tbuckley/cabot-search huggingface dataset:
Abstract 169: c-fos and Caspase 8 Mediate Palmitate-induced Cardiomyocyte Apoptosis
Authors: Charles C Oh, Michael Nguy, D’Souza Karen, Raymond Migrino, Dawn Schwenke, Kent Thornburg, Peter Reaven
Journal: Circulation Research (2015)

Background: We previously demonstrated that p38α activation mediates palmitate (PA)-induced cardiomyocyte apoptosis, and that specific p38α siRNA markedly and dose-dependently attenuates apoptosis rates in the presence of PA. We tested the hypothesis that c-fos and caspase 8 would be up-regulated concurrently with p38a. Methods and Results: Immortalized human adult ventricular cardiomyocytes ( AC16 cells) were exposed to high physiological levels of PA. The p38α-dependent pathway was evaluated using p38α siRNA knockdown. PA dose-dependently increased transcription of an AP-1 factor, c-fos, in AC16 cardiomyocytes (control:0.34±0.11, 150 μM PA:0.83±0.19, 300 μM PA:1.58±0.45, n=5, p&lt;0.05). c-fos protein expression increased dose-dependently with PA treatment (control:0±0%, 150 μM PA:26%±28%, 300 μM PA:258%±103%, n=4, p&lt;0.05). Phospho-c-fos levels increased dose-dependently as well (control:0±0%, 150 μM PA:73%±41%, 300 μM PA:302%±62%, n=4, p&lt;0.05). Transcription of a putative downstream effector, caspase 8, also increased (control:0.94±0.10, 150 μM PA:1.40±0.10, 300 μM PA:1.42±0.11, n=3, p&lt;0.05) but protein levels did not. p38α knockdown dose-dependently blocked the PA-induced increase in phospho-c-fos protein level (control siRNA:0±0%, 300 μM PA:206±47%, 300 μM PA+30 pmol siRNA:98±31%, 300 μM PA+60 pmol siRNA:58±40%, 300 μM PA+120 pmol siRNA:-21±19%, n=4, p&lt;0.05), without a clear reduction in total c-fos. Interestingly, caspase 8 level was also dose-dependently reduced by p38α knockdown (control siRNA:0±0%, 300 μM PA:-25±3%, 300 μM PA+30 pmol p38α siRNA:-38±13%, 300 μM PA+60 pmol p38α siRNA:-54±7%, 300 μM PA+120 pmol p38α siRNA:-46±11%, n=3, p&lt;0.05). Conclusions: This study in cardiomyocytes demonstrated that 1) PA dose-dependently increases gene expression of c-fos and protein levels of total c-fos and phospho-c-fos, 2) PA increases transcription of caspase 8, and 3) reduced p38α expression dose-dependently attenuates PA-induced increases in c-fos and phospho-c-fos protein levels, and decreases caspase 8. Our results suggest that p38α activated by PA up-regulates the downstream transcription factor, c-fos, and maintains caspase 8 level. These molecules may underlie PA-induced cardiomyocyte apoptosis.
Optimization of IA Regimen with Homoharringtonine for Induction in Younger AML Based on Peripheral Blast Clearance Rate: First Result of the RJ-AML 2014 Trial
Authors: Junmin Li, Yunxiang Zhang, Qiusheng Chen, Zhao Liu, Chen Yu, Jiong Hu, Xiangqin Weng, Bing Chen, Saijuan Chen, Zhu Chen
Journal: Blood (2016)
Serum metabolomics as biomarkers to differentiate early from metastatic disease and predict relapse in elderly colorectal cancer (CRC) patients.
Authors: Anna Rachelle Austria Mislang, Alessia Vignoli, Samantha Di Donato, Chiara Biagioni, Stefania Vitale, Christopher David Hart, Elena Mori, Dimitri Becheri, Francesca Del Monte, Claudio Luchinat, Angelo Di Leo, Giuseppe Mottino, Leonardo Tenori, Laura Biganzoli
Journal: Journal of Clinical Oncology (2016)

10042 Background: Adjuvant chemotherapy improves survival in stage II and III CRC, although a significant proportion of patients (pts) are cured by surgery alone. Improved risk stratification is required to reduce the number of pts treated unnecessarily, particularly in elderly populations at risk for higher toxicity. Serum metabolomic profiles may act as biomarkers of residual (micrometastatic) disease, a prerequisite for relapse, and have been prognostic in other tumor types. This study aims to (1) identify in elderly pts a metabolomic “signature” for metastatic disease (mCRC) that differentiates it from early disease (eCRC) and (2) create a metabolomic index for eCRC pts that correlates with clinical outcomes and may be predictive for relapse. Methods: Serum samples from 105 elderly pts (aged ≥ 70) with CRC, (48 mCRC and 57 eCRC with ≥ 5 years follow up) were pooled from 4 previous clinical trials. Samples were analyzed via Proton Nuclear Magnetic Resonance (NMR) and the spectra were used to characterize the metabolic profiles of the two cohorts. Principal component analysis (PCA) and canonical analysis (CA) were applied to obtain the supervised separation of eCRC and mCRC spectra. For the purpose of classification, the K-nearest neighbors (k-NN) method was applied to the PCA-CA scores. Wilcoxon test was then used to compare the levels of 34 quantified metabolites between eCRC and mCRC pts. A model that assigns a risk score is being built based on the degree to which an eCRC serum profile resembles the metastatic profiles. This risk score will be compared to the Adjuvant!Online estimated risk of relapse score and the actual outcome. Results: PCA-CA-kNN classification of NMR spectra was able to discriminate eCRC and mCRC with an accuracy of 74%. Four metabolites (2-methylbutyrate, 2-methylsuccinate, histidine and formate) were found to differ significantly (p < 0.05) between eCRC and mCRC metabolomic profiles. Conclusions: NMR metabolomic profiles can discriminate early and metastatic CRC. A model to assess the likelihood of relapse, based on the degree to which an eCRC serum profile resembles the metastatic profiles, is being built, and results will be presented at the meeting.
一時的血管閉塞のための生体吸収性放射線不透過性水応答性形状記憶塞栓術プラグ【Powered by NICT】
Authors: Wong Yee Shan, Salvekar Abhijit Vijay, Zhuang Kun Da, Liu Hui, R Birch William, Tay Kiang Hiong, Huang Wei Min, S Venkatraman Subbu
Journal: Biomaterials (2016)
Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)
Authors: Harjit Dadi, Tyler A. Jones, Daniele Merico, Nigel Sharfe, Adi Ovadia, Yael Schejter, Brenda Reid, Mark Sun, Linda Vong, Adelle Atkinson, Sasson Lavi, Joel L. Pomerantz, Chaim M. Roifman
Journal: Journal of Allergy and Clinical Immunology (2017)
Activated CD4+ T cells as radiosensitizer: enhancement of irradiation-induced cytotoxicity by pretreatment of tumor cell with activated CD4+ T cells
Authors: Yixiang Wang, Soroosh Radfar, Hung khong
Journal: Cancer Research (2007)

3116   Background: Radiotherapy is one of the standard modalities for the treatment of cancer. Irradiation causes not only tumor cell death, but also can up-regulate tumor antigen and MHC class I molecule expression, thereby promoting the accumulation and activation of immune cells in tumor tissue. We hypothesize that activated CD4+ T cells (aCD4) can presensitize tumor cells and enhance gamma-irradiation -induced cytotoxicity. The rationale is that aCD4 release multiple cytokines, which may regulate gene-expression in tumor cells, thereby affecting their proliferation and apoptosis. Methods: Human cervical carcinoma cell line Hela was  used as our initial tumor model. Hela cells were irradiated with 4 Gy after presensitization with aCD4 for 48 hours. The cells were cultured for 2 or 5 more days for apoptosis and cell proliferation assays, respectively. Transwell system was used to determine whether cell contact, soluble factors released by aCD4, or both were essential in this model. Several cytokines including IFN- γ were used to replace aCD4 to determine the contribution of each cytokine. Other cancer cell lines used  to validate the strategy included cervical carcinoma cell line Caski, glioma cell lines LN229 and U373, and prostate carcinoma cell line DU145. Results: For Hela cells, growth inhibition was 25.8 ±3.3% in group treated with irradiation alone, 31.5±11.3% in group treated with aCD4 alone, and 60.5±1.3% in the combination group; while the percentage of apoptotic cells as determined by flow cytometry assay using Annexin V was 7.15±0.6%, 9.25±0.4% and 15.65±4.6%, respectively. Similar results were also obtained with other cancer cell lines. For example, for DU145, cell growth inhibition was 35.4±4.0 % in group treated with irradiation alone, 32.65±2.7% in group treated with aCD4 alone, and 70.3±0.14% in the combination group. This effect was aCD4 and irradiation dose dependent. Transwell experiments showed that soluble factors secreted by aCD4 were responsible for the observed activity.  Of the cytokines tested, IFN-γ was found to play major role in our model. Growth inhibition was 10.15±1.0% in group treated with IFN- γ alone and 57.03±1.9% in the IFN- γ and gamma-irradiation combination group. Conclusion: We have demonstrated that aCD4 can act as a radiosensitizer to enhance the cytotoxic effect of gamma irradiation in multiple cancer cell lines. Soluble factors released by aCD4 were essential in this effect. IFN- γ was found to play a major role. We are currently working on the mechanism underlying the observed activity. In a separate project, we have also demonstrated great synergism when chemotherapy was given after tumor cells had been presensitized with activated immune cells.
複合高分子クルクミン共役と上衣前駆/幹細胞治療は脊髄損傷の機能的回復を増強する【Powered by NICT】
Authors: Requejo-Aguilar Raquel, Alastrue-Agudo Ana, Cases-Villar Marta, Lopez-Mocholi Eric, England Richard, J Vicent Maria, Moreno-Manzano Victoria
Journal: Biomaterials (2017)
C13orf31(FAMIN)は免疫代謝機能の中心的調節因子である
Authors: Cader M Zaeem, Boroviak Katharina, Zhang Qifeng, Assadi Ghazaleh, Kempster Sarah L, Sewell Gavin W, Saveljeva Svetlana, Ashcroft Jonathan W, Clare Simon, Mukhopadhyay Subhankar, Brown Karen P, Tschurtschenthaler Markus, Raine Tim, Doe Brendan, Chilvers Edwin R, Griffin Jules L, Kaneider Nicole C, Floto R Andres, D’Amato Mauro, Bradley Allan, Wakelam Michael J O, Dougan Gordon, Kaser Arthur
Journal: Nature Immunology (2016)
Comment on Young-Hyman et al. Psychosocial Care for People With Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016;39:2126–2140
Authors: Gemma C. Macdonald, Lesley V. Campbell
Journal: Diabetes Care (2017)

Articles in the December 2016 issue of Diabetes Care addressing psychosocial issues are important for diabetes care (1). Our recent comment in The Lancet also addresses the “forgotten burden” of mental illness in diabetes (2). We highlight our concerns below.

Although the recommendations of the American Diabetes Association (ADA) (3) are based on “patient-centered care” (now becoming cliche), we have yet to see this model in action, despite extensive publication about it over past decades. Many well-intentioned care providers, believing they already practice “patient-centered care,” continue to increase the patient’s anxiety and guilt by implying blame for above-target glycemic control and emphasizing the patient’s risk of complications because of “noncompliance.” We are concerned that these traditional attitudes, ingrained …
合衆国におけるバルーン肺動脈形成術(BPA)の初期経験:U.S.大規模肺動脈血栓内膜摘除術(PTE)単一施設における経験
Authors: S Poch David, Mahmud Ehtisham, Patel Mitul, M Madani Michael, H Kim Nick
Journal: Circulation (2016)
A marker-driven phase II trial of neoadjuvant chemotherapy in locally advanced colon cancer.
Authors: Anders Kristian Moeller Jakobsen, Fahimeh Andersen, Anders Fischer, Lars Henrik Jensen, Jens Christian Riis Joergensen, Ole Larsen, Jan Lindebjerg, John Ploeen, Soeren Rafael Rafaelsen, Jesper Vilandt
Journal: Journal of Clinical Oncology (2014)

3621 Background: The treatment of locally advanced colon cancer faces many challenges and new approaches are needed. Neoadjuvant chemotherapy has proven valuable in several tumors, but it has not been elucidated in colon cancer. One major reason has been the lack of validated methods for selection, but recent improvement in CT scanning has allowed for identification of high-risk patients in need of adjuvant chemotherapy. Methods: Patients with resectable colon cancer fulfilling the following criteria were offered inclusion; Histopathological verification of adenocarcinoma, T3 tumor on CT scan with extramural tumor invasion > 5 mm or T4 tumor, age ≥ 18 years, PS ≤ 2, adequate hematology, and informed consent. Patients with KRAS, BRAF, or PIK3CA mutation or unknown mutational status received 3 cycles of capecitabine 2000 mg/m2days 1-14 q3w and oxaliplatin 130 mg iv day 1 q3w. Wildtype patients received the same chemotherapy supplemented with panitumumab 9 mg/kg iv q3w. After the operation, patients fulfilling the international criteria for adjuvant chemotherapy received 5 cycles of the same chemotherapy without panitumumab. Patients not fulfilling the criteria (converted patients) were offered follow-up only. The primary endpoint was the fraction of converted patients. Secondary endpoints were 2-year disease free survival (DFS) and toxicity. The study was approved by the Regional Scientific Ethical Committee (S-20100014) and registered at ClinicalTrials.gov (NCT01918527). Results: The study included 77 patients. The conversion rate was 42% in the wildtype group compared to 51% in patients with a mutation. The objective response rate by CT scan was 45%. Three patients had complete pathological remission. The cumulative recurrence rate in converted vs. non-converted patients was 3% vs. 27% (p=0.003) translating into a 2-year DFS of 96% vs. 54% (p=0.004). Toxicity was manageable and 90% received ≥ two cycles of the three planned cycles of neoadjuvant chemotherapy. Conclusions: Neoadjuvant chemotherapy in colon cancer is feasible and the results suggest that a major part of the patients can be spared adjuvant chemotherapy. A randomized trial is warranted. Clinical trial information: NCT01918527.
The report of the American Heart Association task force on strategies to increase federal research funding
Authors: M. R. Rosen, H. C. Strauss, H. G. Atkinson, A. P. Fishman, C. K. Francis, A. M. Katz, A. M. Watanabe, F. M. Abboud, M. L. Weisfeldt, W. F. Friedman, B. P. Healy, S. D. Ballin, C. Louis, R. D. Starke, W. G. Frasher
Journal: Circulation Research (1990)
Abstract 19642: Consistent Benefit of Ticagrelor Both Early and Late in Patients With Prior MI in PEGASUS-TIMI 54
Authors: Marc P Bonaca, Robert F Storey, Pierre Theroux, P. Gabriel Steg, Deepak L Bhatt, KyungAh Im, Giulia Magnani, Ton Oude Ophuis, Mikhail Ruda, Alexander Parkhomenko, Daniel Isaza, Gabriel Kamensky, Assen Goudev, Dayi Hu, Gilles Montalescot, Eva C Jensen, Peter Held, Eugene Braunwald, Marc S Sabatine
Journal: Circulation (2015)

Objectives: Ticagrelor reduced the risk of CV death, MI or stroke in stable patients with prior MI in PEGASUS-TIMI 54. We investigated the consistency of ticagrelor’s efficacy and safety over time and quantified the magnitude of benefit in patients who tolerated ticagrelor for the first year, analogous to the clinical situation of extending therapy in patients after 1 year. Methods: PEGASUS-TIMI 54 randomized pts with a prior MI (median 1.7 yrs prior to randomization) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily or placebo. The rate CVD/MI/stroke and TIMI major bleeding were analyzed for the pooled ticagrelor doses compared to placebo for the first year of observation and then as a landmark analysis beginning after the first year in all patients alive at that time point. Results: 21,162 patients were randomized and followed for a median of 33 months, with 29% of patients ≥5 yrs from their most recent MI by the end of the trial. The rate of CVD/MI/stroke in the placebo arm remained roughly constant over the trial at ∼3%/y. Ticagrelor significantly reduced CVD/MI/stroke both over the first year (HR 0.84, 95% CI 0.71-0.98, P=0.029, Figure Left) and after year one (HR 0.85, 95% CI 0.74-0.97, P=0.017, Figure Right), with the event curves continuing to diverge through the end of follow-up. TIMI Major bleeding was increased with ticagrelor within the first year (HR 3.46, 95% CI 2.07-5.77) but numerically less so after the first year (HR 2.06, 95% CI 1.43-2.96). When examining patients who successfully completed one year of treatment, continued ticagrelor significantly reduced CVD/MI/Stroke by over 20% over the following two years (HR 0.79, 95% CI 0.68-0.91). Conclusion: Patients with a history of MI remain at persistent risk for CVD/MI/Stroke over time. Ticagrelor reduces this risk during the first year as well as in the subsequent years of treatment, supporting prolonged therapy.
Transmission of yellow fever vaccine virus through breast-feeding - Brazil, 2009.
Authors: A. M. Couto, M. R. Salomão, M. T. Schermann, R. Mohrdieck, A. Suzuki, S. M. D. Carvalho, D. M. de Assis, W. N. Araújo, B. Flannery
Journal: MMWR Morbidity and Mortality Weekly Report (2010)
MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis
Authors: Jun Lu, Ming-liang Ji, Xue-jun Zhang, Pei-liang Shi, Hao Wu, Chen Wang, Hee-Jeong Im
Journal: Molecular Therapy (2017)

Emerging evidence suggests that dysregulated microRNAs (miRNAs) play a pivotal role in osteoarthritis (OA), but the role of specific miRNAs remains unclear. Accordingly, we identified OA-associated miRNAs and functional validation of results. Here, we demonstrate that miR-218-5p is significantly upregulated in moderate and severe OA and correlates with scores on a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-218-5p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28/I2 cells, PIK3C2A mRNA was identified as a target of miR-218-5p. Downregulation of miR-218-5p dramatically promoted expression of PIK3C2A and its downstream target proteins, such as Akt, mTOR, S6, and 4EBP1. More importantly, OA mice exposed to a miR-218-5p inhibitor were protected from cartilage degradation and had reduced proteoglycan loss and reduced loss of articular chondrocyte cellularity compared with control mice. miR-218-5p is a novel inducer of cartilage destruction via modulation of PI3K/Akt/mTOR signaling. Inhibition of endogenous miR-218-5p expression/activity appears to be an attractive approach to OA treatment.
Improving regional influenza surveillance through a combination of automated outbreak detection methods: the 2015/16 season in France
Authors: Camille Pelat, Isabelle Bonmarin, Marc Ruello, Anne Fouillet, Céline Caserio-Schönemann, Daniel Levy-Bruhl, Yann Le Strat
Journal: Eurosurveillance (2017)

The 2014/15 influenza epidemic caused a work overload for healthcare facilities in France. The French national public health agency announced the start of the epidemic – based on indicators aggregated at the national level – too late for many hospitals to prepare. It was therefore decided to improve the influenza alert procedure through (i) the introduction of a pre-epidemic alert level to better anticipate future outbreaks, (ii) the regionalisation of surveillance so that healthcare structures can be informed of the arrival of epidemics in their region, (iii) the standardised use of data sources and statistical methods across regions. A web application was developed to deliver statistical results of three outbreak detection methods applied to three surveillance data sources: emergency departments, emergency general practitioners and sentinel general practitioners. This application was used throughout the 2015/16 influenza season by the epidemiologists of the headquarters and regional units of the French national public health agency. It allowed them to signal the first influenza epidemic alert in week 2016-W03, in Brittany, with 11 other regions in pre-epidemic alert. This application received positive feedback from users and was pivotal for coordinating surveillance across the agency’s regional units.
秩序化した準安定DNAナノ構造の自律集合と細胞内マイクロRNAのin situ可視化【Powered by NICT】
Authors: Xu Jianguo, Wu Zai-Sheng, Wang Zhenmeng, Le Jingqing, Zheng Tingting, Jia Lee
Journal: Biomaterials (2017)
Dysfunction of the MDM2/p53 axis is linked to premature aging
Authors: Davor Lessel, Danyi Wu, Carlos Trujillo, Thomas Ramezani, Ivana Lessel, Mohammad K. Alwasiyah, Bidisha Saha, Fuki M. Hisama, Katrin Rading, Ingrid Goebel, Petra Schütz, Günter Speit, Josef Högel, Holger Thiele, Gudrun Nürnberg, Peter Nürnberg, Matthias Hammerschmidt, Yan Zhu, David R. Tong, Chen Katz, George M. Martin, Junko Oshima, Carol Prives, Christian Kubisch
Journal: Journal of Clinical Investigation (2017)

The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome. We show that this mutation abrogates MDM2 activity, thereby resulting in enhanced levels and stability of p53. Analysis of the patient's primary cells, genome-edited cells, and in vitro and in vivo analyses confirmed the MDM2 mutation's aberrant regulation of p53 activity. Functional data from a zebrafish model further demonstrated that mutant Mdm2 was unable to rescue a p53-induced apoptotic phenotype. Altogether, our findings indicate that mutant MDM2 is a likely driver of the observed segmental form of progeria.
First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors.
Authors: Ranee Mehra, D. Ross Camidge, Sunil Sharma, Enriqueta Felip, Daniel Shao-Weng Tan, Johan F. Vansteenkiste, Tommaso Martino De Pas, Dong-Wan Kim, Armando Santoro, Geoffrey Liu, Meredith Goldwasser, David Dai, Marietta Radona, Anthony Boral, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2012)

3007 Background: LDK378 is a novel, potent and selective small molecule anaplastic lymphoma kinase (ALK) inhibitor (IC 50 0.00015 μM), that does not inhibit c-MET (IC 50 3.2 μM). Tumor regression has been observed in ALK-driven NSCLC xenografts. A first-in-human, Phase I study is being conducted to determine the MTD and safety profile in patients (pts) with tumors with ALK rearrangement, amplification or mutation. Other objectives were safety, PK and antitumor activity in pts with ALK-driven NSCLC, both naïve to ALK inhibitors and relapsed following previous ALK inhibitor treatment, and other ALK-positive cancers. Methods: Adult pts with advanced malignancies harboring a genetic alteration in ALK who progressed on standard therapy or for whom there was no effective therapy, were given once daily oral LDK378 on a continuous 21-day schedule. Dose escalation, starting at 50 mg/day, was guided by a Bayesian logistic regression model (BLRM) to determine the MTD. Results: At a January 5 th 2012 cutoff,31 pts (primary site: lung 26 pts; breast 3 pts; other 2 pts; median age 52 years; 87% ECOG PS 0/1) were enrolled and received LDK378 at doses of 50–750 mg/day. Two dose limiting toxicities, Grade (Gr) 3 alanine aminotransferase elevation (1 pt), and Gr 3 hypophosphatemia (1 pt) occurred in 8 pts at a 400 mg dose level. BLRM allowed dose escalation, and there were no DLTs in 4 pts at 500 mg. Median duration of treatment with LDK378 was 7 weeks (range &lt;1–22+). At the cutoff date, 13 (42%) pts discontinued treatment: 1 (3%) due to adverse events (AEs), and 12 (39%) due to disease progression; 18 (58%) pts were still on treatment. The most frequent AEs (all Gr) were nausea (45%), vomiting (36%), and diarrhea (29%). The most frequent Gr 3/4 AEs were diarrhea and dyspnea (2 pts [7%] each). At doses ≥400 mg steady state exposures exceeded efficacious exposures in xenograft models. Of 16 pts with available response data (RECIST, per investigator) there were 4/6 responses in crizotinib (CRZ)-treated pts, and 2/10 responses in CRZ-naïve pts, of whom 7 were treated below 400 mg. All responses were in NSCLC. Conclusions: Daily oral LDK378 is well tolerated up to 500 mg/day, and escalation continues at 750 mg/day. Preliminary responses have been seen in both CRZ-naïve and CRZ-relapsed pts.