tbuckley/cabot-search huggingface dataset:
RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition
Authors: Lisa Hunihan, Dejian Zhao, Heather Lazowski, Man Li, Yuping Qian, Laura Abriola, Yulia V. Surovtseva, Viswanathan Muthusamy, Lynn T. Tanoue, Bonnie E. Gould Rothberg, Kurt A. Schalper, Roy S. Herbst, Frederick H. Wilson
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The identification of actionable oncogenic alterations has enabled targeted therapeutic strategies for subsets of patients with advanced malignancies, including lung adenocarcinoma (LUAD). We sought to assess the frequency of known drivers and identify new candidate drivers in a cohort of LUAD from patients with minimal smoking history. Experimental Design: We performed genomic characterization of 103 LUADs from patients with ≤10 pack-year smoking history. Tumors were subjected to targeted molecular profiling and/or whole-exome sequencing and RNA sequencing in search of established and previously uncharacterized candidate drivers. Results: We identified an established oncogenic driver in 98 of 103 tumors (95%). From one tumor lacking a known driver, we identified a novel gene rearrangement between OCLN and RASGRF1. The encoded OCLN-RASGRF1 chimera fuses the membrane-spanning portion of the tight junction protein occludin with the catalytic RAS-GEF domain of the RAS activator RASGRF1. We identified a similar SLC4A4-RASGRF1 fusion in a pancreatic ductal adenocarcinoma cell line lacking an activating KRAS mutation and an IQGAP1-RASGRF1 fusion from a sarcoma in The Cancer Genome Atlas. We demonstrate these fusions increase cellular levels of active GTP-RAS, induce cellular transformation, and promote in vivo tumorigenesis. Cells driven by RASGRF1 fusions are sensitive to targeting of the RAF-MEK-ERK pathway in vitro and in vivo. Conclusions: Our findings credential RASGRF1 fusions as a therapeutic target in multiple malignancies and implicate RAF-MEK-ERK inhibition as a potential treatment strategy for advanced tumors harboring these alterations. See related commentary by Moorthi and Berger, p. 2983
18F-FDG PET/CT and 68Ga-DOTATATE PET/CT Findings in a Patient With Primary Renal Well-Differentiated Neuroendocrine Tumor
Authors: Rahime Şahin, Sevim Baykal Koca, Uğur Yücetaş, Tevfik Fikret Çermik, Nurhan Ergül
Journal: Clinical Nuclear Medicine (2022)

Primary renal well-differentiated neuroendocrine tumors (WDNETs), also called renal carcinoids, are extremely rare. Since first described in 1966, approximately 100 cases have been reported in the literature. However, there have been no cases shown by PET/CT to date. We presented a patient with primary renal WDNET who had undergone both 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT for diagnosis and staging. This case illustrated that 68Ga-DOTATATE PET/CT scanning could play a role in the diagnosis, staging, and follow-up of primary renal WDNETs.
Bedside formulation of a personalized multi-neoantigen vaccine against mammary carcinoma
Authors: Mona O Mohsen, Daniel E Speiser, Justine Michaux, HuiSong Pak, Brian J Stevenson, Monique Vogel, Varghese Philipose Inchakalody, Simone de Brot, Said Dermime, Georges Coukos, Michal Bassani-Sternberg, Martin F Bachmann
Journal: Journal for ImmunoTherapy of Cancer (2022)

Harnessing the immune system to purposely recognize and destroy tumors represents a significant breakthrough in clinical oncology. Non-synonymous mutations (neoantigenic peptides) were identified as powerful cancer targets. This knowledge can be exploited for further improvements of active immunotherapies, including cancer vaccines, as T cells specific for neoantigens are not attenuated by immune tolerance mechanism and do not harm healthy tissues. The current study aimed at developing an optimized multitarget vaccine using short or long neoantigenic peptides utilizing virus-like particles (VLPs) as an efficient vaccine platform. Mutations of murine mammary carcinoma cells were identified by integrating mass spectrometry-based immunopeptidomics and whole exome sequencing. Neoantigenic peptides were synthesized and covalently linked to virus-like nanoparticles using a Cu-free click chemistry method for easy preparation of vaccines against mouse mammary carcinoma. As compared with short peptides, vaccination with long peptides was superior in the generation of neoantigen-specific CD4+ and CD8+ T cells, which readily produced interferon gamma (IFN-γ) and tumor-necrosis factor α (TNF-α). The resulting anti-tumor effect was associated with favorable immune re-polarization in the tumor microenvironment through reduction of myeloid-derived suppressor cells. Vaccination with long neoantigenic peptides also decreased post-surgical tumor recurrence and metastases, and prolonged mouse survival, despite the tumor's low mutational burden. Integrating mass spectrometry-based immunopeptidomics and whole exome sequencing is an efficient approach for identifying neoantigenic peptides. Our multitarget VLP-based vaccine shows a promising anti-tumor effect in an aggressive murine mammary carcinoma model. Future clinical application using this strategy is readily feasible and practical, as click chemistry coupling of personalized synthetic peptides to the nanoparticles can be done at the bedside directly before injection.
Roxadustat Versus Epoetin Alfa for Treating Anemia in Patients with Chronic Kidney Disease on Dialysis: Results from the Randomized Phase 3 ROCKIES Study
Authors: Steven Fishbane, Carol A. Pollock, Mohamed El-Shahawy, Elizabeth T. Escudero, Anjay Rastogi, Bui Pham Van, Lars Frison, Mark Houser, Maksym Pola, Dustin J. Little, Nicolas Guzman, Pablo E. Pergola
Journal: Journal of the American Society of Nephrology (2022)

Concerns regarding cardiovascular safety with current treatments for anemia in patients with dialysis-dependent (DD)-CKD have encouraged the development of alternatives. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis by increasing endogenous erythropoietin and iron availability.In this open-label phase 3 study, patients with DD-CKD and anemia were randomized 1:1 to oral roxadustat three times weekly or parenteral epoetin alfa per local clinic practice. Initial roxadustat dose depended on erythropoiesis-stimulating agent dose at screening for patients already on them and was weight-based for those not on them. The primary efficacy end point was mean hemoglobin change from baseline averaged over weeks 28‒52 for roxadustat versus epoetin alfa, regardless of rescue therapy use, tested for noninferiority (margin, -0.75 g/dl). Adverse events (AEs) were assessed.Among 2133 patients randomized (n=1068 roxadustat, n=1065 epoetin alfa), mean age was 54.0 years, and 89.1% and 10.8% were on hemodialysis and peritoneal dialysis, respectively. Mean (95% confidence interval) hemoglobin change from baseline was 0.77 (0.69 to 0.85) g/dl with roxadustat and 0.68 (0.60 to 0.76) g/dl with epoetin alfa, demonstrating noninferiority (least squares mean difference [95% CI], 0.09 [0.01 to 0.18]; P<0.001). The proportion of patients experiencing ≥1 AE and ≥1 serious AE was 85.0% and 57.6% with roxadustat and 84.5% and 57.5% with epoetin alfa, respectively.Roxadustat effectively increased hemoglobin in patients with DD-CKD, with an AE profile comparable to epoetin alfa.Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis.gov Identifier: NCT02174731.
Cannabinoid receptor 1 signaling in hepatocytes and stellate cells does not contribute to NAFLD
Authors: Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K. Bence, Mingjian Lu, Carlos M. Castorena, Shangang Zhao, Joel K. Elmquist, Philipp E. Scherer, Jay D. Horton
Journal: Journal of Clinical Investigation (2021)

The endocannabinoid system regulates appetite and energy expenditure and inhibitors of cannabinoid receptor 1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 in hepatocytes did not alter the development of NAFLD in mice fed a high-sucrose diet (HSD) or a high-fat diet (HFD). Similarly, deletion of CB-1 specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD, nor did it protect mice from carbon tetrachloride-induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.
TREATMENT AT RELAPSE: WHAT TO DO FIRST?
Authors: Maria-Victoria Mateos
Journal: HemaSphere (2022)

Over the last years and because of the introduction of novel drugs, autologous stem cell transplant as well as maintenance as part of the first line of therapy, together with the better knowledge of the disease biology and new techniques to measure the residual disease, the duration of the response after the diagnosis is longer than in the past. However, most patients will finally progress and we have to consider some patients and disease-based factors in order to make the right choice: i) chronological age; ii) frailty; ii) organ function; iii) risk status; iv) life style and family support and vi) treatment history. The first consideration at the moment of the relapse is if we should treat biochemical or clinical relapses and it is highly recommended to treat at the biochemical relapse with the only exception of indolent diseases at the diagnosis (ISS-1, anaemia as the only myeloma defining event….). The second consideration is to evaluate the treatment history and the refractoriness to the previous drugs. Today, most patients at the moment of first relapse, are exposed to proteasome inhibitors and immunomodulatory drugs and refractory to lenalidomide and over the last months, some patients are also exposed to the anti-CD38 monoclonal antibodies. According to the most recent guidelines and phase 3 clinical trials, if the patient is eligible for anti-CD38 monoclonal antibodies because the patient is naïve or sensitive, the optimal choices are carfilzomib-dexamethasone plus either daratumumab or isatuximab or pomalidomide-dexamethasone plus daratumumab. If the patient is not eligible for anti-CD38 monoclonal antibodes, the possibilities would be either pomalidomide-dexamethasone plus bortezomib or Selinexor-dexamethasone plus bortezomib. Of note, venetoclax-dexamethasone alone or in combination will be reserved for patients with t(11;14). These recommendations would be applicable to patients in first relapse. There are some other combination recommended for third line and beyond, and based on pomalidomide-dexamethasone, if the patient has not been previously exposed, in combination with either isatuximab or elotuzumab although it is also possible to combine with cyclophosphamide. In summary, we have to follow the current guidelines for the management of MM at first relapse although the treatment landscape is rapidy evolving and phase 3 trials are ongoing with the objective of incorporating the BCMA-targeted therapy at first relapse.
Gene therapy reforms photoreceptor structure and restores vision in NPHP5-associated Leber congenital amaurosis
Authors: Gustavo D. Aguirre, Artur V. Cideciyan, Valérie L. Dufour, Ana Ripolles-García, Raghavi Sudharsan, Malgorzata Swider, Roman Nikonov, Simone Iwabe, Sanford L. Boye, William W. Hauswirth, Samuel G. Jacobson, William A. Beltran
Journal: Molecular Therapy (2021)

(Molecular Therapy 29, 2456–2468; March 27, 2021) Due to an oversight during the proof corrections stage, the supplemental information in the original published article did not include Figure S5. This has since been corrected online. We apologize to our readers for any confusion that may have resulted from the oversight. Gene therapy reforms photoreceptor structure and restores vision in NPHP5-associated Leber congenital amaurosisAguirre et al.Molecular TherapyMarch 27, 2021In BriefUsing the canine NPHP5 model of Leber congenital amaurosis, the authors show that gene therapy is highly effective at the stage of disease when there is rapid cell death and active degeneration. After treatment, cone outer segments reform, retinal and visual function is restored, and degeneration is arrested. Full-Text PDF
Toward Personalization of Cytarabine Dosing in Acute Myeloid Leukemia
Authors: Lars Petter Jordheim
Journal: Journal of Clinical Oncology (2022)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation. January 06, 2022 ARTICLE CITATION DOI: 10.1200/JCO.21.02723 Journal of Clinical Oncology - published online before print January 13, 2022 PMID: 35025625 Toward Personalization of Cytarabine Dosing in Acute Myeloid Leukemia Lars Petter Jordheim, PharmD, PhD1xLars Petter JordheimSearch for articles by this author Show More 1Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France https://doi.org/10.1200/JCO.21.02723 First Page Full Text PDF Figures and Tables © 2022 by American Society of Clinical OncologyAUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTToward Personalization of Cytarabine Dosing in Acute Myeloid LeukemiaThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).No potential conflicts of interest were reported. Companion Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation
The Oncogenic PI3K-Induced Transcriptomic Landscape Reveals Key Functions in Splicing and Gene Expression Regulation
Authors: Erik Ladewig, Flavia Michelini, Komal Jhaveri, Pau Castel, Javier Carmona, Lauren Fairchild, Adler G. Zuniga, Amaia Arruabarrena-Aristorena, Emiliano Cocco, Ryan Blawski, Srushti Kittane, Yuhan Zhang, Mirna Sallaku, Laura Baldino, Vasilis Hristidis, Sarat Chandarlapaty, Omar Abdel-Wahab, Christina Leslie, Maurizio Scaltriti, Eneda Toska
Journal: Cancer Research (2022)

Abstract The phosphoinositide 3–kinase (PI3K) pathway regulates proliferation, survival, and metabolism and is frequently activated across human cancers. A comprehensive elucidation of how this signaling pathway controls transcriptional and cotranscriptional processes could provide new insights into the key functions of PI3K signaling in cancer. Here, we undertook a transcriptomic approach to investigate genome-wide gene expression and transcription factor activity changes, as well as splicing and isoform usage dynamics, downstream of PI3K. These analyses uncovered widespread alternatively spliced isoforms linked to proliferation, metabolism, and splicing in PIK3CA-mutant cells, which were reversed by inhibition of PI3Kα. Analysis of paired tumor biopsies from patients with PIK3CA-mutated breast cancer undergoing treatment with PI3Kα inhibitors identified widespread splicing alterations that affect specific isoforms in common with the preclinical models, and these alterations, namely PTK2/FRNK and AFMID isoforms, were validated as functional drivers of cancer cell growth or migration. Mechanistically, isoform-specific splicing factors mediated PI3K-dependent RNA splicing. Treatment with splicing inhibitors rendered breast cancer cells more sensitive to the PI3Kα inhibitor alpelisib, resulting in greater growth inhibition than alpelisib alone. This study provides the first comprehensive analysis of widespread splicing alterations driven by oncogenic PI3K in breast cancer. The atlas of PI3K-mediated splicing programs establishes a key role for the PI3K pathway in regulating splicing, opening new avenues for exploiting PI3K signaling as a therapeutic vulnerability in breast cancer. Significance: Transcriptomic analysis reveals a key role for the PI3K pathway in regulating RNA splicing, uncovering new mechanisms by which PI3K regulates proliferation and metabolism in breast cancer. See related commentary by Claridge and Hopkins, p. 2216 Watch the interview with Eneda Toska, PhD, recipient of the 2023 Cancer Research Early Career Award: https://vimeo.com/847434965
There's more to consider than knowledge and belief
Authors: David M. Sobel
Journal: Behavioral and Brain Sciences (2021)

Abstract Phillips et al. present a number of arguments for the premise that knowledge is more basic than belief. Although their arguments are coherent and sound, they do not directly address numerous cases in which belief appears to be a developmental precursor to knowledge. I describe several examples, not necessarily as a direct challenge, but rather to better understand their framework.
Abstract EP53: The Association Of Oral Hypofunction/locomotive Syndrome And Increased Arterial Stiffness
Authors: Chisa Matsumoto, Hirofumi Tomiyama, Mari Matsuura, Hiroki Nakano, Kazuki Shiina, Akira Yamashina
Journal: Circulation (2022)

Background: Frailty is associated with higher risk of cardiovascular disease (CVD). Recently, oral hypofunction, a disease in which the oral function is complexly reduced not only by ageing but also by a variety of factors, is regarded as a risk factor for frailty. Also, locomotive syndrome, which is defined as reduced mobility due to impaired locomotive organs, is reported to have close association with frailty and oral hypofunction. However, no studies evaluated the association of oral hypofunction / locomotive syndrome and arterial stiffness, a marker of CVD. The objective of this study is to evaluate the association of oral hypofunction / locomotive syndrome and arterial stiffness. Hypothesis: We hypothesized that subjects with oral hypofunction or locomotive syndrome have increased arterial stiffness compared to those without oral hypofunction and locomotive syndrome. Methods: Japanese Subjects above 50 years old who underwent annual health-checkup were enrolled in this cross-sectional study. Subjects with history of CVD and dementia were excluded. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). Oral hypofunction was evaluated the methods based on the guidance by the Japanese Association for Dental Science. Seven oral factors, oral hygiene, oral moisture, occlusal force, tongue-lip motor function, tongue pressure, masticatory function, and swallowing function were assessed. Oral hypofunction was diagnosed if more than 3 factors showed deterioration. Locomotive syndrome was evaluated by the questionnaires (GLFS-25) and physical performance tests consisted of those for quadriceps muscle strength, a two-step test, and a stand-up test according to the guidance by the Japanese Orthopedic Association. The association of oral hypofunction / locomotive syndrome and baPWV was assessed by multivariable linear regression analysis adjusted for conventional CVD risk factors. Results: Among 148 subjects (mean age: 59±7 years), 82 subjects (55%) had either oral hypofunction or locomotive syndrome (oral hypofunction: 33 subjects, locomotive syndrome: 65 subjects). BaPWV in subjects with either oral hypofunction or locomotive syndrome was significantly higher than subjects with none of them (mean baPWV: 1501±292 v.s. 1368±238cm/sec, p=0.003). Multivariable linear regression analysis revealed that the existence of either oral hypofunction or locomotive syndrome was significantly associated with increased arterial stiffness (β=100±39, p=0.01). Conclusion: The existence of either oral hypofunction or locomotive syndrome was associated with increased arterial stiffness. Further research on oral hypofunction / locomotive syndrome and CVD is warranted.
5MO Patient reported outcomes (PROs) with 1L durvalumab (D), with or without tremelimumab (T), plus chemotherapy (CT) in metastatic (m) NSCLC: Results from POSEIDON
Authors: E.B. Garon, B.C. Cho, A. Luft, J. Alatorre-Alexander, S.L. Geater, D. Trukhin, S-W. Kim, G. Ursol, M. Hussein, F.L. Lim, C-T. Yang, L.H. Araujo, H. Saito, N. Reinmuth, N. Medic, H. Mann, X. Shi, S. Peters, T.S.K. Mok, M. Johnson
Journal: Annals of Oncology (2022)
Fibroblast Activation Protein–Targeted PET Imaging of Metastatic Castration-Resistant Prostate Cancer Compared With 68Ga-PSMA and 18F-FDG PET/CT
Authors: Emine Goknur Isik, Duygu Has-Simsek, Oner Sanli, Yasemin Sanli, Serkan Kuyumcu
Journal: Clinical Nuclear Medicine (2021)

Abstract Herein we present 2 mCRPC (metastatic castration-resistant prostate cancer) patients who underwent 68 Ga-PSMA PET/CT for PSMA-targeted radioligand therapy eligibility. Prior studies have noted aggressive clinical behavior and poor prognosis associated with discordant FDG positivity and low PSMA expression. Accordingly, the patients also underwent 18 F-FDG PET/CT, which revealed intratumoral heterogeneity. Therefore, an additional PET/CT targeting fibroblast activation proteins (FAPs) using 68 Ga-FAPI-04 was performed to assess the potential for an FAP-targeted therapy. This report highlights the theranostic potential of FAP imaging in mCRPC, particularly in patients with heterogeneous tumor phenotypes.
JAFFAL: detecting fusion genes with long-read transcriptome sequencing
Authors: Nadia M. Davidson, Ying Chen, Teresa Sadras, Georgina L. Ryland, Piers Blombery, Paul G. Ekert, Jonathan Göke, Alicia Oshlack
Journal: Genome biology (2022)

In cancer, fusions are important diagnostic markers and targets for therapy. Long-read transcriptome sequencing allows the discovery of fusions with their full-length isoform structure. However, due to higher sequencing error rates, fusion finding algorithms designed for short reads do not work. Here we present JAFFAL, to identify fusions from long-read transcriptome sequencing. We validate JAFFAL using simulations, cell lines, and patient data from Nanopore and PacBio. We apply JAFFAL to single-cell data and find fusions spanning three genes demonstrating transcripts detected from complex rearrangements. JAFFAL is available at https://github.com/Oshlack/JAFFA/wiki .
One-Year Major Cardiovascular Events After Restrictive Versus Liberal Blood Transfusion Strategy in Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Trial
Authors: Jose Gonzalez-Juanatey, Gilles Lemesle, Etienne Puymirat, Gregory Ducrocq, Marine Cachanado, Joan Albert Arnaiz, Manuel Martínez-Sellés, Johanne Silvain, Albert Ariza-Solé, Emile Ferrari, Gonzalo Calvo, Nicolas Danchin, Cristina Avendano-Solá, Alexandra Rousseau, Eric Vicaut, Teba Gonzalez-Ferrero, Philippe Gabriel Steg, Tabassome Simon
Journal: Circulation (2022)