scholarly journals A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway

Oncotarget ◽  
2015 ◽  
Vol 6 (39) ◽  
pp. 41736-41749 ◽  
Author(s):  
Azadeh Cheraghchi-Bashi ◽  
Christine A. Parker ◽  
Ed Curry ◽  
Jean-Frederic Salazar ◽  
Hatice Gungor ◽  
...  
Keyword(s):  
Clinical Data ◽  
Mtorc1 Pathway ◽  
Biomarker Signature

scholarly journals Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

2011 ◽  
pp. 141-151
Author(s):  
Daniele Santini ◽  
Maria Elisabetta Fratto ◽  
Bruno Vincenzi ◽  
Silvia Angeletti ◽  
Giordano Dicuonzo ◽  
...  
Keyword(s):  
Clinical Data ◽  
Survival Data ◽  
Clinical Evidence ◽  
Bisphosphonate Therapy ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Phase Iii Trial ◽  
Skeletal Disease

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.

scholarly journals mTORC1 controls phase-separation and the biophysical properties of the cytoplasm by tuning crowding

2017 ◽  
Author(s):  
M. Delarue ◽  
G.P. Brittingham ◽  
S. Pfeffer ◽  
I.V. Surovtsev ◽  
S. Ping-lay ◽  
...  
Keyword(s):  
Phase Separation ◽  
Fluorescent Protein ◽  
Effective Diffusion ◽  
Reaction Rates ◽  
Biophysical Properties ◽  
Cell Interior ◽  
Profound Impact ◽  
Mtorc1 Pathway

Summary (Abstract)Macromolecular crowding has a profound impact on reaction rates and the physical properties of the cell interior, but the mechanisms that regulate crowding are poorly understood. We developed Genetically Encoded Multimeric nanoparticles (GEMs) to dissect these mechanisms. GEMs are homomultimeric scaffolds fused to a fluorescent protein. GEMs self-assemble into bright, stable fluorescent particles of defined size and shape. By combining tracking of GEMs with genetic and pharmacological approaches, we discovered that the mTORC1 pathway can tune the effective diffusion coefficient of macromolecules ≥15 nm in diameter more than 2-fold without any discernable effect on the motion of molecules ≥5 nm. These mTORCI-dependent changes in crowding and rheology affect phase-separation both in vitro and in vivo. Together, these results establish a role for mTORCI in controlling both the biophysical properties of the cytoplasm and the phase-separation of biopolymers.

GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

2021 ◽  
Author(s):  
Wang Zhang ◽  
Zhendong Liu ◽  
Binchao Liu ◽  
Miaomiao Jiang ◽  
Shi Yan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Clinical Data ◽  
Poor Prognosis ◽  
Glioma Cells ◽  
Diagnosis And Treatment ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

Abstract Background: Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas.Methods: We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells.Results: GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration.Conclusions: Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

scholarly journals Expression analysis and implication of Rab1A in gastrointestinal relevant tumor

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Menglin Xu ◽  
Xinyu Shao ◽  
Xiaoyi Kuai ◽  
Liping Zhang ◽  
Chunli Zhou ◽  
...  
Keyword(s):  
Strongly Correlated ◽  
Gastrointestinal Cancers ◽  
Gastrointestinal Tumor ◽  
Expression Levels ◽  
Promising Therapeutic Target ◽  
Tumor Tissues ◽  
Mtorc1 Pathway ◽  
And Migration

Abstract Gastrointestinal cancers have become increasingly prevalent worldwide. Previous studies have reported an oncogenic function of Rab1A in colorectal cancer and hepatocellular carcinomas via the mTOR pathway. However, the exact role of Rab1A in gastrointestinal cancers remains elusive. We detected significantly higher expression of Rab1A in the gastrointestinal tumor tissues compared to that in other cancer types following an in silico analysis of TGCA and GTEX databases. Furthermore, Rab1A was overexpressed in the gastrointestinal tumor tissues compared to the para-tumor tissues. Although Rab1A expression levels were not associated with the tumor-lymph node-metastasis (TNM) stage, Rab1A overexpression in the tumor tissues of a gastric cancer (GC) cohort was strongly correlated with poor prognosis in the patients. In addition, Rab1A knockdown significantly inhibited the in vitro proliferation and migration abilities of GC cells, as well as the growth of GC xenografts in vivo. Furthermore, a positive correlation was observed between Rab1A expression levels and that of different upstream/downstream mTOR targets. Taken together, Rab1A regulates the PI3K-AKT-mTORC1 pathway through the mTORC1 complex consisting of mTORC1, Rheb and Rab1A, and is a promising therapeutic target in GC.

Noninvasive Dentistry: A Dream or Reality?

2015 ◽  
Vol 49 (Suppl. 1) ◽  
pp. 11-17 ◽  
Author(s):  
B.H. Clarkson ◽  
R.A.M. Exterkate
Keyword(s):  
Clinical Data ◽  
Surface Integrity ◽  
Clinical Studies ◽  
Pathogenic Bacteria ◽  
Caries Prevention

Various caries prevention and repair strategies are reviewed in this article ranging from the use of fluoride to nanohydroxyapatite particles. Several of the strategies which combine fluoride and calcium and phosphate treatments have both in vitro and in vivo data showing them to be efficacious if the surface integrity of the lesion is not breached. Once this has occurred, the rationale for cutting off the nutrient supplies to the pathogenic bacteria without the removal of the infected dentine, a noninvasive restorative technique, is discussed using existing clinical studies as examples. Finally two novel noninvasive restorative techniques using fluorohydroxyapatite crystals are described. The need for clinical data in support of emerging caries-preventive and restorative strategies is emphasized.

scholarly journals GNG5 is a novel oncogene associated with cell migration, proliferation, and poor prognosis in glioma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wang Zhang ◽  
Zhendong Liu ◽  
Binchao Liu ◽  
Miaomiao Jiang ◽  
Shi Yan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Clinical Data ◽  
Poor Prognosis ◽  
Glioma Cells ◽  
Diagnosis And Treatment ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

Abstract Background Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. GNG5, which is part of the G-protein family, has been associated with different malignant tumors, though the role of GNG5 in glioma has not been studied. Therefore, we aimed to identify the relationship between GNG5 and glioma prognosis and identify a new biomarker for the diagnosis and treatment of gliomas. Methods We used data on more than a thousand gliomas from multiple databases and clinical data to determine the expression of GNG5 in glioma. Based on clinical data and CGGA database, we identified the correlation between GNG5 and multiple molecular and clinical features and prognosis using various analytical methods. Co-expression analysis and GSEA were performed to detect GNG5-related genes in glioma and possible signaling pathways involved. ESTIMATE, ssGSEA, and TIMER were used to detect the relationship between GNG5 and the immune microenvironment. Functional experiments were performed to explore the function of GNG5 in glioma cells. Results GNG5 is highly expressed in gliomas, and its expression level is positively correlated with pathological grade, histological type, age, and tumor recurrence and negatively correlated with isocitrate dehydrogenase mutation, 1p/19 co-deletion, and chemotherapy. Moreover, GNG5 as an independent risk factor was negatively correlated with the overall survival time. GSEA revealed the potential signaling pathways involved in GNG5 function in gliomas, including cell adhesion molecules signaling pathway. The ssGSEA, ESTIMATE, and TIMER based analysis indicated a correlation between GNG5 expression and various immune cells in glioma. In vivo and in vitro experiments showed that GNG5 could participate in glioma cell proliferation and migration. Conclusions Based on the large data platform and the use of different databases to corroborate results obtained using various datasets, as well as in vitro and in vivo experiments, our study reveals for the first time that GNG5, as an oncogene, is overexpressed in gliomas and can inhibit the proliferation and migration of glioma cells and lead to poor prognosis of patients. Thus, GNG5 is a potential novel biomarker for the clinical diagnosis and treatment of gliomas.

scholarly journals EXTH-38. ORTHOGONAL IN VIVO MODELS WERE THE SOLE PRECLINICAL PREDICTOR OF CLINICAL EFFICACY IN PHASE 1 TRIALS OF TARGETED THERAPIES FOR GLIOBLASTOMA: RESULTS OF A SYSTEMATIC REVIEW

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii95-ii95
Author(s):  
Ashray Gunjur ◽  
Adithya Balasubramanian ◽  
Umbreen Hafeez ◽  
Siddharth Menon ◽  
Lawrence Cher ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cell Line ◽  
Clinical Efficacy ◽  
Clinical Data ◽  
Orthogonal Group ◽  
Phase 1 ◽  
Targeted Agents ◽  
In Vivo Models

Abstract INTRODUCTION No drug has improved survival in recurrent glioblastoma despite encouraging activity preclinically. We undertook a systematic review of matched preclinical and Phase 1 trials (P1Ts) of targeted agents to investigate potential preclinical predictors of clinical efficacy. METHODS We identified all adult glioblastoma monotherapy P1Ts of targeted agents & preceding preclinical data published between 2006–2019 via structured searches of EMBASE/MEDLINE/PUBMED. For preclinical studies, data regarding in vitro models, in vivo models (species, implantation site, cell-line type) and efficacy (growth inhibition, regression rate, survival) were extracted. For P1T, response rate (RR) data were collected as absolute (%) and categorical (RR< 5% vs. RR≥ 5%) variables. Associations were compared by chi-square/Fisher’s exact test, Kruskal-Wallis or Mann-Whitney U testing as appropriate with 2-sided p-values. RESULTS We found 28 P1Ts with median RR 2.9% (range 0.0–33.3%) and mOS 8.0mo (range 4.6–13.0mo). Seven (25%) had ‘minimal’ published pre-clinical data (5 missing entirely; 2 in vitro only); 12 (43%) utilised one cell line in vivo (‘single model’ group); and 9 (32%) used 2+ biologically distinct in vivo models (‘orthogonal’ group). There was strong reliance on U87-based cell lines (14/21 (71%)) in the latter groups. None of the variables tested were associated with RR except for use of ‘orthogonal models’. Compared to the ‘orthogonal’ group, the P1T RR rate was lower in ‘single’ and ‘minimal’ groups (6.8% vs 1.2%, p= 0.043 and 6.8% vs 0.0%, p= 0.026 respectively). The frequency of P1T with a RR > 5% was also higher in the ‘orthogonal’ compared to the same two groups (78% vs 20%, p= 0.042 and 78% vs 17%, p= 0.041). CONCLUSION The availability of good quality pre-clinical data, especially the use of orthogonal models in vivo, was significantly associated with P1T response rates and warrants further investigation as a minimal threshold of evidence in future drug development.

Injectable Drug Delivery Systems of Doxorubicin Revisited: In Vitro-In Vivo Relationships Using Human Clinical Data

2021 ◽  
pp. 121073
Author(s):  
Harshvardhan Modh ◽  
Daniel Juncheng Fang ◽  
Yi Hsuan Ou ◽  
Jia Ning Nicolette Yau ◽  
Tatyana Kovshova ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Clinical Data ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Injectable Drug

scholarly journals The GARDpotency Assay for Potency-Associated Subclassification of Chemical Skin Sensitizers—Rationale, Method Development, and Ring Trial Results of Predictive Performance and Reproducibility

2020 ◽  
Vol 176 (2) ◽  
pp. 423-432
Author(s):  
Robin Gradin ◽  
Angelica Johansson ◽  
Andy Forreryd ◽  
Emil Aaltonen ◽  
Anders Jerre ◽  
...  
Keyword(s):  
Gene Expression ◽  
Method Development ◽  
Expression Profiles ◽  
Hazard Identification ◽  
Predictive Toxicology ◽  
Ring Trial ◽  
Biomarker Signature

Abstract Proactive identification and characterization of hazards attributable to chemicals are central aspects of risk assessments. Current legislations and trends in predictive toxicology advocate a transition from in vivo methods to nonanimal alternatives. For skin sensitization assessment, several OECD validated alternatives exist for hazard identification, but nonanimal methods capable of accurately characterizing the risks associated with sensitizing potency are still lacking. The GARD (Genomic Allergen Rapid Detection) platform utilizes exposure-induced gene expression profiles of a dendritic-like cell line in combination with machine learning to provide hazard classifications for different immunotoxicity endpoints. Recently, a novel genomic biomarker signature displaying promising potency-associated discrimination between weak and strong skin sensitizers was proposed. Here, we present the adaptation of the defined biomarker signature on a gene expression analysis platform suited for routine acquisition, confirm the validity of the proposed biomarkers, and define the GARDpotency assay for prediction of skin sensitizer potency. The performance of GARDpotency was validated in a blinded ring trial, in accordance with OECD guidance documents. The cumulative accuracy was estimated to 88.0% across 3 laboratories and 9 independent experiments. The within-laboratory reproducibility measures ranged between 62.5% and 88.9%, and the between-laboratory reproducibility was estimated to 61.1%. Currently, no direct or systematic cause for the observed inconsistencies between the laboratories has been identified. Further investigations into the sources of introduced variability will potentially allow for increased reproducibility. In conclusion, the in vitro GARDpotency assay constitutes a step forward for development of nonanimal alternatives for hazard characterization of skin sensitizers.

scholarly journals UBE2T-regulated H2AX monoubiquitination induces hepatocellular carcinoma radioresistance by facilitating CHK1 activation

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Jingyuan Sun ◽  
Zhenru Zhu ◽  
Wenwen Li ◽  
Mengying Shen ◽  
Chuanhui Cao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Dna Repair ◽  
Clinical Data ◽  
Underlying Mechanism ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Checkpoints

Abstract Background Radioresistance is the major obstacle in radiation therapy (RT) for hepatocellular carcinoma (HCC). Dysregulation of DNA damage response (DDR), which includes DNA repair and cell cycle checkpoints activation, leads to radioresistance and limits radiotherapy efficacy in HCC patients. However, the underlying mechanism have not been clearly understood. Methods We obtained 7 pairs of HCC tissues and corresponding non-tumor tissues, and UBE2T was identified as one of the most upregulated genes. The radioresistant role of UBE2T was examined by colony formation assays in vitro and xenograft tumor models in vivo. Comet assay, cell cycle flow cytometry and γH2AX foci measurement were used to investigate the mechanism by which UBE2T mediating DDR. Chromatin fractionation and immunofluorescence staining were used to assess cell cycle checkpoint kinase 1(CHK1) activation. Finally, we analyzed clinical data from HCC patients to verify the function of UBE2T. Results Here, we found that ubiquitin-conjugating enzyme E2T (UBE2T) was upregulated in HCC tissues, and the HCC patients with higher UBE2T levels exhibited poorer outcomes. Functional studies indicated that UBE2T increased HCC radioresistance in vitro and in vivo. Mechanistically, UBE2T-RNF8, was identified as the E2-E3 pair, physically bonded with and monoubiquitinated histone variant H2AX/γH2AX upon radiation exposure. UBE2T-regulated H2AX/γH2AX monoubiquitination facilitated phosphorylation of CHK1 for activation and CHK1 release from the chromatin to cytosol for degradation. The interruption of UBE2T-mediated monoubiquitination on H2AX/γH2AX, including E2-enzyme-deficient mutation (C86A) of UBE2T and monoubiquitination-site-deficient mutation (K119/120R) of H2AX, cannot effectively activate CHK1. Moreover, genetical and pharmacological inhibition of CHK1 impaired the radioresistant role of UBE2T in HCC. Furthermore, clinical data suggested that the HCC patients with higher UBE2T levels exhibited worse response to radiotherapy. Conclusion Our results revealed a novel role of UBE2T-mediated H2AX/γH2AX monoubiquitination on facilitating cell cycle arrest activation to provide sufficient time for radiation-induced DNA repair, thus conferring HCC radioresistance. This study indicated that disrupting UBE2T-H2AX-CHK1 pathway maybe a promising potential strategy to overcome HCC radioresistance.

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