187 research outputs found
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HumanLight: Incentivizing ridesharing via human-centric deep reinforcement learning in traffic signal control
po 472 microrna as biomarkers of resistance to regorafenib in metastatic colorectal cancer patient
Introduction Regorafenib demonstrated efficacy in pre-treated metastatic colorectal cancer (mCRC) patients. Limited clinical benefit in unselected patient populations highlights the unmet need for better patient selection and identification of mechanisms of action. MicroRNAs (miRs) are small non-coding RNAs involved in cell homeostasis, carcinogenesis and control multiple oncogenic pathways. Numerous miRs deregulation in mCRC are associated with clinical outcome and cancer progression. Material and methods We ran a translational phase II trial of regorafenib in chemo-refractory mCRC patients with biopsiable metastases. Tissue biopsies were obtained at baseline (BL), after 2 months of treatment, and at disease progression (PD). Patient Derived Organoids (PDOs) and PDO-xenotransplants were generated to study primary and acquired resistance to regorafenib. MiR profiling was performed in BL serum of all patients by NanoString nCounter platform and validated with digital droplet (dd)PCR in serum, plasma and exosomes and by In Situ Hybridization (ISH) in matching tissue biopsies. Fisher's exact test investigated potential associations between patient groups and categorical variables whilst t-test or non-parametric equivalent tests were used for continuous variables. Progression Free Survival (PFS) was measured from date of registration to date of first progression/relapse or death from cancer progression. Overall Survival (OS) was measured from date of randomisation to death from cancer. The Kaplan-Meier method summarised the survival estimates while the Cox proportional hazards model used to compare the survival rates between patient groups with and without adjustment for the effect of covariates. Results and discussions MiR expression was tested in 43 BL sera. Dysregulation in 28 miRs was associated with PFS and/or OS. Among these miRs, up-regulation of miR-652â3âp and down-regulation of miR-3614â3âp was associated with worse PFS and OS. Results were validated by ddPCR on the same serum samples, and matching plasmas. ISH confirmed dysregulation of two miRs in sequential tissues biopsies, PDOs and PDO-xenotransplants of patients with primary and acquired resistance. Validation in an independent patient's cohort (n=70) is ongoing. Functional experiments to define miR-mediated resistance are ongoing. Conclusion Circulating miR-652â3âp and miR-3614â3âp might be exploited as biomarkers for the upfront selection of patients' candidate to regorafenib treatment and might be used to track and forecast acquired resistance to treatment
MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer.
Junctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (nâ=â947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (nâ=â1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC
MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma
Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors
Global Perspectives on Task Shifting and Task Sharing in Neurosurgery.
BACKGROUND: Neurosurgical task shifting and task sharing (TS/S), delegating clinical care to non-neurosurgeons, is ongoing in many hospital systems in which neurosurgeons are scarce. Although TS/S can increase access to treatment, it remains highly controversial. This survey investigated perceptions of neurosurgical TS/S to elucidate whether it is a permissible temporary solution to the global workforce deficit. METHODS: The survey was distributed to a convenience sample of individuals providing neurosurgical care. A digital survey link was distributed through electronic mailing lists of continental neurosurgical societies and various collectives, conference announcements, and social media platforms (July 2018-January 2019). Data were analyzed by descriptive statistics and univariate regression of Likert Scale scores. RESULTS: Survey respondents represented 105 of 194 World Health Organization member countries (54.1%; 391 respondents, 162 from high-income countries and 229 from low- and middle-income countries [LMICs]). The most agreed on statement was that task sharing is preferred to task shifting. There was broad consensus that both task shifting and task sharing should require competency-based evaluation, standardized training endorsed by governing organizations, and maintenance of certification. When perspectives were stratified by income class, LMICs were significantly more likely to agree that task shifting is professionally disruptive to traditional training, task sharing should be a priority where human resources are scarce, and to call for additional TS/S regulation, such as certification and formal consultation with a neurosurgeon (in person or electronic/telemedicine). CONCLUSIONS: Both LMIC and high-income countries agreed that task sharing should be prioritized over task shifting and that additional recommendations and regulations could enhance care. These data invite future discussions on policy and training programs
Exploiting evolutionary steering to induce collateral drug sensitivity in cancer
Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108-109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance
Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine
[This corrects the article DOI: 10.1186/s13054-016-1208-6.]
MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma.
BACKGROUND & AIMS:Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors. METHODS:We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice. RESULTS:Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21. CONCLUSIONS:miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents
Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.
Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer
Electrified thin film flow at finite Reynolds number on planar substrates featuring topography
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