tbuckley/cabot-search huggingface dataset:
Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies
Authors: E. J. Emanuel, G. Bedarida, K. Macci, N. B. Gabler, A. Rid, D. Wendler
Journal: BMJ (2015)

<b>Objective</b> To quantify the frequency and seriousness of adverse events in non-oncology phase I studies with healthy participants. <b>Design</b> Meta-analysis of individual, healthy volunteer level data. <b>Setting</b> Phase I studies with healthy volunteers conducted between September 2004 and March 2011 at Pfizer's three dedicated phase I testing sites in Belgium, Singapore, and the United States. These included studies in which drug development was terminated. <b>Participants</b> 11 028 participants who received the study drug in 394 distinct non-oncology phase I studies, which involved 4620 unique individuals. A total of 2460 (53.2%) participants were involved in only one study, whereas others participated in two or more studies. <b>Main outcome measures</b> Adverse events classified as mild, moderate, and severe as well as serious adverse events—defined by the Food and Drug Administration as events that result in death, a life threatening event, admission to hospital, prolongation of existing hospital stay, a persistent or major disability, or a congenital anomaly or birth defect. Pfizer researchers of phase I trials determined adverse events, and serious adverse events were those filed with the FDA. <b>Results</b> Overall, 4000 (36.3%) participants who received the study drug experienced no adverse events and 7028 (63.7%) experienced 24 643 adverse events. Overall, 84.6% (n=20 840) of adverse events were mild and 1.0% (n=255) were severe. 34 (0.31%) serious adverse events occurred among the 11 028 participants who received the study agent, with no deaths or life threatening events. Of the 34 serious adverse events, 11 were related to the study drug and seven to study procedures, whereas 16 were unrelated to a study drug or procedure, including four that occurred when the participant was receiving a placebo. Overall, 24.1% (n=5947) of adverse events were deemed to be unrelated to the study drug. With a total of 143 (36%) studies involving placebo, 10.3% (n=2528) of all adverse events occurred among participants receiving placebo. The most common adverse events were headache (12.2%, n=3017), drowsiness (9.8%, n=2410), and diarrhea (6.9%, n=1698). Research on drugs for neuropsychiatric indications had the highest frequency of adverse events (3015 per 1000 participants). <b>Conclusion</b> Among 11 028 healthy participants who received study drug in non-oncology phase I studies, the majority (85%) of adverse events were mild. 34 (0.31%) serious adverse events occurred, with no life threatening events or deaths. Half of all adverse events were related to the study drug or to procedures. Extrapolation of these data to other types of phase I studies, especially with biological agents, may not be warranted.
Surgical training and clinical trial involvement--the trainees' view
Authors: A. Bhangu
Journal: BMJ (2015)

As surgical trainees across multiple disciplines, it is our collective aim for all surgical patients to have the opportunity to participate in at least one clinical trial during their hospital episode.1 We recognise that most patients wish to have this option,2 and we want our training to facilitate this. Because patients have the right to be involved in improving surgical …
Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment
Authors: A. Wollenberg, S. Reitamo, G. Girolomoni, M. Lahfa, T. Ruzicka, E. Healy, A. Giannetti, T. Bieber, J. Vyas, M. Deleuran
Journal: Allergy (2008)

Long-term treatment for atopic dermatitis (AD) using low dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent relapses. This 12-month, European, multicentre, randomized study investigated whether the proactive use of 0.1% tacrolimus ointment applied twice weekly can keep AD in remission and reduce the incidence of disease exacerbations (DE).During the initial open-label period, 257 adults with AD applied 0.1% tacrolimus ointment twice daily (b.i.d.) for up to 6 weeks to affected areas. When an Investigator Global Assessment (IGA) score of <or=2 was achieved, the patient entered the disease control period (DCP) and was randomized to either proactive tacrolimus (n = 116) or vehicle ointment (n = 108) twice weekly for 12 months. Exacerbations were treated with 0.1% tacrolimus ointment b.i.d. until an IGA <or=2 was regained, then randomized treatment was restarted. The primary endpoint was the number of DEs during the DCP that required a substantial therapeutic intervention.Proactive tacrolimus 0.1% ointment application significantly reduced the number of DEs requiring substantial therapeutic intervention (median difference 2; P < 0.001; Wilcoxon rank sum test), the percentage of DE treatment days (median difference: 15.2%; P < 0.001; Wilcoxon rank sum test) and increased the time to first DE (median 142 vs 15 days; P < 0.001; stratified log-rank test). The adverse event profile was similar for the two treatment approaches.A 12-month, twice weekly proactive tacrolimus ointment application was an effective treatment in most study patients which prevented, delayed and reduced the occurrence of AD exacerbations
Ethylmalonic-Adipic Aciduria
Authors: Stephanos Mantagos, Myron Genel, Kay Tanaka
Journal: Journal of Clinical Investigation (1979)

The mechanisms underlying ethylmalonic-adipic aciduria were studied in a 5-yr-old girl. Oxidation of radioactive substrates by cultured skin fibroblasts from the proband and asymptomatic family members was also determined and compared to that by normal fibroblasts and that by cells from a patient with glutaric aciduria type II. Feeding medium-chain triglycerides promptly induced vomiting and lethargy accompanied by a pronounced increase of urinary ethylmalonate. Significant increases of serum isovalerate and urinary isovalerylglycine were observed after leucine feeding, but urinary glutarate increased only slightly after lysine feeding. Thus, the results from clinical investigation remained equivocal as to whether pathways other than fatty acid oxidation were blocked in our patient. Oxidation of [1-(14)C]butyrate by cultured skin fibroblasts from the proband was reduced to 14% of control. In vitro oxidation of [2-(14)C]lysine and [2-(14)C]leucine was also reduced to 28 and 23% of control, respectively. Much more severe reduction in oxidation of these three substrates (3, 9, and 9%, respectively) was observed in glutaric aciduria type II cells. These results indicated that in the proband, degradative pathways of fatty acids, lysine, and leucine are blocked at the steps of butyryl-CoA, glutaryl-CoA, and isovaleryl-CoA dehydrogenases, respectively, as in the case of glutaric aciduria type II. Because activities of multiple acyl-CoA dehydrogenases are reduced, a deficiency of electron-transferring flavoprotein, which serves as a hydrogen-acceptor for these dehydrogenases, is postulated as the underlying mechanisms of these two diseases, but a genetic heterogeneity was indicated by significant differences in the residual activities in these two types of cells. The hypothesis of more than one mutant allele of an autosomal recessive gene was also suggested by the study on cells from asymptomatic members of the family.
Abstract 810: O6 methylguanine DNA methyltransferase inhibition sensitizes pancreatic cancer cells to temozolomide
Authors: George C. Bobustuc, Jonathan Ticku, Anand Patel, Kalkunte S. Srivenugopal, Santhi D. Konduri
Journal: Cancer Research (2014)

Abstract O6 methylguanine DNA methyltransferease (MGMT) is overexpressed in majority of cancers including pancreatic cancer. MGMT has been the focus of significant research for its role in the repair of DNA damage caused by alkylating agents. In the present study, we tested the administration of the MGMT inhibitor O6-benzylguanine (BG) at non-toxic doses in combination with an alkylator TMZ (temozolomide) on pancreatic cancer cells (L3.6 pl and PANC1) in cell culture and xenograft model. Here, we report that TMZ decreases pancreatic cancer cell growth in a dose dependent manner. BG further sensitizes pancreatic cancer cells to TMZ and significantly inhibits pancreatic cancer growth. We also report that BG, either alone or in combination with TMZ, inhibits the expression of MGMT, Ki-67 and BIRC5 (survivin), which are involved in pancreatic tumorigenesis and cell division, and induces the expression of p21cip1 cell cycle inhibitor. Microarray analysis revealed that BG significantly decreased the transcription of a group of proto-oncogenes, growth factors, cell cycle and overall transcription regulators involved in tumorigenesis like ARHGDIB, IGFL1, KIF20A, CA9, MMP10 and E2F2 and increased the transcription of a variety of genes involved in tissue differentiation, cell cycle regulation and invasion inhibitors like GDF15, CDKN1A and TIMP1. In our pancreatic cancer xenograft model, BG +/- TMZ significantly inhibited pancreatic tumor growth in vivo compared to single agent TMZ or controls. Further, BG promotes p53 function leading to growth inhibition, in part substantiating the underlying mechanism of BIRC5 (survivin) inhibition and p21cip1 induction. In conclusion, our findings suggest that MGMT inhibition may potentially provide a novel therapeutic approach in pancreatic cancer by opening the option of using (oral) alkylators like TMZ. Citation Format: George C. Bobustuc, Jonathan Ticku, Anand Patel, Kalkunte S. Srivenugopal, Santhi D. Konduri. O6 methylguanine DNA methyltransferase inhibition sensitizes pancreatic cancer cells to temozolomide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 810. doi:10.1158/1538-7445.AM2014-810
A phase II study of mitoxantrone, etoposide, and thiotepa with autologous marrow support for patients with relapsed breast cancer.
Authors: R Wallerstein, G Spitzer, F Dunphy, S Huan, G Hortobagyi, J Yau, A Buzdar, F Holmes, R Theriault, M Ewer
Journal: Journal of Clinical Oncology (1990)

To further improve the effect of high-dose chemotherapy in the treatment of locally advanced and metastatic breast cancer, we sought to develop a second active high-dose noncross-resistant regimen to use in tandem with our customary high-dose regimen of cyclophosphamide, etoposide, and cisplatin (CVP). We performed a phase II trial of high-dose mitoxantrone 30 mg/m2, etoposide 200 mg/m2 every 12 hours x 6, and thiotepa 250 mg/m2 x 3 days (MVT) in 31 patients with heavily pretreated metastatic breast cancer and one with locally advanced chemotherapy-refractory breast cancer. These patients were ineligible for high-dose CVP chemotherapy because of the amount of prior treatment and poor-response status. Of the 32 patients, 14 responded to cycle 1, did not experience any grade 4 toxicity, and received a second cycle of MVT. Overall, seven of 31 patients achieved a complete response (CR; 23%). Four of the 14, who were partial responders to the first cycle, achieved a CR after the second cycle. The overall response rate was 19 of 31 (61%) with an overall median freedom from progression of 4 to 5 months and an overall median survival of 9 months. Toxicity consisted primarily of mucositis (grade 3 or 4 in 69%). The results indicate that high-dose MVT produces significant activity, even in heavily pretreated patients. Administration of a second cycle of high-dose therapy with MVT increased the CR rate, and the morbidity and mortality from the second cycle were not greater than that for the first cycle. Because of the high incidence of grade 3 or 4 mucositis with this regimen, we are currently completing a follow-up study of high-dose mitoxantrone and thiotepa alone.
Altered Clearance of Gadolinium Diethylenetriaminepentaacetic Acid Aerosol from Bleomycin-injured Dog Lungs
Authors: Kazuyoshi Suga, Yue Yuan, Nobuhiko Ogasawara, Toshinobu Tsukuda, Naofumi Matsunaga
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

To characterize altered alveolar transfer to solute in bleomycin (BLM)-injured lungs, eight dogs underwent a gadolinium diethylenetriaminepentaacetic acid aerosol (Gd-AS) magnetic resonance imaging study before and on Days 7 and 40 after tracheal instillation of BLM (0.75 mg) in the left lungs. Consecutive fast-gradient echo magnetic resonance imaging was acquired during and after spontaneous inhalation of 200-mM Gd-AS. The slope (Kep) and clearance half-time (T1/2) of logarithmic regression lines for clearance curves were estimated. Histology on Day 40 was compared with that on Day 7 in another three dogs. On Days 7 and 40, Gd-AS deposition was heterogeneously reduced in the affected lungs. On Day 7 with multifocal intraalveolar exudative changes, Kep in affected areas was significantly increased compared with baseline (2.5 × 10−3 minutes−1 ± 0.3 versus 1.7 × 10−3 minutes−1 ± 0.2, p < 0.0001), with significant decrease in T1/2 (121.6 ± 19.7 minutes vs. 170.4 ± 15.8 minutes, p < 0.001). However, on Day 40 with multifocal interstitial fibrosis, Kep and T1/2 were recovered toward baseline. BLM-injured lungs can be characterized by accelerated Gd-AS clearance during the acute exudative phase and their recovery during the chronic fibrotic phase. This technique is acceptable for monitoring alveolar transfer changes in BLM-injured lungs.
Abstract 13228: Direct Modulation of Myocardial Tissue Inhibitor of Matrix Metalloproteinase-4 Alters the Course of Myocardial Growth and Matrix Remodeling with Pressure Overload
Authors: William M Yarbrough, An Van Laer, William T Rivers, Richard A McKinney, Elizabeth C O'Quinn, Laurel E Black, Robert E Stroud, Michael R Zile, Rupak Mukherjee, Francis G Spinale
Journal: Circulation (2010)

Background: Recent basic in vitro studies have identified that the tissue inhibitors of the matrix metalloproteinases (TIMPs), such as TIMP-4 which is highly expressed in the cardiovascular system, may regulate multiple biological pathways including myocardial growth as well as matrix remodeling. However, the direct effects of TIMP-4 with respect to LV remodeling in vivo and in a relevant pathophysiological context, remains unknown. This study tested the hypothesis that myocardial selective overexpression (TIMP-4exp) or targeted deletion (TIMP-4KO) would directly affect LV growth and matrix remodeling with pressure overload (PO). Methods/Results: PO (transverse aortic constriction) was induced in wild-type (WT; FVB n=15), TIMP-4exp (n=20; full length human TIMP-4), and TIMP-4KO (n=11) and results compared to non-PO WT (n=10; TABLE). At 4 weeks post-PO, LV mass increased in all groups, but was lower with TIMP-4exp and higher with TIMP-4KO, and was paralleled by changes in myocyte cross sectional area (CSA)...
Epitope mapping of BP230 leading to a novel enzyme‐linked immunosorbent assay for autoantibodies in bullous pemphigoid
Authors: I.M. Blöcker, C. Dähnrich, C. Probst, L. Komorowski, S. Saschenbrecker, W. Schlumberger, W. Stöcker, D. Zillikens, E. Schmidt
Journal: British Journal of Dermatology (2012)

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by circulating autoantibodies against BP180 and BP230. For BP180, the NC16A domain has previously been identified as the main antigenic target in BP, while data about the diagnostic value of epitopes on BP230 were inconclusive.To identify the most appropriate epitopes on BP230 to be applied in a simple, sensitive, and highly specific enzyme-linked immunosorbent assay (ELISA) for routine detection of serum autoantibodies.Ten overlapping linear fragments covering the whole length of BP230 were expressed in Escherichia coli. Based on Western blot analysis with sera from patients with BP (n = 49) and healthy controls (n = 94), the diagnostic performance of the fragments was compared by receiver operating characteristics curve analysis. The BP230-C3 fragment comprising the C-terminal portion (amino acids 2326-2649) was subsequently applied in a novel ELISA. The operating characteristics of this ELISA were analysed by probing sera from patients with BP (n = 118), pemphigus vulgaris (n = 50), rheumatoid arthritis and other inflammatory arthritides (n = 170), and systemic lupus erythematosus (n = 56), and from healthy blood donors (n = 483).Among all the fragments, BP230-C3 provided the best efficiency in serologically diagnosing BP by Western blot. An ELISA employing BP230-C3 revealed a diagnostic sensitivity of 56·8% and specificity of 97·6%. Its diagnostic added value amounted to 4·2% compared with the anti-BP180-NC16A-4X ELISA alone.Recombinant BP230-C3 is a suitable target antigen for the detection of serum autoantibodies against BP230.
Abstract 1513: Use of complex oligonucleotide libraries for concurrent high-resolution fluorescence imaging of both DNA and RNA in various sample types
Authors: Robert A. Ach, Peter Tsang, Alicia Scheffer-Wong, Laurakay Bruhn, Weston Powell, Jesse Engreitz, Janine LaSalle, Mitchell Guttman, Alice Yamada
Journal: Cancer Research (2014)

Abstract Fluorescence in situ Hybridization (FISH) is a powerful technique for determining the localization specific nucleic acid sequences within individual cells. Previously, the use of FISH has often been dependent upon access to cloned template DNA for the generation of probes, which can be difficult if clones for specific regions are unavailable, or if the genomic region of interest contains repetitive and/or other problematic sequences. We have developed the ability to chemically synthesize DNA in massively parallel reactions, which we have used to produce libraries of oligonucleotides up to 200 bases in length that can be utilized for the generation of FISH probes. The sequences of the oligonucleotides in these libraries are selected in silico using empirically determined criteria so as to avoid repetitive elements or regions homologous to other non-targeted loci. We have found that these oligonucleotide library-derived FISH probes can detect human genomic regions as small as 1.8 kb and as large as whole chromosomes in both metaphase and interphase cells, using the same simple assay protocol. Because of the inherent flexibility in our probe design methods, we can readily visualize regions rich in repeats and/or GC content. We have also used these oligonucleotide library-derived FISH probes to detect the localization of a variety of both coding and non-coding RNAs in fixed tissue culture cells and formalin-fixed paraffin-embedded tissue sections, using both conventional fluorescence and structured illumination microscopy. Simultaneous hybridization of FISH probes labeled with different fluorophores enables visualization of multiple sequences at once. Using probes designed specifically to transcribed vs. non-transcribed regions has enabled the simultaneously detect DNA and RNA from the same locus, or from two different loci, in the same FISH assay. The ability to generate high performance FISH probes using chemically synthesized oligo libraries that can simultaneously detect DNA and RNA yields a valuable tool for studies of how localization of specific nucleic acids impacts biological function. Citation Format: Robert A. Ach, Peter Tsang, Alicia Scheffer-Wong, Laurakay Bruhn, Weston Powell, Jesse Engreitz, Janine LaSalle, Mitchell Guttman, Alice Yamada. Use of complex oligonucleotide libraries for concurrent high-resolution fluorescence imaging of both DNA and RNA in various sample types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1513. doi:10.1158/1538-7445.AM2014-1513
Genetic Identification of <i>SEMA3F</i> as an Antilymphangiogenic Metastasis Suppressor Gene in Head and Neck Squamous Carcinoma
Authors: Colleen L. Doçi, Constantinos M. Mikelis, Michail S. Lionakis, Alfredo A. Molinolo, J. Silvio Gutkind
Journal: Cancer Research (2015)

Abstract Head and neck squamous cell carcinomas (HNSCC) often metastasize to locoregional lymph nodes, and lymph node involvement represents one of the most important prognostic factors of poor clinical outcome. HNSCCs are remarkably lymphangiogenic and represent a clear example of a cancer that utilizes the lymphatic vasculature for malignant dissemination; however, the molecular mechanisms underlying lymphangiogenesis in HNSCC is still poorly understood. Of interest, we found that an axon guidance molecule, Semaphorin 3F (SEMA3F), is among the top 1% underexpressed genes in HNSCC, and that genomic loss of SEMA3F correlates with increased metastasis and decreased survival. SEMA3F acts on its coreceptors, plexins and neuropilins, among which neuropilin-2 (NRP2) is highly expressed in lymphatic endothelial cells (LEC) but not in oral epithelium and most HNSCCs. We show that recombinant SEMA3F promotes LEC collapse and potently inhibits lymphangiogenesis in vivo. By reconstituting all possible plexin and neuropilin combinations, we found that SEMA3F acts through multiple receptors, but predominantly requires NRP2 to signal in LECs. Using orthotopic HNSCC metastasis mouse models, we provide direct evidence that SEMA3F re-expression diminishes lymphangiogenesis and lymph node metastasis. Furthermore, analysis of a large tissue collection revealed that SEMA3F is progressively lost during HNSCC progression, concomitant with increased tumor lymphangiogenesis. SEMA3F is localized to 3p21, an early and frequently deleted locus in HNSCC and many other prevalent human malignancies. Thus, SEMA3F may represent an antilymphangiogenic metastasis suppressor gene widely lost during cancer progression, hence serving as a prognostic biomarker and an attractive target for therapeutic intervention to halt metastasis. Cancer Res; 75(14); 2937–48. ©2015 AACR.
Optimization of PH diagnostic process with IVUS during right heart catheterization
Authors: Elena Belyatko, N.M. Danilov, R.V. Atanesyan, M.G. Mitroshkin, Y.G. Matchin, T.V. Martynyuk, I.E. Chazova
Journal: European Respiratory Journal (2014)

Objective:To assess the vasodilator effect of inhaled NO during RHC and morphological changes of pulmonary arteries by IVUS in patients with PAH. Design and Method: We have prospectively enrolled 10 consecutive patients with PH (9 fem and 1 men), at the age of 49 +_13 years.  Our pts including IPAH (n=5), CTEPH (n=1), associated with CVD (n=1), FPAH (n=3), who underwent RHC including the IVUS. All pts underwent RHC including IVUS evaluation (Eagle Eye Gold ; Volcano Therapeutics,) and general characteristics of different tissues by IVUS. We used IVUS parameters such as: intima-media thickness and pulsatility index (PI). All patients were divided into respondents and non-respondents (after the acute probe).  Results: Pulmonary angiography showed dilatation of the main artery (3,2 cm). We attempted to use radiofrequent analysis (Virtual histology by IVUS). In one IPAH pt mean PA pressure (mPAP) from 53 mm Hg increased to 56 mm Hg after iNO; pulmonary vascular resistance (PVR) values were 1790 dyne ×c/cm 5  and 1429 dyne ×c/cm 5  respectively before and after NO. IVUS data: intima - media thickness before and after NO was 2,4 and 2,0 mm. PI increased from 14,3 % to 16.6% after NO IVUS with virtual histology (VH) demonstrates proximal right PA with irregular intimal surface and intimal disruption. The soft tissue echoes (arrow) are consistent with an atherosclerotic lesion.  Conclusions: IVUS gives unique data about PA morphology. At present the noninvasive identification of pulmonary atherosclerosis in vivo is an unrealizable task. From diagnostic point of view IVUS may be considered an important method to improve the visualization capability for the treatment optimization of patients with PAH.