tbuckley/cabot-search huggingface dataset:
Biallelic mutations in novel candidate tumor suppressor genes promoting cancer progression of microsatellite-unstable colon carcinomas
Authors: Susanne Dihlmann, Stefan M. Woerner, Baohua Yu, Anja Germann, Magnus Von Knebel Doeberitz
Journal: Cancer Research (2005)

5710  Loss of negative growth regulation by inactivation of tumor suppressor gene function is a major characteristic of colon cancer and other malignancies. The type and spectrum of affected genes markedly differs between chromosomal unstable (CIN) and microsatellite unstable (MSI) colon tumors. In CIN-tumors the most frequently mutated growth regulating genes have been well characterized as members of signaling pathways, whereas the pathways of carcinogenesis in MSI tumors are largely unknown. In consequence of a defective mismatch repair system, MSI tumors accumulate frameshift mutations in multiple genes harboring repetitive DNA sequences, only a subset of which is expected to promote cancer progression. By using a statistical model that we recently proposed to predict mutations with functional impact on MSI tumors, we identified 27 candidate tumor suppressor genes, 18 of which were previously not reported to be involved in colon carcinogenesis. Here, we report analysis of these genes for expression differences and/or inactivation in 20 paired samples of MSI-H colon carcinomas and normal mucosal tissue, 15 MSI-H and 8 microsatellite stable (MSS) cell lines. A strong transcript expression of all but three candidate genes was detected by RT-PCR in each of the samples analyzed. Biallelic frameshift mutations of AIM2, FLJ11383, HT001, PTHL3, and RGS12 genes were frequently observed in MSI-H colon tumors and cell lines, whereas these genes were unaffected in MSS cell lines and normal mucosae. This implicates selection for complete inactivation of these genes during cancer progression and suggests a function in negative growth regulation. One of the genes, encoding AIM2 (absent in melanoma 2), was previously described to retard proliferation and to increase susceptibility to cell death when overexpressed in murine fibroblasts. To further elucidate the role of AIM2 in colorectal cancer cells we restored its function by transfecting wild-type AIM2-cDNA into a colorectal cancer cell line carrying a biallelic AIM2 frameshift mutation. Transient expression of a wt-AIM2-EGFP fusion protein revealed that AIM2 is predominantly located in the cytoplasm. Although we could easily detect the wt-AIM2-EGFP protein in cell lysates by Western blots two days after transfection, efforts to achieve stable expression of wt-AIM2 were unsuccessful, indicating that continuous AIM2 expression was inhibitory to cell growth. Our ongoing studies will clarify the effects of AIM2 restoration on cell growth and apoptosis, thereby suggesting a mechanism how frameshift mutations in AIM2 may contribute to MSI-H colon cancer progression. In summary, our results provide support for the statistical model to be a useful tool for the identification of mutations in genes with functional impact on MSI tumor progression and to discriminate it from mutations in bystander genes.
PATH-33. GERMLINE PREDICTORS OF HEMATOLOGIC TOXICITY IN PATIENTS WITH GLIOMA TREATED WITH CHEMOTHERAPY
Authors: Ugur Sener, Ankush Bhatia, Lisa DeAngelis, Diana Mandelker, Prakirthi Yerram
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Temozolomide is an alkylating agent commonly used in treatment of gliomas. While this agent is generally well-tolerated, hematologic toxicity is a known complication with grade 3/4 thrombocytopenia in 4% and grade 3/4 neutropenia in 8% of adults. Recent data in several non-CNS malignancies suggested that patients with germline mutations may carry an increased risk of hematological toxicity in the setting of alkylator chemotherapy. We aimed to investigate if germline mutations in glioma patients are associated with myelotoxicity during alkylating chemotherapy. METHODS In this retrospective single-institution study, we reviewed patients with glioma treated at Memorial Sloan Kettering Cancer Center (MSKCC) who had confirmed germline mutations identified by the institution’s Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing. MSK-IMPACT evaluates DNA for mutations in 76 genes known to be associated with hereditary cancer predisposition. RESULTS In 283 patients with glioma who underwent MSK-IMPACT testing, 16 distinct germline mutations were identified in 40 (14%) individuals. 27 had high-grade and 13 had low-grade glioma. Median age was 47 (range 1–79), 12 patients were women. 30 patients received temozolomide chemotherapy. Of the patients treated, four (13%) developed severe hematologic toxicity. Two cases of grade 3 neutropenia and four cases of grade 3/4 thrombocytopenia were identified. Temozolomide was stopped during radiation therapy for three patients with grade 4 thrombocytopenia or neutropenia, and dose-reduced in one patient with grade 3 thrombocytopenia. In patients who had hematologic toxicity, germline mutations were identified in genes NBN, ATM, EPCAM, and FANCC. NBN, ATM, and FANCC are involved in DNA repair. EPCAM is involved in cell adhesion. CONCLUSIONS Hematologic toxicity is a known complication with alkylator chemotherapy. Germline testing may identify patients at increased risk, leading to closer monitoring, modified dosing regimens to minimize myelosuppression, and quicker intervention to prevent interruptions in treatment.
Response to mTOR and PI3K inhibitors in enzalutamide-resistant luminal androgen receptor triple-negative breast cancer patient-derived xenografts
Authors: Florence Coussy, Marion Lavigne, Leanne de Koning, Rania El Botty, Fariba Nemati, Adnan Naguez, Guillaume Bataillon, Berengère Ouine, Ahmed Dahmani, Elodie Montaudon, Pierre Painsec, Sophie Chateau-Joubert, Fuhrmann Laetitia, Thibaut Larcher, Sophie Vacher, Walid Chemlali, Adrien Briaux, Samia Melaabi, Anne Vincent Salomon, Jean Marc Guinebretiere, Ivan Bieche, Elisabetta Marangoni
Journal: Theranostics (2020)

et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Over 600 practices in England have no female GPs, investigation finds
Authors: Abi Rimmer
Journal: BMJ (2019)

Over a million women in England do not have access to a regular female GP, an investigation by the Times newspaper has revealed.

Despite there being slightly more female than male GPs working in England (25 263 compared with 19 675 in September 20191), the Times found that in some areas as many as three in four GPs are male.2

Using figures from NHS Digital, the newspaper discovered that 614 practices in England —9.2% of all …
Deregulated Notch and Wnt signaling activates early-stage myeloid regeneration pathways in leukemia
Authors: Yoon-A Kang, Eric M. Pietras, Emmanuelle Passegué
Journal: The Journal of Experimental Medicine (2019)

Targeting commonly altered mechanisms in leukemia can provide additional treatment options. Here, we show that an inducible pathway of myeloid regeneration involving the remodeling of the multipotent progenitor (MPP) compartment downstream of hematopoietic stem cells (HSCs) is commonly hijacked in myeloid malignancies. We establish that differential regulation of Notch and Wnt signaling transiently triggers myeloid regeneration from HSCs in response to stress, and that constitutive low Notch and high Wnt activity in leukemic stem cells (LSCs) maintains this pathway activated in malignancies. We also identify compensatory crosstalk mechanisms between Notch and Wnt signaling that prevent damaging HSC function, MPP production, and blood output in conditions of high Notch and low Wnt activity. Finally, we demonstrate that restoring Notch and Wnt deregulated activity in LSCs attenuates disease progression. Our results uncover a mechanism that controls myeloid regeneration and early lineage decisions in HSCs and could be targeted in LSCs to normalize leukemic myeloid cell production.
Intraoperative detection of lymph node metastasis using one-step nucleic acid amplification (OSNA) in breast cancer patients: Effect on second surgery rate and delay for adjuvant therapy.
Authors: Sophie Klingler, Frederic Marchal, Philippe Rauch, Ouarda Kenouchi, Anne-Sophie Chrétien, Pascal Genin, Agnès Leroux, Jean-Louis Merlin
Journal: Journal of Clinical Oncology (2012)

10517 Background: Sentinel lymph node (SLN) analysis is conventionally analysed using HES and CK19 immunohistochemistry. In case of SLN involvement, a second surgery is required for axillary lymph node (ALN) resection thus delaying the initiation of adjuvant therapies. Methods: 381 pts with invasive breast cancer were considered in this retrospective study. SLN were detected using combined radio-isotope and color detection. SLN involvement was analysed using OSNA for CK19 mRNA, in 100 pts (group 1) and compared to conventional histopathology in 281 pts (reference population, group 2). In all cases, control cytology was performed. Results: No significant difference was found between group 1 and 2 regarding patients characteristics, tumor localization, size, grade, steroid receptors and HER2 expression and the mean number of SLN analysed per pt, 2.4 (range 1-7) and 2.5 (range 1-8), respectively. Considering positive SLN as “++” (CK19 mRNA copy number&gt;5000), “+” (250 &lt; CK19 mRNA copy number &lt; 5000) and positive by inhibition in group 1 and macro-, micrometastases and isolated tumor cells in group 2, no difference in lymph node involvement rate was found between the two groups with 29.0 and 29.9% of positive SLN, respectively. Only one discordance case was observed with negative OSNA analysis and positive cytology with isolated tumor cells. Using OSNA intraoperatively, the mean time to process SLN was 42 min (range 10-104) allowing immediate ALN resection. Significant (P&lt;.01) reduction of re-intervention rate was observed when OSNA was used (9 vs 39%), including margins insufficiency (5 vs 13%), ALN resection (3 vs 15%) or both (1 vs 11%). Delay before adjuvant therapy was also significantly (P &lt;.01) reduced when OSNA was used with 43 (range 20-82) vs 59 (range 14-212) days. Conclusions: Results achieved with OSNA are fully consistent with those achieved using conventional immunohistochemistry analysis. SLN analysis using OSNA avoids a second operation in most patients for ALN resection and shortens the delay for adjuvant therapy.
Questioning the Benefit of Statins for Low-risk Populations—Medical Misinformation or Scientific Evidence?
Authors: John Abramson, Robert M. Kaplan, Rita F. Redberg
Journal: JAMA Cardiology (2019)

To the Editor In our opinion, the Viewpoint by Navar1 deserves comment. We are especially concerned about the analogy of antivaxxers with those who raise concerns about widespread use of statins. We believe that scientific discourse should focus on the evidence.
Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia
Authors: Kim-Hien T. Dao, Jason Gotlib, Michael M.N. Deininger, Stephen T. Oh, Jorge E. Cortes, Robert H. Collins, Elliot F. Winton, Dana R. Parker, Hyunjung Lee, Anna Reister, None Schultz, Samantha Savage, None Stevens, Chase Brockett, Nan Subbiah, Richard D. Press, Philipp W. Raess, Michael Cascio, Jennifer Dunlap, Yiyi Chen, Catherine Degnin, Julia E. Maxson, Cristina E. Tognon, Tara Macey, Brian J. Druker, Jeffrey W. Tyner
Journal: Journal of Clinical Oncology (2019)

Colony-stimulating factor-3 receptor (
PDCT-16. A PHASE I STUDY OF SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) WITH TEMSIROLIMUS IN CHILDREN WITH NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Soumen Khatua, Joya Chandra, Vidya Gopalakrishnan, Leena Ketonen, Michael Johnson, David Sandberg, Greg Fuller, Miriam Morrell, Heather Meador, Krystal Bolton, Ginger Butterworth, Farah Mukheef, Zsila Sadighi, Wafik Zaky
Journal: Neuro-Oncology (2019)

Abstract Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. Thus targeting these pathways with mTOR inhibitors could hold promise. Genomic and epigenetic insights have shown the role of histone deacetylase (HDAC) in these tumors. Both temsirolimus (mTOR inhibitor) and SAHA (HDAC inhibitor) are well described in pediatric clinical trials with an established maximum tolerated dose (MTD) for phase II studies. This is the first ongoing phase I multi-targeted therapeutic study, in pediatric DIPG, using SAHA and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules (NCT02420613 currently recruiting). Patients with a performance score of 50 or greater, with newly diagnosed (Stratum I), or progressive (stratum II) DIPG will be eligible. Biopsy is not mandatory. A standard 3 + 3 design is being used for this study. 1 dose escalation and 2 dose de-escalations are permitted beyond the starting dose level. In stratum I patients receive radiation therapy concurrently with vorinostat on the days of radiation, followed by adjuvant therapy with vorinostat and temsirolimus for 10 cycles if they do not have progressive disease. In stratum II patients receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if they do not have progressive disease. Correlative studies evaluating histone acetylation, phosphorylated 70S6K and Akt are being performed. Currently 5 patients have been enrolled, and the study is at the dose escalation level with no dose limiting toxicity (DLT) seen so far. Safety, adverse effects, biological correlatives, and clinical outcomes will be reported once study is completed.
Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation
Authors: Matthias Guckenberger, Yolande Lievens, Angelique B Bouma, Laurence Collette, Andre Dekker, Nandita M deSouza, Anne-Marie C Dingemans, Beatrice Fournier, Coen Hurkmans, Frédéric E Lecouvet, Icro Meattini, Alejandra Méndez Romero, Umberto Ricardi, Nicola S Russell, Daniel H Schanne, Marta Scorsetti, Bertrand Tombal, Dirk Verellen, Christine Verfaillie, Piet Ost
Journal: The Lancet Oncology (2020)
GENE-01. THE MUTATIONAL LANDSCAPE OF PRIMARY CHORDOMAS AND THEIR SENSITIVE DETECTION IN PLASMA ctDNA BY MULTIPLE NEXT GENERATION SEQUENCING TECHNOLOGIES
Authors: Austin Mattox, Yuchen Jiao, Cherie Blair, Nickolas Papadopoulos, Chetan Bettegowda
Journal: Neuro-Oncology (2019)

Abstract CNS-associated tumors are notoriously difficult to detect in plasma. Chordomas are the most common primary spinal column malignancy, and extensive surgical procedures, along with chemotherapy and radiation are required to reduce recurrence. Currently CT, MRI, and PET are used to monitor for recurrence but are limited by surgical sequalae. In addition, needle biopsy risks tumor seeding along the biopsy track. In the largest cohort of chordomas described thus far, we characterize the mutational landscape of these tumors and show that liquid biopsy is a sensitive method for detecting cancers. 34 patients with a biopsy-confirmed diagnosis of chordoma had blood drawn before surgery, at the time of surgery, and/or at follow up appointments. Mutations in the primary tumor were identified by whole exome sequencing (WES) and droplet digital PCR (ddPCR) and/or Rapid Amplification of cDNA Ends Sequencing (RACE-Seq) was used to detect one or more of these mutations in plasma ctDNA at concurrent or later time points. The primary endpoint was detection of mutations in ctDNA in biopsy-confirmed chordoma samples. 87.9% of patients were ctDNA positive at the time of initial blood draw (p &amp;lt; 0.001). Follow up blood draws in twenty of the patients demonstrated that ctDNA levels reflected the clinical status of the disease. Patients with positive ctDNA levels were more likely to undergo radiotherapy (p = 0.004), and the presence of ctDNA may predict response to systemic chemotherapy and/or disease recurrence. Given the significant sequelae of biopsy and spinal surgery, liquid biopsy may be the best tool for detection and monitoring of chordomas.
Degos-Like Cutaneous Findings in an Adult Woman With NXP-2–Associated Dermatomyositis
Authors: Serena Giacalone, Chiara Moltrasio, Gianluca Nazzaro
Journal: JAMA Dermatology (2019)

This case report describes a woman in her 20s with progressive myalgia, proximal muscle weakness, and fever followed by facial edema, heliotrope erythema of the eyelids, and lesions resembling malignant atrophic papulosis.
A Multi-Center Quality Improvement Intervention to Reduce the Inappropriate Use of Aspirin Among Patients Anticoagulated with Warfarin for Atrial Fibrillation or Venous Thromboembolism
Authors: Jordan K Schaefer, Josh Errickson, Xiaokui Gu, Tina Alexandris-Souphis, Mona A Ali, Brian Haymart, Scott Kaatz, Eva Kline-Rogers, Jay H Kozlowski, Gregory D Krol, Suman L Sood, James B Froehlich, Geoffrey D Barnes
Journal: Blood (2019)
Misrepresenting “Usual Care” in Research: An Ethical and Scientific Error
Authors: Ruth Macklin, Charles Natanson
Journal: The American Journal of Bioethics (2020)

Comparative effectiveness studies, referred to here as “usual-care” trials, seek to compare current medical practices for the same medical condition. Such studies are presumed to be safe and involve only minimal risks. However, that presumption may be flawed if the trial design contains “unusual” care, resulting in potential risks to subjects and inaccurately informed consent. Three case studies described here did not rely on clinical evidence to ascertain contemporaneous practice. As a result, the investigators drew inaccurate conclusions, misinformed research participants, and subjects’ safety was compromised. Before approving usual-care protocols, IRBs and scientific review committees should evaluate the quality and completeness of information documenting usual-care practices. Guidance from governmental oversight agencies regarding evidence-based documentation of current clinical practice could prevent similar occurrences in future usual-care trials. Accurate information is necessary to ensure that trials comply with government regulations that require minimizing research risks to subjects and accurate informed consent documents.
CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer
Authors: Hua Zhang, Camilla L. Christensen, Ruben Dries, Matthew G. Oser, Jiehui Deng, Brian Diskin, Fei Li, Yuanwang Pan, Xuzhu Zhang, Yandong Yin, Eleni Papadopoulos, Val Pyon, Cassandra Thakurdin, Nicholas Kwiatkowski, Kandarp Jani, Alexandra R. Rabin, Dayanne M. Castro, Ting Chen, Heather Silver, Qingyuan Huang, Mirna Bulatovic, Catríona M. Dowling, Belen Sundberg, Alan Leggett, Michela Ranieri, Han Han, Shuai Li, Annan Yang, Kristen E. Labbe, Christina Almonte, Vladislav O. Sviderskiy, Max Quinn, Jack Donaghue, Eric S. Wang, Tinghu Zhang, Zhixiang He, Vamsidhar Velcheti, Peter S. Hammerman, Gordon J. Freeman, Richard Bonneau, William G. Kaelin, Kate D. Sutherland, Ariena Kersbergen, Andrew J. Aguirre, Guo-Cheng Yuan, Eli Rothenberg, George Miller, Nathanael S. Gray, Kwok-Kin Wong
Journal: Cancer Cell (2019)
Global matching and fluency attribution in familiarity assessment
Authors: Haopei Yang, Stefan Köhler
Journal: Behavioral and Brain Sciences (2019)

Abstract In the integrative memory model proposed by Bastin et al., familiarity is thought to arise from attribution of fluency signals. We suggest that, from a computational and anatomical perspective, this conceptualization converges with a global-matching account of familiarity assessment. We also argue that consideration of global matching and evidence accumulation in decision making could help further our understanding of the proposed attribution system.
Indium-111 labelling of liposomal HEGF for radionuclide delivery via ultrasound-induced cavitation
Authors: Joshua Owen, Eloise Thomas, Jyothi Menon, Michael Gray, Irini Skaripa-Koukelli, Martin R. Gill, Sheena Wallington, Rebecca L. Miller, Katherine A. Vallis, Robert Carlisle
Journal: Journal of Controlled Release (2019)
KBTBD13 and the ever-expanding sarcomeric universe
Authors: Stuart G. Campbell, Steven A. Niederer
Journal: Journal of Clinical Investigation (2020)

KBTBD13 is a protein expressed in striated muscle whose precise function is unknown. Work by de Winter et al. in this issue of the JCI provides evidence that KBTBD13 localizes to the sarcomere and can directly bind actin. A mutation in KBTBD13 that is associated with nemaline myopathy alters the protein's effects on actin, apparently increasing thin-filament stiffness and ultimately depressing contractile force and relaxation rate. We discuss here the implications of this new sarcomeric protein, some alternate explanations for the effects of KBTBD13R408C, and the advantages of using computational models to interpret functional data from muscle.
Abstract 11801: The Effect of Influenza Vaccination on the Systemic Inflammatory Response and Myocardial Protection in Patients Undergoing Cardiac Surgery: A Randomized Controlled Trial
Authors: Fady Ebrahim, John Mireau, Kevin Saroka, Janet McElhaney, Rony Atoui
Journal: Circulation (2019)

Introduction: Despite improvement in cardioprotective strategies, myocardial dysfunction after cardiac surgery remains an ongoing problem. CABG with cardiopulmonary bypass (CPB) induces an acute in...
Effects of lazaroid U-74389G liposomes in a glioblastoma mouse model.
Authors: Fady Ibrahim, Pamela Z. New, Kemi Cui, Hong Zhao, Lulu Wang, Diana Chow, Stephen Wong
Journal: Journal of Clinical Oncology (2012)

2098 Background: Lazaroid U-74389G (LAZ) is a 21-aminosteroid that has radioprotective effects against radiation-induced lipid peroxidation. Also in vitro antiproliferative effects have been reported against glioblastoma cell lines. The aim of this study was to use a liposomal formulation to evaluate LAZ radioprotective and antiproliferative effects in a glioblastoma mouse model. Methods: LAZ PEGylated liposomes (Lipo G) were developed at the University of Houston, College of Pharmacy. Glioblastoma cell line U87-expressing firefly luciferase reporter gene (100,000 cells in 2 μL) was injected intracranially in each male SCID hairless outbred mouse. There were 4 treatment groups (n=8-9, each): brain model (M) without treatment (control), radiation 2Gy weekly (M+R), Lipo G at 5 mg/kg dose IP twice per week (M+L) and radiation with Lipo G (M+R+L). Treatment lasted three weeks. Tumor size was monitored using non-invasive bioluminescence imaging (BLI), in each mouse. Mice were sacrificed after 3 weeks. Brain was harvested for immunohistochemistry examinations. Lipid peroxidation of brain tissues was quantified by measuring malondialdehyde (MDA) as a surrogate biomarker. Survival was evaluated using Kaplan Meier analysis at P= 0.05. Results: The relative BLI intensity was 4002.03±1737.67, 2034±737.72, 1387.36±684.53 and 2498.89±2521.32 % for M, M+R, M+L and M+R+L, respectively. The tumor size of the M+L group was reduced by 65% compared to control . For the radiation treated groups (M+R and M+R+L), there was no significant difference in tumor size compared to control group. MDA brain concentration in M+L and M+R+L groups was significantly less than in M+R group (8.27±0.78 and 10.37±3.30 µM/gm vs. 23.09± 3.79 µM/gm). The survival mean was 22.67, 25.33, 25.22 and 27.13 days for M, M+R, M+R+L and M+L groups, respectively. Mean survival of LAZ treated groups (M+L and M+R+L) was significantly longer than that of the control group Conclusions: LAZ liposomal formulations administered at 5 mg/kg dose reduced tumor growth by 65%. LAZ also protected brain tissue from radiation-induced lipid peroxidation by reducing MDA concentration by 50%. These provocative data warrant further investigation of LAZ as a radiation protectant and chemotherapeutic agent.