tbuckley/cabot-search huggingface dataset:
A phase II study of the c-Met inhibitor tivantinib (tiv) in combination with FOLFOX for the treatment of patients (pts) with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach.
Authors: Shubham Pant, Manish R. Patel, Carla Kurkjian, Michael Brian Hemphill, Maria Regina C. Flores, Dana Shelton Thompson, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2015)

4065 Background: C-Met protein is a receptor tyrosine kinase that is amplified in gastric and esophageal cancers causing downstream activation of multiple signaling pathways. Tivantinib is an orally bioavailable c-met inhibitor. This phase II study evaluated the response rate (RR) of the combination of tiv plus FOLFOX as treatment for pts with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach. Methods: Pts with advanced GE cancer received standard mFOLFOX6 day 1 and tiv (360mg PO BID) days 1-14 of each 2-week cycle. Restaging occurred every 4 cycles. The primary endpoint was RR. Secondary endpoints included progression-free survival (PFS), time to progression (TTP), overall survival (OS), and safety. Results: Thirty-four pts were enrolled: median age 65 yrs (range, 34-88), 76% male, 53% KPS 90. Forty-seven percent of pts underwent prior surgery, 32% received prior radiation, and 15% received prior systemic treatment. Two pts did not receive treatment due to patient request and anemia prior to cycle 1 day 1. 32 pts were treated for a median of 8 cycles (range, 1-38). Treatment-related toxicities (% G1/2; % G3/4) included neutropenia (9%; 53%), fatigue (47%; 9%), diarrhea (41%; 9%), nausea (44%; 0), and peripheral neuropathy (44%; 0). Of the 26 pts evaluable for response, 10 pts (38%) achieved objective response (1 CR, 9 PRs), with a best response of stable disease noted in 13 pts (50%). The overall RR was 29%. Median PFS was 6.1 months (95% CI: 3.6-8) with a median TTP of 6.1 months (95% CI: 5.2-11.5). Median OS was 9.6 months (95% CI: 7.2-NA). Three pts remain on study and have been on treatment for a median of 16 months (range, 14-19). Their best response was PR (2) and SD (1). One of these pts was met high by IHC. Met status by FISH is unknown at this time. Conclusions: The combination treatment of tiv plus mFOLFOX6 in pts with advanced GE cancer showed a RR and PFS in the range of historical controls for first-line FOLFOX therapy. However, 3 pts had extended time on study treatment, and these pts may represent pts with met-driven tumors. Clinical trial information: NCT01611857.
Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study
Authors: Karl Heinz Weiss, Frederick K Askari, Anna Czlonkowska, Peter Ferenci, Jeff M Bronstein, Danny Bega, Aftab Ala, David Nicholl, Susan Flint, Lars Olsson, Thomas Plitz, Carl Bjartmar, Michael L Schilsky
Journal: The Lancet. Gastroenterology & hepatology (2017)
Surveillance of anti-tuberculosis drug resistance in Europe, 1999
Authors: A Infuso, D Antoine, P Barboza, D Falzon
Journal: Eurosurveillance (2002)

With the exception of Israel, representative data from Western and Central Europe indicate consistently low levels of resistance to isoniazid (0-9,3%) or rifampicin (0-2,1%) and of multidrug resistance (0-2,1%) among new tuberculosis (TB) cases. Resistance is more frequent among previously treated cases, but comparisons of data should be done cautiously, as criteria for inclusion in TB notifications may vary across countries. In Western Europe, drug resistance is more frequent among cases of foreign origin, a group with high TB incidence. In 1999, cases of foreign origin accounted for over 90% of the MDR cases in the West, and for all MDR cases notified in Israel. The majority of foreign born cases notified originated from Africa or Asia. In the East, representative data from the Baltic States show that overall, 15% of TB cases notified in 1999 were MDR, among the highest proportion worldwide and indicating inadequacies in previous treatment programmes. In the other countries of the former Soviet Union, non-representative data show high levels of resistance which, along with data from the Baltic states and results of surveys, are very alarming.
NKG2D Gene Polymorphism Is Associated with Disease Control of Chronic Myeloid Leukemia By Dasatinib
Authors: Ryujiro Hara, Makoto Onizuka, Erika Matsusita, Eri Kikkawa, Yoshihiko Nakamura, Daisuke Ogiya, Hiromichi Murayama, Ken Omachi, Yukari Shirasugi, Yoshiaki Ogawa, Hiroshi Kawada, Kiyoshi Ando
Journal: Blood (2016)
Inhibition of CK2 by CX4945 to induce autophagy-mediated cell death through dephosphorylating acetyl-CoA carboxylase in squamous cell carcinoma of head and neck cancer.
Authors: Ying-Wen Su, Jun-Jia Cheng, Wen-Yu Huang, Yi-Fang Chang
Journal: Journal of Clinical Oncology (2017)

e17503 Background: Accumulating evidence has shown that overexpression of casein kinase 2 (CK2) in patients with squamous cell carcinoma of head and neck (SCCHN) correlates with worsened survival. Strong expression of phosphorylated acetyl CoA carboxylase (pACC) was found to be an independent prognostic marker for patients with node-positive SCCHN. Computational analysis showed that ACC was a potential substrate for CK2, and CK2 inhibition can suppress ACC phosphorylation in non-cancer cells. CX-4945, also known as silmitasertib, is an orally administered, highly specific, ATP-competitive inhibitor of CK2 and is under clinical investigation for treating malignancies. Methods: We investigated the anticancer activity of CX-4945 in 3 aggressive SCCHN cell lines. Autophagy induction and interference with cellular metabolism were characterized. Results: CX-4945 induced autophagic cell death in SCCHN cells. CX-4945 treatment caused time- and dose-dependent lipid droplet accumulation, inhibition of ACC phosphorylation, depressed cellular levels of acetyl Co-A, and severely suppressed mitochondrial respiration, without altering the expression of stress-related proteins in the endoplasmic reticulum. Conclusions: The findings demonstrated that inhibition of CK2 by CX-4945 contributed to deranged cellular energy metabolism in SCCHN cells, leading to autophagy-mediated programmed cell death. CX-4945 targeting to CK2 may be a promising therapeutic strategy against SCCHN cancer.
Lung Cancer Screening and Smoking Cessation Clinical Trials. SCALE (Smoking Cessation within the Context of Lung Cancer Screening) Collaboration
Authors: Anne M. Joseph, Alexander J. Rothman, Daniel Almirall, Abbie Begnaud, Caroline Chiles, Paul M. Cinciripini, Steven S. Fu, Amanda L. Graham, Bruce R. Lindgren, Anne C. Melzer, Jamie S. Ostroff, Elizabeth L. Seaman, Kathryn L. Taylor, Benjamin A. Toll, Steven B. Zeliadt, David M. Vock
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

National recommendations for lung cancer screening for former and current smokers aged 55-80 years with a 30-pack-year smoking history create demand to implement efficient and effective systems to offer smoking cessation on a large scale. These older, high-risk smokers differ from participants in past clinical trials of behavioral and pharmacologic interventions for tobacco dependence. There is a gap in knowledge about how best to design systems to extend reach and treatments to maximize smoking cessation in the context of lung cancer screening. Eight clinical trials, seven funded by the National Cancer Institute and one by the Veterans Health Administration, address this gap and form the SCALE (Smoking Cessation within the Context of Lung Cancer Screening) collaboration. This paper describes methodological issues related to the design of these clinical trials: clinical workflow, participant eligibility criteria, screening indication (baseline or annual repeat screen), assessment content, interest in stopping smoking, and treatment delivery method and dose, all of which will affect tobacco treatment outcomes. Tobacco interventions consider the "teachable moment" offered by lung cancer screening, how to incorporate positive and negative screening results, and coordination of smoking cessation treatment with clinical events associated with lung cancer screening. Unique data elements, such as perceived risk of lung cancer and costs of tobacco treatment, are of interest. Lung cancer screening presents a new and promising opportunity to reduce morbidity and mortality resulting from lung cancer that can be amplified by effective smoking cessation treatment. SCALE teamwork and collaboration promise to maximize knowledge gained from the clinical trials.
Targeted Sequencing of Diagnostic Samples Correlated to Clinical Outcome: Data from the Nordic Mantle Cell Lymphoma (MCL2 and MCL3) Studies with Long-Term Follow-up
Authors: Christian Winther Eskelund, Jakob W Hansen, Maj Karoline Westman, Catja Freiburghaus, Sara Ek, Lone B Pedersen, Mette K Andersen, Riikka Räty, Arne Kolstad, Mats Jerkeman, Peter de Nully Brown, Christian H Geisler, Kirsten Groenbaek
Journal: Blood (2016)
Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy
Authors: Liad Hinden, Shiran Udi, Adi Drori, Asaad Gammal, Alina Nemirovski, Rivka Hadar, Saja Baraghithy, Anna Permyakova, Matan Geron, Merav Cohen, Sabina Tsytkin-Kirschenzweig, Yael Riahi, Gil Leibowitz, Yaakov Nahmias, Avi Priel, Joseph Tam
Journal: Journal of the American Society of Nephrology (2017)

Export Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.
Sorveglianza sentinella dell'infezione da HIV in strutture di screening per l'HIV in Spagna, 1992-2002
Authors: A Barrasa, J Castilla, J del Romero, I Pueyo, C de Armas, J A Varela, J M Ureña, F J Bru, J R Ordoñana, L M Sáez de Vicuña
Journal: Eurosurveillance (2004)

In Spagna, l'infezione da HIV e stata stimata a partire delle persone che hanno subito, tra il 1992 e il 2002, un test volontario di screening per l'HIV in 10 cliniche sentinella. Sono state incluse solo le persone per le quali si trattava del pri
The role of FDG-PET/CT in detecting bone marrow involvement in diffuse large b-cell lymphoma
Authors: A. Bulbul, E.A. Mino, S. Chouial, A. Bautista, A. Mustafa, H. Abboud, S. Rashad, T. Braik, K. Masoud
Journal: Annals of Oncology (2017)
OlympiA: A randomized phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer (BC) and a germline BRCA1/2 mutation (gBRCAm)
Authors: A. Tutt, B. Kaufman, J. Garber, R. Gelber, E. McFadden, C. Goessl, G. Viale, C. Geyer, D. Zardavas, A. Arahmani, D. Fumagalli, E. De Azambuja, N. Ponde, P. Herbolsheimer, W. Wu, J. Constantino, P. Rastogi
Journal: Annals of Oncology (2017)
Impact of the duration of diabetes mellitus (DM) on the outcomes of metastatic pancreatic cancer (mPC) treated with gemcitabine (G): A retrospective study
Authors: K. Ohashi, S. Iizumi, A. Kuchiba, M. Ikeda, Y. Sakamoto, S. Kondo, C. Morizane, H. Ueno, K. Osame, S. Mitsunaga, I. Ohno, H. Imaoka, Y. Hashimoto, H. Takahashi, M. Sasaki, T. Okusaka
Journal: Annals of Oncology (2017)
Donaciones de sangre y productos sanguíneos en Alemania en 2000-2002 : el riesgo de transmisión vírica y el impacto de la prueba de ácidos nucleicos (NAT)
Authors: Ruth Offergeld, D Faensen, S Ritter, O Hamouda
Journal: Eurosurveillance (2005)

En Alemania, las donaciones de sangre y de plasma son recogidas por varios organismos, que son: la Cruz Roja alemana, los servicios de transfusion publicos y hospitalarios, los centros de transfusion privados, los establecimientos comerciales de hemodonaciones y los servicios de transfusion del ejercito. Cada trimestre, los centros de transfusion deben declarar al Instituto Robert Koch los datos sobre los marcadores de infecciones para que se disponga de datos epidemiologicos detallados y actualizados. La prevalencia y la incidencia de infecciones viricas importantes son bajas en la poblacion de donantes de sangre en Alemania, con una tendencia decreciente desde 1997 para las infecciones de la hepatitis C, tanto en donantes repetidores como en los nuevos donantes. El implemento del NAT para el virus de la hepatitis C (VHC), obligatorio desde 1999, mejoro considerablemente la seguridad de los hemoderivados. Para el VIH, el NAT es obligatorio desde 2004, aunque ya se usaba de forma voluntaria en la mayoria de los servicios de transfusion sanguinea. La ventaja potencial del NAT en minipool no es evidente para el virus de la hepatitis B (VHB), pues los portadores cronicos con muy baja carga viral podrian donar sangre sin ser identificados. El riesgo residual de infeccion durante el periodo ventana de una donacion que formara parte de un lote de sangre, se puede estimar con la formula matematica siguiente: Tasa de incidencia multiplicada por el numero de dias durante los cuales la infeccion puede estar presente pero no detectable, o sea la duracion del periodo ventana serologico. En 2001-2002, sin NAT, se estimaba el riesgo de una infeccion no detectada en 1 por 2.770.000 para el VIH, 1 por 670.000 para el VHC y 1 por 230.000 para el VHB. Con NAT en minipool, este riesgo representa 1 por 5.540.000 para el VIH, 1 por 4.400.000 para el VHC y 1 por 620.000 para el VHB. Estos resultados muestran que la utilizacion del NAT reduce todavia mas el riesgo de entrada de donaciones infecciosas en el suministro sanguineo, ya de por si muy bajo.
Association between systemic inflammation and symptoms in advanced cancer patients
Authors: D. Viñal Lozano, A. Alonso-Babarro, Y. Vilches-Aguirre, L. Diez-Porres, M. Varela-Cerdeira, J. Villamayor Sanchez, L. Gutierrez Sainz, R. Madero-Jarabo
Journal: Annals of Oncology (2017)
Death and Cardiac Arrest in U.S. Triathlon Participants, 1985 to 2016
Authors: Kevin M. Harris, Lawrence L. Creswell, Tammy S. Haas, Taylor Thomas, Monica Tung, Erin Isaacson, Ross F. Garberich, Barry J. Maron
Journal: Annals of Internal Medicine (2017)

Background: Reports of race-related triathlon fatalities have raised questions regarding athlete safety. Objective: To describe death and cardiac arrest among triathlon participants. Design: Case series. Setting: United States. Participants: Participants in U.S. triathlon races from 1985 to 2016. Measurements: Data on deaths and cardiac arrests were assembled from such sources as the U.S. National Registry of Sudden Death in Athletes (which uses news media, Internet searches, LexisNexis archival databases, and news clipping services) and USA Triathlon (USAT) records. Incidence of death or cardiac arrest in USAT-sanctioned races from 2006 to 2016 was calculated. Results: A total of 135 sudden deaths, resuscitated cardiac arrests, and trauma-related deaths were compiled; mean (±SE) age of victims was 46.7 ± 12.4 years, and 85% were male. Most sudden deaths and cardiac arrests occurred in the swim segment (n = 90); the others occurred during bicycling (n = 7), running (n = 15), and postrace recovery (n = 8). Fifteen trauma-related deaths occurred during the bike segment. Incidence of death or cardiac arrest among USAT participants (n = 4 776 443) was 1.74 per 100 000 (2.40 in men and 0.74 in women per 100 000; P < 0.001). In men, risk increased substantially with age and was much greater for those aged 60 years and older (18.6 per 100 000 participants). Death or cardiac arrest risk was similar for short, intermediate, and long races (1.61 vs. 1.41 vs. 1.92 per 100 000 participants). At autopsy, 27 of 61 decedents (44%) had clinically relevant cardiovascular abnormalities, most frequently atherosclerotic coronary disease or cardiomyopathy. Limitations: Case identification may be incomplete and may underestimate events, particularly in the early study period. In addition, prerace medical history is unknown in most cases. Conclusion: Deaths and cardiac arrests during the triathlon are not rare; most have occurred in middle-aged and older men. Most sudden deaths in triathletes happened during the swim segment, and clinically silent cardiovascular disease was present in an unexpected proportion of decedents. Primary Funding Source: Minneapolis Heart Institute Foundation.
10 years follow up of the RASTER study; implementing a genomic signature in daily practice
Authors: S.B. Vliek, V. Retel, C. Drukker, E. Rutgers, H. van Tinteren, M.J. van de Vijver, J.M. Bueno-De-Mesquita, J. Wesseling, W. van Harten, S.C. Linn
Journal: Annals of Oncology (2017)
Biomarker prediction of efficacy to vandetanib plus gemcitabine in a phase II double blind multicenter randomized placebo-controlled trial in locally advanced or metastatic pancreatic carcinoma.
Authors: John P. Neoptolemos, Daniel Palmer, William Greenhalf, Paula Ghaneh, Richard Jackson, Anthony Evans, Victoria Shaw, Jonathan Wadsley, Juan W. Valle, Harpreet Wasan, Stephen Falk, David Cunningham, Fareeda Y. Coxon, Paul J. Ross, Nick Wadd, Tamas Hickish, Eithne Costello, Fiona Campbell, Charlotte Rawcliffe, Gary William Middleton
Journal: Journal of Clinical Oncology (2017)

4104 Background: We investigated the potential of biomarkers to predict efficacy of vandetanib and gemcitabine in patients with locally advanced (N = 41) or metastatic (N = 101) pancreatic cancer in a phase II double-blind multicentre randomised placebo-controlled trial. Methods: All patients were 18y or above, (ECOG = 0-2), with at least 3 mths life expectancy had gemcitabine (1000mg/m 2 30min iv wkly for 7 wks, followed by a 1wk break, then cycles of wkly treatment for 3wks with a 1-wk break) and randomly assigned to 300mg/d vandetanib or placebo once daily until disease progression. The primary outcome was overall survival (OS) by intention to treat. A panel of potential biomarkers was tested to predict best survival with vandetanib and gemcitabine. Results: 142 patients were randomised, median FU = 24·9 mths with 131 deaths. The median (95% CI) OS in the 70 gemcitabine-placebo patients was 8·95 (6·55-11·7) mths and 8·83 (7·11-11·6) mths in the 72 gemcitabine-vandetanib patients (HR = 1·21, 95% CI = 0·85, 1·73; log rank X 2 1df = 1·1; P = 0·303). A CTCAE V.4.02 rash grade 2 or above occurred in 4 (6 %) of 70 placebo patients versus 14 (19%) of 72 vandetanib patients. The median OS for the 14 vandetanib patients and with rash was 11·92 (10·89 – NA) mths, 7·76 (4·34 – 11·5) mths for the 58 vandetanib patients and without rash and 8·95 (6·55 – 11·7) mths for the gemcitabine-placebo patients (log rank Χ 2 2df = 7·23; P = 0·03). We identified two biomarkers that could select patients for response to vandetanib (JN101, JN102). The biomarker combination was present in 26 patients with median OS of 12.1 (10.9, 16.0) mths versus 8.15 (6.67, 11.7) mths for 23 patients with the same biomarker profile in the placebo group (HR = 0.53 [0.29, 0.97], p = 0.0396). A logistic regression model showed that patients with JN102 were more likely to develop a rash (OR =0.81 [0.713, 0.925] p = 0.002). Conclusions: A two biomarker combination and a rash grade 2 or above may predict response to vandetanib and gemcitabine. This requires prospective evaluation. Clinical trial information: 96397434.
First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G.
Authors: Vassiliki Papadimitrakopoulou, Shirish M. Gadgeel, Hossein Borghaei, Leena Gandhi, Amita Patnaik, Steven Francis Powell, Ryan D. Gentzler, Renato G. Martins, James Stevenson, Shadia Ibrahim Jalal, Amit W. Panwalkar, James Chih-Hsin Yang, Matthew A. Gubens, Lecia V. Sequist, Mark M. Awad, Joseph Fiore, Joy Yang Ge, Harry Raftopoulos, Corey J. Langer
Journal: Journal of Clinical Oncology (2017)

9094 Background: Data from the randomized, phase 2 cohort G of KEYNOTE-021 (NCT02039674) showed that adding pembro to first-line CP in patients (pts) with advanced nonsquamous NSCLC significantly improved the primary end point of ORR (55% vs 29%, P = 0.0016) and the key secondary end point of PFS (HR 0.53, P= 0.0102) compared with CP alone and had a manageable safety profile (grade 3-4 treatment-related AEs, 39% vs 26%; treatment-related AEs leading to discontinuation, 10% vs 13%). We present updated efficacy for cohort G based on 5 mo additional follow-up. Methods: 123 pts with stage IIIB/IV, chemotherapy-naive, nonsquamous NSCLC and no EGFR mutation or ALK translocation were randomized to 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m 2 Q3W ± 24 mo of pembro 200 mg Q3W; maintenance pemetrexed was permitted in both arms. Eligible pts in the CP arm who had radiologic progression could crossover to pembro monotherapy. Response was assessed per RECIST v1.1 by blinded, independent central review. All Pvalues are nominal. Results: As of Dec 31, 2016, median follow-up was 14.5 mo (range, 0.8-24.0). 36 of 48 pts (75.0%) in the CP arm who discontinued CP received subsequent anti–PD-1 or PD-L1 therapy. There was 1 additional response in each arm, and ORR was 56.7% (95% CI 43.2%-69.4%) with pembro + CP vs 30.2% (95% CI 19.2%-43.0%) with CP ( P = 0.0016). Median DOR was not reached for pembro + CP (range, 1.4+ to 18.6+ mo) and was 16.2 mo (range, 2.8 to 20.7+) for CP alone. PFS remained longer with pembro + CP (HR 0.49, 95% CI 0.29-0.83, P = 0.0035; median [95% CI] NR [9.7 mo-NR] vs 8.9 mo [6.2-10.3]; 12-mo estimate, 56% vs 34%). With 16 deaths in the pembro + CP arm and 23 deaths in the CP arm, HR for OS was 0.69 (95% CI 0.36-1.31, P= 0.13). Median OS was not reached in either arm; at 12 mo, estimated OS was 76% in the pembro + CP arm and 69% in the CP alone arm. Conclusions: With 5 mo additional follow-up, first-line pembro + CP continues to provide a substantial, clinically relevant improvement in efficacy over CP alone in pts with advanced nonquamous NSCLC, including an almost doubled ORR, halved risk of progression or death, and a trend toward improved OS despite a 75.0% crossover rate in the CP arm. Clinical trial information: NCT02039674.
FOXFIRE-SIRFLOX-FOXFIRE global prospective randomised studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer: KRAS mutation and tumour site analysis
Authors: H. Wasan, R. Sharma, V. Heinemann, N. Sharma, J. Taieb, J. Ricke, M. Peeters, M. Findlay, P.S. Virdee, S. Love, J. Moschandreas, P. Dutton, V. Gebski, A.M. Gray, D. Price, G. Bower, A. Montazeri, P. Gibbs, G. Van Hazel
Journal: Annals of Oncology (2017)
Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming
Authors: Martin Vaeth, Mate Maus, Stefan Klein-Hessling, Elizaveta Freinkman, Jun Yang, Miriam Eckstein, Scott Cameron, Stuart E. Turvey, Edgar Serfling, Friederike Berberich-Siebelt, Richard Possemato, Stefan Feske
Journal: Immunity (2017)