tbuckley/cabot-search huggingface dataset:
A phase II study evaluating systemic sagopilone (ZK-EPO) treatment in patients with recurrent malignant gliomas
Authors: A. Silvani, A. Fiumani, V. Scaioli, E. Lamperti, P. Gaviani, M. Eoli, C. Falcone, A. Salmaggi, A. Boiardi
Journal: Journal of Clinical Oncology (2008)

2083 Background: Sagopilone (ZK-EPO) is a fully synthetic epothilone that exhibits activity in MDR tumors, and has demonstrated antitumor activity in orthotopic human glioma models in vivo. This 2-arm, phase II study aims to evaluate the safety and efficacy of sagopilone in patients (pts) with pretreated, recurrent malignant glioma who have received 2 or ≥3 prior lines of therapy, respectively. Methods: Sagopilone (16 mg/m2) was administered iv for 3 h every 21 d. The primary end point was 6-month progression- free survival (PFS-6), and secondary end points were safety, toxicity, and response rate. MRI evaluations (McDonald criteria) were performed every 2 cycles and toxicity was evaluated using CTCAE 3.0. Clinical and electrophysiological tests were undertaken before the 1st and at the 3rd and 6th cycle. Data are presented from a protocoled independent analysis of ≥3-line arm. Results: A total of 15 pts with recurrent malignant gliomas (glioblastoma multiforme [n=11] or anaplastic astrocytoma [n=4]) who had received prior surgery, radiotherapy, and ≥3 lines of chemotherapy (temozolomide/BCNU) were recruited. A median of 4 (1–6) cycles was administered and 3 pts are still receiving treatment. No objective responses were observed but stable disease of >6 wks was reported in 9 pts. Median TTP was 13 wks (1.3 to 38 wks) and 5/15 pts (target 3 pts) reached PFS-6, excluding a lower rate of 12%, although in the absence of a control arm this may be a self- selecting group and requires confirmation. The most frequent AE was neuropathy, which improved after treatment cessation. Grade 3/4 peripheral neuropathy occurred in 4 pts, with 1 requiring morphine treatment for neuropathy affecting their activities. Neuropathy presented as a mixture of paresthesia and dysesthesia, typically in a stocking distribution. Electromyography assessments showed axonal sensorimotor polyneuropathy with slight reductions of sensory action potential consistent with a primarily sensory defect. Only 1 pt had grade 4 toxicity (prolonged neutropenia) during the 1st cycle. Conclusions: Sagopilone demonstrated an acceptable safety profile and clinically relevant activity in pts with pretreated, recurrent malignant gliomas. The study continues in the 2nd-line arm and mature data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Schering
MIF Maintains the Tumorigenic Capacity of Brain Tumor–Initiating Cells by Directly Inhibiting p53
Authors: Raita Fukaya, Shigeki Ohta, Tomonori Yaguchi, Yumi Matsuzaki, Eiji Sugihara, Hideyuki Okano, Hideyuki Saya, Yutaka Kawakami, Takeshi Kawase, Kazunari Yoshida, Masahiro Toda
Journal: Cancer Research (2016)

Abstract Tumor-initiating cells thought to drive brain cancer are embedded in a complex heterogeneous histology. In this study, we isolated primary cells from 21 human brain tumor specimens to establish cell lines with high tumorigenic potential and to identify the molecules enabling this capability. The morphology, sphere-forming ability upon expansion, and differentiation potential of all cell lines were indistinguishable in vitro. However, testing for tumorigenicity revealed two distinct cell types, brain tumor–initiating cells (BTIC) and non-BTIC. We found that macrophage migration inhibitory factor (MIF) was highly expressed in BTIC compared with non-BTIC. MIF bound directly to both wild-type and mutant p53 but regulated p53-dependent cell growth by different mechanisms, depending on glioma cell line and p53 status. MIF physically interacted with wild-type p53 in the nucleus and inhibited its transcription-dependent functions. In contrast, MIF bound to mutant p53 in the cytoplasm and abrogated transcription-independent induction of apoptosis. Furthermore, MIF knockdown inhibited BTIC-induced tumor formation in a mouse xenograft model, leading to increased overall survival. Collectively, our findings suggest that MIF regulates BTIC function through direct, intracellular inhibition of p53, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant brain cells. Cancer Res; 76(9); 2813–23. ©2016 AACR.
Characterization of Formylpeptide Chemoattractant Binding on Neutrophils and Monocytes From Patients With Head and Neck Cancer2
Authors: Robert J. Walter, John R. Danielson
Journal: JNCI Journal of the National Cancer Institute (1987)

Monocytes from patients with head and neck tumors display a marked chemotactic deficiency in response to formylpeptide chemoattractants. Normal leukocytes possess receptors known to bind to chemotactic formylpeptides such as the hexapeptide N-formyl-nor-leucyl-leucyl-phenylalanyl-nor-leucyl-tyrosyl-lysine, with high specificity and great avidity. Light microscopic autoradiography was used to visualize the binding and subsequent cellular processing of the formylhexapeptide N-formyl-nor-leucyl-leucyl-phenylalanyl-nor-leucyl-[125I]tyrosyl-lysine to polymorphonuclear leukocytes (PMN) and monocytes from patients with epidermoid tumors of the head and neck. Surface-adherent leukocytes were exposed to 5 nM125I-rabeled hexapeptide for 15 minutes at 4°C and were either fixed immediately or rinsed and then further incubated for 20 minutes at 37°C prior to fixation. Cells underwent autoradiography, and silver grains associated with 400 cells were counted. There were no significant differences between the numbers of formylpeptide receptors on control and cancer patient PMN. However, there were significantly larger numbers of formylpeptide receptors (P<.02) on cancer patient monocytes than on control monocytes. Cells that were allowed to process bound hexapeptide at 37°C prior to fixation showed large decreases in the number of cell-associated silver grains. However, the amount of hexapeptide associated with PMN and monocytes treated in this way was the same for both control and tumor patients. In addition, histograms were plotted showing the amount of hexapeptide bound versus the frequency of cells at each level of binding. Examination of these histograms revealed that two major peaks or sub-populations occurred in each for neutrophils and monocytes from control patients. Histograms of grain counts for neutrophils and monocytes from tumor patients did not display two separate peaks of formylhexapeptide binding; instead, only one broad peak was evident. These observations indicated that: 1) Tumor patient PMN expressed as many formylpeptide receptors as did control PMN, and tumor patient monocytes possessed significantly more receptors than did control monocytes. 2) The disposition of formylpeptide initially bound to control and tumor patient leukocytes appeared to be essentially the same. 3) Subpopulations existed in each control neutrophil and monocyte sample, one exhibiting approximately 30% more formylpeptide binding than the other. However, in the leukocytes obtained from tumor patients, the distinction between these two subpopulations had become obscured such that only one cell population was evident.
Glycosylation and cancer: A potential target for therapeutic intervention.
Authors: Gouri Baldwin, Brendan O'Sullivan, Anant Desai, David Gourevitch, Ciaran Woodman, Philippe Taniere, Philip James Johnson
Journal: Journal of Clinical Oncology (2012)

e13507 Background: Aberrant glycosylation is a hallmark of cancer progression. Altered expression of glycosyltransferases and molecular facilitators within the ER and Golgi apparatus contributes to these changes. The tetraspanin are a family of molecular facilitators, expression of which have been shown to either promote or suppress cancer progression. CD151, a member of this family, modulates the glycosylation of its partner, the α3β1 integrin, affecting the integrin’s affinity towards its laminin ligand. Methods: We have characterised the glycosylation characteristics of CD151 and CD63 using glycosylation inhibitors and glycosidases to explore their patho-physiological role. Results: Inhibition of glucosidaseI/II resulted in the downregulation of CD151 and its partners, α3β1 and α6β1 integrins. 3D cell culture of the glioblastoma cell line (U87MG) in the presence of the inhibitor restrained its dendrite-like invasive growth. Similarly, the migration potential of the breast cancer cell line, MDA-MB-231, towards Lm332 decreased by 90% upon glycosylation inhibitor treatment. Since brain tumours have been shown to have elevated expression of α3β1 and Laminin332 our results suggest that glycosylation inhibitors might have a potential for investigation of therapeutic agents. Glyco-analysis of CD63 in MDA-231 cells indicated the presence of phosphomannosylated(PM) group, which might contribute to its role in lysosomal targeting. Compared to MDA-231, U87MG cells showed markedly reduced PM of CD63. Increased sialylation has previously been identified as a signature for brain metastasis in MDA-231 cells. Accordingly, comparison of CD63 in high and low sialylated populations of MDA-231 showed, upon sorting, showed similarity between the highly sialylated population of MDA-231 and U87MG. Conclusions: Using glycosylation inhibitors, we have identified a novel use for these compounds in down-regulating two major cancer associated integrins, α3β1 and α6β1. We have also uncovered a previously unknown glycomodification of CD63, phosphomannosylation which may affect the metastatic potential of cancer cells. Both findings suggest a potential for glycosylation inhibitors as part of cancer therapy.
Projecting WEIRD features on ancient religions
Authors: Pascal Boyer, Nicolas Baumard
Journal: Behavioral and Brain Sciences (2016)

Abstract The proposed narrative relies on an anachronistic projection of current religions onto prehistorical and historical cultures that were not concerned with prosocial morality or with public statement of belief. Prosocial morality appeared in wealthier post-Axial environments. Public demonstrations of belief are possible and advantageous when religious diversity starts interacting with coalitional recruitment dynamics in large-scale societies, a typical feature of modern, so-called WEIRD societies.
Antibiotic resistance in children with<i>E coli</i>urinary tract infection
Authors: Grant Russell
Journal: BMJ (2016)

It's not an unusual presentation in primary care-an alert, responsive preschool child with a temperature of 39°C, unremarkable findings on examination, but with leucocytes and nitrites in the urine.Given a strong suspicion of a urinary tract infection, and with Escherichia coli being the most likely organism, empirical management with one of a small number of cheap and available antibiotics would follow.
Hair and Nail Changes During Long-term Therapy With Ibrutinib for Chronic Lymphocytic Leukemia
Authors: Carole Bitar, Mohammed Z. H. Farooqui, Janet Valdez, Nakhle S. Saba, Susan Soto, Amanda Bray, Gerald Marti, Adrian Wiestner, Edward W. Cowen
Journal: JAMA Dermatology (2016)

Ibrutinib, a Bruton tyrosine kinase inhibitor, is a new targeted agent approved by the US Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström macroglobulinemia. Ibrutinib is overall well tolerated but long-term treatment is required until disease progression or intolerable toxic effects occur. Little is known regarding its cutaneous adverse effects.To describe the hair and nail manifestations associated with the long-term use of ibrutinib for the treatment of CLL.Prospective study of 66 patients with CLL enrolled in a single-arm phase 2 clinical trial of ibrutinib for CLL between March 2014 and October 2015 at the National Institutes of Health.The primary outcome, nail and hair changes associated with ibrutinib therapy, was assessed by an 11-question survey. In addition, the severity of nail changes was determined from a 0 to 3 rating scale for both onychoschizia and onychorrhexis.Among 66 patients (43 men and 23 women with ages ranging from 55 to 85 years), 44 (67%) reported brittle fingernails at a median of 6.5 (95% CI, 6-12) months after starting ibrutinib therapy. Fifteen patients (23%) developed brittle toenails after a median of 9 (95% CI, 6-15) months of ibrutinib therapy. Textural hair changes were reported in 17 patients (26%), at a median of 9 (95% CI, 6-12) months of ibrutinib treatment.Hair and nail abnormalities are commonly associated with ibrutinib and appear several months after initiating therapy. Ibrutinib inhibits Bruton tyrosine kinase by covalently binding to cysteine 481. Whether ibrutinib affects the hair and nails by binding and altering cysteine-rich proteins of hair and nails or by means of another mechanism remains unknown.clinicaltrials.gov Identifier: NCT01500733.
Real-world recurrence rate of cancer-associated-VTE treated with Low Molecular Weight Heparin Therapy: The Mayo Clinic Experience.
Authors: Roma Bhatia, Robert McBane, Waldemar Wysokinski, Aneel Ashrani, Rajiv Pruthi
Journal: Journal of Clinical Oncology (2015)

e17687 Background: Patients with cancer associated VTE have a 4-fold higher risk of mortality compared to cancer patients with no VTE. If anticoagulants are discontinued, patients with cancer associated VTE have 30% recurrence rates at one year . In controlled clinical trials, low molecular weight heparin (LMWH) reduced cancer associated VTE recurrence compared to vitamin K antagonists (VKA) by nearly 50%. VTE recurrence rates in a “real world” setting are unknown Methods: Using a retrospective study design, consecutive Mayo Clinic patients with pancreatic, breast, and lung cancer associated VTE treated solely with weight-based LMWH were assessed from Jan 1st 2012-Dec 31st2013. Patients were analyzed by clinical presentation of VTE, LMWH dose, major bleeding and objectively confirmed VTE recurrence. Patients were followed until death or until their last oncologic follow up. Results: 103 patients with breast cancer (40.8%; n = 42), pancreatic cancer (31.1%; n = 33), or lung cancer (27.2%; n = 28) were followed for a mean 597 days (range: 21-9756 days). Of these, 73.8 % had stage IV disease. Just over half received once daily ( 57.2 %) compared to twice-daily LMWH (40.7%). Over the study period, 17/103 (16.5%) patients experienced an objectively defined VTE recurrence. Of these, most occurred while on therapeutic LMWH (15/17). Recurrence rates were numerically more than twice as frequent for pancreatic cancer (25.8%) compared to breast cancer (11.3%) or lung cancer (14.2%). Of 17 recurrences, 6 were PE, while 11 had DVT (p = 0.001). The recurrence rate for patients on QD LMWH dosing was 13.5% (8/59) vs. 21.4% (9/42) for patients with BID LMWH dosing. On binary logistic regression, recurrence was not influenced by LMWH dosing frequency (once daily vs. twice daily), sex, active chemotherapy, cancer type, cancer stage, and biomarkers, including creatinine, WBC, and platelets. Conclusions: Real world cancer associated VTE recurrence rates are high at 16.5% (17/103) and comparable to published RCT data. There were no significant predictors for VTE recurrence.
Effects of Ribonuclease nuclease on a Murine (Rauscher)&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Frank Padgett, Virginia Kearns-Preston, Herbert Voelz, Alvin S. Levine
Journal: JNCI Journal of the National Cancer Institute (1966)

Plasma pellets and femoral bone marrow from BALB/cJ mice infected with the Rauscher leukemia virus were fixed, embedded, and sectioned. The thin sections were incubated in ribonuclease and deoxyribonuclease solutions, stained, and examined in the electron microscope. Specific attention was paid to the action of the nucleases on characteristic virus particles in the plasma preparations and on viruses being produced by the “budding” phenomenon in the femoral bone marrow. Ribonuclease solutions digested the nucleoids of the virus particles in the plasma preparations from mice infected with Rauscher leukemia virus. The nucleoid portion of the “budding” virus particles in bone marrow, and the connecting cytoplasm of the stalks were also digested by ribonuclease solutions. In addition, the outer coat of the “budding” particles was affected in a nonspecific manner. The centers of the “budding” particles in the bone marrow and the nucleoids of viruses in plasma preparations were not digested by deoxyribonuclease solutions. Influenza virus, a known ribonucleic acid (RNA) virus, was used as a control for nuclease activity. The nucleoids of influenza virus particles were digested by ribonuclease but not by deoxyribonuclease solutions. After coriphosphine staining of the plasma virus preparations, the fluorescence was quenched in preparations treated with ribonuclease, but did not appear to be diminished in those treated with deoxyribonuclease. This study suggests that infection of mice with Rauscher leukemia virus produces virus particles in plasma and “budding” particles in bone marrow, both of which contain RNA.
Nearly half of general practices are failing to investigate complaints properly
Authors: Anne Gulland
Journal: BMJ (2016)

Nearly 50% of general practices are failing to deal with complaints properly, a joint report by NHS England, the parliamentary and health service ombudsman, Healthwatch England, and the Care Quality Commission has found.1

A review of 137 complaints received by general practices from November 2014 to November 2015 found that more than half of the cases were dealt with in a way that was considered good (46%) or outstanding (9%). However, more …
The Effect of Vitamin D Supplementation on Mucosal IL-5, MMP9 and Cathelicidin after Nasal Allergen Challenge with Grass Pollen
Authors: Natasha C. Gunawardana, Gaynor Campbell, Sarah Lindsley, Elizabeth E. Mann, Peter J.M. Openshaw, Sebastian L. Johnston, Catherine M. Hawrylowicz, Trevor Thomas Hansel
Journal: Journal of Allergy and Clinical Immunology (2016)
Characterization of an Antiserum Against Human Myeloma Cells2
Authors: L. D. Staneck, R. G. Krueger, R. A. Kyle
Journal: JNCI Journal of the National Cancer Institute (1974)

An antiserum was generated in rabbits against malignant human plasma cells isolated from a patient with IgG-λ-chain myeloma and maintained in tissue culture (RPMI 8226). New Zealand White rabbits were immunized with washed, intact RPMI cells in complete Freund adjuvant. The antimyeloma cell serum did not react with human serum proteins or immunoglobulins (lgG-, IgM-, IgA-K, or λ-chains) by immunodiffusion, complement fixation, or passive hemagglutination. Immunofluorescent studies showed that the antiserum reacted strongly with the RPMI cell but did not recognize immunoglobulin markers; the reactivity was not significantly reduced by absorption with normal bone marrow preparations but was reduced by absorption with RPMI cells. A strong immunofluorescent reaction was observed with a subpopulatlon of plasma cells, but not with lymphocytes or polymorphonuclear leukocytes, in the bone marrows of patients with multiple myeloma (3 IgG-K, 3 IgG-λ, 3 IgA-K, 1 IgA-λ, and 1 IgD-λ or Waldenström's macroglobulinemia.
Patterns of relapse and prognosis after bevacizumab (BEV) failure in recurrent glioblastoma (GBM)
Authors: A. B. Lassman, F. M. Iwamoto, P. H. Gutin, L. E. Abrey
Journal: Journal of Clinical Oncology (2008)

2028 Background: BEV has shown promise for recurrent GBM in phase II trials. However, the patterns of relapse and prognosis of patients (pts) with GBM following BEV have not been studied systematically. This may have important implications for efficacy analysis of post-BEV therapies. Methods: We reviewed departmental databases to identify pts with recurrent GBM treated with BEV on or off clinical trials following IRB approval of this study. Pts who discontinued BEV for progressive disease (PD) were included. Records were assessed for post-BEV outcomes. Results: There were 21 pts (14 men, 7 women; median age 53 yrs, range 30–80) who discontinued BEV for PD. The median number of recurrences prior to starting BEV was 1 (range, 1–2). Patients received BEV alone (n=1) or in combination with irinotecan (n=10), hypo-fractionated re-irradiation (hyRT) (n=8), temozolomide (n=1) or temozolomide plus hyRT (n=1). The median overall survival (OS) after stopping BEV was 2.5 months (95% CI, 1.6 to 5.9); 15 patients have died. At the time BEV was discontinued, seven pts had local recurrence (initial site of disease) whereas 14 had recurred in a multifocal tumor/gliomatosis cerebri pattern. Median KPS at recurrence for those with a local pattern was 70 (range, 70–90) compared to a median of 60 (range, 40–80) in patients with a multifocal pattern (p< 0.001). Multifocal tumor/gliomatosis pattern of relapse was associated with increased risk of death (Hazard Ratio [HR]=13, 95% CI: 1.7- 101, p=0.01) compared to local relapse. KPS ≤ 60 at the time of BEV failure was also associated with increased risk of death (HR=11, 95% CI: 2.3–49, p=0.002). Additional tumor directed therapy following BEV failure was given to 11 pts (8 chemotherapy, 2 resection and chemotherapy, 1 resection). Median PFS for the therapy after BEV failure was 2.3 months (95% CI: 0.7 to 4), median OS was 4.5 months (95% CI:1.4-NR), and 6 month-PFS was 0%. Conclusions: A multifocal tumor/gliomatosis cerebri pattern of recurrence/progression is common following treatment with BEV for GBM, and is correlated with poor KPS and short survival. Treatments after BEV failure may provide only transient tumor control. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology
miRNA‐Regulated Key Components of Cytokine Signaling Pathways and Inflammation in Rheumatoid Arthritis
Authors: Ashish Ranjan Sharma, Garima Sharma, Sang‐Soo Lee, Chiranjib Chakraborty
Journal: Medicinal Research Reviews (2016)

Abstract Rheumatoid arthritis (RA) is an inflammatory disease that primarily affects joints. This autoimmune disease pathogenesis is related to cytokine signaling. In this review, we have described the existence of various microRNAs (miRNAs) involved in regulation of major protein cascades of cytokine signaling associated with RA. Moreover, we have tried to portray the role of various miRNAs in different cytokines such as TNF‐α, IL‐1, IL‐6, IL‐10, IL‐17, IL‐18, IL‐21, and granulocyte macrophage colony‐stimulating factor (GMCSF). Along with this, we have also discussed the miRNA regulation in T cells and synovial tissue. From the analyzed data, we suggest that miR‐146a and miR‐155 might be the potential therapeutic target for treating RA. The insight illustrated in this review will offer a better understanding of the role of miRNA in cytokine signaling pathways and inflammation during RA and could project them as diagnostic or therapeutic agents in near future.
Prognosis of Phosphorylated-Insulin Growth Factor Receptor (P-Igf-1R) and Metalloproteinase-3 (Mmp3) Expression in Advanced Gastrointestinal Stromal Tumors (Gist) Patients Treated with Imatinib. a Geis Study
Authors: J. Maurel, A. Lopez-Pousa, S. Calabuig, S. Bagué, X. García Del Muro, X. Sanjuan, J. Rubió, M. Cuatrecasas, J. Martinez-Trufero, C. Horndler, J. Fra, C. Valverde Morales, A. Redondo, A.M. Poveda, I. Sevilla, N. Lainez, M. Rubini, X. García Albéniz, J. Martin Broto, E. De Álava
Journal: Annals of Oncology (2014)