<i>EPS8</i> Inhibition Increases Cisplatin Sensitivity in Lung Cancer Cells

Cisplatin, a commonly used chemotherapeutic, is associated with ototoxicity, renal toxicity and neurotoxicity, thus identifying means to increase the therapeutic index of cisplatin may allow for improved outcomes. A SNP (rs4343077) within EPS8, discovered through a genome wide association study of cisplatin-induced cytotoxicity and apoptosis in lymphoblastoid cell lines (LCLs), provided impetus to further study this gene. The purpose of this work was to evaluate the role of EPS8 in cellular susceptibility to cisplatin in cancerous and non-cancerous cells. We used EPS8 RNA interference to determine the effect of decreased EPS8 expression on LCL and A549 lung cancer cell sensitivity to cisplatin. EPS8 knockdown in LCLs resulted in a 7.9% increase in cisplatin-induced survival (P = 1.98×10−7) and an 8.7% decrease in apoptosis (P = 0.004) compared to control. In contrast, reduced EPS8 expression in lung cancer cells resulted in a 20.6% decrease in cisplatin-induced survival (P = 5.08×10−5). We then investigated an EPS8 inhibitor, mithramycin A, as a potential agent to increase the therapeutic index of cisplatin. Mithramycin A decreased EPS8 expression in LCLs resulting in decreased cellular sensitivity to cisplatin as evidenced by lower caspase 3/7 activation following cisplatin treatment (42.7%±6.8% relative to control P = 0.0002). In 5 non-small-cell lung carcinoma (NSCLC) cell lines, mithramycin A also resulted in decreased EPS8 expression. Adding mithramycin to 4 NSCLC cell lines and a bladder cancer cell line, resulted in increased sensitivity to cisplatin that was significantly more pronounced in tumor cell lines than in LCL lines (pEPS8, such as mithramycin A, could improve cisplatin treatment by increasing sensitivity of tumor relative to normal cells.</p

Genome-Wide Local Ancestry Approach Identifies Genes and Variants Associated with Chemotherapeutic Susceptibility in African Americans

Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5′-deoxyfluorouridine (5′-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−4). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5′-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−3). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (pTP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.</p

Balancing the playing field: collaborative gaming for physical training.

BACKGROUND: Multiplayer video games promoting exercise-based rehabilitation may facilitate motor learning, by increasing motivation through social interaction. However, a major design challenge is to enable meaningful inter-subject interaction, whilst allowing for significant skill differences between players. We present a novel motor-training paradigm that allows real-time collaboration and performance enhancement, across a wide range of inter-subject skill mismatches, including disabled vs. able-bodied partnerships. METHODS: A virtual task consisting of a dynamic ball on a beam, is controlled at each end using independent digital force-sensing handgrips. Interaction is mediated through simulated physical coupling and locally-redundant control. Game performance was measured in 16 healthy-healthy and 16 patient-expert dyads, where patients were hemiparetic stroke survivors using their impaired arm. Dual-player was compared to single-player performance, in terms of score, target tracking, stability, effort and smoothness; and questionnaires probing user-experience and engagement. RESULTS: Performance of less-able subjects (as ranked from single-player ability) was enhanced by dual-player mode, by an amount proportionate to the partnership's mismatch. The more abled partners' performances decreased by a similar amount. Such zero-sum interactions were observed for both healthy-healthy and patient-expert interactions. Dual-player was preferred by the majority of players independent of baseline ability and subject group; healthy subjects also felt more challenged, and patients more skilled. CONCLUSION: This is the first demonstration of implicit skill balancing in a truly collaborative virtual training task leading to heightened engagement, across both healthy subjects and stroke patients

Genome-Wide Local Ancestry Approach Identifies Genes and Variants Associated with Chemotherapeutic Susceptibility in African Americans

Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5′-deoxyfluorouridine (5′-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−4). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5′-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−3). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information

A glacial lake outburst floods hazard assessment in the Patagonian Andes combining inventory data and case-studies

We present a glacial-related lake inventory for a region spanning 41.5° - 47° S in Patagonian Andes, where information on past glacier lake outburst floods (GLOF's) has hitherto remained significantly underreported. Analyzing remotely sensed images, we obtained data on 702 glacial-related lakes. Through detailed geomorphic assessments and manual supervision, we revised current inventories and added 35 GLOFs triggered from moraine/bedrock dammed lakes failures. The regional GLOF inventory presented contains information on 71 historical failures of moraine/bedrock dammed glacial lakes. From this database we analyzed outburst timing and managed to constrain 37 events occurrences within a period of 1 year. Around 40 % of them have occurred since the early 2000's, most of them originating from lakes probably formed as a delayed response to the glacial retreat imposed by the end of the Little Ice Age. On the other hand, we analyzed meteorological conditions for a sub-set of 10 events constrained within a 10-days period, finding a strong link between atmospheric rivers, cut-off lows impacting the southern Andes, and GLOFs. Only one case is likely to have been triggered by a Mw 4.9 earthquake. Based on topographic potential for avalanching, we estimated GLOF hazard potential, recognizing at least 3 subregions with high hazard, which moreover can be highly susceptible to climate conditions that regionally affect GLOF occurrence

<i>EPS8</i> Inhibition Increases Cisplatin Sensitivity in Lung Cancer Cells

<div><p>Cisplatin, a commonly used chemotherapeutic, is associated with ototoxicity, renal toxicity and neurotoxicity, thus identifying means to increase the therapeutic index of cisplatin may allow for improved outcomes. A SNP (rs4343077) within <i>EPS8</i>, discovered through a genome wide association study of cisplatin-induced cytotoxicity and apoptosis in lymphoblastoid cell lines (LCLs), provided impetus to further study this gene. The purpose of this work was to evaluate the role of <i>EPS8</i> in cellular susceptibility to cisplatin in cancerous and non-cancerous cells. We used <i>EPS8</i> RNA interference to determine the effect of decreased <i>EPS8</i> expression on LCL and A549 lung cancer cell sensitivity to cisplatin. <i>EPS8</i> knockdown in LCLs resulted in a 7.9% increase in cisplatin-induced survival (<i>P</i> = 1.98×10⁻⁷) and an 8.7% decrease in apoptosis (<i>P</i> = 0.004) compared to control. In contrast, reduced <i>EPS8</i> expression in lung cancer cells resulted in a 20.6% decrease in cisplatin-induced survival (<i>P</i> = 5.08×10⁻⁵). We then investigated an <i>EPS8</i> inhibitor, mithramycin A, as a potential agent to increase the therapeutic index of cisplatin. Mithramycin A decreased <i>EPS8</i> expression in LCLs resulting in decreased cellular sensitivity to cisplatin as evidenced by lower caspase 3/7 activation following cisplatin treatment (42.7%±6.8% relative to control <i>P</i> = 0.0002). In 5 non-small-cell lung carcinoma (NSCLC) cell lines, mithramycin A also resulted in decreased <i>EPS8</i> expression. Adding mithramycin to 4 NSCLC cell lines and a bladder cancer cell line, resulted in increased sensitivity to cisplatin that was significantly more pronounced in tumor cell lines than in LCL lines (p<0.0001). An EGFR mutant NSCLC cell line (H1975) showed no significant change in sensitivity to cisplatin with the addition of mithramycin treatment. Therefore, an inhibitor of <i>EPS8</i>, such as mithramycin A, could improve cisplatin treatment by increasing sensitivity of tumor relative to normal cells.</p></div

Effect of mithramycin on sensitivity of molecularly distinct non-small-cell lung carcinoma cell lines.

<p>+ : Wild-type mt : Mutant.</p><p>*Mutation status of each cell line was provided from ATCC (Manassas, Virginia).</p

LCL caspase 3/7 activity for 5 µM cisplatin treatment alone compared to cisplatin plus 0.01 µM mithramycin.

<p>Each LCL experienced lower cisplatin-induced apoptotic activity with the added mithramycin relative to a no drug treatment control. Mithramycin treated 10859, 11830, 11840, and 12156 resulted in a 47.1, 40.8, 48.9, and 34.0% decrease from cisplatin alone, respectively. Data represents two separate experiments, each done in triplicate with standard error of the mean.</p

Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy.

PurposePaclitaxel is used worldwide in the treatment of breast, lung, ovarian, and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented, or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCL) and Asian patients.MethodsGWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare with a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human-induced pluripotent stem cells were used for functional validation of candidate genes.ResultsSNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P &lt; 10(-6)). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphologic changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P &lt; 0.05), including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphologic characteristics.ConclusionsWe identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy