tbuckley/cabot-search huggingface dataset:
IMST-32. T CELL EXHAUSTION IN PATIENTS AND MICE WITH GBM
Authors: Karolina Woroniecka, S. Harrison Farber, Pakawat Chongsathidkiet, Aladine A. Elsamadicy, Xiuyu Cui, Peter Fecci
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) persists as the most common primary brain tumor in adults and is one of few cancers that remain uniformly lethal despite multiple advances in therapy. Despite offering the promise of improved survival, a ceiling on the efficacy of immunotherapies is imposed by GBM’s potent capacities for sabotaging immune responses and propagating T cell dysfunction. Exhaustion is a well-recognized mode of T cell dysfunction whereby cells become hyporesponsive following repeated antigen exposure. While exhaustion is an increasingly revealed impediment to T cell function in cancer, its contribution to immune escape in GBM has not been well-evaluated. We therefore newly characterized a broad array of T-cell exhaustion markers in human and murine GBM and murine models of CNS metastasis. TILs and matched peripheral blood from 8 patients with GBM, as well as blood from 8 age-matched controls, were evaluated for expression of T-cell exhaustion markers by flow cytometry. The same assessments were repeated in mice with CT2A and SMA-560 gliomas, Lewis lung carcinomas (LLC), or B16F10 melanomas implanted either intracranially (IC) or subcutaneously (SC). Expression of PD-1, CTLA-4, LAG-3, TIM-3, 2B4, BTLA, CD160, VISTA, TIGIT, and CD39, as well as the cytokines IFN-g, TNF-a, and IL-2 were analyzed. In both human and murine glioma, we found significantly increased expression of exhaustion markers on TILs compared to patient blood and control blood. In murine models, the expression of specific exhaustion markers was consistent across tumor histology and did not vary across IC or SC location for a given tumor, while glioma models demonstrated most severe exhaustion phenotypes. Our findings suggest that tumors, and particularly GBM, exhibit characteristic and varying mechanisms for eliciting an exhaustion “fingerprint” among infiltrating lymphocyte that is tumor- and not microenvironment-intrinsic.
Web: SARS Reference
Authors: James Maskalyk
Journal: BMJ (2003)

On 6 June 2003, as has become my habit, I glanced at the World Health Organization's global epidemic curve for severe acute respiratory syndrome (SARS). With infection control procedures finally taking hold in China, the shape of the curve was moving downwards and approximating the bell shape so cleanly described in epidemiology textbooks.

The relative brevity of the bell for the 21st century's first major epidemic can be attributed to an aspect of 21st century medicine that had never before been tested so singularly, and completely: multinational collaboration, real time epidemiological updates, and online medical publication all made possible through digital connections. The speed with which data, experience, successes, and failures were shared appears to have slowed the epidemic.

The recent spate of online SARS offerings has provided more than graphs and data: it has also given us a SARS textbook. SARS Reference intends to summarise information on the SARS outbreak each month for the duration of the epidemic. The first edition, covering information available since the outbreak began in November 2002 and current as of 6 May 2003, was written over 14 days by a group of volunteers and posted at SARSreference.com on 8 May 2003. So far, it has been translated into Chinese and Spanish, and the editors promise to release copyright to individuals who are willing to translate it into other languages. They report that there is currently no sponsorship for the site, nor would any be accepted.

SARS Reference is a comprehensive summary of what we know to date. It is well organised into nine chapters, from the epidemiology of outbreaks in different countries to SARS in children. Each is available in printable format, and extensively referenced. The strongest sections are those on virology and diagnostic testing. Sections on transmission/prevention and case definition rely heavily on recommendations from the US Centers for Disease Control and WHO, with some support from the published literature.

Both for SARS medicine and for online publishing, this is an important step forward. Its greatest strengths are its comprehensive review of the literature, an abundance of links to authoritative internet sites, and refreshingly clear writing. Unfortunately, there is no mention of peer review and no assurance that the information offered is accurate enough to guide appropriate management of a group of SARS patients. Further, as evidence of varying quality accumulates, and changes from observational to experimental, the task of synthesising and summarising it will be less easy, and will require critical analysis that is not offered here.

Clicking on WHO's website, I opened the epidemiological curve for Toronto, my home. It also showed a nice bell curve. Two of them, actually, and the second seemed not quite done. Apparently, there are lessons that this disease has yet to teach us, and for the time being, there seems no better record than SARSreference.com
IFCT-1003 LADIE trial: Randomized phase II trial evaluating treatment with EGFR-TKI versus EGFR-TKI associated with anti-estrogen in women with non-squamous advanced stage NSCLC
Authors: J. Mazieres, F. Barlesi, O. Molinier, I. Monnet, C. Audigier-Valette, B. Besse, A.-C. Toffart, P.A. Renault, S. Hiret, S. Fraboulet-Moreau, B. Mennecier, P. Masson, V. Westeel, P.-J. Souquet, E. Pichon, E. Amour, F. Morin, D. Moro-Sibilot
Journal: Annals of Oncology (2016)
STMC-38. EYA1 IDENTIFIED BY IN VITRO AND IN VIVO PHAGE DISPLAY BIOPANNING DEMONSTRATES ROLE IN GLIOBLASTOMA STEM CELL PROLIFERATION THROUGH ONCOGENE INTERACTION
Authors: Ping Huang, Qiulian Wu, Jeremy Rich, James Liu
Journal: Neuro-Oncology (2016)

Glioblastoma stem cells (GSC) comprise of a subpopulation of tumor cells that possess the unique ability to self renew and facilitate tumor growth. Further characterization of these cells will help to understand the unique mechanisms that drive these cells, which will lead to the development of more advanced therapeutic strategies at effectively and specifically targeting these cells. In order to identify novel target proteins that may play a critical role in the maintenance of glioma stem cells, we have employed two separate phage display biopanning strategies to isolate novel 7 amino acid peptides sequences that display preferential binding for GSCs. An in vitro biopanning strategy was employed against GSCs grown in culture, and an in vivo biopanning strategy was performed against intracranially xenografted GSCs. From the peptides that were isolated from each of the two strategies, one peptide sequence combination was found to be isolated in both biopanning strategies. In silico analysis revealed a protein match with Eyes Absent (EYA1) protein, a transcriptional co-activator involved in cell proliferation, as well as DNA damage repair. We demonstrated that EYA1 was preferentially expressed in GSCs and co-localizes with known GSC markers. Inhibition of EYA1 expression through ribonucleic acid interference inhibited GSC formation as evidence by decrease in cell viability, tumorsphere formation, and in vivo tumorigenesis. EYA1 was also found to be present in the tumor vasculature, corresponding with endothelial cell markers. Inhibition of EYA1 expression resulted in hindrance of tumor derived endothelial cell formation, indicating a potential role in tumor angiogenesis. Furthermore, co-localization of EYA1 and c-Myc was found in GSCs, as well as a decrease in c-Myc expression with EYA1 inhibition, suggesting EYA1 may interact with c-Myc to induce tumor proliferation.
NTOX-05. LOSS OF PERICYTE IN RADIATION NECROSIS
Authors: Soon-Tae Lee, Young-Bem Se, Ji-Yeon Bae, Sung-Hye Park, Chul-kee Park
Journal: Neuro-Oncology (2016)

Radiation necrosis in brain tumor patients is often symptomatic, persistent without immediate resolution, and confused with tumor recurrence. Cerebral vascular pericytes are essential for endothelial function, vascular integrity and angiogenesis. Here we show that the loss of pericyte is involved in the pathogenesis of radiation necrosis. From a prospective brain tumor tissue repository since 2011, we identified three patients with surgically-resected and pathologically-confirmed radiation necrosis after the standard treatment of glioblastoma. The radiation necrosis and their pre-radiation glioblastoma tissues were serially processed to Western blotting using cell-type specific antibodies against endothelial (CD31, active RhoA), pericyte [platelet-derived growth factor receptor-beta (PDGFR-β)], astrocyte (GFAP), myelin sheath protein (MBP), and microglial markers (Iba1). Normal brain tissues from a brain bank were used as normal controls. The changes in vascular compositions were confirmed histopathologically. Results showed that the expressions of pericyte marker (PDGFR-β) were remarkably reduced in the radiation necrosis tissues while the levels were preserved in their original glioblastoma. However, the levels of CD31 or RhoA were not different between the two groups, suggesting no change in the amount of endothelial cells or their cytoskelectal assembly. The radiation necrosis tissues showed a decreased ratio of pericyte/endothelial markers and an increased level of Iba1 compared to the glioblastoma and even to the normal brain tissues. The levels of GFAP and MBP were not changed in the radiation necrosis. In the immunohistochemistry, the PDGFR-β-positive pericyte was nearly absent in the radiation necrosis, resulting in pericyte-unsupported endothelial cells. In contrast, the endothelial cells in the glioblastoma tissues were well supported by pericytes. In conclusion, the radiation necrosis was characterized by the loss of pericyte and unsupported endothelial cells. Radiation necrosis might be induced by the pericyte loss rather than endothelial or glial damage, and the pericytes might be more vulnerable to the radiation.
Transient IKK2 activation in astrocytes initiates selective non-cell-autonomous neurodegeneration
Authors: Michael Lattke, Stephanie N. Reichel, Alexander Magnutzki, Alireza Abaei, Volker Rasche, Paul Walther, Dinis P. Calado, Boris Ferger, Thomas Wirth, Bernd Baumann
Journal: Molecular Neurodegeneration (2017)

Neuroinflammation is associated with a wide range of neurodegenerative disorders, however the specific contribution to individual disease pathogenesis and selective neuronal cell death is not well understood. Inflammatory cerebellar ataxias are neurodegenerative diseases occurring in various autoimmune/inflammatory conditions, e.g. paraneoplastic syndromes. However, how inflammatory insults can cause selective cerebellar neurodegeneration in the context of these diseases remains open, and appropriate animal models are lacking. A key regulator of neuroinflammatory processes is the NF-κB signalling pathway, which is activated by the IκB kinase 2 (IKK2) in response to various pathological conditions. Importantly, its activation is sufficient to initiate neuroinflammation on its own. To investigate the contribution of IKK/NF-κB-mediated neuroinflammation to neurodegeneration, we established conditional mouse models of cerebellar neuroinflammation, which depend either on the tetracycline-regulated expression of IKK2 in astrocytes or Cre-recombination based IKK2 activation in Bergmann glia. We demonstrate that IKK2 activation for a limited time interval in astrocytes is sufficient to induce neuroinflammation, astrogliosis and loss of Purkinje neurons, resembling the pathogenesis of inflammatory cerebellar ataxias. We identified IKK2-driven irreversible dysfunction of Bergmann glia as critical pathogenic event resulting in Purkinje cell loss. This was independent of Lipocalin 2, an acute phase protein secreted by reactive astrocytes and well known to mediate neurotoxicity. Instead, downregulation of the glutamate transporters EAAT1 and EAAT2 and ultrastructural alterations suggest an excitotoxic mechanism of Purkinje cell degeneration. Our results suggest a novel pathogenic mechanism how diverse inflammatory insults can cause inflammation/autoimmune-associated cerebellar ataxias. Disease-mediated elevation of danger signals like TLR ligands and inflammatory cytokines in the cerebellum activates IKK2/NF-κB signalling in astrocytes, which as a consequence triggers astrogliosis-like activation of Bergmann glia and subsequent non-cell-autonomous Purkinje cell degeneration. Notably, the identified hit and run mechanism indicates only an early window for therapeutic interventions.
Making “health tourists” pay for care
Authors: Johanna Hanefeld, Kate Mandeville, Richard Smith
Journal: BMJ (2017)

A pointless and damaging distraction from bigger problems in NHS 

Concern that patients normally resident in one country use a tax based national health system in another without financial contribution is not unique to the NHS. Similar discussions are occurring elsewhere, including in South Africa1 and Thailand.2 The recent announcement by the secretary of state for health that all hospitals will need to charge patients not eligible for free NHS treatment before they receive non-urgent care seeks to address this in England.3 The question is, will it work?

The first barrier to success is the lack of a unique identifier of eligibility to NHS care. Passports or utility bills are not reliable indicators. Research funded by the Department of Health showed that British expatriates, holding British passports but no longer eligible for NHS care, incur the highest average cost of all visitor types.4 Given the chequered history of information technology in the NHS, implementing a reliable system of identification that will cost less to run …
Effectiveness of Axitinib second-line therapy for metastatic renal cell carcinoma: preliminary results from real-word “SAX” observational study
Authors: S. Rossetti, C. D'Aniello, M.G. Vitale, A. Farnesi, L. Calvetti, M.M. Laterza, C. Cavaliere, C. Della Pepa, A. Crispo, M. Di Napoli, S.C. Cecere, S. Pisconti, F. De Vita, F. Grillone, E. Ricevuto, M. De Tursi, R. De Vivo, L. Galli, U. De Giorgi, G. Cartenì, G. Facchini
Journal: Annals of Oncology (2016)
p16 protein status and response to treatment in a prospective clinical trial (ECOG 2303) of patients with head and neck squamous cell carcinoma (HNSCC).
Authors: A. Psyrri, M. S. Ghebremichael, E. Pectasides, A. T. Dimou, B. Burtness, D. Rimm, H. J. Wanebo, A. A. Forastiere
Journal: Journal of Clinical Oncology (2011)

e16032 Background: p16 immunoexpression is considered a surrogate biomarker for the presence of functional Human Papillomavirus oncoprotein E7 in HNSCC. We sought to determine the association between p16 status and response/survival in a prospective phase II clinical trial in patients with HNSCC. Methods: Sixty-three eligible patients with operable stage III/IV HNSCC participated in Eastern Cooperative Oncology Group (ECOG) phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel and carboplatin x 6 followed by chemoradiotherapy with weekly cetuximab. paclitaxel, carboplatin. P16 protein expression status was assessed using automated quantitative protein analysis (AQUA). The objectives of this analysis were to determine whether p16 status was correlated with response to treatment, progression-free survival (PFS) and overall survival (OS). Fisher’s exact tests were used to compare response rates whereas survival distributions were estimated using the Kaplan-Meier method using log rank test to compare survival curves between p16 categories. Results: The median p16 tumor mask AQUA score was 42.9 (Range=6-491). Of the 63 tumors included in this study, 38 (60.3%) had sufficient tissue for analysis of p16. Using a cut-off score of 80, 16 out of 38 eligible cases (i.e., 42%) were classified as p16+. Almost 58% of the responders had low p16 tumor mask AQUA scores. However, there was no significant association between p16 status and objective response (p-value=1.00). Moreover, 2-year PFS for p16 high and low categories were, respectively, 0.74 [95% CI (0.53, 0.96)] and 0.58 [95% CI (0.37, 0.79)]. The 2-year overall survival rates for p16 high and low categories were, respectively, 0.81 [95% CI (0.61, 1.00)] and 0.77 [95% CI (0.60, 0.95)]. Conclusions: There was no significant association between p16 AQUA status and response/ survival in this small subset of patients treated in the prospective E2303 study. Large prospective studies will determine the association between p16 status and response to cetuximab in HNSCC.
BMET-35. RAD 1002: PHASE I DOSE FINDING STUDY OF PRE-OPERATIVE STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES
Authors: Markus Bredel, John Stewart
Journal: Neuro-Oncology (2016)

To determine the toxicity and recommended dose for pre-operative (pre-op) stereotactic radiosurgery (SRS) in management of brain metastases and the rate of subsequent leptomeningeal disease (LMD). Twenty newly diagnosed brain metastasis patients were enrolled into a phase I dose escalation/de-escalation trial between 01/2011 and 11/2015. Eligible patients included those with operable (≤4) metastases (other than SCLC/lymphoma) measuring 2-6cm in maximum diameter, age >19yo, KPS ≥60, life expectancy >12 weeks. Patients were divided into two cohorts (Group A: 2-4cm [n=11], Group B: >4-6cm [n=9]), with starting dose level for Groups A and B of 15Gy and 12Gy, respectively. All patients had surgical resection within 30 days of SRS. Toxicity was recorded using CTCAEv4.0. Dose-limiting toxicity (DLT) was defined as any grade ≥3 seizure, wound complication, or somnolence; any grade ≥4 neurologic/dermatologic event; any grade 5 event within 30 days of surgery. Serious adverse events were defined as death or treatment-related prolonged (>5 days) or new hospitalization. LMD was defined as diffuse carcinomatosis and/or distant focal pachymeningeal (dural) tumor within the 1-year study period. All patients had a gross total resection. For Group A, two DLTs occurred at the 15Gy level (grade 3 wound complication/CSF leak requiring surgery). No DLT was noted in the initial cohort (n=3) of Group B at 12Gy and dose was escalated to 15Gy (n=6) with no DLT. Other acute therapy-related toxicities included grade 2 nausea/vomiting (n=1), grade 3 pseudomeningocele requiring shunt (n=1), and grade 3 hemorrhage requiring craniotomy (n=1). No grade ≥4 toxicity occurred. Within the first year of follow up, one patient developed LMD. Pre-op SRS is feasible with doses as high as 15Gy for targets as large as 6cm and associated with a low LMD rate. Larger studies are required to determine the optimal sequence of SRS and surgery.
Impact of AR-V7 protein localization in the prediction of therapeutic benefit of taxanes over androgen receptor signaling inhibitors (ARSi) in metastatic castration resistant prostate cancer (mCRPC)
Authors: H. Scher, R. Graf, N. Schreiber, D. Lu, J. Louw, H.A. Vargas Alvarez, R. Bambury, D. Danila, B. McLaughlin, G. Heller, M. Fleisher, R. Dittamore
Journal: Annals of Oncology (2016)
Protecting Adolescents From Harm
Authors: Michael D. Resnick
Journal: JAMA (1997)

<h3>Context.</h3> —The main threats to adolescents' health are the risk behaviors they choose. How their social context shapes their behaviors is poorly understood. <h3>Objective.</h3> —To identify risk and protective factors at the family, school, and individual levels as they relate to 4 domains of adolescent health and morbidity: emotional health, violence, substance use, and sexuality. <h3>Design.</h3> —Cross-sectional analysis of interview data from the National Longitudinal Study of Adolescent Health. <h3>Participants.</h3> —A total of 12118 adolescents in grades 7 through 12 drawn from an initial national school survey of 90118 adolescents from 80 high schools plus their feeder middle schools. <h3>Setting.</h3> —The interview was completed in the subject's home. <h3>Main Outcome Measures.</h3> —Eight areas were assessed: emotional distress; suicidal thoughts and behaviors; violence; use of 3 substances (cigarettes, alcohol, marijuana); and 2 types of sexual behaviors (age of sexual debut and pregnancy history). Independent variables included measures of family context, school context, and individual characteristics. <h3>Results.</h3> —Parent-family connectedness and perceived school connectedness were protective against every health risk behavior measure except history of pregnancy. Conversely, ease of access to guns at home was associated with suicidality (grades 9-12:<i>P</i>&lt;.001) and violence (grades 7-8:<i>P</i>&lt;.001; grades 9-12:<i>P</i>&lt;.001). Access to substances in the home was associated with use of cigarettes (<i>P</i>&lt;.001), alcohol (<i>P</i>&lt;.001), and marijuana (<i>P</i>&lt;.001) among all students. Working 20 or more hours a week was associated with emotional distress of high school students (<i>P</i>&lt;.01), cigarette use (<i>P</i>&lt;.001), alcohol use (<i>P</i>&lt;.001), and marijuana use (<i>P</i>&lt;.001). Appearing "older than most" in class was associated with emotional distress and suicidal thoughts and behaviors among high school students (<i>P</i>&lt;.001); it was also associated with substance use and an earlier age of sexual debut among both junior and senior high students. Repeating a grade in school was associated with emotional distress among students in junior high (<i>P</i>&lt;.001) and high school (<i>P</i>&lt;.01) and with tobacco use among junior high students (<i>P</i>&lt;.001). On the other hand, parental expectations regarding school achievement were associated with lower levels of health risk behaviors; parental disapproval of early sexual debut was associated with a later age of onset of intercourse (<i>P</i>&lt;.001). <h3>Conclusions.</h3> —Family and school contexts as well as individual characteristics are associated with health and risky behaviors in adolescents. The results should assist health and social service providers, educators, and others in taking the first steps to diminish risk factors and enhance protective factors for our young people.
Long-Term Outcomes of Renal Function in Patients with TTP Associated with Severe ADAMTS13 Deficiency
Authors: Jessica A Reese, Cassandra C Deford, Zayd Al-Nouri, Deirdra Terrell, Sara K. Vesely, Johanna A. Kremer Hovinga Strebel, Bernhard Lammle, James N. George
Journal: Blood (2011)
ABT-737 Targets Leukemic Stem Cells In Mouse Models of Mutant NRASD12/hBCL-2- Mediated Acute Myeloid Leukemia Progression with Increased Survival
Authors: Rose Ann Padua, Stephanie Beurlet, Patricia Krief, Nader Omidvar, Carole Le Pogam, Didier Auboeuf, Pierre de la Grange, Annie Soulie, Anne Janin, Maria-Elena Noguera, Pascal Merlet, Laure Sarda-Mantel, Pierre Fenaux, Marina Konopleva, Michael Andreeff, Andrea Tu, Phoebe Yang, Alice C. Fan, Scott C. Kogan, Irving L. Weissman, Dean W. Felsher, Marika Pla, Robert West, Christine Chomienne
Journal: Blood (2010)