD1 +CTLA-4)) and who developed clinically significant colitis (requiring systemic corticosteroids) were identified retrospectively from two academic centers. Clinical data were collected for all patients; endoscopic and histopathological data were examined in a subset. Results From May 2013 to May 2019, 118/1507 (7.8%) patients developed significant colitis; 80/553 (14.5%) after PD1+CTLA-4, 35/1000 (3.5%) PD1 alone, and three patients after Ipilimumab (IPI) alone. Combination therapy-induced colitis was more frequent (14.5% vs 3.5% in PD1 alone, p=&lt;0.0001), had an earlier onset (6.3 weeks vs 25.7 weeks, p=&lt;0.001), was more severe (grade 3/4 69% vs 31%, p=&lt;0.001), and are more likely to require higher doses of steroids (91% vs 74%, p=0.01) than PD1 colitis. Among all patients treated with steroids (N=114), 54 (47%) responded and required no further therapy (steroid sensitive), 47 patients (41%) responded to infliximab (infliximab sensitive), and 13 (11%) were infliximab refractory and needed further immunosuppressive drugs. Infliximab-refractory patients all had onset within 4 weeks of immunotherapy commencement and were more likely to have an underlying autoimmune disease, have higher grade colitis, and require longer immunosuppression, yet had similar response and survival than other patients with colitis. Of 43 (37%) patients re-resumed treatment with PD1 monotherapy after colitis resolution, 16 (37%) of whom developed recurrent colitis. Endoscopic and histopathologic data were available for 64 patients. Most had left-sided colitis, with an increase in chronic inflammatory cells and neutrophils within the lamina propria, an increase in neutrophils in the surface epithelium, without increased lymphocytes or increased eosinophils. Infliximab-refractory colitis had a trend towards more confluent pancolitis with edema, erythema, ulceration, and absent vascularity with neutrophilic infiltration and erosion. Conclusion Clinically significant colitis varies in presentation, response to immunosuppression, and endoscopic/histologic features depending on the immunotherapy type. Infliximab-refractory colitis occurs early, is often high grade, and has adverse endoscopic and histopathologic features
47MO Efficacy and quality of life (QOL) in premenopausal Asian patients (pts) with hormone receptor–positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) treated in the MONALEESA (ML)-7 study
Authors: Y-S. Lu, J. Sohn, K.S. Lee, K.H. Jung, G.K. Babu, M-C. Liu, V. Srimuninnimit, Y.S. Yap, L. Chow, A. Gaur, Y. Wang, M. Gao, S-A. Im
Journal: Annals of Oncology (2020)
BATF regulates innate lymphoid cell hematopoiesis and homeostasis
Authors: Qingyang Liu, Myung H. Kim, Leon Friesen, Chang H. Kim
Journal: Science Immunology (2020)

Early hematopoietic progenitors undergo sophisticated developmental processes to become committed innate lymphoid cell (ILC) progenitors and ultimately mature ILC subsets in the periphery. Basic leucine zipper ATF-like transcription factor (Batf) plays important roles in lymphocyte biology. We report here that Batf regulates the production of bone marrow ILC progenitors and maintenance of peripheral ILCs. The expression of Batf is induced during ILC development at the α-lymphoid progenitor stage in response to the cytokine IL-7. As a potential mechanism, up-regulated Batf binds and activates transcription of the