tbuckley/cabot-search huggingface dataset:
TMOD-02. Developing models of therapy resistance for the identification of treatment-refractory cell population(s) in human glioblastoma
Authors: Maleeha Qazi, Parvez Vora, Chitra Venugopal, David Bakhshinyan, Allison Nixon, Kevin Brown, Minomi Subapanditha, Chirayu Chokshi, Naresh Murty, Jason Moffat, Sheila Singh
Journal: Neuro-Oncology (2016)

Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolving hGBM biology in response to chemoradiotherapy will allow for the identification of cellular pathways that govern GBM therapy failure. In this study, we have developed a novel model to profile the clonal evolution of treatment naïve brain tumour initiating cell (BTIC) enriched hGBMs through chemoradiotherapy using: stem cell assays, BTIC marker expression and transcriptome analysis, immunohistochemistry, and cellular DNA barcoding technology. We report that treatment of hGBM BTICs leads to increased self-renewal capacity and higher transcript expression of stem cell genes Bmi1 and Sox2. Based on global transcriptome analysis of the in vitro treated hGBM, we also identify a hyper-aggressive form of glioma. Using our therapy-adapted hGBM-mouse xenograft model, we discover that despite tumour regression and increased mouse survival post-therapy, tumour relapse remains inevitable. The treatment-refractory cells again have increased self-renewal capacity and higher expression of Bmi1 and Sox2. Furthermore, by combining cellular DNA barcoding technology, which barcodes hGBM at single cell resolution, with our novel in vitro and in vivo therapy models, we are able to determine whether a pre-existing or a therapy driven subpopulation(s) seeds hGBM tumour relapse. Preliminary data shows a chemoradiotherapy driven selection of subclonal barcoded GBM populations, suggesting a divergent clonal evolution pattern in hGBM recurrence. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to the identification of novel therapeutic targets for the treatment of recurrent hGBM.
Retrospective analysis of metastatic non-clear cell renal carcinoma (NCCRC): the Spanish Grupo Centro Experience
Authors: L. Rodriguez Lajusticia, A. Martín, A. Pinto Marin, C. Aguado, T. Alonso Gordoa, A. Herrero, C. Maximiano, M. Garrido Arevalo, I. Gallegos, L. Villalobos, J. Cassinello, I. Garcia, J. Espinosa Arranz, J. Garcia-Donas, J.J. Tafalla, G. Torres, J. Puente, E. Grande Pulido
Journal: Annals of Oncology (2016)
CBFβ-SMMHC regulates ribosomal gene transcription and alters ribosome biogenesis
Authors: G Cordonnier, A Mandoli, A Radhouane, G Hypolite, L Lhermitte, M Belhocine, V Asnafi, E Macintyre, J H A Martens, S Fumagalli, J Bond
Journal: Leukemia (2017)
A phase II study of TKI258 in patients with castration-resistant prostate cancer (KCSG-GU11-05)
Authors: Y.J. Choi, H.S. Kim, S.H. Park, B.S. Kim, K.H. Kim, H.J. Lee, H.S. Song, D.Y. Shin, H.Y. Lee, H.-G. Kim, K.H. Lee, J.-L. Lee, K.H. Park
Journal: Annals of Oncology (2016)
GENT-52. MUTATIONAL HOTSPOT ANALYSIS OF SECONDARY GLIOSARCOMA REVEALS POTENTIAL TARGETS OF THERAPY-DRIVEN TUMOR EVOLUTION
Authors: Margaret Pain, Matthew Gallitto, Huaien Wang, Robert Sebra, Jun Zhu, Raymund Yong
Journal: Neuro-Oncology (2016)

Gliosarcoma is a rare variant of glioblastoma with a poorly understood mutational profile. Previous case series have described this tumor as a de novo primary brain tumor or as the secondary degeneration of an existing tumor. Secondary gliosarcomas are almost always described in the context of prior adjuvant treatment of a glioblastoma. We report the clinical history and molecular findings of a patient who presented with glioblastoma, underwent a full course of treatment, then progressed locally six months later with secondary gliosarcoma. Both the primary and relapsed tumors were resected and processed fresh for tissue culture. Deep targeted next-generation sequencing of these samples revealed the clonal architecture of the tumors and several TP53 mutations previously undescribed in gliosarcoma. We hypothesize that expansion of subclones driven by these mutations induced the change in tumor phenotype and development of treatment resistance in this patient. Previous work regarding the genetic basis of gliosarcoma suggests that TP53 mutations are common but little has been done to characterize the nature of those mutations. Our findings suggest that the TP53 mutations common to all sections of the recurrent tumor act as gain-of-function mutations. Appreciation of the aberrant transcriptional networks activated by TP53 missense mutations may help to elucidate the pathogenesis of gliosarcoma and explain its particularly dismal prognosis.
CSIG-15. CIC REGULATES NEURAL STEM/PROGENITOR PROLIFERATION AND DIFFERENTIATION
Authors: Shiekh Tanveer Ahmad, Alexandra D. Rogers, Rajiv Dixit, Samuel O. Lawn, Myra Joy Chen, Lata Adnani, Mana Alshehri, Stephen M. Robbins, Carol Schuurmans, Gregory Cairncross, Jennifer A. Chan
Journal: Neuro-Oncology (2016)

Capicua (Cic) is an evolutionarily conserved HMG box-containing transcriptional repressor. Mutations in the CIC gene (encoded on human chr 19q) have been found in a diverse range of human cancers, but are most striking in their association with oligodendrogliomas (ODGs), where tumor cells bear resemblance to immature oligodendrocytes or OPCs. CIC mutations are present in two thirds of ODGs and occur in the setting of concurrent 1p/19q loss and IDH1/2 mutation. Although its link to ODGs is established, little is known of the role that Cic plays during normal cortical development or how its loss may contribute to gliomagenesis. Here, we examine the relationship between CIC expression and cell identity in the developing mouse brain and begin to determine its importance in the regulation of proliferation and cell fate of cortical progenitors. We found strong nuclear localization in mature cells of astrocytic and neuronal lineages but weaker or absent nuclear localization in stem cells and oligodendroglial lineage cells. CIC loss-of-function studies showed increased proliferative and self-renewal capacity of neural stem/progenitor populations in vitro and in vivo. In addition, CIC loss biased cultured neural stem cells away from neuronal and astrocytic lineages and toward the oligodendrocyte lineage. Our data further suggest an overproduction of OPCs from cells in which CIC is lost. Taken together, our results indicate that CIC is an important regulator of fate decisions in neural development and suggest that its loss may contribute to oligodendroglioma formation by both dysregulating proliferation and by promoting an OPC-like identity.
CANCER OF THE RECTUM
Authors: D. Drew
Journal: BMJ (1910)

<h3>ABSTRACT</h3> <h3>Introduction</h3> Individuals who have knowledge of an infectious disease and also perceive the risks associated with such infectious disease tend to engage more in precautionary behaviour; however, little is known about this association as it relates to the novel Coronavirus (COVID-19). There is possibility of moderated mediation effect in the association between these variables. <h3>Objectives</h3> To examine whether risk perception determines the association between COVID-19 knowledge and precautionary behaviour among Nigerians, taking into consideration the gender differentials that may exist in the process. <h3>Design</h3> A web-based cross-sectional study. <h3>Setting</h3> Participants were recruited via social media platform, WhatsApp using google form from March 28 to April 4, 2020. <h3>Participants</h3> 1500-Nigerian (mean age =27.43, SD=9.75 with 42.7% females and 57.3% males) were recruited from 180 cities in Nigeria using snowball sampling technique. They responded to an online survey form comprising demographic questions and adapted versions of the Ebola knowledge scale, SARS risk perception scale and a precautionary behavior scale. <h3>Result</h3> Moderated mediation analysis showed that risk perception mediated the association between COVID-19 knowledge and precautionary behavior and this indirect effect was moderated by gender. Having correct knowledge of COVID-19 was linked to higher involvement in precautionary behavior through risk perception for females but not for males. COVID-19 awareness campaigns may target raising more awareness of the risks associated with the infection in order to make individuals engage more in precautionary behaviors. <h3>Conclusion:</h3> Awareness campaigns and psychological intervention strategies may be particularly important at the moment, for males more than females.
PDCT-10. FIRST IN PEDIATRICS PHASE I STUDY OF CRENOLANIB BESYLATE (CP-868,596-26) ADMINISTERED DURING AND AFTER RADIATION THERAPY (RT) IN NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND RECURRENT HIGH GRADE GLIOMA (HGG)
Authors: Cynthia Wetmore, David Turner, Larry Kun, Arzu Onar-Thomas, Jie Huang, Amar Gajjar, Suzanne Baker, Clinton Stewart, Alberto Broniscer
Journal: Neuro-Oncology (2016)

Children diagnosed with DIPG have a median survival of less than one year despite RT, the primary modality of therapy. PDGF pathway activation has been noted in tumor tissue analyzed from approximately 70 % of pediatric DIPG and 50% of HGG patients, suggesting that inhibition of this pathway may be of clinical benefit. Crenolanib is a highly selective antagonist of the PDGF pathway with in vitro IC50 of 35- and 185- fold lower than observed with dasatinib and imatinib, respectively. We used a rolling-6 design to study the MTD of once-daily crenolanib administered during and after local RT in children with newly diagnosed DIPG (Stratum A), and in recurrent/progressive HGG, including DIPG (Stratum B).We have completed accrual of 55 patients, 30 and 20 evaluable in Stratum A and B, respectively. Serum pharmacokinetic analyses were performed using non-compartmental techniques on all patients for samples collected on days 1 and 28 of course 1. Fifty evaluable patients were enrolled on the two strata and the maximum tolerated dosage (MTD) of 170 mg/m2has been established in each stratum. Dose limiting toxicities (DLTs) were primarily elevated liver enzymes in both strata (<15% of patients), and the most common Grade 3 toxicity seen on Stratum A was leukopenia that resolved with drug interruption. PFS and OS at 2 years were 8% (± 4.5%) and 22% (±7%) for Stratum A, and 5% (± 3.5%) and 30% (± 9%) for stratum B. The PK and current preliminary toxicity data indicate that crenolanib is well tolerated in children at doses slightly higher than the established MTD from Phase I trial in adults (280 mg/day).The spectrum of toxicities observed in children is similar to those observed in adults, though leukopenia is a novel toxicity.
Phenotypic Changes Associated with Acute Reductions In Leukemia Cell Counts In Patients with Chronic Lymphocytic Leukemia (CLL) Receiving Lenalidomide as Initial Therapy
Authors: Danelle F. James, Jennifer R Brown, Lillian Werner, Januario E Castro, Kanti R. Rai, William G. Wierda, Andrew Greaves, Laura Z Rassenti, Donna Neuberg, Thomas J. Kipps
Journal: Blood (2010)
Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury
Authors: Ying-Ying Wang, Hong Jiang, Jun Pan, Xiao-Ru Huang, Yu-Cheng Wang, Hong-Feng Huang, Ka-Fai To, David J. Nikolic-Paterson, Hui-Yao Lan, Jiang-Hua Chen
Journal: Journal of the American Society of Nephrology (2017)

Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with fibrosis in renal allografts, but how these cells contribute to this damaging response is not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition in interstitial fibrosis in human and experimental chronic renal allograft injury. In biopsy specimens from patients with active chronic allograft rejection, we identified cells undergoing macrophage-to-myofibroblast transition by the coexpression of macrophage (CD68) and myofibroblast (α-smooth muscle actin [α-SMA]) markers. CD68+/α-SMA+ cells accounted for approximately 50% of the myofibroblast population, and the number of these cells correlated with allograft function and the severity of interstitial fibrosis. Similarly, in C57BL/6J mice with a BALB/c renal allograft, cells coexpressing macrophage markers (CD68 or F4/80) and α-SMA composed a significant population in the interstitium of allografts undergoing chronic rejection. Fate-mapping in Lyz2-Cre/Rosa26-Tomato mice showed that approximately half of α-SMA+ myofibroblasts in renal allografts originated from recipient bone marrow-derived macrophages. Knockout of Smad3 protected against interstitial fibrosis in renal allografts and substantially reduced the number of macrophage-to-myofibroblast transition cells. Furthermore, the majority of macrophage-to-myofibroblast transition cells in human and experimental renal allograft rejection coexpressed the M2-type macrophage marker CD206, and this expression was considerably reduced in Smad3-knockout recipients. In conclusion, our studies indicate that macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. Moreover, the transition of bone marrow-derived M2-type macrophages to myofibroblasts in the renal allograft is regulated via a Smad3-dependent mechanism.
ACTR-34. ANALYSIS OF PLASMATIC SIGNATURE OF GLIOBLASTOMA PATIENTS OBTAINED BY DIFFERENTIAL SCANNING CALORIMETRY REVEALS THREE PROGNOSTIC CLUSTERS
Authors: Philipp O Tsvetkov, Emeline Tabouret, Andrei Roman, Olga Ishimbaeva, Alexander A Kubatiev, Sylvie Romain, Dominique Figarella-Branger, Olivier Chinot, François Devred
Journal: Neuro-Oncology (2016)

Glioblastoma (GB) is the most aggressive primary brain tumor of adult characterized by the inevitable relapse. Currently tool that allows monitoring GB evolution exhibit some limitations. It was shown that DSC (Differential Scanning Calorimetry), a method used to obtain proteins thermostability profiles, could be used to get specific signatures of CSF of GB patients. Here we present DSC analysis of the plasma samples from recurrent GB patients. Plasma samples were collected before and after one cycle of bevacizumab and alkylating agent. Plasma of healthy individuals was analyzed as control. Several parameters were extracted from DSC curves, such as minimal and maximal Cp values or area under the curve (AUC) and were used in K-means and hierarchical cluster analysis of data. We included 10 healthy volunteers and 17 patients with a median age of 62.5 years (42–89) and a median Karnofsky Performance Status (KPS) of 70 (60–90) at GB relapse. DSC profiles of plasma of healthy individuals were significantly different from those of GB patients. DSC profiles from GB patients were characterized by negative peak around 80°C. DSC profiles were not correlated to prognostic factors (age, steroid dose, KPS, tumor size). No difference was observed between DSC profiles before and after one cycle of treatment. DSC characteristics were not correlated to response but the temperatures of minimal (p=0.035) and maximal (p=0.014) Cp values were associated with progression-free survival (PFS), while the AUC was associated with overall survival (OS) (p=0.025). Further analysis of DSC profiles using clustering found three clusters for GB patients at baseline, significantly correlated to PFS (p<0.001) and OS (p<0.001). DSC profiles were different between healthy and GB patients. Theses DSC profiles may identify clusters associated with distinct outcomes. These data suggest that DSC is a promising monitoring tool for GB evolution.
Trends in Central Nervous System–Active Polypharmacy Among Older Adults Seen in Outpatient Care in the United States
Authors: Donovan T. Maust, Lauren B. Gerlach, Anastasia Gibson, Helen C. Kales, Frederic C. Blow, Mark Olfson
Journal: JAMA Internal Medicine (2017)

This study uses data from the National Ambulatory Medical Care Survey to describe the central nervous system polypharmacy practices among outpatient older adults.
Novel IL23R Splice Variant Is Associated with Worse Prognosis in Pediatric Patients with AML.
Authors: Derek L. Stirewalt, Todd A. Alonzo, Era L. Pogosova-Agadjanyan, Robert B. Gerbing, Janet Franklin, Susana C. Raimondi, Betsy A. Hirsch, Alan S. Gamis, Soheil Meshinchi
Journal: Blood (2012)
Dasatinib (D) in previously treated metastatic colorectal cancer (mCRC) patients: A phase II trial of the University of Chicago phase II consortium.
Authors: M. Sharma, K. Wroblewski, M. Kozloff, S. S. Modi, B. G. Sleckman, D. Taber, E. E. Vokes, W. M. Stadler, B. N. Polite, H. L. Kindler
Journal: Journal of Clinical Oncology (2011)

506 Background: Dasatinib (Sprycel, Bristol-Myers Squibb), an oral inhibitor of SRC family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models. Since treatment options for mCRC are limited after a fluoropyrimidine (F), oxaliplatin (O), and irinotecan (I), novel agents need to be explored in this setting. Methods: We conducted a phase II trial of D in unresectable, previously treated mCRC patients (pts) at 9 centers. No more than 2 prior chemotherapy regimens were permitted, which must have contained F, O and I. Disease progression on or after treatment was required. Eligible patients also had to have measurable disease per RECIST criteria; normal organ function; PS 0-2. Pts received D 70 mg PO BID continuously. CT scans were obtained every 8 weeks. The primary endpoint was progression-free survival (PFS) at 4 months. We employed a Simon, two-stage design with 19 pts enrolled in the first stage, and a second stage planned if ≥ 5 were progression-free at 4 months. 19 pts enrolled 10/07-11/08. Pt characteristics: male 58%; median age 64 (range 38-83); PS 0: 47%, 1: 53%. Results: The study was terminated after the first stage due to lack of efficacy. A median of two 4 week cycles were administered (range &lt;1-8). 2 pts discontinued due to adverse events, 2 others withdrew, and 2 had early deaths before the first CT scan. Grade 3/4 toxicities (% pts): anemia 11%; fatigue 16%; anorexia 11%; dyspnea 11%; nausea/vomiting 11%; pleural effusion 5%; diarrhea 5%; pneumonitis 5%; dehydration 5%. There were no objective responses; 1 pt (5%) had stable disease for 7 months. PFS rate at 4 months was 5% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Conclusions: Dasatinib is inactive in previously treated mCRC pts. Novel agents are still needed for this patient population. Supported by NCI grant N01-CM-62201. [Table: see text]
Differential expression profile of lung squamous cell carcinoma (LSCC) and druggable targets to be combined with necitumumab (N)
Authors: A. Verlicchi, C. Lazzari, C. Codony Servat, M.A. Molina Vila, J. Codony Servat, I. Chaib, J.L. Ramírez Serrano, N. Karachaliou, C. Dazzi, R. Rosell
Journal: Annals of Oncology (2016)
A Phase II Study of Nilotinib, a Novel Tyrosine Kinase Inhibitor Administered to Imatinib Resistant or Intolerant Patients with Chronic Myelogenous Leukemia (CML) in Blast Crisis (BC) or Relapsed/Refractory Ph+ Acute Lymphoblastic Leukemia (ALL).
Authors: Oliver Ottmann, Hagop Kantarjian, Richard Larson, Philipp le Courte, Michele Baccarani, Teresa Rafferty, Aaron Weitzman, Francis Giles
Journal: Blood (2006)
Experts debate Trump’s mental health in US press
Authors: Michael McCarthy
Journal: BMJ (2017)

Although the American Psychiatric Association and the American Psychological Association both hold that it is unethical for their members to diagnose conditions in public figures from afar, providers from both specialties have weighed in on the US president’s mental fitness.

In a letter to the New York Times on 13 February,1 35 mental health professionals said that “too much was at stake” for them to remain silent any longer about Donald Trump’s mental health. Through his speech and actions, they wrote, the president has demonstrated that he was unable to tolerate views different from his own, leading him …
Cost-effectiveness of Intensive Blood Pressure Management—Is There an Additional Price to Pay?
Authors: Mario Naranjo, Muhammad Masab, Janani Rangaswami
Journal: JAMA Cardiology (2017)

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Silencing of SHP1 Is Frequent in Phospho-STAT3 Positive Diffuse Large Cell Lymphoma and This Silencing Is Independent of Methylation of Cpg Islands,
Authors: Mamta Gupta, Gaungzhen Hu, Linda Wellik, Steven Offer, Robert B. Diasio, Ahmet Dogan, Thomas E. Witzig
Journal: Blood (2011)