Event-related desynchronization (ERD), as a proxy for mirror neuron activity, has been used as a neurophysiological marker for motor execution after mirror visual feedback (MVF). Using EEG, this ...study investigated ERD upon the immediate effects of single-session MVF in unimanual arm movements compared with the ERD effects occurring without a mirror, in two groups: stroke patients with left hemiplegia and their healthy counterparts. During EEG recordings, each group performed one session of mirror therapy training in three task conditions: with a mirror, with no mirror, and with a covered mirror. An asymmetry index was calculated from the subtraction of the event-related spectrum perturbations between the C3 and C4 electrodes located over the sensorimotor cortices contralateral and ipsilateral to the moved arm. Results of the effect of task versus group in contralateral and ipsilateral motor areas showed that there was a significant effect of task condition at the contralateral motor area in the high beta band (17–35 Hz) at C3. High beta ERD showed that the suppression was greater over the contralateral hemisphere than it was over the ipsilateral hemisphere in both study groups. The magnitude of low beta (12–16 Hz) ERD in patients with stroke was more suppressed in contralesional C3 under the no mirror compared to that of the covered mirror and similarly more suppressed in ipsilesional C4 ERD under the no mirror compared to that of the mirror condition. The correlation analysis revealed that the magnitude of ERSP power correlated significantly with arm severity in the low and high beta bands in patients with stroke, and a higher asymmetry index in the low beta band was associated with higher arm functioning under the no-mirror condition. There was a shift in sensorimotor ERD toward the contralateral hemisphere as induced by MVF accompanying unimanual movement in both stroke patients and healthy controls. The use of ERD in the low beta band as a neurophysiological marker to indicate the relationships between the amount of MVF-induced ERD attenuation and motor severity, and the outcome indicator for improving stroke patients’ neuroplasticity in clinical trials using MVF are warranted to be explored in the future.
Our previous studies demonstrated that mental imagery intervention enhanced poststroke patients relearning daily task performance. This study aimed to test the efficacy of mental imagery for ...promoting generalization of the task skills learned in a training environment to trained and untrained tasks carried out in a novel environment.
Thirty-five acute poststroke patients were randomly assigned to the mental imagery (MI; n=18) or conventional functional rehabilitation (FR; n=17) group. The MI intervention was 3-week standardized practices and daily tasks using the chunking-regulation-rehearsal strategies. Outcome measurements were the performances on trained and untrained tasks in the training and novel environments.
The MI patients showed significantly better performances on 4 of 5 trained tasks (P=0.001 to 0.026) versus only 1 task in the FR patients (P=0.021). The MI patients also outperformed their FR counterpart on the 3 (of 5) (P=0.025 to 0.049) trained and 2 (of 3) untrained tasks (P=0.042 to 0.045) carried out in the novel environment.
The mental imagery intervention was useful for improving patients' ability on performing the tasks which they did not previously trained on and in places different from the training environments. These involved generalization of the skills learned at the task performance level. Our findings are limited to poststoke patients who share similar characteristics with those in this study.
Neoadjuvant chemotherapy for breast cancer provides critical information about tumor response; how best to leverage this for predicting recurrence-free survival (RFS) is not established. The I-SPY 1 ...TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) was a multicenter breast cancer study integrating clinical, imaging, and genomic data to evaluate pathologic response, RFS, and their relationship and predictability based on tumor biomarkers.
Eligible patients had tumors ≥ 3 cm and received neoadjuvant chemotherapy. We determined associations between pathologic complete response (pCR; defined as the absence of invasive cancer in breast and nodes) and RFS, overall and within receptor subsets.
In 221 evaluable patients (median tumor size, 6.0 cm; median age, 49 years; 91% classified as poor risk on the basis of the 70-gene prognosis profile), 41% were hormone receptor (HR) negative, and 31% were human epidermal growth factor receptor 2 (HER2) positive. For 190 patients treated without neoadjuvant trastuzumab, pCR was highest for HR-negative/HER2-positive patients (45%) and lowest for HR-positive/HER2-negative patients (9%). Achieving pCR predicted favorable RFS. For 172 patients treated without trastuzumab, the hazard ratio for RFS of pCR versus no pCR was 0.29 (95% CI, 0.07 to 0.82). pCR was more predictive of RFS by multivariate analysis when subtype was taken into account, and point estimates of hazard ratios within the HR-positive/HER2-negative (hazard ratio, 0.00; 95% CI, 0.00 to 0.93), HR-negative/HER2-negative (hazard ratio, 0.25; 95% CI, 0.04 to 0.97), and HER2-positive (hazard ratio, 0.14; 95% CI, 0.01 to 1.0) subtypes are lower. Ki67 further improved the prediction of pCR within subsets.
In this biologically high-risk group, pCR differs by receptor subset. pCR is more highly predictive of RFS within every established receptor subset than overall, demonstrating that the extent of outcome advantage conferred by pCR is specific to tumor biology.
Abstract
Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune ...infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.
Cognitive impairment is not uncommon in patients with end-stage renal disease and can make it more difficult for these patients to carry out peritoneal dialysis (PD) on their own. Their attempts to ...do so may result in adverse consequences such as peritonitis. PD exchange is a complex procedure demanding knowledge and skill which requires close supervision and guidance by a renal nurse specialist. In this study, a non-immersive virtual reality (VR) training program using a Leap motion hand tracking device was developed to facilitate patients’ understanding and learning of the PD exchange procedure before attempting real task practice. This study was a two-center single-blinded randomized controlled trial on 23 incident PD patients. Patients in the experimental group received 8 sessions of VR training, while patients in the control were provided with printed educational materials. The results showed that there were significant differences between the two groups in performance of the overall PD exchange sequence, especially on the crucial steps. VR had a patient satisfaction rate of 89%, and all patients preferred to have the VR aid incorporated in PD training. Our findings conclude VR can be a useful aid in the training and reinforcement of PD exchange procedures, with distinct merits of being free from restrictions of time, space, and manpower.
Various multigene predictors of breast cancer clinical outcome have been commercialized, but proved to be prognostic only for hormone receptor (HR) subsets overexpressing estrogen or progesterone ...receptors. Hormone receptor negative (HRneg) breast cancers, particularly those lacking HER2/ErbB2 overexpression and known as triple-negative (Tneg) cases, are heterogeneous and generally aggressive breast cancer subsets in need of prognostic subclassification, since most early stage HRneg and Tneg breast cancer patients are cured with conservative treatment yet invariably receive aggressive adjuvant chemotherapy.
An unbiased search for genes predictive of distant metastatic relapse was undertaken using a training cohort of 199 node-negative, adjuvant treatment naive HRneg (including 154 Tneg) breast cancer cases curated from three public microarray datasets. Prognostic gene candidates were subsequently validated using a different cohort of 75 node-negative, adjuvant naive HRneg cases curated from three additional datasets. The HRneg/Tneg gene signature was prognostically compared with eight other previously reported gene signatures, and evaluated for cancer network associations by two commercial pathway analysis programs.
A novel set of 14 prognostic gene candidates were identified as outcome predictors: CXCL13, CLIC5, RGS4, RPS28, RFX7, EXOC7, HAPLN1, ZNF3, SSX3, HRBL, PRRG3, ABO, PRTN3, MATN1. A composite HRneg/Tneg gene signature index proved more accurate than any individual candidate gene or other reported multigene predictors in identifying cases likely to remain free of metastatic relapse. Significant positive correlations between the HRneg/Tneg index and three independent immune-related signatures (STAT1, IFN, and IR) were observed, as were consistent negative associations between the three immune-related signatures and five other proliferation module-containing signatures (MS-14, ONCO-RS, GGI, CSR/wound and NKI-70). Network analysis identified 8 genes within the HRneg/Tneg signature as being functionally linked to immune/inflammatory chemokine regulation.
A multigene HRneg/Tneg signature linked to immune/inflammatory cytokine regulation was identified from pooled expression microarray data and shown to be superior to other reported gene signatures in predicting the metastatic outcome of early stage and conservatively managed HRneg and Tneg breast cancer. Further validation of this prognostic signature may lead to new therapeutic insights and spare many newly diagnosed breast cancer patients the need for aggressive adjuvant chemotherapy.
Co-expression modules are groups of genes with highly correlated expression patterns. In cancer, differences in module activity potentially represent the heterogeneity of phenotypes important in ...carcinogenesis, progression, or treatment response. To find gene expression modules active in breast cancer subpopulations, we assembled 72 breast cancer-related gene expression datasets containing ∼5,700 samples altogether. Per dataset, we identified genes with bimodal expression and used mixture-model clustering to ultimately define 11 modules of genes that are consistently co-regulated across multiple datasets. Functionally, these modules reflected estrogen signaling, development/differentiation, immune signaling, histone modification, ERBB2 signaling, the extracellular matrix (ECM) and stroma, and cell proliferation. The Tcell/Bcell immune modules appeared tumor-extrinsic, with coherent expression in tumors but not cell lines; whereas most other modules, interferon and ECM included, appeared intrinsic. Only four of the eleven modules were represented in the PAM50 intrinsic subtype classifier and other well-established prognostic signatures; although the immune modules were highly correlated to previously published immune signatures. As expected, the proliferation module was highly associated with decreased recurrence-free survival (RFS). Interestingly, the immune modules appeared associated with RFS even after adjustment for receptor subtype and proliferation; and in a multivariate analysis, the combination of Tcell/Bcell immune module down-regulation and proliferation module upregulation strongly associated with decreased RFS. Immune modules are unusual in that their upregulation is associated with a good prognosis without chemotherapy and a good response to chemotherapy, suggesting the paradox of high immune patients who respond to chemotherapy but would do well without it. Other findings concern the ECM/stromal modules, which despite common themes were associated with different sites of metastasis, possibly relating to the "seed and soil" hypothesis of cancer dissemination. Overall, co-expression modules provide a high-level functional view of breast cancer that complements the "cancer hallmarks" and may form the basis for improved predictors and treatments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We investigated the effects of mirror visual feedback (MVF), with reference to using a glass wall or a covered mirror, on the reduction of spatial neglect for patients with stroke. A total of 21 ...subacute patients with left spatial neglect after right-hemispheric stroke were randomly assigned to 3 groups: MVF, sham 1 (viewing the hemiparetic arm through the transparent glass during bilateral arm movement) and sham 2 (using a covered mirror). The 3-week treatment program for all groups consisted of 12 sessions of movement tasks for the hemiparetic arm graded according to the severity of arm impairments. Blinded assessments were administered at pre/post and a three-week follow-up. The results showed that there was no significant advantage for MVF than sham 1; however, MVF was more beneficial than sham 2, as shown by the line crossing (
= 0.022). Improvement in discriminating the left-gap figures on the left and right side of the page in the Gap Detection Test was greater in MVF than using the covered mirror (
= 0.013;
= 0.010), showing a slight advantage of MVF in alleviating allocentric symptoms. Our study confirms that MVF was superior to using a covered mirror as a method for reducing spatial neglect and in alleviating its allocentric symptoms, but no significant advantage over bilateral arm movement through transparent glass was found. Further research in comparing their therapeutic effects is warranted.
Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and ...non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments.
A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1ness signature was then tested in HER2-negative patients (n = 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in combination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1ness and pathologic complete response in the V-C and control arms alone using Fisher's exact test, and the relative performance between arms (biomarker × treatment interaction, likelihood ratio p < 0.05) using a logistic model and adjusting for hormone receptor status (HR).
We developed a gene expression signature to identify BRCA1-like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature associated significantly with response to V-C (p = 0.03), but not in the control arm (p = 0.45). We identified a significant interaction between BRCA1ness and V-C (p = 0.023) after correcting for HR.
A genomic-based BRCA1-like signature was successfully translated to an expression-based signature (BRC1Aness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone.
I-SPY 2 TRIAL beginning December 31, 2009: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2), NCT01042379 .
PDF
