Pharmacogenomics and cancer stem cells: a changing landscape?

Pharmacogenomics in oncology holds the promise to personalize cancer therapy. However, its clinical application is still limited to a few genes, and, in the large majority of cancers, the correlation between genotype and clinical outcome has been disappointing. One possible explanation is that current pharmacogenomic studies do not take into account the emerging role of cancer stem cells (CSCs) in drug sensitivity and resistance. CSCs are a subpopulation of cells driven by specific signal-transduction pathways, but genetic variants affecting their activity are generally neglected in current pharmacogenomic studies. Moreover, in several malignancies, CSCs represent a rare sub-population; therefore, whole tumor profiling might mask CSC gene expression patterns. This article reviews current evidence on CSC chemoresistance and shows how common genetic variations in CSC-related genes may predict individual response to anti-cancer agents. Furthermore, we provide insights into the design of pharmacogenomic studies to address the clinical usefulness of CSC genetic profiling

Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P <0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation

Post-streptococcal reactive arthritis in children: a distinct entity from acute rheumatic fever

There is a debate whether post-streptococcal reactive arthritis (PSRA) is a separate entity or a condition on the spectrum of acute rheumatic fever (ARF). We believe that PSRA is a distinct entity and in this paper we review the substantial differences between PSRA and ARF. We show how the demographic, clinical, genetic and treatment characteristics of PSRA differ from ARF. We review diagnostic criteria and regression formulas that attempt to classify patients with PSRA as opposed to ARF. The important implication of these findings may relate to the issue of prophylactic antibiotics after PSRA. However, future trials will be necessary to conclusively answer that question

Embodiment and Presence in Virtual Reality After Stroke. A Comparative Study With Healthy Subjects

[EN] The ability of virtual reality (VR) to recreate controlled, immersive, and interactive environments that provide intensive and customized exercises has motivated its therapeutic use after stroke. Interaction and bodily presence in VR-based interventions is usually mediated through virtual selves, which synchronously represent body movements or responses to events on external input devices. Embodied self-representations in the virtual world not only provide an anchor for visuomotor tasks, but their morphologies can have behavioral implications. While research has focused on the underlying subjective mechanisms of exposure to VR on healthy individuals, the transference of these findings to individuals with stroke is not evident and remains unexplored, which could affect the experience and, ultimately, the clinical effectiveness of neurorehabilitation interventions. This study determined and compared the sense of embodiment and presence elicited by a virtual environment under different perspectives and levels of immersion in healthy subjects and individuals with stroke. Forty-six healthy subjects and 32 individuals with stroke embodied a gender-matched neutral avatar in a virtual environment that was displayed in a first-person perspective with a head-mounted display and in a third-person perspective with a screen, and the participants were asked to interact in a virtual task for 10 min under each condition in counterbalanced order, and to complete two questionnaires about the sense of embodiment and presence experienced during the interaction. The sense of body-ownership, self-location, and presence were more vividly experienced in a first-person than in a third-person perspective by both healthy subjects (p < 0.001, eta(2)(p) = 0.212; p = 0.005, eta(2)(p) = 0.101; p = 0.001, eta(2)(p) = 0.401, respectively) and individuals with stroke (p = 0.019, eta(2)(p) = 0.070; p = 0.001, eta(2)(p) = 0.135; p = 0.014, eta(2)(p) = 0.077, respectively). In contrast, no agency perspective-related differences were found in any group. All measures were consistently higher for healthy controls than for individuals with stroke, but differences between groups only reached statistical significance in presence under the first-person condition (p < 0.010, eta(2)(p) = 0.084). In spite of these differences, the participants experienced a vivid sense of embodiment and presence in almost all conditions. These results provide first evidence that, although less intensively, embodiment and presence are similarly experienced by individuals who have suffered a stroke and by healthy individuals, which could support the vividness of their experience and, consequently, the effectiveness of VR-based interventions.This study was funded by Ministerio de Economía y Competitividad of Spain (Project RTC-2017-6051-7 and Grant BES-2014-068218), Fundació la Marató de la TV3 (Grant 201701-10), and Universitat Politècnica de València (Grant PAID-10-18). We acknowledge the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research.Borrego, A.; Latorre, J.; Alcañiz Raya, ML.; Llorens Rodríguez, R. (2019). Embodiment and Presence in Virtual Reality After Stroke. A Comparative Study With Healthy Subjects. Frontiers in Neurology. 10:1-8. https://doi.org/10.3389/fneur.2019.01061S1810Berlucchi, G., & Aglioti, S. (1997). 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Consciousness and Cognition, 36, 277-288. doi:10.1016/j.concog.2015.07.008Kilteni, K., Maselli, A., Kording, K. P., & Slater, M. (2015). Over my fake body: body ownership illusions for studying the multisensory basis of own-body perception. Frontiers in Human Neuroscience, 9. doi:10.3389/fnhum.2015.00141Clark, A., Kiverstein, J., & Vierkant, T. (Eds.). (2013). Decomposing the Will. doi:10.1093/acprof:oso/9780199746996.001.0001Frith, C. D., Blakemore, S.-J., & Wolpert, D. M. (2000). Abnormalities in the awareness and control of action. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 355(1404), 1771-1788. doi:10.1098/rstb.2000.0734Bermúdez i Badia, S., Fluet, G. G., Llorens, R., & Deutsch, J. E. (2016). Virtual Reality for Sensorimotor Rehabilitation Post Stroke: Design Principles and Evidence. Neurorehabilitation Technology, 573-603. doi:10.1007/978-3-319-28603-7_28Perez-Marcos, D., Sanchez-Vives, M. V., & Slater, M. (2011). Is my hand connected to my body? The impact of body continuity and arm alignment on the virtual hand illusion. Cognitive Neurodynamics, 6(4), 295-305. doi:10.1007/s11571-011-9178-5IJsselsteijn, W. A., de Kort, Y. A. W., & Haans, A. (2006). Is This My Hand I See Before Me? The Rubber Hand Illusion in Reality, Virtual Reality, and Mixed Reality. Presence: Teleoperators and Virtual Environments, 15(4), 455-464. doi:10.1162/pres.15.4.455Banakou, D., Groten, R., & Slater, M. (2013). Illusory ownership of a virtual child body causes overestimation of object sizes and implicit attitude changes. Proceedings of the National Academy of Sciences, 110(31), 12846-12851. doi:10.1073/pnas.1306779110Yee, N., & Bailenson, J. (2007). The Proteus Effect: The Effect of Transformed Self-Representation on Behavior. Human Communication Research, 33(3), 271-290. doi:10.1111/j.1468-2958.2007.00299.xSteed, A., Frlston, S., Lopez, M. M., Drummond, J., Pan, Y., & Swapp, D. (2016). An ‘In the Wild’ Experiment on Presence and Embodiment using Consumer Virtual Reality Equipment. IEEE Transactions on Visualization and Computer Graphics, 22(4), 1406-1414. doi:10.1109/tvcg.2016.2518135Colomer, C., Llorens, R., Noé, E., & Alcañiz, M. (2016). Effect of a mixed reality-based intervention on arm, hand, and finger function on chronic stroke. Journal of NeuroEngineering and Rehabilitation, 13(1). doi:10.1186/s12984-016-0153-6Laver, K. E., Lange, B., George, S., Deutsch, J. E., Saposnik, G., & Crotty, M. (2017). Virtual reality for stroke rehabilitation. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd008349.pub4Llorens, R., Borrego, A., Palomo, P., Cebolla, A., Noé, E., i Badia, S. B., & Baños, R. (2017). Body schema plasticity after stroke: Subjective and neurophysiological correlates of the rubber hand illusion. Neuropsychologia, 96, 61-69. doi:10.1016/j.neuropsychologia.2017.01.007Zeller, D., Gross, C., Bartsch, A., Johansen-Berg, H., & Classen, J. (2011). Ventral Premotor Cortex May Be Required for Dynamic Changes in the Feeling of Limb Ownership: A Lesion Study. Journal of Neuroscience, 31(13), 4852-4857. doi:10.1523/jneurosci.5154-10.2011Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). «Mini-mental state». Journal of Psychiatric Research, 12(3), 189-198. doi:10.1016/0022-3956(75)90026-6Romero, M., Sánchez, A., Marín, C., Navarro, M. D., Ferri, J., & Noé, E. (2012). Clinical usefulness of the Spanish version of the Mississippi Aphasia Screening Test (MASTsp): validation in stroke patients. Neurología (English Edition), 27(4), 216-224. doi:10.1016/j.nrleng.2011.06.001Latorre, J., Llorens, R., Colomer, C., & Alcañiz, M. (2018). Reliability and comparison of Kinect-based methods for estimating spatiotemporal gait parameters of healthy and post-stroke individuals. Journal of Biomechanics, 72, 268-273. doi:10.1016/j.jbiomech.2018.03.008Lloréns, R., Noé, E., Naranjo, V., Borrego, A., Latorre, J., & Alcañiz, M. (2015). Tracking Systems for Virtual Rehabilitation: Objective Performance vs. Subjective Experience. A Practical Scenario. Sensors, 15(3), 6586-6606. doi:10.3390/s150306586Slater, M., & Steed, A. (2000). A Virtual Presence Counter. Presence: Teleoperators and Virtual Environments, 9(5), 413-434. doi:10.1162/105474600566925Slater, M., Spanlang, B., Sanchez-Vives, M. V., & Blanke, O. (2010). First Person Experience of Body Transfer in Virtual Reality. PLoS ONE, 5(5), e10564. doi:10.1371/journal.pone.0010564Petkova, V. I., Khoshnevis, M., & Ehrsson, H. H. (2011). The Perspective Matters! Multisensory Integration in Ego-Centric Reference Frames Determines Full-Body Ownership. Frontiers in Psychology, 2. doi:10.3389/fpsyg.2011.00035Maselli, A., & Slater, M. (2013). The building blocks of the full body ownership illusion. Frontiers in Human Neuroscience, 7. doi:10.3389/fnhum.2013.00083Debarba, H. G., Molla, E., Herbelin, B., & Boulic, R. (2015). Characterizing embodied interaction in First and Third Person Perspective viewpoints. 2015 IEEE Symposium on 3D User Interfaces (3DUI). doi:10.1109/3dui.2015.7131728Burin, D., Livelli, A., Garbarini, F., Fossataro, C., Folegatti, A., Gindri, P., & Pia, L. (2015). Are Movements Necessary for the Sense of Body Ownership? Evidence from the Rubber Hand Illusion in Pure Hemiplegic Patients. PLOS ONE, 10(3), e0117155. doi:10.1371/journal.pone.0117155Post-stroke cognitive disorders TeasellR SalterK FaltynekP CotoiA EskesG Evidence-Based Review of Stroke Rehabilitatio

Genotranscriptomic meta-analysis of the Polycomb gene CBX2 in human cancers: initial evidence of an oncogenic role

Background: Polycomb group (PcG) proteins are histone modifiers known to transcriptionally silence key tumour suppressor genes in multiple human cancers. The chromobox proteins (CBX2, 4, 6, 7, and 8) are critical components of PcG-mediated repression. Four of them have been associated with tumour biology, but the role of CBX2 in cancer remains largely uncharacterised. Methods: Addressing this issue, we conducted a comprehensive and unbiased genotranscriptomic meta-analysis of CBX2 in human cancers using the COSMIC and Oncomine databases. Results: We discovered changes in gene expression that are suggestive of a widespread oncogenic role for CBX2. Our genetic analysis of 8013 tumours spanning 29 tissue types revealed no inactivating chromosomal aberrations and only 40 point mutations at the CBX2 locus. In contrast, the overall rate of CBX2 amplification averaged 10% in all combined neoplasms but exceeded 30% in ovarian, breast, and lung tumours. In addition, transcriptomic analyses revealed a strong tendency for increased CBX2 mRNA levels in many cancers compared with normal tissues, independently of CDKN2A/B silencing. Furthermore, CBX2 upregulation and amplification significantly correlated with metastatic progression and lower overall survival in many cancer types, particularly those of the breast. Conclusions: Overall, we report that the molecular profile of CBX2 is suggestive of an oncogenic role. As CBX2 has never been studied in human neoplasms, our results provide the rationale to further investigate the function of CBX2 in the context of cancer cells

Green housing transition in the Chinese housing market : a behavioural analysis of real estate enterprises

The concept of green housing has been introduced in China to deal with climate issues in the housing sector. Green housing development requires a complex socio-technical transition based not just on green materials or technologies, but also, and most importantly, on the behavioural transition of housing market actors. Little is known about how Chinese real estate enterprises are responding to the green housing transition within a Chinese context. Addressing this gap, our research aims to determine whether, and to what, extent Chinese real estate enterprises are transitioning toward greener housing practices and what constraints may exist. This research gap is particularly pressing given the Chinese government’s ambitions to promote energy efficiency in the new urban building sector by requiring 50% of urban new buildings to be green buildings by 2020 (NDRC, 2016). Our research reveals Chinese real estate enterprises face a dilemma of ‘going green’ and a range of institutional constraints that currently frustrate their uptake of green housing practices. Our research furthers knowledge on environmental and housing market governance within non-western and non-liberal contexts

Adjustable Intragastric Balloons: A 12-Month Pilot Trial in Endoscopic Weight Loss Management

Intragastric balloons are associated with (1) early period intolerance, (2) diminished effect within 3–4 months, and (3) bowel obstruction risk mandating removal at 6 months. The introduction of an adjustable balloon could improve comfort and offer greater efficacy. A migration prevention function, safely enabling prolonged implantation, could improve efficacy and weight maintenance post-extraction. The first implantations of an adjustable balloon with an attached migration prevention anchor are reported. The primary endpoint was the absence of bowel perforation, obstruction, or hemorrhage. Eighteen patients with mean BMI of 37.3 were implanted with the Spatz Adjustable Balloon system (ABS) for 12 months. Balloon volumes were adjusted for intolerance or weight loss plateau. Mean weight loss at 24 weeks was 15.6 kg with 26.4% EWL (percent of excess weight loss) and 24.4 kg with 48.8% EWL at 52 weeks. Sixteen adjustments were successfully performed. Six downward adjustments alleviated intolerance, yielding additional mean weight loss of 4.6 kg. Ten upward adjustments for weight loss plateau yielded a mean additional weight loss of 7 kg. Seven balloons were removed prematurely. Complications necessitating early removal included valve malfunction (1), gastritis (1), Mallory–Weiss tear (1), NSAID (2× dose/2 weeks) perforating ulcer (1), and balloon deflation (1). Two incidents of catheter shear from the chain: one passed uneventfully and one caused an esophageal laceration without perforation during extraction. The Spatz ABS has been successfully implanted in 18 patients. (1) Upward adjustments yielded additional weight loss. (2) Downward adjustments alleviated intolerance, with continued weight loss. (3) Preliminary 1-year implantation results are encouraging

Angiographic correlations of patients with small vessel disease diagnosed by adenosine-stress cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging (CMR) with adenosine-stress myocardial perfusion is gaining importance for the detection and quantification of coronary artery disease (CAD). However, there is little knowledge about patients with CMR-detected ischemia, but having no relevant stenosis as seen on coronary angiography (CA). The aims of our study were to characterize these patients by CMR and CA and evaluate correlations and potential reasons for the ischemic findings. 73 patients with an indication for CA were first scanned on a 1.5T whole-body CMR-scanner including adenosine-stress first-pass perfusion. The images were analyzed by two independent investigators for myocardial perfusion which was classified as subendocardial ischemia (n = 22), no perfusion deficit (n = 27, control 1), or more than subendocardial ischemia (n = 24, control 2). All patients underwent CA, and a highly significant correlation between the classification of CMR perfusion deficit and the degree of coronary luminal narrowing was found. For quantification of coronary blood flow, corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) was evaluated for the left anterior descending (LAD), circumflex (LCX) and right coronary artery (RCA). The main result was that corrected TFC in all coronaries was significantly increased in study patients compared to both control 1 and to control 2 patients. Study patients had hypertension or diabetes more often than control 1 patients. In conclusion, patients with CMR detected subendocardial ischemia have prolonged coronary blood flow. In connection with normal resting flow values in CAD, this supports the hypothesis of underlying coronary microvascular impairment. CMR stress perfusion differentiates non-invasively between this entity and relevant CAD

Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients

BACKGROUND: The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC) patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. METHODS: CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition), 4326C>G (432LeuVal), and 4390A>G (453AsnSer) polymorphisms and treatment response, progression-free-survival (PFS) and overall-survival (OS) was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test. RESULTS: Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014), shorter progression-free-survival (P = 0.032) and overall-survival (P < 0.001). Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS. No significant associations were found among other polymorphisms and both response and clinical outcome. CONCLUSIONS: CYP1B1-4326C>G (432LeuVal) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment

Prostate Cancer Cell Lines under Hypoxia Exhibit Greater Stem-Like Properties

Hypoxia is an important environmental change in many cancers. Hypoxic niches can be occupied by cancer stem/progenitor-like cells that are associated with tumor progression and resistance to radiotherapy and chemotherapy. However, it has not yet been fully elucidated how hypoxia influences the stem-like properties of prostate cancer cells. In this report, we investigated the effects of hypoxia on human prostate cancer cell lines, PC-3 and DU145. In comparison to normoxia (20% O2), 7% O2 induced higher expressions of HIF-1α and HIF-2α, which were associated with upregulation of Oct3/4 and Nanog; 1% O2 induced even greater levels of these factors. The upregulated NANOG mRNA expression in hypoxia was confirmed to be predominantly retrogene NANOGP8. Similar growth rates were observed for cells cultivated under hypoxic and normoxic conditions for 48 hours; however, the colony formation assay revealed that 48 hours of hypoxic pretreatment resulted in the formation of more colonies. Treatment with 1% O2 also extended the G0/G1 stage, resulting in more side population cells, and induced CD44 and ABCG2 expressions. Hypoxia also increased the number of cells positive for ABCG2 expression, which were predominantly found to be CD44bright cells. Correspondingly, the sorted CD44bright cells expressed higher levels of ABCG2, Oct3/4, and Nanog than CD44dim cells, and hypoxic pretreatment significantly increased the expressions of these factors. CD44bright cells under normoxia formed significantly more colonies and spheres compared with the CD44dim cells, and hypoxic pretreatment even increased this effect. Our data indicate that prostate cancer cells under hypoxia possess greater stem-like properties