المؤلفون: Moosburner, Marie, Alibegovic, Lamija, Hasselmann, Korbinian, Gaiderov, Anton, Hildebrand, Johannes, Philippou‐Massier, Julia, Blum, Helmut, Fischer, Luca, Dreyling, Martin, Silkenstedt, Elisabeth

المصدر: Hematological Oncology; Dec2023, Vol. 41 Issue 5, p858-868, 11p

مصطلحات موضوعية: MANTLE cell lymphoma, CRIZOTINIB, CELL lines, DRUG resistance, MTOR inhibitors

مستخلص: Constitutive activation of the PI3K/AKT/mTOR‐pathway plays an important role in the pathogenesis of mantle cell lymphoma (MCL), leading to approval of the mTOR inhibitor temsirolimus for relapsed or refractory MCL. Yet, despite favorable initial response rates, early relapses under treatment have been observed. Therefore, understanding the underlying mechanisms of temsirolimus resistance and developing strategies to overcome it is highly warranted. Here, we established a new temsirolimus‐resistant MCL cell line to evaluate the molecular background of resistance to this drug. Transcriptome profiling and gene set enrichment analysis comparing temsirolimus‐sensitive and ‐resistant cell lines showed significant upregulation of PI3K/AKT/mTor‐, RAS signaling‐ and the RTK‐dependent PDGFR‐, FGFR‐, Met‐ and ALK‐signaling‐pathways in the resistant cells. Furthermore, MET, known as important proto‐oncogene and mediator of drug resistance, was among the most upregulated genes in the resistant cells. Importantly, Met protein was overexpressed in both, MCL cells with acquired as well as intrinsic temsirolimus resistance, but could not be detected in any of the temsirolimus sensitive ones. Combined pharmacological inhibition of mTOR and Met signaling with temsirolimus and the RTK inhibitor crizotinib significantly restored sensitivity to temsirolimus. Furthermore, this combined treatment proved to be synergistic in all MCL cell lines investigated and was also active in primary MCL cells. In summary, we showed for the first time that overexpression of MET plays an important role for mediating temsirolimus resistance in MCL and combined treatment with temsirolimus and crizotinib is a very promising therapeutic approach for MCL and an effective strategy to overcome temsirolimus resistance. [ABSTRACT FROM AUTHOR]

: Copyright of Hematological Oncology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المصدر: World Council of Enterostomal Therapists Journal; Dec2023, Vol. 43 Issue 4, p32-39, 8p

مصطلحات موضوعية: WOUND healing, ONLINE information services, ADRENOCORTICAL hormones, RAPAMYCIN, SYSTEMATIC reviews, MTOR inhibitors, MONOCLONAL antibodies, IMMUNOSUPPRESSIVE agents, MEDLINE

مصطلحات جغرافية: CANADA

مستخلص: Objective A review of recent literature to provide clinicians with an understanding of how different classes of immunosuppressants affect wound healing. Data sources A literature search was conducted in PubMed, Google Scholar, and the University of Calgary Health Sciences Library. Study Selection Studies chosen for inclusion were screened initially based on title using key words including "immunosuppressive medication, wound healing, and immunosuppression." If the title and/or abstract contained these key words and addressed wound healing related to immunosuppressant medications and had been published after 2000, they were included in the review. When human data was not available for an immunosuppressant (class), animal studies were included. Data Extraction Selected papers underwent full text review and summarisation. Data Synthesis Data were synthesised in a descriptive manner. Corticosteroids and mechanistic target of rapamycin (mTOR) inhibitors most consistently demonstrate detrimental effects on wound healing. For other classes of immunosuppressants, evidence is limited with varying effects on wound healing described. Conclusions Larger high-quality studies are required to better understand the effects of immunosuppressants particularly with development of new classes of these drugs on wound healing in order to identify those at highest risk of impairing wound healing. [ABSTRACT FROM AUTHOR]

: Copyright of World Council of Enterostomal Therapists Journal is the property of Cambridge Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Davoodi-Moghaddam, Zeinab, Jafari-Raddani, Farideh, Delshad, Mahda, Pourbagheri-Sigaroodi, Atieh, Bashash, Davood

المصدر: Journal of Cancer Research & Clinical Oncology; Nov2023, Vol. 149 Issue 16, p15293-15310, 18p

مصطلحات موضوعية: CLINICAL trials, PHOSPHOINOSITIDES, PHOSPHATIDYLINOSITOL 3-kinases, MTOR inhibitors, TUMOR growth, DATA extraction

الشركة/الكيان: UNITED States. Food & Drug Administration

مستخلص: The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway regulates proliferation, survival and metabolism, and its dysregulation is one of the most frequent oncogenic events across human malignancies. Over the last two decades, there has been significant focus on the clinical development of PI3K pathway inhibitors. More than 40 different inhibitors of this axis have reached various stages of clinical trials, but only a few of them have been approved by the Food and Drug Administration (FDA) for cancer treatment. These clinical results, however, could be improved given the importance of PI3K signaling in cancer and its role in linking cancer growth with metabolism. In this systematic review, after a glance at PI3K/AKT/mTOR pathway and its different inhibitors, we retrieved registered clinical trials evaluating the efficacy and safety of PI3K/AKT/mTOR inhibitors on Clinicaltrials.gov. Following the extraction of the data, finally we analyzed 2250 included studies in multiple steps, beginning with an overview and moving on to the details about type of malignancies, inhibitors, and treatment strategies. We also took a closer look at more than 100 phase III-IV clinical trials to pinpoint promising therapies, hoping that presenting a comprehensive picture of current clinical trials casts a flash of light on what remains to be done in future clinical trials of PI3K/AKT/mTOR inhibitors in human malignancies. [ABSTRACT FROM AUTHOR]

: Copyright of Journal of Cancer Research & Clinical Oncology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Zhang, Minghui, Ma, Zonghua, Qi, Hao, Cui, Xu, Li, Rui, Gao, Xuejun

المصدر: British Journal of Nutrition; 11/28/2023, Vol. 130 Issue 10, p1665-1677, 13p

مصطلحات موضوعية: METHIONINE metabolism, BIOLOGICAL models, LACTATION, PROTEINS, SEQUENCE analysis, ANIMAL experimentation, CELL receptors, PUBERTY, MTOR inhibitors, MILK proteins, GENE expression profiling, BREAST, TISSUES, CELL proliferation, DESCRIPTIVE statistics, RESEARCH funding, POLYMERASE chain reaction, EPITHELIAL cells, CELL lines, FATTY acids, MICE, PHOSPHORYLATION

مستخلص: The G protein-coupled receptors (GPCR) sensing nutritional signals (amino acids, fatty acids, glucose, etc.) are not fully understood. In this research, we used transcriptome sequencing to analyse differentially expressed genes (DEG) in mouse mammary gland tissues at puberty, lactation and involution stages, in which eight GPCR were selected out and verified by qRT-PCR assay. It was further identified the role of GPR110-mediating nutrients including palmitic acid (PA) and methionine (Met) to improve milk synthesis using mouse mammary epithelial cell line HC11. PA but not Met affected GPR110 expression in a dose-dependent manner. GPR110 knockdown decreased milk protein and fat synthesis and cell proliferation and blocked the stimulation of PA on mechanistic target of rapamycin (mTOR) phosphorylation and sterol-regulatory element binding protein 1c (SREBP-1c) expression. In summary, these experimental results disclose DEG related to lactation and reveal that GPR110 mediates PA to activate the mTOR and SREBP-1c pathways to promote milk protein and fat synthesis. [ABSTRACT FROM AUTHOR]

: Copyright of British Journal of Nutrition is the property of Cambridge University Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Zhong, Qing, Wang, Hua‐Gen, Yang, Ji‐Hong, Tu, Ru‐Hong, Li, An‐Yao, Zeng, Gui‐Rong, Zheng, Qiao‐Ling, Yu Liu, Zhi‐, Shang‐Guan, Zhi‐Xin, Bo Huang, Xiao‐, Huang, Qiang, Li, Yi‐Fan, Zheng, Hua‐Long, Lin, Guang‐Tan, Huang, Ze‐Ning, Xu, Kai‐Xiang, Qiu, Wen‐Wu, Jiang, Mei‐Chen, Zhao, Ya‐Jun, Lin, Jian‐Xian

المصدر: Advanced Science; 11/14/2023, Vol. 10 Issue 32, p1-17, 17p

مصطلحات موضوعية: CANCER stem cells, ADENOCARCINOMA, DRUG resistance in cancer cells, MTOR inhibitors, ANIMAL models in research

مستخلص: Gastric cancer stem cells (GCSCs) are self‐renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA‐seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1‐CreERT2; Rosa26Tdtomato and Tff1‐CreERT2; Apcfl/fl; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest‐specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency‐induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency. [ABSTRACT FROM AUTHOR]

: Copyright of Advanced Science is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Li, Meng, Feng, Zhen, Han, Rui, Hu, Benchuang, Zhang, Renfeng, Wang, Hui

المصدر: Thoracic Cancer; Nov2023, Vol. 14 Issue 31, p3089-3096, 8p

مصطلحات موضوعية: PROTEIN kinases, IN vitro studies, REVERSE transcriptase polymerase chain reaction, FLOW cytometry, BIOLOGICAL models, IN vivo studies, WESTERN immunoblotting, ANIMAL experimentation, APOPTOSIS, MTOR inhibitors, CELLULAR signal transduction, CELL survival, COMPARATIVE studies, GLYCOPROTEINS, RESEARCH funding, DESCRIPTIVE statistics, PACLITAXEL, CELL lines, TUMOR markers, ESOPHAGEAL tumors, MICE, PHARMACODYNAMICS

مستخلص: Background: The aim of this study was to analyze the effect of paclitaxel on the apoptosis of esophageal cancer cells in relation to MUC20. Methods: RT‐qPCR analysis, a CCK‐8 assay, western blotting, and flow cytometry were used to analyze the anticancer effects of paclitaxel treatment or OE‐MUC20 in vitro and in vivo. Results: The in vitro results showed that paclitaxel significantly induced MUC20 upregulation and that paclitaxel treatment or OE‐MUC20 significantly decreased esophageal cancer cell viability and increased mTOR signaling activation and apoptosis. In addition, PKM2, a key downstream molecule of mTOR signaling, similarly showed significant upregulation after paclitaxel treatment in cells with OE‐MUC20, and its expression was attenuated after treatment with mTOR inhibitors. In a nude mouse model, tumor growth was slow in the OE‐MUC20 group and accelerated after inhibition of mTOR signaling. Conclusion: These data suggest that MUC20 is an important target of paclitaxel in esophageal cancer and promotes apoptosis through activation of mTOR signaling. [ABSTRACT FROM AUTHOR]

: Copyright of Thoracic Cancer is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Jung, Seong-Chan, Jung, Tae-Young, Lee, Tae-Kyu, Kim, Yeong Jin, Baek, Hee Jo, Kim, Sung Soon

المصدر: Child's Nervous System; Nov2023, Vol. 39 Issue 11, p3289-3294, 6p

مصطلحات موضوعية: CHILD patients, SKULL base, SKULL tumors, MAGNETIC resonance imaging, MTOR inhibitors, NEUROFIBROMATOSIS 1

مستخلص: Kaposiform hemangioendothelioma is an extremely rare vascular tumor which shows aggressive local growth. We present a case of rapid growing vascular skull tumor with dura invasion in a pediatric patient with neurofibromatosis type 1. A 14-year-old male complained of headache and dizziness for 1 month after minor head trauma. Brain magnetic resonance imaging (MRI) revealed a 5-cm-sized tumor in the left frontotemporal bone with internal hemorrhage and cystic changes. The gross total resection of tumor was done. At the 7-month follow-up, brain MRI revealed a recurrent skull tumor with intracranial dura mass. He underwent second surgery, and the pathologic diagnosis was suggestive of Kaposiform hemangioendothelioma. For this vascular proliferative tumor, mTOR inhibitor was treated for 6 months, and there was the recurred nodular-enhancing mass along the sphenoid ridge. After additional 2 months of medication, the following MRI revealed a decreased nodular-enhancing mass. [ABSTRACT FROM AUTHOR]

: Copyright of Child's Nervous System is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Zhu, Shenyu, Yu, Wenbo, Gao, Jianfeng, Xiong, Jianxian

المصدر: International Wound Journal; Nov2023, Vol. 20 Issue 9, p3491-3497, 7p

مصطلحات موضوعية: HEART transplantation, MEDICAL databases, ONLINE information services, CONFIDENCE intervals, META-analysis, MEDICAL information storage & retrieval systems, SYSTEMATIC reviews, PATIENTS, MTOR inhibitors, SURGICAL complications, RISK assessment, SURGICAL site infections, RESEARCH funding, ODDS ratio, MEDLINE, TRANSPLANTATION of organs, tissues, etc., DISEASE risk factors

مستخلص: A meta‐analysis investigation was executed to measurethe wound complications (WCs) frequency in heart transplant (HT) recipients on mammalian target of rapamycin inhibitors (MTRIs). A comprehensive literature investigation till February 2023 was applied and 978 interrelated investigations were reviewed. The 10 chosen investigations enclosed 2173 individuals with HT were in the chosen investigations' starting point, 1164 of them were utilising MTRIs, and 1009 were utilising control. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were utilised to compute the value of the WCs frequency in HT recipients on MTRIs by the dichotomous approaches and a fixed or random model. MTRIs had significantly higher WCs (OR, 1.53; 95% CI, 1.19–1.98, P =.001) compared with those with control in individuals with HT. MTRIs had significantly higher WCs compared with those with control in individuals with HT. However, care must be exercised when dealing with its values because of the low number of the nominated investigations and the low sample size of some of the nominated investigations for the meta‐analysis. [ABSTRACT FROM AUTHOR]

: Copyright of International Wound Journal is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Poddar, Nitesh Kumar, Khan, Arshma, Fatima, Falak, Saxena, Anshulika, Ghaley, Garima, Khan, Shahanavaj

المصدر: Cellular & Molecular Neurobiology; Nov2023, Vol. 43 Issue 8, p3815-3832, 18p

مصطلحات موضوعية: C-reactive protein, NEURODEGENERATION, ALZHEIMER'S disease, MTOR inhibitors, IMMUNOMODULATORS

مستخلص: Inflammatory biomarkers have been very useful in detecting and monitoring inflammatory processes along with providing helpful information to select appropriate therapeutic strategies. C-reactive protein (CRP) is a nonspecific, but quite useful medical acute inflammatory biomarker and is associated with persistent chronic inflammatory processes. Several studies suggest that different levels of CRP are correlated with neurological disorders such as Alzheimer's disease (AD). However, dynamics of CRP levels have also been observed in virus/bacterial-related infections leading to inflammatory responses and this triggers mTOR-mediated pathways for neurodegeneration diseases. The biophysical structural transition from CRP to monomeric CRP (mCRP) and the significance of the ratio of CRP levels on the onset of symptoms associated with inflammatory response have been discussed. In addition, mTOR inhibitors act as immunomodulators by downregulating the expression of viral infection and can be explored as a potential therapy for neurological diseases. [ABSTRACT FROM AUTHOR]

: Copyright of Cellular & Molecular Neurobiology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Goto, Hiroaki, Ohtsu, Takashi, Ito, Mieko, Sagisaka, Maiko, Naruto, Takuya, Nagai, Jun-ichi, Kitagawa, Norihiko, Tanaka, Mio, Yanagimachi, Masakatsu, Hiroshima, Yukihiko, Miyagi, Yohei

المصدر: Human Cell; Nov2023, Vol. 36 Issue 6, p2152-2161, 10p

مصطلحات موضوعية: EWING'S sarcoma, DRUG efficacy, PROTEASOME inhibitors, TUMORS, MTOR inhibitors

مستخلص: The feasibility of a short-term, three-dimensional (3D) culture–based drug sensitivity test (DST) for surgically resected malignant bone tumors, including osteosarcoma (OS), was evaluated utilizing two OS cell line (KCS8 or KCS9)–derived xenograft (CDX) models. Twenty-three (KCS8) or 39 (KCS9) of 60 tested drugs were likely effective in OS cells derived from a cell line before xenografting. Fewer drugs (19: KCS8, 26: KCS9) were selected as effective drugs in cells derived from a CDX tumor, although the drug sensitivities of 60 drugs significantly correlated between both types of samples. The drug sensitivity of a CDX tumor was not significantly altered after the depletion of non-tumorous components in the sample. In a surgically resected metastatic tumor obtained from a patient with OS, for whom a cancer genome profiling test detected a pathogenic PIK3CA mutation, DST identified mTOR and AKT inhibitors as effective drugs. Of two CDX and six clinical samples of OS and Ewing's sarcoma, DST identified proteasome inhibitors (bortezomib, carfilzomib) and CEP-701 as potentially effective drugs in common. This unique method of in vitro drug testing using 3D-cell cultures is feasible in surgically resected tissues of metastatic malignant bone tumors. [ABSTRACT FROM AUTHOR]

: Copyright of Human Cell is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)