Menée in vitro, cette étude met en évidence un nouveau mécanisme par lequel les rayonnements infrarouges lointains peuvent, en supprimant la sécrétion de la clusterine, inhiber la prolifération, la migration et l'angiogenèse des cellules endothéliales de veine ombilicale humaine

Far-infrared radiation inhibits proliferation, migration, and angiogenesis of human umbilical vein endothelial cells by suppressing secretory clusterin levels

Hwang, Soojin ; Lee, Dong-Hoon ; Lee, In-Kyu ; Park, Young Mi ; Jo, Inho

Far-infrared (FIR) radiation is known to lessen the risk of angiogenesis-related diseases including cancer. Because deficiency of secretory clusterin (sCLU) has been reported to inhibit angiogenesis of endothelial cells (EC), we investigated using human umbilical vein EC (HUVEC) whether sCLU mediates the inhibitory effects of FIR radiation. Although FIR radiation ranging 3-25 μm wavelength at room temperature for 60 min did not alter EC viability, further incubation in the culture incubator (at [...]

Cet article passe en revue les nouvelles approches de radiothérapie pour traiter un cancer du poumon non à petites cellules de stade localement avancé

New radiotherapy approaches in locally advanced non-small cell lung cancer

Christodoulou, Marianna ; Bayman, Neil ; McCloskey, Paula ; Rowbottom, Carl ; Faivre-Finn, Corinne

Radiotherapy plays a major role in the treatment of patients with locally advanced non-small cell lung cancer (NSCLC), particularly since most patients are not suitable for surgery due to the extent of their disease, advanced age and multiple co-morbidities. Despite advances in local and systemic therapies local control and survival remain poor and there is a sense that a therapeutic plateau has been reached with conventional approaches. Strategies for the intensification of radiotherapy such [...]

Cette étude évalue la pertinence d'un curage ganglionnaire chez les patientes atteintes d'un cancer du sein avec micro- ou macro-métastases au niveau du ganglion sentinelle (155 cas)

When is a completion axillary lymph node dissection necessary in the presence of a positive sentinel lymph node?

Suyoi, A. ; Bains, S. K. ; Kothari, A. ; Douek, M. ; Agbaje, O. ; Hamed, H. ; Fentiman, I. ; Pinder, S. ; Purushotham, A. D.

Background : The management of the axilla in the presence of positive sentinel lymph node (SLN) remains controversial. Many centres forgo completion axillary lymph node dissection (cALND) in the presence of micrometastatic disease. The American College of Surgeons Oncology Group (ACOSOG) Z0011 trialists argue for extending this to macrometastasis. The aim of this study was to correlate tumour burden in SLNs with that in the residual lymph node basin to determine the likelihood of residual [...]

A partir d'une revue systématique de la littérature publiée jusqu'en juillet 2012 (30 études, 1 121 patients), cette étude analyse l'utilisation et le rôle de la radiothérapie moléculaire à base de métaiodobenzylguanidine (131I) dans le traitement d'un neuroblastome

A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma

Wilson, Jayne S. ; Gains, Jennifer E. ; Moroz, Veronica ; Wheatley, Keith ; Gaze, Mark N.

The optimal use and effectiveness of 131I-meta iodobenzylguanidine (131I-mIBG) molecular radiotherapy for neuroblastoma remain unclear despite extensive clinical experience. This systematic review aimed to improve understanding of the current data and define uncertainties for future clinical trials. Bibliographic databases were searched for neuroblastoma and 131I-mIBG. Clinical trials and non-comparative case series of 131I-mIBG therapy for neuroblastoma were included. Two reviewers assessed [...]

Cet article passe en revue les perspectives offertes par le ciblage des canaux ioniques potassiques pour le traitement des cancers

The roles of K+ channels in cancer

Pardo, Luis A. ; Stuhmer, Walter

Potassium channels are transmembrane proteins that selectively facilitate the flow of potassium ions down an electrochemical gradient. These molecules have been studied in great detail in the context of cell excitability, but their roles in less cell type-specific functions, such as cell proliferation, angiogenesis or cell migration, have only recently been assessed. Moreover, the importance of these channels for tumour biology has become evident. This, coupled with the fact that they are [...]

Cet article passe en revue les perspectives offertes par le ciblage des éléments de la voie de signalisation Hippo pour le traitement des cancers

The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment

Johnson, Randy ; Halder, Georg

The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can [...]

Menée in vitro et in vivo, cette étude analyse les mécanismes d'action d'une immunothérapie mettant en œuvre des récepteurs d’antigènes chimériques inhibiteurs basés sur PD-1 et CTLA-4

PD-1– and CTLA-4–Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses

Fedorov, Victor D. ; Themeli, Maria ; Sadelain, Michel

T cell therapies have demonstrated long-term efficacy and curative potential for the treatment of some cancers. However, their use is limited by damage to bystander tissues, as seen in graft-versus-host disease after donor lymphocyte infusion, or “on-target, off-tumor” toxicities incurred in some engineered T cell therapies. Nonspecific immunosuppression and irreversible T cell elimination are currently the only means to control such deleterious responses, but at the cost of abrogating [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude suggère l'intérêt de l'acide gambogique, une petite molécule dérivée d'une plante (gomme-gutte du Cambodge), pour surmonter une résistance à l'imatinib dans les cellules de leucémie myéloïde chronique

Gambogic Acid Induces Apoptosis in Imatinib-Resistant Chronic Myeloid Leukemia Cells via Inducing Proteasome Inhibition and Caspase-Dependent Bcr-Abl Downregulation

Shi, Xianping ; Chen, Xin ; Li, Xiaofen ; Lan, Xiaoying ; Zhao, Chong ; Liu, Shouting ; Huang, Hongbiao ; Liu, Ningning ; Liao, Siyan ; Song, Wenbin ; Zhou, Ping ; Wang, Shunqing ; Xu, Li ; Wang, Xuejun ; Dou, Q. Ping ; Liu, Jinbao

Purpose: Chronic myelogenous leukemia (CML) is characterized by the constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl-T315I is the predominant mutation that causes resistance to imatinib, cytotoxic drugs, and the second-generation tyrosine kinase inhibitors. The emergence of imatinib resistance in patients with CML leads to searching for novel approaches to the treatment of CML. Gambogic acid, a small molecule derived from Chinese herb gamboges, has been approved for phase II clinical [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes de leucémie myéloïde aiguë, cette étude met en évidence des mécanismes par lesquels une molécule appelée ABT-199, un antagoniste sélectif de BCL-2, exerce une activité antitumorale

Selective BCL-2 Inhibition by ABT-199 Causes On Target Cell Death in Acute Myeloid Leukemia

Pan, Rongqing ; Hogdal, Leah J ; Benito, Juliana Maria ; Bucci, Donna ; Han, Lina ; Borthakur, Gautam ; Cortes, Jorge E. ; DeAngelo, Daniel J ; Debose, LaKeisha ; Mu, Hong ; Döhner, Hartmut ; Gaidzik, Verena ; Galinsky, Ilene ; Golfman, Leonard S. ; Haferlach, Torsten ; Harutyunyan, Karine G. ; Hu, Jianhua ; Leverson, Joel D ; Marcucci, Guido ; Müschen, Markus ; Newman, Rachel ; Park, Eugene ; Ruvolo, Peter ; Ruvolo, Vivian ; Ryan, Jeremy ; Schindela, Sonja ; Zweidler-McKay, Patrick A ; Stone, Richard M. ; Kantarjian, Hagop ; Andreeff, Michael ; Konopleva, Marina ; Letai, Anthony

B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nM, and cell death occurred within 2 h. [...]

Menée in vitro et in vivo sur des modèles de myélome multiple, cette étude évalue l'activité antitumorale de deux composés appelés I-BET151 et I-BET762, des inhibiteurs de BET

Potent anti-myeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762

Chaidos, Aristeidis ; Caputo, Valentina ; Goudevenou, Katerina ; Liu, Binbin ; Marigo, Ilaria ; Chaudhry, Mohammed Suhail ; Rotolo, Antonia ; Tough, David F. ; Smithers, Nicholas N. ; Bassil, Anna K. ; Chapman, Trevor D. ; Harker, Nicola R. ; Barbash, Olena ; Tummino, Peter ; Al-Mahdi, Niam ; Haynes, Andrea C. ; Cutler, Leanne ; Le, BaoChau ; Rahemtulla, Amin ; Roberts, Irene ; Kleijnen, Maurits ; Witherington, Jason J. ; Parr, Nigel J. ; Prinjha, Rab K. ; Karadimitris, Anastasios

The bromodomain and extra terminal (BET) protein BRD2-4 inhibitors hold therapeutic promise in preclinical models of hematologic malignancies. However, translation of these data to molecules suitable for clinical development has yet to be disclosed. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong anti-proliferative effect in vitro and in vivo. This is associated with [...]

Cet article passe en revue les travaux récents sur le développement d'immunothérapies pour le traitement d'un cancer du pancréas

Review: Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies

Sideras, K. ; Braat, H. ; Kwekkeboom, J. ; van Eijck, C. H. ; Peppelenbosch, M. P. ; Sleijfer, S. ; Bruno, M.

Traditional chemotherapeutics have largely failed to date to produce significant improvements in pancreatic cancer survival. One of the reasons for the resilience of pancreatic cancer towards intensive treatment is that the cancer is capable of high jacking the immune system: during disease progression the immune system is converted from a system that attacks tumor cells into a support structure for the cancer, exerting trophic actions on the cancer cells. This turn-around of immune system [...]

Menée in vitro et in vivo, cette étude analyse l'activité antitumorale des inhibiteurs de PI3K dans les cancers du sein HER2+ avec mutations du gène PI3KCA, puis suggère que la mesure de l'expression de la protéine P-Rex1 pourrait permettre de prédire la réponse thérapeutique

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

Ebi, Hiromichi ; Costa, Carlotta ; Faber, Anthony C. ; Nishtala, Madhuri ; Kotani, Hiroshi ; Juric, Dejan ; Della Pelle, Patricia ; Song, Youngchul ; Yano, Seiji ; Mino-Kenudson, Mari ; Benes, Cyril H. ; Engelman, Jeffrey A.

The PI3K pathway is genetically altered in excess of 70% of breast cancers, largely through PIK3CA mutation and HER2 amplification. Preclinical studies have suggested that these subsets of breast cancers are particularly sensitive to PI3K inhibitors; however, the reasons for this heightened sensitivity are mainly unknown. We investigated the signaling effects of PI3K inhibition in PIK3CA mutant and HER2 amplified breast cancers using PI3K inhibitors currently in clinical trials. Unexpectedly, [...]

Menée sur des lignées cellulaires de cancer du sein triplement négatif et à l'aide de xénogreffes, cette étude met en évidence l'intérêt de développer des thérapies ciblées sur la protéine Akt3

Targeting Akt3 Signaling in Triple Negative Breast Cancer

Chin, Y Rebecca ; Yoshida, Taku ; Marusyk, Andriy ; Beck, Andrew H. ; Polyak, Kornelia ; Toker, Alex

Triple negative breast cancer (TNBC) is currently the only major breast tumor subtype without effective targeted therapy and as a consequence in general has poor outcome. To identify new therapeutic targets in TNBC we performed an shRNA screen for protein kinases commonly amplified and overexpressed in breast cancer. Using this approach, we identified AKT3 as a gene preferentially required for the growth of TNBCs. Downregulation of Akt3 significantly inhibits the growth of TNBC lines in 3D [...]

Mené sur 60 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale du nératinib en combinaison avec le temsirolimus

Phase I Study of Neratinib in Combination With Temsirolimus in Patients With Human Epidermal Growth Factor Receptor 2–Dependent and Other Solid Tumors

Gandhi, Leena ; Bahleda, Rastislav ; Tolaney, Sara M. ; Kwak, Eunice L. ; Cleary, James M. ; Pandya, Shuchi S. ; Hollebecque, Antoine ; Abbas, Richat ; Ananthakrishnan, Revathi ; Berkenblit, Anna ; Krygowski, Mizue ; Liang, Yali ; Turnbull, Kathleen W. ; Shapiro, Geoffrey I. ; Soria, Jean-Charles

Purpose Human epidermal growth factor (HER) –mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) –AKT/protein kinase B–mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer [...]

Mené sur 29 patients atteints d'un lymphome associé au virus d'Epstein-Barr, cet essai évalue l'efficacité et la toxicité d'un traitement à base de lymphocytes T autologues manipulés pour exprimer les antigènes LMP1 et/ou LMP2

Sustained Complete Responses in Patients With Lymphoma Receiving Autologous Cytotoxic T Lymphocytes Targeting Epstein-Barr Virus Latent Membrane Proteins

Bollard, Catherine M. ; Gottschalk, Stephen ; Torrano, Vicky ; Diouf, Oumar ; Ku, Stephanie ; Hazrat, Yasmin ; Carrum, George ; Ramos, Carlos ; Fayad, Luis ; Shpall, Elizabeth J. ; Pro, Barbara ; Liu, Hao ; Wu, Meng-Fen ; Lee, Daniel ; Sheehan, Andrea M. ; Zu, Youli ; Gee, Adrian P. ; Brenner, Malcolm K. ; Heslop, Helen E. ; Rooney, Cliona M.

Purpose Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP–cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and [...]

Cet article passe en revue les travaux récents sur le développement d'inhibiteurs de BRAF

BRAF inhibitors: from the laboratory to clinical trials

Rahman, A. ; Salajegheh, A. ; Smith, R. A. ; Lam, A. K. Y.

BRAF is one of the most commonly mutated proto-oncogenes and plays a significant role in the development of numerous cancers of high clinical impact. Due to the commonality of BRAF mutations, a number of BRAF inhibitors have been developed as tools in the management of patients with cancers dependent on the action of mutant BRAF to drive cellular proliferation. In this review, we examine the current state of clinical trials and laboratory research concerning BRAF inhibitors in development and [...]

Menée sur des échantillons tumoraux prélevés sur 133 patients atteints d'un myélome multiple récidivant et inclus dans un essai de phase II ou III, cette étude montre que des mutations du gène NRAS, et non des mutations du gène KRAS, modifient la sensibilité des cellules tumorales au bortézomib

Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

Mulligan, George ; Lichter, David I. ; Di Bacco, Alessandra ; Blakemore, Stephen J. ; Berger, Allison ; Koenig, Erik ; Bernard, Hugues ; Trepicchio, William ; Li, Bin ; Neuwirth, Rachel ; Chattopadhyay, Nibedita ; Bolen, Joseph B. ; Dorner, Andrew J. ; van de Velde, Helgi ; Ricci, Deborah ; Jagannath, Sundar ; Berenson, James R. ; Richardson, Paul G. ; Stadtmauer, Edward A. ; Orlowski, Robert Z. ; Lonial, Sagar ; Anderson, Kenneth C. ; Sonneveld, Pieter ; San Miguel, Jesús F. ; Esseltine, Dixie-Lee ; Schu, Matthew

Various translocations and mutations have been identified in myeloma and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41 known oncogenes and tumor suppressor genes in tumor samples from 133 relapsed myeloma patients participating in phase 2 or 3 clinical trials of bortezomib. DNA mutations were identified in 14 genes. BRAF as well as [...]

Mené sur 873 patients atteints d'un cancer métastatique de la prostate résistant à la castration, cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'ajout de sunitinib à la prednisone après l'échec d'un traitement à base de docétaxel

Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer

Michaelson, M. Dror ; Oudard, Stéphane ; Ou, Yen-Chuan ; Sengeløv, Lisa ; Saad, Fred ; Houédé, Nadine ; Ostler, Peter ; Stenzl, Arnulf ; Daugaard, Gedske ; Jones, Robert ; Laestadius, Fredrik ; Ullèn, Anders ; Bahl, Amit ; Castellano, Daniel ; Gschwend, Juergen ; Maurina, Tristan ; Chow Maneval, Edna ; Wang, Shaw-Ling ; Lechuga, Maria Jose ; Paolini, Jolanda ; Chen, Isan

Purpose We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two [...]

Menée in vitro et à l'aide de xénogreffes de cancer gastrique, cette étude évalue l'efficacité de nanoparticules de type PEG-Pep-PCL (polyéthylèneglycol- peptide-polycaprolactone) et chargées en docétaxel pour augmenter la sensibilité aux rayonnements ionisants des cellules tumorales surexprimant la gélatinase

Enhancement of Radiotherapy Efficacy by Docetaxel-loaded Gelatinase-stimuli PEG-Pep-PCL Nanoparticles in Gastric Cancer

Cui, Fang-bo ; Li, Ru-Tian ; Liu, Qin ; Wu, Pu-yuan ; Hu, Wen-jing ; Yue, Guo-feng ; Ding, Hui ; Yu, Li-Xia ; Qian, Xiao-Ping ; Liu, Bao-Rui

Docetaxel (DOC) is widely used as radiosensitizer in various tumors, including gastric cancer (GC), but its therapeutic effect remains to be improved. In this study, using docetaxel-loaded nanoparticles (DOC-NPs) based on gelatinase-stimuli strategy, we compared their radioenhancement efficacy with docetaxel in GC. Compared with DOC, radiosensitization of DOC-NPs was improved significantly (Sensitization enhancement ratio increased 1.09-fold to 1.24-fold, P<0.01) in all three gelatinase [...]

Mené sur 12 patients atteints d'un adénocarcinome résécable de l'œsophage, cet essai prospectif de phase II évalue, du point de vue du taux de réponse complète et du taux de résécabilité, l'intérêt d'ajouter une radiothérapie plus cétuximab à une chimiothérapie pré-opératoire

Adding Preoperative Radiotherapy Plus Cetuximab to Perioperative Chemotherapy for Resectable Esophageal Adenocarcinoma: A Single-Center Prospective Phase II Trial

Ubink, Inge ; van der Sluis, Pieter ; Schipper, Marguerite ; Reerink, Onne ; Voest, Emile ; Borel-Rinkes, Inne ; Wijrdeman, Harm ; Vleggaar, Frank ; Agterof, Marriete ; Overkleeft, Esther ; Siersema, Peter ; van Hillegersberg, Richard ; Lolkema, Martijn

Background : Local and systemic recurrence are important sources of treatment failure following surgical resection of esophageal adenocarcinoma. We hypothesized that adding preoperative cetuximab and radiotherapy (cetux-RT) to perioperative chemotherapy would increase treatment efficacy with acceptable toxicity. Methods : In this prospective phase II trial, patients were treated with three cycles of epirubicin, cisplatin, and capecitabine (ECX), followed by cetux-RT. After surgery with curative [...]

A partir d'une revue systématique de la littérature publiée jusqu'en mai 2013 (5 études), cette étude évalue, du point de vue du taux de survie sans progression à 6 mois et de la survie à 1 an, l'intérêt d'ajouter le témozolomide à une radiothérapie pour traiter un glioblastome multiforme

Temozolomide and Radiotherapy for Newly Diagnosed Glioblastoma Multiforme: A Systematic Review

Yang, Li-Juan ; Zhou, Chang-FU ; Lin, Zhi-Xiong

To systematically review the efficacy/safety of radiotherapy/temozolomide (TMZ) vs. radiotherapy for treating glioblastoma (GBM), Medline, Current Contents, and Cochrane database were searched. Five studies were reviewed. Median survival ranged from 9.4 to 19.0 months (radiotherapy/TMZ) vs. 7.3–17.1 months (radiotherapy). Survival ranged from 80.2% to 95.0% (radiotherapy/TMZ) vs. 8.3–84.2% (radiotherapy) at 0.5 years and from 20.0% to 61.1% (radiotherapy/TMZ) vs. 5.0–50.6% (radiotherapy) at 1 [...]

A partir d'une revue de la littérature (175 articles identifiés, avec des données portant sur un total de 96 125 patients), cette étude analyse, du point de vue des recommandations CONSORT, la façon dont les publications d'essais cliniques en oncologie décrivent les effets indésirables des traitements évalués

Adverse Event Reporting in Cancer Clinical Trial Publications

Sivendran, Shanthi ; Latif, Asma ; McBride, Russell B. ; Stensland, Kristian D. ; Wisnivesky, Juan ; Haines, Lindsay ; Oh, William K. ; Galsky, Matthew D.

Purpose Reporting adverse events is a critical element of a clinical trial publication. In 2003, the Consolidated Standards of Reporting Trials (CONSORT) group generated recommendations regarding the appropriate reporting of adverse events. The degree to which these recommendations are followed in oncology publications has not been comprehensively evaluated. Methods A review of citations from PubMed, Medline, and Embase published between Jan 1, 2009 and December 31, 2011, identified eligible [...]

Menée à partir des données portant sur 1 065 patients atteints d'un cancer localisé de la prostate, cette étude analyse l'intérêt d'un outil, basé sur la catégorisation et la cartographie des incisions intra-prostatiques, pour améliorer la qualité d'une prostatectomie radicale par voie ouverte

Assessing the extirpative quality of a radical prostatectomy technique: categorisation and mapping of technical errors

Barré, Christian ; Thoulouzan, Matthieu ; Aillet, Geneviève ; Nguyen, Jean-Michel

Objective : To examine the extirpative quality of an open radical prostatectomy (RP) technique by first categorising and mapping all intraprostatic incisions into benign tissue and then determining a cumulative technical error rate given by all intraprostatic incisions into benign and malignant tissue. Patients and Methods : We performed a retrospective review of prospectively collected data relating to 1065 men with clinically localised prostate cancer who underwent open retropubic RP (70.6% [...]