tbuckley/cabot-search huggingface dataset:
Proof of concept: Weekly metronomic dosing of paclitaxel/gemcitabine (PaG) followed by paclitaxel/oxaliplatin/leucovorin/5-FU (POLF) for advanced stage pancreatic adenocarcinoma (PC)
Authors: B. M. Chue
Journal: Journal of Clinical Oncology (2008)

15638 Background: We previously reported excellent results for patients with stage IV PC with weekly “metronomic dosing” of POLF. We attribute these excellent results to the increase dose density/intensity and the anti-angiogenic effects of the regimen. Work with the anti-angiogenic agent bevacizumab has shown that it can make chemotherapy more effective by increasing chemotherapy to the tumor bed. Weekly paclitaxel may play a similar role in our regimen. As proof of the concept, we report the results of patients first treated with 12 weeks of PaG, followed by at least 12 weeks of POLF in advanced stage inoperable PC. Methods: 9 patients ages 47 to 75 with biopsy proven inoperable PC were treated with PaG (P: 60mg/m2, G: 800–1,000 mg/m2) for 12 weeks followed by weekly POLF (P: 60 mg/m2, O: 50 mg/m2, L: 20 mg/m2, F: 425 mg/m2) for at least twelve weeks. 1 had nab-paclitaxel (B.M.) due to reaction to paclitaxel. 1 patient (Ju. S.) also received erlotinib. Glutathione, calcium, and magnesium were used to prevent oxaliplatin-related neuropathy with POLF. Results: After treatment with 12 weeks of PaG and at least 12 weeks of POLF, 3 out of 4 patients with stage III and 5 out of 6 patients with stage IV are still alive with median survival not reached. For stage IV patients, survival is currently greater than 9 months. The regimen is well tolerated, with one patient (J.C.) and possibly a second patient (S.H.) with interstitial pneumonitis from PaG. 1 patient with grade III diarrhea (Ja.S.) and 1 patient with grade III neuropathy (S.S) with POLF. Conclusions: Weekly “metronomic dosing” of PaG followed by POLF has significant activity against PC and manageable side effects. This strategy of sequential treatment may be useful in the neoadjuvant setting for tumor shrinkage to bring more patients to surgery for potential cure, in the adjuvant setting after potential curative surgery to improve cure rates or in the adjuvant setting in stage IV disease to extend survival. Patient Gender Age Stage Response Survival With PaG With POLF With PaG and POLF Ja.S. Male 51 III SD PR PR 14.4+ P.E. Female 57 III PR SD/PR PR 12.6+ J.G-D. Female 54 III PD PD PD 8.4 S.S. Male 53 III SD PD PD 8.4+ S.H. Female 65 IV SD PR PR 12.4+ D.B. Male 75 IV PR SD PR 11.4 J.C. Male 47 IV PR SD PR 7.3+ J.N. Male 52 IV SD SD SD/PR 12.1+ B.M. Female 59 IV SD SD SD 9.3+ Ju.S. Female 69 IV SD SD/PR PR 6.3+ No significant financial relationships to disclose.
Incidence of carcinoma in situ (CIS) and muscle-invasive bladder cancer by gender: Analysis of 600 primary cases at initial presentation.
Authors: S. Kruck, M. Burger, S. Denzinger, J. Hennenlotter, W. Otto, A. Hartmann, F. Fend, W. F. Wieland, A. Stenzl, K. Sievert
Journal: Journal of Clinical Oncology (2010)

e15103 Background: Bladder cancer is significantly more frequent in men than in women, which mostly is explained by greater exposure to carcinogenic influences in men. It has been repeatedly reported however, that cancer specific outcome is significantly adverse in female versus male patients. While this has been attributed to socioeconomic factors and worse tumor biology of cancers unrelated to carcinogens, no distinct analysis of tumor stages in primary cases at initial presentation has been reported to date. Aim of this contribution was to clarify if women tend to present with adverse tumour stages initially which might contribute to poorer outcome opposed to men. Methods: Clinicopathological factors of all primary bladder cancer void of prior history of urothelial neoplasia initially presenting at the Departments of Urology, University of Regensburg (R) and University of Tuebingen (T) were assessed. A recent time period of four years was chosen for better comparability of TUR technique and histopathological evaluation. Photodynamic diagnostics assisted TUR in most cases; the current WHO classification was used in all cases. Results: Between 01/2005 and 01/2009 n=604 (160 female; 444 male) primary bladder cancers presented at R (255) and T (349), respectively. There were no differences in any characteristics between the R and T series. Initial muscle invasive stages (≥pT2) were found in 26% of female and 20% of male patients (p=0.036). Overall CIS was found in 16% of female and 13% male patients, respectively (p=0.067). CIS only or in association with non-muscle invasive stages was found in 12% of female and 10% of male patients, respectively (p= 0.095). Conclusions: The incidence rate of initial CIS does tend to be greater in women in the present series, a significantly greater proportion of women presented with muscle invasive tumor stages. This aspect certainly contributes to the poorer outcome of women as opposed to men. While women overall are less likely to develop bladder cancer, the women who do require intense urological attention and respective awareness should be raised. Further studies in larger series and on further, e.g. molecular parameters, are warranted. No significant financial relationships to disclose.
Pre-clinical evaluation of a novel and selective PI3K δ/γ inhibitor in pulmonary fibrosis
Authors: Kasiviswanath Routhu, Babu Govindrajulu, Sridhar Veeraraghavan, Srikant Viswanadha, Swaroop Vakkalanka
Journal: European Respiratory Journal (2014)

Introduction: Pulmonary fibrosis (PF) represents a debilitating disease of the lung that is often fatal without any known treatment. Although pirfenidone was approved for treatment of PF, patient response is limited and accompanied by severe adverse events. We evaluated the therapeutic potential of a novel, selective, and potent dual PI3Kδ/γ inhibitor, RP6503, in preclinical models of PF.

Methods: PDGF or TGFβ induced primary rat and human lung fibroblast proliferation was determined after 48 h incubation with RP6503 as a single agent or in combination with pirfenidone. Combination Index (CI) was calculated using CompuSyn version 1.0. In vivo efficacy was evaluated in a bleomycin induced pulmonary fibrosis model in Wistar rat.

Results: RP6503 inhibited PDGF induced rat primary lung fibroblast proliferation with an EC50 of 467 nM . A synergistic effect ( CI <1 ) on inhibition of PDGF induced primary human fibroblast proliferation was noticed upon combining RP6503 with pirfenidone. Intranasal administration of 1 mg/kg RP6503 resulted in a 30% reduction in lung weight compared to the control. Body weight was not affected by treatment. Reduction in fibrosis and inflammation upon histopathological evaluation were 53% and 71% respectively. In addition, RP6503 reduced lung hydroxyproline content by 41% .

Conclusions: Data demonstrate the therapeutic potential of RP6503 in pulmonary fibrosis. Efficacy studies using a combination of RP6503 and pirfenidone are currently in progress.
Predictive validity of the ASAS classification criteria for axial and peripheral spondyloarthritis after follow-up in the ASAS cohort: a final analysis
Authors: Alexandre Sepriano, Robert Landewé, Désirée van der Heijde, Joachim Sieper, Nurullah Akkoc, Jan Brandt, Jürgen Braun, Eduardo Collantes-Estevez, Maxime Dougados, Oliver Fitzgerald, Feng Huang, Jieruo Gu, Yesim Kirazli, Walter P Maksymowych, Helena Marzo-Ortega, Ignazio Olivieri, Salih Ozgocmen, Euthalia Roussou, Salvatore Scarpato, Inge J Sørensen, Rafael Valle-Oñate, Filip Van den Bosch, Irene van der Horst-Bruinsma, Ulrich Weber, James Wei, Martin Rudwaleit
Journal: Annals of the Rheumatic Diseases (2016)

Objective To establish the predictive validity of the Assessment of SpondyloArthritis international Society (ASAS) spondyloarthritis (SpA) classification criteria. Methods 22 centres (N=909 patients) from the initial 29 ASAS centres (N=975) participated in the ASAS-cohort follow-up study. Patients had either chronic (&gt;3 months) back pain of unknown origin and age of onset below 45 years (N=658) or peripheral arthritis and/or enthesitis and/or dactylitis (N=251). At follow-up, information was obtained at a clinic visit or by telephone. The positive predictive value (PPV) of the baseline classification by the ASAS criteria was calculated using rheumatologist's diagnosis at follow-up as external standard. Results In total, 564 patients were assessed at follow-up (345 visits; 219 telephone) with a mean follow-up of 4.4 years (range: 1.9; 6.8) and 70.2% received a SpA diagnosis by the rheumatologist. 335 patients fulfilled the axial SpA (axSpA) or peripheral SpA (pSpA) criteria at baseline and of these, 309 were diagnosed SpA after follow-up (PPV SpA criteria: 92.2%). The PPV of the axSpA and pSpA criteria was 93.3% and 89.5%, respectively. The PPV for the ‘clinical arm only’ was 88.0% and for the ‘clinical arm’±‘imaging arm’ 96.0%, for the ‘imaging arm only’ 86.2% and for the ‘imaging arm’+/-‘clinical arm’ 94.7%. A series of sensitivity analyses yielded similar results (range: 85.1–98.2%). Conclusions The PPV of the axSpA and pSpA criteria to forecast an expert's diagnosis of ‘SpA’ after more than 4 years is excellent. The ‘imaging arm’ and ‘clinical arm’ of the axSpA criteria have similar predictive validity and are truly complementary.
New prognostic staging system from the multivariate survival analysis (MVA) of the patients with unresectable hepatocellular carcinoma (HCC) treated with doxorubicin drug eluting beads transarterial chemoembolization (DEB TACE).
Authors: Hasmukh J. Prajapati, Hyun Sik Kim
Journal: Journal of Clinical Oncology (2015)

236 Background: To develop the staging system from MVA in pts with unresectable HCC treated with DEB TACE. Methods: Consecutive unresectable and non-tranplantable pts with HCC, who received DEB TACE over the 88 months(m), were studied. 420 pts (mean age, 61.4 yrs) were included in the study. Survivals were analyzed according to different parameters from the time of the 1st DEB TACE. Kaplan Meier estimator by log rank test and Cox Proportional Hazard model were used for survival analysis. The staging system was constructed from the survival analyses. Results: The overall median survival (OS) was 20m. Pts with Child Pugh (CP) class A(54.5%), B(40.2%) and C(5.3%) had OSs of 28m, 12.9m and 4.1m respectively (p&lt;0.0001). Pts with BCLC A(9.3%), B(21.2%), C(61.4%) and D(8.1%) had OSs of 37m, 30m, 17.2 and 4.4m respectively (p&lt;0.0001). In HCC pts with venous thrombosis (VT) of large vein (main PV, right or left PV, HV, IVC) (72.7%) versus (vs) small vein (segmental/subsegmental PV) had OSs of 5.8m versus 17.3m accordingly (p=0.008). Pts with Alfa-feto protein (AFP) &gt;400ng/dl had OS of 7.6m vs 24.3 m with AFP&lt;400 (p&lt;0.0001). On MVA, the significant independent PFs of survival were CP class, ECOG PS, number (no) of HCC, index HCC (iHCC) size, site of Portal or hepatic VT, extra-hepatic metastasis (mets), serum(s) creatinine, and s.AFP. Based on these PFs, the staging system was constructed, which is shown in table 1 and named as CIS (Clinical, Imaging and Serum examination) staging system. The OSs of stage I, II, III and IV were 40.4m, 24m, 10.6m, and 2.6m respectively (p&lt;0.0001). Conclusions: We propose the new CIS prognostic staging system for advanced HCC from the MVA of survival after DEB TACE in pts with unresectable HCC. [Table: see text]
Search for the optimal treatment of ovarian cancer: heavy metals, "belly baths," and ... yew trees.
Authors: F Muggia
Journal: Journal of Clinical Oncology (1992)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1992.10.5.683 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 1569441 Search for the optimal treatment of ovarian cancer: heavy metals, "belly baths," and ... yew trees. F MuggiaxF MuggiaSearch for articles by this author https://doi.org/10.1200/JCO.1992.10.5.683 First Page PDF © 1992 by American Society of Clinical Oncology
Temporal Synthesis of Band 3 Oligomers During Terminal Maturation of Mouse Erythroblasts. Dimers and Tetramers Exist in the Membrane as Preformed Stable Species
Authors: Manjit Hanspal, David E. Golan, Yva Smockova, Scott J. Yi, Michael R. Cho, Shih-Chun Liu, Jiri Palek
Journal: Blood (1998)
The Importance of Age and Smoking in Evaluating Adverse Cytogenetic Effects of Exposure to Environmental Agents
Authors: James D. Tucker, Dan H. Moore
Journal: Environmental Health Perspectives (1996)

Fluorescence in situ hybridization with chromosome-specific composite DNA probes (chromosome painting) is a reliable and efficient method for detecting structural chromosome aberrations.Painting is now being used to quantify chromosome damage in many human populations.In one such study we evaluated 91 unexposed people ranging in age from birth (cord bloods) to 79.We established a baseline frequency of stable aberrations that showed a highly significant curvilinear increase with age (p < 0.00001) that accounted for 70% of the variance among donors.The mag- nitude of this effect illustrates the importance of understanding the cytogenetic changes that occur with age, which is particularly important for quantifying the effects of prior adverse envi- ronmental, occupational, or accidental exposure.In this paper we use the data obtained in our previous study to characterize the distribution of stable aberrations by age and pack-years of cigarette smoking.We also provide estimates of the number of cell equivalents that need to be scored to detect a given increase in aberrations above the background level surveyed in this population.
Colony Formation by Simian Virus 40-Transformed Human Parapharyngeal Cells Cultured in Semisolid Agar&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: R L Ruben, K A Rafferty
Journal: JNCI Journal of the National Cancer Institute (1978)

A simian virus 40 (SV40)-transformed line of human parapharyngeal cells (SV-TGo) was cultured in semisolid agar to determine its ability to grow in the absence of an anchoring substratum and to evaluate any phenotypic changes that might have resulted during the isolation of sublines specifically selected for anchorage independence. After 2--3 weeks and 14--15 population doublings in culture, SV-TGo plated with over 1,000% higher efficiency than negative controls (F2408 cells). Sublines, 0.3--2.0 mm in diameter, were isolated and transferred to Leighton tubes in which they underwent an additional 0--7 divisions before senescence after 39--44 total population doublings. Subline phenotype was identical to the original parental phenotype, including epithelioid morphology, organized pattern of growth, extreme sensitivity to density-dependent inhibition of growth, and continuous production of infectious SV40 as detected by the combined tests of cocultivation and direct isolation. Limited division potential was within the range observed for the parental line. The ability to grow in agar without identifiable phenotypic changes was therefore confirmed for this line of SV40-transformed human epithelioid cells.
Abstract 27: The Transcription Cofactor Eya4 Mediates the Development of Acquired Cardiac Hypertrophy
Authors: Tatjana Williams, Jost Schoenberger, Moritz Hundertmark, Peter Nordbeck, Sabine Voll, Martin Czolbe, Vera Pekarek, Oliver Ritter
Journal: Circulation Research (2012)

Introduction: Eyes absent 4 (Eya4) is a transcription cofactor involved in a number of cellular and developmental processes. We have previously shown that a mutation in Eya4 (E193) leads to late-onset familial dilated cardiomyopathy and heart failure. A precise role for Eya4 in the myocardium has not yet been identified. It appears to regulate the cyclin dependent kinase inhibitor p27 kip1 (p27), a protein shown to regulate hypertrophic responses in the adult cardiomyocyte. This study was aimed to explore the role of Eya4 in induced cardiac hypertrophy. Methods and results: We generated transgenic mice with cardiac-specific overexpression of HA-tagged Eya4 or E193 to elucidate the function of these proteins in the development of heart failure in vivo . These and wildtype littermates were challenged with angiotensin II (ATII) or subjected to transaortic constriction (TAC). Magnetic resonance imaging to visualize cardiac structures in detail showed that in response to sustained ATII stimulation and TAC, Eya4 mice exhibited a phenotype with significantly increased parameters of hypertrophy compared to WT and E193 overexpressing animals as judged by increases in heart weight and LV free wall diameter, cross-sectional cell surface areas and fibrosis. MRI also showed mild cardiac hypertrophy in Eya4 transgenic mice already under baseline conditions in an age dependent fashion. Moreover, Eya4 overexpression induced a significant suppression of p27 protein expression and resulted in increased levels of phosphorylated histone deacetylase 2 (HDAC2). E193 overexpression induced age dependent wall thinning and ventricular dilation under baseline conditions with no obvious structural or functional defects. ATII or TAC induced significant changes in HW/BW ratio, IVS, fibrosis, hemodynamic and cell size measurements, albeit to a lesser extent than seen with Eya4 mice. p27 expression and pHDAC2 levels were only slightly altered. Conclusion: In summary, we have demonstrated a mutation in Eya4 to disturb cardiac physiology. We now provide evidence that Eya4 is also involved in forms of acquired heart disease. It seems to suppress p27, which leads to phosphorylation and activation of HDAC2 and results in the development of cardiac hypertrophy.
Mucormycosis in Australia: contemporary epidemiology and outcomes
Authors: K.J. Kennedy, K. Daveson, M.A. Slavin, S.J. van Hal, T.C. Sorrell, A. Lee, D.J. Marriott, B. Chapman, C.L. Halliday, K. Hajkowicz, E. Athan, N. Bak, E. Cheong, C.H. Heath, C.O. Morrissey, S. Kidd, R. Beresford, C. Blyth, T.M. Korman, J.O. Robinson, W. Meyer, S.C.-A. Chen, Julia Clark, Joseph McCormack, David Looke, E. Geoffrey Playford, Sharon Chen, Thomas Gottlieb, Catriona Halliday, Deborah Marriott, Brendan McMullan, Wieland Meyer, Tania Sorrell, Sebastian van Hal, Michelle Ananda-Rajah, C. Orla Morrissey, Monica Slavin, Narin Bak, Sarah Kidd, Ian Arthur, Christopher Blyth, Christopher Heath, Karina Kennedy, Kathryn Daveson, Arthur Morris, Steve Chambers
Journal: Clinical Microbiology and Infection (2016)
Various Authentic Chemoattractants Mediating Leukocyte Adherence Inhibition&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: D M Thomson
Journal: JNCI Journal of the National Cancer Institute (1984)

This study resulted from the finding that cancer extract-induced leukocyte adherence inhibition (LAI) depends on release of arachidonic acid metabolites of which leukotriene B4 (LTB4) is a chemoattractant. Leukotrienes, the chemotactic fragment of the fifth component of complement (C5a des arg), N-formyl-L-methionylyl-L-leucyl-L-phenylalanine (FMLP), platelet-activating factor (PAF), and phorbol myristate acetate (PMA) increased the nonadherence of human leukocytes to glass with bell-shaped dose-response curves. For maximum nonadherence, the optimum concentration was about 2 X 10(-11) M LTB4, 10(-9) M C5a des arg, 2 X 10(-8) M FMLP, 2 X 10(-9) M PAF, and 2 X 10(-8) M PMA. Of the adherent leukocytes, 29% became nonadherent. Higher concentrations of leukotriene E4, FMLP, PAF, and PMA induced leukocyte hyperadhesiveness. Chemoattractant-induced LAI was antagonized by inhibitors of glycolysis, oxidative metabolism, electron transport, microfilaments, and microtubules, whereas the same concentration of inhibitors did not alter the adherence of leukocytes to glass in control tubes. T-cells, neutrophils, and mononuclear cells showed LAI to LTB4, C5a des arg, and FMLP. Moreover, no additive effect was observed when leukocytes exposed to a first chemoattractant at its optimum concentration were exposed to a second. A competitive inhibitor of leukotriene slow-reacting substance of anaphylaxis, FPL 55712, blocked in a dose-response fashion LTB4-, C5a des arg-, and FMLP-triggered LAI. Eicosatetraenoic acid and nordihydroguaiaretic acid, cyclo-oxygenase-lipoxygenase pathway inhibitors, also markedly antagonized LTB4-, C5a des arg-, and FMLP-triggered LAI. Indomethacin (10(-5) M), piroxicam (10(-6) M), and aspirin, cyclooxygenase antagonists, negated LTB4-, C5a des arg-, and FMLP-induced LAI. Prostaglandins E2, E1, and F2 and prostacyclin did not trigger LAI. However, selective thromboxane synthetase antagonists completely negated chemoattractant-triggered LAI. Our studies indicated that chemoattractants stimulated leukocytes to produce thromboxanes, which increased leukocyte nonadherence.
XIAP mRNA levels but not XAF1 or XIAP/XAF1 mRNA levels predict pathological response in bladder cancer patients treated with neoadjuvant chemotherapy
Authors: M. B. Pinho, J. Sellos, F. Costas, D. Herchenhorn, F. A. Peixoto, R. Diengsmann, I. A. Small, H. Cardoso, D. P. Guimarães, C. G. Ferreira
Journal: Journal of Clinical Oncology (2006)

20030 Background: The relation between apoptosis-related molecules and chemosensitivity has been extensively studied. In recent years, attention has shifted to a new family of inhibitor of apoptosis proteins (IAPs). XIAP (X- linked inhibitor of apoptosis) is the most versatile and potent member of the IAP family. To date, the overexpression of XIAP has been detected in various cancers. XAF1 (X-linked inhibitor of apoptosis associated factor 1) is a new protein identified for its ability to interact with XIAP. Neither XIAP nor XAF1 or XIAP/XAF1 mRNA expression have been studied in bladder cancer patients. Methods: The expression of XIAP and XAF1 mRNA was analyzed by a real time quantitative fluorogenic PCR method in a group of 17 patients with locally advanced bladder cancer treated with a combination of neoadjuvant Gemcitabine and Cisplatin. The prognostic significance of XIAP and XAF1 mRNA expression and the correlation with several clinicopathological variables was evaluated. Results: XIAP and XAF1 mRNA expression was detected in all 17 (100%) case samples. The levels of XIAP mRNA expression showed a moderate variation among samples. In contrast, XAF1 and XIAP/XAF1 mRNA levels showed significant variation among samples. Bivariate correlation analyses revealed a significant positive Spearman direct correlation coefficient between the XIAP expression and the pathological response. No significant correlation was found for XAF1 expression as well as for the XIAP/XAF1 ratio and clinical and pathological response. Conclusions: This is first study to address the role of XIAP, its negative regulator XAF1, and the XIAP/XAF1 ratio in bladder cancer patients. The positive correlation between the XIAP mRNA expression and the pathological response is in line with a previous study from our group in which a correlation was found between XIAP expression and survival. All these observations point to a complex role of XIAP in tumor biology. XAF1 mRNA expression in bladder carcinomas did not achieve significance as an independent predictive and prognostic factor in a bivariate analysis. Further studies are necessary in order to better assess a possible clinical value for XIAP and XAF1 as predictive and prognostic markers in cancer patients. No significant financial relationships to disclose.