Article
Biochemistry & Molecular Biology
Diana Salvador, Veronica Bastos, Helena Oliveira
Summary: This study evaluated the combinatorial effect of doxorubicin and hyperthermia on melanoma cells and found that the combined treatment enhanced doxorubicin's effect through cell cycle arrest, oxidative stress, and apoptotic cell death.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Shiqi Long, Yangzhuo Gu, Yuanyuan An, Xiaojin Lin, Xiaoqing Chen, Xianyao Wang, Chunxiang Liao, Weiwei Ouyang, Nianxue Wang, Zhixu He, Xing Zhao
Summary: This study demonstrated that exposing NK cells to reovirus enhanced their cytotoxicity in a dose-dependent manner, leading to greater anti-tumor efficacy when combined with cetuximab against CRC cells. The activation of NK cells by reovirus, in conjunction with cetuximab, resulted in significantly stronger anti-tumor efficacy, providing a potential strategy for the clinical treatment of CRC.
JOURNAL OF TRANSLATIONAL MEDICINE
(2021)
Article
Oncology
Anke Bruening-Richardson, Gary C. Shaw, Daniel Tams, Tim Brend, Hitesh Sanganee, Simon T. Barry, Gregory Hamm, Richard J. A. Goodwin, John G. Swales, Henry King, Lynette Steele, Ruth Morton, Anastasia Widyadari, Thomas A. Ward, Filomena Esteves, Marjorie Boissinot, Georgia Mavria, Alastair Droop, Sean E. Lawler, Susan C. Short
Summary: The GSK-3 inhibitor AZD2858 induces cell death in glioma by disrupting centrosome function and promoting mitotic failure, showing significant effects in patient-derived glioma cell lines and in vivo xenograft models, and enhancing the efficacy when combined with radiation therapy.
Article
Food Science & Technology
Ho-Jeong Bang, Mok-Ryeon Ahn
Summary: This study found that pinobanksin exhibits antiangiogenic effect by inducing endothelial cell apoptosis, and it can be developed as an antiangiogenic agent. The mechanism involves inactivation of the Raf/MEK/ERK pathway and activation of apoptotic signaling such as caspase cascades.
JOURNAL OF FUNCTIONAL FOODS
(2021)
Article
Chemistry, Medicinal
Mahmoud M. Habibullah, Syam Mohan, Nabeel Kashan Syed, Hafiz A. Makeen, Qazi Mohammad Sajid Jamal, Hani Alothaid, Farkad Bantun, Alaa Alhazmi, Ali Hakamy, Yahia A. Kaabi, Ghalia Samlan, Mohtashim Lohani, Neelaveni Thangavel, Mohamed Ahmed Al-Kasim
Summary: In this study, the anticancer efficacy of Chitosan nanoparticles loaded with human growth hormone hGH fragment 176-191 peptide plus the clinical chemotherapeutic doxorubicin was evaluated. Molecular docking simulations and viability assays were used to determine the impact of hGH fragment 176-191 peptide on the binding affinities and efficacy of doxorubicin against breast cancer cells. The synthesized dual-loaded Chitosan nanoparticles showed greater anti-proliferative activity than doxorubicin-loaded Chitosan, suggesting that this dual-loading strategy may enhance the potency of doxorubicin and reduce non-target tissue exposure.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2022)
Article
Oncology
Diwakar Suresh, Akshatha N. Srinivas, Akila Prashant, Suchitha Satish, Prashant Vishwanath, Suma M. Nataraj, Srinivas V. Koduru, Prasanna K. Santhekadur, Divya P. Kumar
Summary: This study aims to identify the key role of apoptosis antagonizing transcription factor (AATF) in tumor angiogenesis and its underlying mechanisms in hepatocellular carcinoma (HCC). The results showed that inhibiting AATF can suppress the proliferation, migration, and invasion of HCC cells, as well as the angiogenic processes. The VEGF-mediated downstream signaling pathway responsible for angiogenesis was suppressed by AATF inhibition.
FRONTIERS IN ONCOLOGY
(2023)
Article
Chemistry, Medicinal
Sheng Cao, Lan Ma, Yulin Liu, Mingming Wei, Yuhong Yao, Chen Li, Ruonan Wang, Ning Liu, Zhiqiang Dong, Xuechun Li, Ming Li, Xiaoji Wang, Cheng Yang, Guang Yang
Summary: In this study, dovitinib was chemically modified into CRBN-recruiting PROTACs, resulting in two active compounds with enhanced antiproliferative effects against FLT3-ITD+ AML cells and the ability to induce degradation of FLT3-ITD and KIT proteins while blocking their downstream signaling pathways. This study presents a promising strategy for developing novel therapies for FLT3-ITD+ AML.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Himalaya Singh, Annaram Thirupathi, Bishwaprava Das, Manojkumar Janni, Renu Kumari, Sandeep Singh, Mamunur Rashid, Mohammad Wahajuddin, Musuvathi Motilal Balamurali, Kumaravelu Jagavelu, Saravanan Peruncheralathan
Summary: The study demonstrates that 2,3-ACBTs inhibit angiogenesis by regulating the Akt/Src signaling pathway and disrupting cytoskeletal filaments of endothelial cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Shaimaa M. Badr-Eldin, Hibah M. Aldawsari, Usama A. Fahmy, Osama A. A. Ahmed, Nabil A. Alhakamy, Omar D. Al-hejaili, Alhanoof A. Alhassan, Ghadeer A. Ammari, Shouq I. Alhazmi, Raghad M. Alawadi, Rana Bakhaidar, Abdulmohsen J. Alamoudi, Thikryat Neamatallah, Singkome Tima
Summary: Ellagic acid has been studied for its potential in preventing and treating cancer. In this study, APA-functionalized emulsomes were used to enhance the cytotoxic activity of ellagic acid against breast cancer cells, resulting in significant inhibition of cell growth and induction of apoptosis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Maohua Huang, Minfeng Chen, Ming Qi, Geni Ye, Jinghua Pan, Changzheng Shi, Yunlong Yang, Luyu Zhao, Xukai Mo, Yiran Zhang, Yong Li, Jincheng Zhong, Weijin Lu, Xiaobo Li, Jiayan Zhang, Jinrong Lin, Liangping Luo, Tongzheng Liu, Patrick Ming-Kuen Tang, An Hong, Yihai Cao, Wencai Ye, Dongmei Zhang
Summary: This study shows that tumour perivascular cells play a key role in tumour revascularization after withdrawal of AA-TKI therapy. Inhibition of perivascular cells can reduce the rebound effect of CRC vascularization, and blocking the Axl signalling pathway may provide a potential anticancer approach to improve the therapeutic outcomes of antiangiogenic drugs in CRC.
JOURNAL OF EXTRACELLULAR VESICLES
(2021)
Article
Biotechnology & Applied Microbiology
Hannah I. Ghasemi, Julien Bacal, Amanda C. Yoon, Katherine U. Tavasoli, Carmen Cruz, Jonathan T. Vu, Brooke M. Gardner, Chris D. Richardson
Summary: The efficiency of gene editing via homology-directed repair (HDR) can be enhanced by covalently modifying the template DNA to form interstrand crosslinks. These crosslinked templates (xHDRTs) significantly increase Cas9-mediated editing efficiencies in various cell types. The increased editing from xHDRTs is dependent on events occurring on the template molecule and requires the ATR kinase and components of the Fanconi anemia pathway.
NATURE BIOTECHNOLOGY
(2023)
Article
Environmental Sciences
Caterina Russo, Alessandro Maugeri, Ambrogina Albergamo, Giacomo Dugo, Michele Navarra, Santa Cirmi
Summary: The study aimed to evaluate the protective effect of a red grape juice extract (RGJe) against the endothelial damage induced by BPA. Results showed that RGJe treatment counteracted BPA-induced cell death and apoptosis, modulated intracellular mechanisms, and demonstrated antioxidant properties. Furthermore, RGJe reduced chemokines and adhesion molecules, which are involved in the formation of atheromatous plaque. Overall, RGJe prevented BPA-induced vascular damage through specific intracellular mechanisms and antioxidant capability.
Article
Immunology
Kayla A. Holder, Kimberley Burt, Michael D. Grant
Summary: This study investigates the role of TIGIT in individuals living with HIV, revealing its expression on CD4(+) T cells, CD8(+) T cells, and NK cells, and its association with HIV-1 disease progression. Therapeutic targeting of TIGIT may enhance NK cell antibody-dependent cytotoxicity against HIV-1.
CLINICAL & TRANSLATIONAL IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Irina Smirnova, George Draghici, Oxana Kazakova, Lavinia Vlaia, Stefana Avram, Alexandra Mioc, Marius Mioc, Ioana Macasoi, Cristina Dehelean, Adrian Voicu, Codruta Soica
Summary: The use of natural compounds as starting points for semisynthetic derivatives has shown to be a valuable source of active anticancer agents. Hollongdione, obtained from dammarane type triterpenoid dipterocarpol, was modified and a series of derivatives were obtained. These derivatives displayed strong anticancer activity, with 2,21-Bis-[3-pyridinyl]-methylidenohollongdione 9 being the most active one. It showed apoptotic and antiangiogenic activities, and also inhibited mitochondrial respiration. Further analysis at the gene level confirmed its pro-survival/proapoptotic activity. Hollongdione derivatives have potential as therapeutic options for melanoma and breast cancer.
BIOORGANIC CHEMISTRY
(2022)
Article
Cell & Tissue Engineering
Chi Zhang, Yinuo Lin, Ke Zhang, Luyang Meng, Xinyang Hu, Jinghai Chen, Wei Zhu, Hong Yu
Summary: The study found that GDF11 can enhance the therapeutic effects of stem cells for ischemic diseases by increasing stem cell viability, mobility, and angiogenic paracrine functions.
STEM CELL RESEARCH & THERAPY
(2021)
Article
Dentistry, Oral Surgery & Medicine
J. I. Sasaki, Z. Zhang, M. Oh, A. M. Pobocik, S. Imazato, S. Shi, J. E. Nor
JOURNAL OF DENTAL RESEARCH
(2020)
Article
Dentistry, Oral Surgery & Medicine
M. Oh, Z. Zhang, A. Mantesso, A. E. Oklejas, J. E. Nor
JOURNAL OF DENTAL RESEARCH
(2020)
Article
Dentistry, Oral Surgery & Medicine
T. Nakano, K. A. Warner, A. E. Oklejas, Z. Zhang, C. Rodriguez-Ramirez, A. G. Shuman, J. E. Nor
Summary: This study demonstrated the therapeutic potential of mTOR inhibitors in targeting cisplatin-resistant cancer stem cells in salivary gland mucoepidermoid carcinoma. Combining mTOR inhibitors with platinum-based chemotherapy may offer a promising treatment strategy for patients with advanced MEC.
JOURNAL OF DENTAL RESEARCH
(2021)
Article
Dentistry, Oral Surgery & Medicine
Carolina Cucco, Zhaocheng Zhang, Tatiana M. Botero, Daniel J. Chiego, Rogerio M. Castilho, Jacques E. Nor
JOURNAL OF ENDODONTICS
(2020)
Article
Cell Biology
Nathalia P. Andrade, Kristy A. Warner, Zhaocheng Zhang, Alexander T. Pearson, Andrea Mantesso, Douglas M. Guimaraes, Albina Altemani, Fernanda Mariano, Fabio D. Nunes, Jacques E. Nor
Summary: The study revealed the crucial role of mTOR signaling pathway in the survival of cancer stem-like cells in salivary gland mucoepidermoid carcinoma, suggesting that targeting the mTOR pathway could be a potential strategy for eliminating these cells.
CELL DEATH & DISEASE
(2021)
Article
Cell Biology
Zhaocheng Zhang, Min Oh, Jun-Ichi Sasaki, Jacques E. Nor
Summary: The study shows that p53/p21 functions through Bmi-1 to prevent the vasculogenic differentiation of dental pulp stem cells.
CELL DEATH & DISEASE
(2021)
Editorial Material
Dentistry, Oral Surgery & Medicine
J. E. Nor
JOURNAL OF DENTAL RESEARCH
(2021)
Article
Dentistry, Oral Surgery & Medicine
Luan Cesar Silva, Gabriell Bonifacio Borgato, Vivian Petersen Wagner, Manoela Domingues Martins, Guilherme Zweig Rocha, Marcio Ajudarte Lopes, Alan Roger Santos-Silva, Gilberto de Castro Junior, Luiz Paulo Kowalski, Jacques E. Nor, Cristiane H. Squarize, Rogerio Moraes Castilho, Pablo Agustin Vargas
Summary: Cephaeline has demonstrated anti-cancer properties in all tested MEC cell lines by regulating tumor cells' viability, migration, proliferation, and disrupting the ability of cancer cells to generate tumorspheres.
JOURNAL OF ORAL PATHOLOGY & MEDICINE
(2022)
Article
Cell Biology
Alexandra E. Herzog, Kristy A. Warner, Zhaocheng Zhang, Emily Bellile, Meera A. Bhagat, Rogerio M. Castilho, Gregory T. Wolf, Peter J. Polverini, Alexander T. Pearson, Jacques E. Nor
Summary: The study highlights the significant role of cancer stem-like cells (CSCs) in the development of head and neck squamous cell carcinoma (HNSCC), and suggests that therapeutic blockade of IL-6R may be a promising strategy to overcome chemoresistance in these patients.
CELL DEATH & DISEASE
(2021)
Article
Cell Biology
Andrea Mantesso, Zhaocheng Zhang, Kristy A. Warner, Alexandra E. Herzog, Ajai J. Pulianmackal, Jacques E. Nor
Summary: Understanding how mesenchymal stem cells form blood vessels is crucial for therapeutic applications, and dental pulp stem cells and stem cells from human exfoliated deciduous teeth are promising sources for tissue engineering. In-depth study revealed that the process of vasculogenesis mediated by dental pulp stem cells is dynamic, with proximity to the sprouting area being critical for cell fate decisions.
Article
Oncology
Christie Rodriguez-Ramirez, Zhaocheng Zhang, Kristy A. Warner, Alexandra E. Herzog, Andrea Mantesso, Zhixiong Zhang, Eusik Yoon, Shaomeng Wang, Max S. Wicha, Jacques E. Nor
Summary: This study reveals the crucial role of p53 in the self-renewal and plasticity of cancer stem cells (CSCs) in mucoepidermoid carcinoma (MEC). Therapeutic activation of p53 reduces the CSC fraction and prevents tumor recurrence, suggesting its clinical utility in treating salivary gland MEC.
CLINICAL CANCER RESEARCH
(2022)
Article
Dentistry, Oral Surgery & Medicine
A. Li, J. Sasaki, T. Inubushi, G. L. Abe, J. E. Nor, T. Yamashiro, S. Imazato
Summary: This study reveals the crucial role of heparan sulfate (HS) in endothelial differentiation and vasculogenesis of dental pulp stem cells (DPSCs). The results show that inhibiting HS activity decreases the proliferation and sprouting ability of DPSCs and reduces the expression of proangiogenic markers. Silencing the HS biosynthesis key enzyme EXT1 alters the gene expression profile and vascular formation capacity of DPSCs. The findings provide new perspectives for the application of HS in tissue engineering and dental pulp regeneration.
JOURNAL OF DENTAL RESEARCH
(2023)
Review
Education & Educational Research
Benjamin D. Zeitlin, Nishanth D. Sadhak
Summary: Computer-based learning applications and mobile technology have transformed education, including the use of electronic flashcards. This study demonstrates the successful use of the Quizlet flashcard application in a tertiary educational setting, improving the learning experience for international dental students.
EDUCATION AND INFORMATION TECHNOLOGIES
(2023)
Article
Dentistry, Oral Surgery & Medicine
Benjamin D. Zeitlin
JOURNAL OF DENTAL EDUCATION
(2023)
Article
Nanoscience & Nanotechnology
Divya Pankajakshan, Sherry L. Voytik-Harbin, Jacques E. Nor, Marco C. Bottino
ACS APPLIED BIO MATERIALS
(2020)
Article
Oncology
Xiaofan Pu, Chaolei Zhang, Guoping Ding, Hongpeng Gu, Yang Lv, Tao Shen, Tianshu Pang, Liping Cao, Shengnan Jia
Summary: This study demonstrated the potential utility of the sEV-miRNA d-signature in the diagnosis of PDAC via machine learning methods. A novel sEV biomarker, miR-664a-3p, was identified for the diagnosis of PDAC. It can also potentially promote angiogenesis and metastasis, provide insight into PDAC pathogenesis, and reveal novel regulators of this disease.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Jiaping Wang, Zhijuan Xu, Yanli Lai, Yanli Zhang, Ping Zhang, Qitian Mu, Shujun Yang, Yongcheng Sun, Lixia Sheng, Guifang Ouyang
Summary: This study demonstrates the significance of PD-1 in EBV-infected lymphoma cells. Silencing PD-1 enhances the tumor targeting effect of EBV-specific killer T cells on B lymphocytes and attenuates the immune escape effect.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Qiliang Peng, Jialong Tao, Yingjie Xu, Yi Shen, Yong Wang, Yang Jiao, Yiheng Mao, Yaqun Zhu, Yulong Liu, Ye Tian
Summary: This study investigates the potential role of lipid metabolism-associated genes (LMAGs) in neoadjuvant chemoradiotherapy (nCRT) and immunotherapy for rectal cancer. The results suggest that the SREBF2 gene is a highly predictive factor for nCRT in rectal cancer and is associated with favorable prognosis. SREBF2 is also closely associated with immune cell infiltration and immunotherapy-related genes.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Shiquan Li, Nan Zhang, Yongping Yang, Tongjun Liu
Summary: This study investigated the potential molecular mechanism of SPDEF in immune evasion of colorectal cancer (CRC) and found that it suppresses immune evasion by activating CCL28 through the modulation of M2 polarization of macrophages. These findings provide a new research direction and potential therapeutic target for immunotherapy in CRC.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Manas Sehgal, Soundharya Ramu, Joel Markus Vaz, Yogheshwer Raja Ganapathy, Srinath Muralidharan, Sankalpa Venkatraghavan, Mohit Kumar Jolly
Summary: This study investigates the relationship between gene expression patterns and phenotypic plasticity and heterogeneity in colorectal cancer (CRC). The results demonstrate the interconnectedness between different Consensus Molecular Subtypes (CMS) of CRC and specific phenotypes such as epithelial and mesenchymal characteristics. Additionally, the study reveals correlations between metabolic pathways and phenotypic scores, as well as between PD-L1 activity and mesenchymal phenotype. Single-cell RNA sequencing analysis further confirms the heterogeneity of different CMS subtypes. These findings have important implications for understanding CRC heterogeneity and developing targeted therapies.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Yutong Zou, Siyao Guo, Yan Liao, Weidong Chen, Ziyun Chen, Junkai Chen, Lili Wen, Xianbiao Xie
Summary: This study found that ceramide metabolism is associated with the progression and clinical outcome of osteosarcoma by analyzing data from osteosarcoma patients. The gene ST3GAL1 plays an important role in osteosarcoma, regulating the tumor immune microenvironment and affecting T cell function. It may become a new target for the treatment of osteosarcoma.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Chuanhui Chen, Mengzhi Wan, Xiong Peng, Qing Zhang, Yu Liu
Summary: This study examines the function and mechanism of the ceRNA network centered around GPR37 in LUAD. The findings show that high expression of GPR37 in LUAD tissue samples is associated with poor prognosis, and it may regulate the expression of downstream target genes by competitively binding to lncRNA DLEU1 and miR-4458.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Junping Li, Hong Hu, Jinping He, Yuling Hu, Manting Liu, Bihui Cao, Dongni Chen, Xiaodie Ye, Jian Zhang, Zhiru Zhang, Wen Long, Hui Lian, Deji Chen, Likun Chen, Lili Yang, Zhenfeng Zhang
Summary: Sequential administration of CDC7 inhibitor XL413 after carboplatin enhances the chemotherapeutic effect of carboplatin on ovarian cancer cells, possibly by inhibiting homologous recombination repair activity and increasing the accumulation of chemotherapy-induced DNA damage.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Madison Catalanotto, Joel Markus Vaz, Camille Abshire, Reneau Youngblood, Min Chu, Herbert Levine, Mohit Kumar Jolly, Ana -Maria Dragoi
Summary: The study demonstrates that loss of FLASH in cancer cells leads to a hybrid E/M phenotype with high epithelial scores, suggesting FLASH acts as a repressor of the epithelial phenotype. Additionally, FLASH expression is inversely correlated with the epithelial score and subsets of mesenchymal markers are distinctly up-regulated in FLASH, NPAT, or SLBP-depleted cells.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Xiaorui Wang, Na Li, Minying Zheng, Yongjun Yu, Shiwu Zhang
Summary: Adipocytes are derived from pluripotent mesenchymal stem cells and histone modifications play a key role in their differentiation. Recent studies have shown that cancer stem cells can differentiate into adipocytes, reducing the malignancy of cancer cells.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Hana Q. Sadida, Alanoud Abdulla, Sara Al Marzooqi, Sheema Hashem, Muzafar A. Macha, Ammira S. Al-Shabeeb Akil, Ajaz A. Bhat
Summary: Cancer heterogeneity and drug resistance are major obstacles to effective cancer treatment, and epigenetic modifications play a pivotal role in these processes. This review explores essential epigenetic modifications, including DNA methylation, histone modifications, and chromatin remodeling, and discusses their complex contributions to cancer biology. However, the interplay of epigenetic and genetic changes in cancer cells presents unique challenges that must be addressed to fully exploit the potential of epigenetic modifications.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Pedro De Marchi, Leticia Ferro Leal, Luciane Sussuchi da Silva, Rodrigo de Oliveira Cavagna, Flavio Augusto Ferreira da Silva, Vinicius Duval da Silva, Eduardo C. A. da Silva, Augusto O. Saito, Vladmir C. Cordeiro de Lima, Rui Manuel Reis
Summary: The TIS and IFN-gamma signatures are predictive biomarkers for identifying NSCLC patients who could potentially benefit from immune checkpoint inhibitor therapies.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Giovanni Marchi, Anna Rajavuori, Mai T. N. Nguyen, Kaisa Huhtinen, Sinikka Oksa, Sakari Hietanen, Sampsa Hautaniemi, Johanna Hynninen, Jaana Oikkonen
Summary: The study shows that ctDNA can adequately represent high-grade serous ovarian carcinoma (HGSC), and the mutations observed at relapse suggest personalized therapy options.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Yuncang Yuan, Jiawei Fan, Dandan Liang, Shijie Wang, Xu Luo, Yongjie Zhu, Nan Liu, Tingxiu Xiang, Xudong Zhao
Summary: This study demonstrates that csGRP78-directed CAR-T cells can selectively kill pancreatic cancer cells, and the combination with chemotherapy enhances cytotoxicity.
TRANSLATIONAL ONCOLOGY
(2024)
Article
Oncology
Niyati Piplani, Tanusri Roy, Neha Saxena, Shamik Sen
Summary: The glycocalyx, a protective barrier surrounding cells, has been found to play a role in cancer cell proliferation, survival, and metastasis. However, its function in maintaining DNA/nuclear integrity during migration through dense matrices has not been explored. This study shows that the bulkiness of the glycocalyx is inversely associated with nuclear stresses, and highlights its mechanical role in shielding migration-associated stresses.
TRANSLATIONAL ONCOLOGY
(2024)