tbuckley/cabot-search huggingface dataset:
Drug-specific risk, and associated factors, of vasculitis-like events in patients exposed to tumour necrosis factor alpha inhibitor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA)
Authors: Meghna Jani, William G Dixon, Lianne Kearsley-Fleet, Ian N Bruce, Hector Chinoy, Anne Barton, Mark Lunt, Kath Watson, Deborah P Symmons, Kimme Hyrich
Journal: The Lancet (2016)
MALDI-TOF mass spectrometry proteomic profiling to discriminate response to the combination of bevacizumab and erlotinib in non-small cell lung cancer (NSCLC)
Authors: J. S. Salmon, A. Sandler, D. Billheimer, R. S. Herbst, H. T. Tran, A. Tsao, T. P. Dang
Journal: Journal of Clinical Oncology (2005)

7022 Background: A multicenter phase I/II study found that inhibition of VEGF and EGFR with the combination of bevacizumab and erlotinib had significant antitumor efficacy in NSCLC, including activity in some tumors without EGFR mutations. We undertook a pilot project to determine if Matrix-Assisted Laser Desorption/Ionization- Time of Flight Mass Spectrometry (MALDI-TOF MS) proteomic analysis of patient serum could determine a profile that predicts response to therapy. Methods: Pretreatment serum was available for 37 of 40 patients with advanced NSCLC treated with bevacizumab and erlotinib. Each serum sample was diluted in a saturated sinapinic acid matrix solution prior to randomized placement on 64-well gold plates. MALDI-TOF mass spectra were obtained with a Voyager-DE STR instrument (PerSeptive Biosystems) and were replicated 9 times for each sample. The raw spectra were calibrated, corrected for baseline, and normalized prior to analysis. A linear mixed effects model was fit to the normalized intensities at each m/z value to evaluate expression differences between responders and progressors, while accounting for replicate sample variability. Results: Among the 37 patients with pretreatment serum, there were 8 (22%) with a partial response (PR), 7 (19%) with progressive disease (PD), and 22 (59%) with stable disease (SD) for a median of 14 wks (range 6 - 50 wks). Of 9 tumors that were tested for EGFR mutation, 1 mutant was identified (in a PR) and 8 had wild-type receptors (including 2 patients with a PR). Usable spectra were obtained from 87% of the MALDI-TOF replicates and reproducibility was excellent. We found 14 distinct m/z regions (2–19 kDa) with different intensity distributions between PR and PD patients at a p<0.001 threshold. Similar patterns were seen for patients with short-term SD (<12 wks) and patients with PD. Conclusions: MALDI-TOF MS proteomic analysis of pretreatment serum was able to identify protein/peptide expression patterns that discriminated between responders and progressors on this novel regimen. Additional work is planned to validate these results in a prospective data set and to identify proteins involved. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech
Effect of sorafenib on cathepsin B-dependent BID-mediated apoptosis in cancer cells.
Authors: Giorgio Santoni, Consuelo Amantini, Matteo Santoni, Maria Beatrice Morelli, Valerio Farfariello, Massimo Nabissi, Sonia Liberati, Luciano Burattini, Laura Bonfili, Anna Maria Eleuteri, Matteo Mozzicafreddo, Rossana Berardi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2013)

e15515 Background: Several tyrosine kinase inhibitors (TKIs), have been developed and approved for clinical use in multi-targeted cancer therapy. Among these, sorafenib is an orally available multikinase inhibitor approved for the treatment of the advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Aim of our study was to evaluate the mechanisms responsible for the cytotoxic effects induced by in vitro use of µM doses of sorafenib in 5637 and J82 bladder cancer (BC) cell lines. Methods: The viability of BC cell lines were tested by MTT assay. Autophagy was evaluated by western blot analysis with the anti-LC3 and anti-p62 antibodies, acridine orange staining and cytofluorimetric analysis. Apoptosis, (ΔΨ m ) dissipation and ROS generation were determined by Annexin-V/PI, JC-1 and DCFDA staining, respectively and cytofluorimetric analysis. The cathepsin B activation was evaluated by western blot using an anti-cathepsin B antibody; the cathepsin B proteolytic activity was determined using the fluorogenic Z-Arg-Arg-AMC peptide and the fluorescence of the hydrolyzed 7-amino-4-methyl-coumarin was detected by a SpectraMax Gemini XPS microplate reader. Results: We found that sorafenib markedly reduced at µM dose the viability of BC cells. Treatment for 24h with 20µM of sorafenib, triggered “Incomplete autophagy”, that induced apoptosis of BC cells. Sorafenib by inducing an increased cathepsin B activity and pro-apoptotic protein BID activation, triggered a ROS-mediated-mitochondrial-dependent apoptosis of BC cells. Moreover, the increase of cathepsin B activity induced by sorafenib was inhibited by a specific tyrosine phosphatase inhibitor (e.g., orthovanadate) strongly suggesting for a contribute of tyrosine-phosphatases in sorafenib-induced apoptosis. Conclusions: Sorafenib by triggering incomplete autophagy, stimulates a cathepsin B-induced-BID-mediated-ROS- and mitochondrial-dependent apoptosis of BC cells, which is likely regulated by tyrosine-phosphatases.
Intensive 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) monochemotherapy and autologous marrow transplantation for malignant glioma.
Authors: G L Phillips, S N Wolff, J W Fay, R H Herzig, H M Lazarus, C Schold, G P Herzig
Journal: Journal of Clinical Oncology (1986)

Intensive monochemotherapy with carmustine (BCNU) (either 1,050, 1,200, or 1,350 mg/m2) and cryopreserved autologous marrow transplantation was administered to 36 patients with malignant glioma: 27 with progressive disease and nine without progression (adjuvant therapy group). Twelve (44%) of the patients with progressive disease responded; two remain disease free 84 and 60 months after BCNU treatment. In the adjuvant therapy group, three patients remain progression free at 70, 48, and 27 months after BCNU therapy. Tumor progression posttransplantation occurred in 25 patients; six others died of therapy-induced complications. In addition, late neurologic deterioration of unknown cause has developed in two surviving patients. Results from this and other series using intensive BCNU monochemotherapy and autologous marrow transplantation for progressive malignant glioma indicate that prolonged progression-free survival can be produced in an occasional patient, an extremely unusual result with conventional chemotherapy. Although intensive BCNU and autologous marrow transplant regimens are toxic, these results are encouraging. The treatment of patients in an adjuvant fashion with BCNU and other active agents may produce improved results.
Abstract 20140: Minibrain Relate Kinase / Dyrk1B Links Skeletal Muscle Glycolytic Metabolism with Insulin Resistance and Causes Metabolic Syndrome
Authors: Mohsen Fathzadeh, Ali Reza Keramati, Gwang Go, Rajvir Singh, Kazem Sarajzadeh, Javad Tavakkoly-Bazzaz, Ali Noorafshan, Mohammad Kasaei, Masoud Amini, Gholam Hossein R Omrani, Mohammad Ali Babaee Bigi, Masoud Babaei, Adalat Hosseinian, Reza Malekzadeh, Richard Lifton, Arya Mani
Journal: Circulation (2014)

We have identified a novel nonconservative mutation in Minibrain related serine/threonine kinase (Mirk/ Dyrk1B) in outlier kindreds with metabolic syndrome. The mutation substitutes cysteine for arginine (R102C) and segregates with most traits of metabolic syndrome, including central obesity, diabetes and hypertension. Oral glucose tolerance test (OGTT) in young nondiabetic mutation carriers revealed insulin resistance compared to noncarrier family members. Since skeletal muscle (SM) is the largest organ for glucose uptake and metabolism, we obtained Vastus Lateralis biopsies of mutation carriers and their unaffected relatives and examined them for gene/protein expression by deep RNA sequencing (RNA-Seq) and Western blot analysis and for fiber composition by immunostaining. The fiber composition data demonstrated fewer slow-twitch fibers (35% vs. 75%) and more fast -twitch fibers (65% vs. 25%) in SM of mutation carriers vs. controls. Interestingly, there were increased protein expression levels of fast-twitch fiber type proteins (MYH11, MYLPF), pyruvate dehydrogenase kinase, pyruvate kinase, and neuronal nitric oxide synthase in SM of mutation carriers vs. noncarriers. Consistent with these findings, the protein expression levels of the master regulator of cellular energy metabolism mitochondrial biogenesis, PPAR-gamma coactivator (PGC-1a), were reduced and the nuclear expression levels of FOXO1 and NFAT were increased. Similar findings were observed when wildtype and mutant (R102C) Dyrk1B were overexpressed in C2C12 cells. The overexpression of the kinase deficient Dyrk1B (Y271/273F) similarly resulted in reduced expression of PGC-1a and increased expression of nuclear FOXO1, suggesting kinase independent effects. Taken together, these findings suggest that enhanced kinase-independent activities of Dyrk1B, either through increased expression or by its gain of function mutation R102C induce insulin resistance by promoting glycolytic metabolism and reducing oxidative phosphorylation. In conclusion, Dyrk1B is a potential target for development of novel drugs that aim to enhance skeletal muscle insulin sensitivity.
A semi-quantitative survey of older adults to assess barriers to participation in early phase clinical trials (EPCTs)
Authors: M. L. Basche, A. E. Barón, S. G. Eckhardt, L. Balducci, N. Jackson, P. Vranas, A. Levin, J. Steiner
Journal: Journal of Clinical Oncology (2005)

8086 Background: The underrepresentation of older adults in EPCTs severely limits knowledge of drug pharmacology, treatment toxicity and efficacy in this population. We conducted a survey of adults aged 65+ years to describe the prevalence of patient-perceived barriers to participation in EPCTs and to identify factors important to older adults when deciding whether an experimental treatment option is acceptable. Methods: Subjects aged 65+ years with advanced solid tumors who had received prior chemotherapy were recruited from private medical oncology offices affiliated with the University of Colorado Comprehensive Cancer Center and Moffitt Cancer Center clinical research networks. Face-to-face interviews were conducted. Results: To date 219 subjects (median age 74 years (range, 65–89)) have been interviewed. One hundred thirty-six (62%, (95% C.I. 55–69)) subjects endorsed at least 1 barrier to participating in EPCTs. The most commonly reported barriers included difficulty getting to the university to participate in an EPCT (N=73, 33% (95% C.I., 27–40)), concern about being experimented on (N=43, 20% (95% C.I., 15–26)), loss of continuity with their oncologist (N=40, 18% (95% C.I., 13–24)) and adequacy of insurance coverage (N=22, 10% (95% C.I., 6–15)). When deciding whether to participate in an EPCT, 212 (97%) of subjects considered the endorsement of their oncologist to be very important, while only 24 (11%) considered information from the Internet to be very important. Possible benefits of experimental treatment reported to be very important included better symptoms (N=208, 95%) and living longer (N=201, 92%). When considering the possible impact of treatment side effects, subjects considered the following very important: being hospitalized (N=130, 59%), needing more care from family or friends (N=130, 59%), and not being able to care for a spouse or family member (N=112, 51%). Conclusion: The majority of older adults seen in private practices face barriers to participating in an EPCT at a local university. These results have been used to formulate a multifocal, targeted intervention to increase accrual of older adults on EPCTs. No significant financial relationships to disclose.
Vemurafenib in Brafv600 Mutated Metastatic Melanoma (Mm): a Subanalysis of the Italian Population of a Global Safety Study
Authors: M. Del Vecchio, P.A. Ascierto, M. Mandala, V. Chiarion Sileni, M. Maio, L. Di Guardo, E. Simeone, P. Queirolo
Journal: Annals of Oncology (2014)
Effect of a Recombinant Dimeric Tumor Necrosis Factor Receptor on Inflammatory Responses to Intravenous Endotoxin in Normal Humans
Authors: T. van der Poll, S.M. Coyle, M.M. Levi, P.M. Jansen, M. Dentener, K. Barbosa, W.A. Buurman, C.E. Hack, J.W. ten Cate, J.M. Agosti, S.F. Lowry
Journal: Blood (1997)
Development of Thymic Lymphomas by Oral Administration of &lt;italic&gt;N&lt;/italic&gt;-Nitroso-&lt;italic&gt;N&lt;/italic&gt;-propylurea and Establishment of Transplantable Lines of Thymic Lymphoma in F344 Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Y Sakura, T Ogiu, N Imamura, K Furuta, C Matsuoka, S Odashima
Journal: JNCI Journal of the National Cancer Institute (1984)

Forty-eight female F344/DuCrj rats were given a 400-ppm solution of N-nitroso-N-propylurea (CAS: 816-57-9) continuously in their drinking water. Thymic lymphomas were induced most frequently (85%) followed by duodenal tumors (48%). Sixteen tumors were examined by the immunofluorescence inhibition test for murine leukemia virus-related antigens; 15 were negative and the other was weakly positive. Twenty-six tumors were intraperitoneally and subcutaneously transplanted syngeneically; 25 (96%) were successfully transplanted intraperitoneally and 24 (92%) subcutaneously. The serial intraperitoneal transplantation was continued, and 22 lines of transplantable lymphoma in an ascites form were established. In almost all tumor lines, tumor cells took in a high percentage of recipient rats and caused the death of the recipients within 12-23 days. The thymus, liver, spleen, greater omentum, and lymph nodes were frequently invaded by transplanted tumor cells. The tumor lines were considered to be of T-cell lineage.
Attitudes towards acupuncture in patients at risk for chemotherapy-related emesis
Authors: W. T. Lim, K. H. Kong, S. P. Choo, Y. B. Cheung, S. S. Leong
Journal: Journal of Clinical Oncology (2004)

8193 Background: Acupuncture has been used for centuries as a treatment and prophylaxis of multiple ailments. For chemotherapy induced emesis, it has been studied in small studies in peer-reviewed literature. The knowledge and attitudes of the patients at risk for emesis are not well-described. Methods: A prospective study of acupuncture for 5HT3 antagonist refractory acute emesis was used to screen patients at risk from moderately emetogenic anthracycline based chemotherapy. Patients were administered a short questionnaire relating to personal attitudes and acceptance of acupuncture, regardless of whether they were accrued onto trial on the basis of post-treatment emetic episodes (>2 episodes). Patients who received acupuncture were administered the same questionnaire after acupuncture to see if there was a difference. Results: One hundred and fifty patients were screened. The median age was 50 years. Most were women with breast cancer. Only 70 (47%) thought it an acceptable procedure and only 18 (12%) felt it would be helpful for emesis. However 65 (43%) would actually try it if available. Fifty-eight (39%) and 70 (47%) of them felt that it would be an uncomfortable and painful procedure respectively. There were 13 patients with > 2 episodes of refractory acute emesis. Six declined acupuncture for fear of needles and side-effects. Seven patients received acupuncture for their subsequent cycle of chemotherapy. There was a reduction in the median number of acute emetic episodes from 4 to 1, with complete control of emesis in two patients, in the 1st 24 hours after chemotherapy. Conclusions: While complementary medicines are ubiquitous, and their use in Asia is perceived as commonplace, not all would agree to use it for reasons cited above. In view of better control of emesis with 5HT3 antagonists and now NK-1 antagonists the role of acupuncture may be small. However there appears to be added benefit in using acupuncture in this select subset of patients. No significant financial relationships to disclose.
High-dose sequential chemo-radiotherapy with peripheral blood progenitor cell support for relapsed or refractory Hodgkin's disease — A 6-year update
Authors: A.M. Gianni, S. Siena, M. Bregni, F. Lombardi, L. Gandola, M. Di Nicola, M. Magni, F. Peccatori, P. Valagussa, G. Bonadonna
Journal: Annals of Oncology (1993)
Abstract 15444: Comparing Quantitative and Qualitative Data to Determine the Impact of Peer Mentoring on Physical Activity in the Heart Healthy Kids Program
Authors: Rebecca Spencer, Jenna Bower, Laurene Rehman, Sara F Kirk, Camille Hancock Friesen
Journal: Circulation (2012)

Background: Childhood physical inactivity is contributing to obesity and preventable chronic disease. The objective of the Heart Healthy Kids (H2K) program is to examine the effectiveness of peer m...
Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer
Authors: José Baselga, Gail D. Lewis Phillips, Sunil Verma, Jungsil Ro, Jens Huober, Alice E. Guardino, Meghna K. Samant, Steve Olsen, Sanne L. de Haas, Mark D. Pegram
Journal: Clinical Cancer Research (2016)

Abstract Purpose: HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody–drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study. Experimental Design: Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations. Results: Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib–treated patients, but not in T-DM1–treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations. Conclusions: Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755–63. ©2016 AACR.
Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors.
Authors: C A Johnson, D Kilpatrick, R von Roemeling, C Langer, M A Graham, D Greenslade, G Kennedy, E Keenan, P J O'Dwyer
Journal: Journal of Clinical Oncology (1997)

PURPOSE AND METHODS Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer. RESULTS The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine. CONCLUSION This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.
Seroepidemiologic Studies of Herpesvirus Type 2 and Carcinoma of the Cervix. I. Case-Control Matching&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Ervin Adam, Allan H. Levy, William E. Rawls, Joseph L. Melnick
Journal: JNCI Journal of the National Cancer Institute (1971)

The occurrence of antibodies to herpesvirus type 2 was examined in women with cervical cancer and control women from two widely separated geographic areas. Cases were matched with controls by use of a match score, which was a weighted sum of the differences between each case and each control in the factors used for matching. Control women were matched with cervical cancer patients according to attributes presumed related to the incidence of cervical carcinoma, such as age at first intercourse, age at first pregnancy, number of live births, number of marriages, and number of sex partners. The matching procedure facilitated the selection of a control group, as similar as possible to the cases, from the available pool of control women. When such pairs of cases and control individuals were analyzed, no significant differences in the occurrence of antibodies to herpesvirus type 2 were found between the cancer patients and the control women.
Proliferation of private online healthcare companies
Authors: Jessica Watson, Chris Salisbury, Helen Atherton, John Campbell, Brian McKinstry, Sue Ziebland
Journal: BMJ (2016)

With an app for just about everything, why not one for contacting your doctor? In the United Kingdom, private companies offering primary healthcare are proliferating, with Dr Morton, a website offering email or telephone consultations, and Dr Now, a smartphone app offering video consultations. Companies in the United States are offering an Uber-type experience, where instead of a car, a doctor appears at your door.

These companies operate in a climate where patients want convenience, flexibility, and speed of access, features which overstretched general practitioners in the UK are struggling to provide. Meanwhile, new companies are appearing regularly, with the UK digital health market currently worth £2bn (€2.6bn; $2.8bn) and expected to grow to £2.9bn by 2018.2 What are the implications for the NHS?