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Serah Choi, Yao Yu, Matthew R Grimmer, Michael Wahl, Susan M Chang, Joseph F Costello
Low-grade gliomas cause considerable morbidity and most will recur after initial therapy. At recurrence, low-grade gliomas can undergo transformation to high-grade gliomas (grade III or grade IV), which are associated with worse prognosis. Temozolomide (TMZ) provides survival benefit in patients with glioblastomas (GBMs) but its value in patients with low-grade gliomas is less clear. A subset of TMZ-treated, IDH-mutant, low-grade astrocytomas recur as more malignant tumors with thousands of de novo, coding mutations bearing a signature of TMZ-induced hypermutation...
February 14, 2018: Neuro-oncology
Nagore I Marín-Ramos, Thu Zan Thein, Hee-Yeon Cho, Stephen D Swenson, Weijun Wang, Axel H Schönthal, Thomas C Chen, Florence M Hofman
Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). The novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10 fold more cytotoxic to glioma stem cells (GSCs) than TMZ, and is active against TMZ-resistant tumor cells...
February 13, 2018: Molecular Cancer Therapeutics
Bing Li, Chun Zhou, Liang Yi, Lunshan Xu, Minhui Xu
Glioma is a malignant tumor of the glial tissue that is difficult to excise through surgery, with poor patient prognosis. The use of chemotherapeutic drugs alone to treat glioma following surgery results in a high probability of sequelae, such as tumor recurrence. The present study investigated the effects of a novel treatment combination on glioma cells and determined the molecular mechanisms underlying its action. The effect of temozolomide (TMZ) combined with rapamycin (RAPA) on the TMZ-induced autophagic death of U251 glioma cells was examined...
February 2018: Oncology Letters
Jun Du, Ruijie Wang, Litian Yin, Yuejun Fu, Yuqing Cai, Zhiyun Zhang, Aihua Liang
Temozolomide (TMZ) is a drug that has been demonstrated to improve the survival time of patients with glioblastoma multiforme (GBM) when administered with concomitant radiotherapy. However, chemoresistance is one of the major obstacles in the treatment of GBM. In the present study, an MTT assay and flow cytometry were used to demonstrate that chlorotoxin-like toxin in the venom of the scorpion Buthus martensii Kirsch (BmK CT) markedly inhibited cell proliferation and induced apoptosis in U251 cells when combined with TMZ...
February 2018: Oncology Letters
Jing Lin, Aihui Ji, Guanzhong Qiu, Huaizhi Feng, Jian Li, Shuo Li, Yongxiang Zou, Yong Cui, Chaoli Song, Hua He, Yicheng Lu
F-box and WD repeat domain-containing 7(FBW7) is a SCF-type E3 ubiquitin ligase targeting a multitude of oncoproteins for degradation. Acting as one of the most important tumor suppressor it is frequently inactivated in various tumors. In this study we aimed to evaluate the relationship of FBW7 with glioma pathology and prognosis, and examine its effect in glioma malignancies and temozolomide(TMZ)-based therapy. Clinical tissues and TCGA database analysis revealed FBW7 expression was correlated inversely with glioma histology and positively with patient survival time...
February 10, 2018: Cancer Science
Xingguo Song, Li Xie, Minghui Chang, Xinran Geng, Xingwu Wang, Thomas C Chen, Xianrang Song
The DNA repair enzyme O6-methylguanin-DNA-methltransferase (MGMT) is able to remove products of alkylating agent such as O6-meG and emerges as a central determinant of cancer resistance to temozolomide (TMZ). Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel TMZ analog developed based on the conjugation of TMZ and POH, displayed strong anticancer potency in multiple cancer types, but seemed not to experience the chemoresistance even in cells with high MGMT expression unlike TMZ and other alkylating agents...
February 9, 2018: Cell Death & Disease
Caroline Happold, Thierry Gorlia, L Burt Nabors, Sara C Erridge, David A Reardon, Christine Hicking, Martin Picard, Roger Stupp, Michael Weller
Glioblastomas are malignant brain tumors with poor prognosis. Lately, data from clinical studies assessing the role of co-medications in different cancer types suggested reduced mortality and potential anti-tumor activity for statins, angiotensin-I converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (sartans). Here, we analysed the association of co-treatment with statins, ACEI or sartans with outcome in a cohort of 810 patients enrolled in the phase III CENTRIC and phase II CORE trials on the role of the integrin antagonist, cilengitide, in newly diagnosed glioblastoma with or without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation...
February 8, 2018: Journal of Neuro-oncology
Margaret Pain, Huaien Wang, Eunjee Lee, Maya Strahl, Wissam Hamou, Robert Sebra, Jun Zhu, Raymund L Yong
Background: Gliosarcoma is a rare variant of glioblastoma (GBM) that exhibits frequent mutations in TP53 and can develop in a secondary fashion after chemoradiation of a primary GBM. Whether temozolomide (TMZ)-induced mutagenesis of the TP53 DNA-binding domain (DBD) can drive the pathogenesis of gliosarcoma is unclear. Methods: We identified a case of a primary GBM that rapidly progressed into secondary gliosarcoma shortly after chemoradiation was initiated. Bulk tumor was collected and gliomasphere cultures derived from both the pre- and post-treatment tumors...
January 5, 2018: Oncotarget
Jun Jin, Kihwan Hwang, Jin-Deok Joo, Jung Ho Han, Chae-Yong Kim
7-O-succinyl macrolactin A has shown anti-inflammatory, anti-angiogenesis, and anti-metastatic effects. It also exhibits strong suppression of tumor growth. In our previous study, we assessed the anti-neoplastic effects of 7-O-succinyl macrolactin A tromethamine salt (SMA salt) on a glioma cell line. Moreover, according to our data, SMA salt might be contributed to the inhibitory effects on migration and invasion, as well as a cytotoxic effect on the glioblastoma cell lines. In the present study, we investigated the anti-tumor effects of combination therapy with SMA salt and temozolomide (TMZ) in glioblastoma cell lines...
January 5, 2018: Oncotarget
Fei Shi, Jinying Zhang, Hongyu Liu, Liangliang Wu, Hongyu Jiang, Qiyan Wu, Tianyi Liu, Meiqing Lou, Hao Wu
Glioblastomas (GBMs) are among the most malignant of all human tumors and have poor prognosis. The current standard of care (SOC) includes maximal surgical tumor resection followed by adjuvant temozolomide (TMZ) and concomitant radiotherapy (RT). However, even with this treatment, the 5-year survival rate is less than 10%, and thus, follow-up treatment is required to improve efficacy. In GBMs as well as many other solid cancers, PI3K/mTOR signaling is overactivated. Therefore, multiple tumor-based PI3K inhibitors have been studied in various cancers...
January 2, 2018: Oncotarget
Zhen Wang, Xiaoshan Xu, Nan Liu, Yingduan Cheng, Weilin Jin, Pengxing Zhang, Xin Wang, Hongwei Yang, Hui Liu, Yanyang Tu
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor with limited therapeutic options. Glioma stem cell (GSC) is thought to be greatly responsible for glioma tumor progression and drug resistance. But the molecular mechanisms of GSC deriving recurrence and drug resistance are still unclear. SOX9 (sex-determining region Y (SRY)-box9 protein), a transcription factor expressed in most solid tumors, is reported as a key regulator involved in maintaining cancer hallmarks including the GSCs state...
January 2, 2018: Oncotarget
Xin Zhang, Xiuting Liu, Wei Zhou, Mengdi Yang, Yang Ding, Qing Wang, Rong Hu
Resistance to temozolomide (TMZ) is a major clinical challenge in glioma treatment, but the mechanisms of TMZ resistance are poorly understood. Here, we provided evidence that ROCK2 acted redundantly to maintain resistance of TMZ in TMZ-resistant gliomas, and as a ROCK2 phosphorylation inhibitor, fasudil significantly suppressed proliferation of TMZ-resistant gliomas in vivo and vitro via enhancing the chemosensitivity of TMZ. Additionally, the membrane translocation of ABCG2 was decreased with fasudil by ROCK2/moesin pathway...
February 7, 2018: Cell Death & Disease
Yu-Chen Cheng, Wen-Chiuan Tsai, Yu-Chi Sung, Hsin-Han Chang, Ying Chen
BACKGROUND/AIMS: Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis. Proteasome subunit beta type-4 (PSMB4) is an essential subunit that contributes to the assembly of the 20S proteasome complex. However, the role of PSMB4 in glioblastomas remains to be clarified. The aim of this study was to investigate the role of PSMB4 in GBM tumor progression. METHODS: We first analyzed the PSMB4 protein and mRNA expression in 80 clinical brain specimens and 77 datasets from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database...
January 31, 2018: Cellular Physiology and Biochemistry
Jacques Grill, Maura Massimino, Eric Bouffet, Amedeo A Azizi, Geoffrey McCowage, Adela Cañete, Frank Saran, Marie-Cécile Le Deley, Pascale Varlet, Paul S Morgan, Tim Jaspan, Chris Jones, Felice Giangaspero, Helen Smith, Josep Garcia, Markus C Elze, Raphaël F Rousseau, Lauren Abrey, Darren Hargrave, Gilles Vassal
Purpose Bevacizumab (BEV) is approved in more than 60 countries for use in adults with recurrent glioblastoma. We evaluated the addition of BEV to radiotherapy plus temozolomide (RT+TMZ) in pediatric patients with newly diagnosed high-grade glioma (HGG). Methods The randomized, parallel group, multicenter, open-label HERBY trial ( identifier: NCT01390948) enrolled patients age ≥ 3 years to ≤ 18 years with localized, centrally neuropathology-confirmed, nonbrainstem HGG. Eligible patients were randomly assigned to receive RT + TMZ (RT: 1...
February 7, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Chao Shang, Wei Tang, Chen Pan, Xuanhao Hu, Yang Hong
PURPOSE: Human glioblastoma multiforme (GBM) is the most malignant intracranial primary cancer and is associated with high mortality and poor prognosis. This study aimed to investigate the regulatory effects and mechanism of tumor suppressor candidate 7 (TUSC7) gene to malignant proliferation and chemotherapy resistance to temozolomide (TMZ) in glioma cells. METHODS: The expression of TUSC7 was detected by quantitative real-time PCR. CCK-8 assay was used to detect cell proliferation ability and chemosensitivity...
February 3, 2018: Cancer Chemotherapy and Pharmacology
Yoshitaka Narita
The effectiveness of chemotherapy or chemoradiotherapy for diffuse astrocytoma (DA) has been largely unknown until recently. However, a randomized controlled study (RTOG 9802) showed that adding of procarbazine, CCNU, and vincristine (PCV) chemotherapy to fractionated radiotherapy (FRT) in patients with "high-risk" WHO grade II gliomas, including DA, has significant positive impact on both progression-free survival and overall survival. Effectiveness of temozolomide (TMZ) in cases of low-grade gliomas was also reported, and a randomized phase III trial comparing FRT alone or in combination with TMZ in cases of unresectable DA (JCOG 1303) is currently ongoing...
2018: Progress in Neurological Surgery
Randi J Cohen, Minesh P Mehta
Malignant gliomas are the most common primary brain tumors and have devastatingly high mortality rates. Most recurrences are close to the surgical bed, despite adjuvant fractionated radiotherapy (FRT). Localized FRT to total dose of 60 Gy with concurrent and adjuvant temozolomide (TMZ) resulted in a statistically significant survival improvement of patients with newly diagnosed glioblastoma compared to those treated with FRT alone, and has emerged as the cornerstone of therapy. Despite this progress, long-term survival remains poor...
2018: Progress in Neurological Surgery
Linwei Jia, Yaohui Tian, Yonghan Chen, Gang Zhang
Introduction: Temozolomide (TMZ) is commonly used for glioma chemotherapy. However, TMZ resistance limits the therapeutic effect of TMZ in glioma treatment. LncRNA-H19 acts as an oncogenic LncRNA in some types of cancers and has been reported to be up-regulated in glioma. Materials and methods: In our present study, we established TMZ-resistant glioma cells (U-251TMZ and M059JTMZ) to explore the effect of H19 on the chemoresistance of glioma cells. Results: We observed that the expression of H19 was significantly increased in U-251TMZ and M059JTMZ cells...
2018: OncoTargets and Therapy
William C Jackson, Christina I Tsien, Larry Junck, Denise Leung, Shawn Hervey-Jumper, Daniel Orringer, Jason Heth, Daniel R Wahl, Daniel E Spratt, Yue Cao, Theodore S Lawrence, Michelle M Kim
We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age ≥ 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution...
February 1, 2018: Journal of Neuro-oncology
Belinda Kramer, Radhika Singh, Jessica Wischusen, Rebecca Velickovic, Amanda Rush, Shiloh Middlemiss, Yu-Wooi Ching, Ian Edward Alexander, Geoffrey B McCowage
Gene transfer targeting haematopoietic stem cells (HSC) in children has shown sustained therapeutic benefit in the treatment of genetic diseases affecting the immune system, most notably in the severe combined immuno-deficiencies affecting T cell function. The HSC compartment has also been successfully targeted using gene transfer in children with genetic diseases affecting the central nervous system, such as metachromatic leukodystrophy and adrenoleukodystrophy. The HSC is also a target for genetic modification in strategies aiming to confer drug resistance to chemotherapy agents so as to reduce off-target toxicity, and to allow for chemotherapy dose escalation with the possibility of enhanced therapeutic benefit...
January 31, 2018: Human Gene Therapy
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