Detection of the 40 Hz auditory steady-state response with optically pumped magnetometers.

Magnetoencephalography (MEG) is a functional neuroimaging technique that noninvasively detects the brain magnetic field from neuronal activations. Conventional MEG measures brain signals using superconducting quantum interference devices (SQUIDs). SQUID-MEG requires a cryogenic environment involving a bulky non-magnetic Dewar flask and the consumption of liquid helium, which restricts the variability of the sensor array and the gap between the cortical sources and sensors. Recently, miniature optically pumped magnetometers (OPMs) have been developed and commercialized. OPMs do not require cryogenic cooling and can be placed within millimeters from the scalp. In the present study, we arranged six OPM sensors on the temporal area to detect auditory-related brain responses in a two-layer magnetically shielded room. We presented the auditory stimuli of 1 kHz pure-tone bursts with 200 ms duration and obtained the M50 and M100 components of auditory-evoked fields. We delivered the periodic stimuli with a 40 Hz repetition rate and observed the gamma-band power changes and inter-trial phase coherence of auditory steady-state responses at 40 Hz. We found that the OPM sensors have a performance comparable to that of conventional SQUID-MEG sensors, and our results suggest the feasibility of using OPM sensors for functional neuroimaging and brain-computer interface applications.

Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia.

BACKGROUND/AIMS: We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. RESULTS: The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. CONCLUSION: Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway.

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Leprdb/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.

Vibration Alert to the Brain: Evoked and Induced MEG Responses to High-Frequency Vibrotactile Stimuli on the Index Finger of Dominant and Non-dominant Hand.

Background: In recent years, vibrotactile haptic feedback technology has been widely used for user interfaces in the mobile devices. Although functional neuroimaging studies have investigated human brain responses to different types of tactile inputs, the neural mechanisms underlying high-frequency vibrotactile perception are still relatively unknown. Our aim was to investigate neuromagnetic brain responses to high-frequency vibrotactile stimulation, using magnetoencephalography (MEG). Methods: We measured 152-channel whole-head MEG in 30 healthy, right-handed volunteers (aged 20-28 years, 15 females). A total of 300 vibrotactile stimuli were presented at the tip of either the left index finger or the right index finger in two separate sessions. Sinusoidal vibrations at 150 Hz for 200 ms were generated with random inter-stimulus intervals between 1.6 and 2.4 s. Both time-locked analysis and time-frequency analysis were performed to identify peak responses and oscillatory modulations elicited by high-frequency vibrations. The significance of the evoked and induced responses for dominant and non-dominant hand stimulation conditions was statistically tested, respectively. The difference in responses between stimulation conditions was also statistically evaluated. Results: Prominent peak responses were observed at 56 ms (M50) and at 100 ms (M100) for both stimulation conditions. The M50 response revealed clear dipolar field patterns in the contralateral side with significant cortical activations in the contralateral primary sensorimotor area, whereas the M100 response was not as prominent as the M50. Vibrotactile stimulation induced significant suppression of both alpha (8-12 Hz) and beta (20-30 Hz) band activity during the mid-latency period (0.2-0.4 s), primarily in sensorimotor areas contralateral to the stimulation side. In addition, a significant alpha enhancement effect in posterior regions was accompanied with alpha suppressions in sensorimotor regions. The alpha suppression was observed in a broader distribution of cortical areas for the non-dominant hand stimulation. Conclusion: Our data demonstrate that high-frequency tactile vibrations, which is known to primarily activate Pacinian corpuscles, elicit somatosensory M50 and M100 responses in the evoked fields and induce modulations of alpha and beta band oscillations during mid-latency periods. Our study is also consistent with that the primary sensorimotor area is significantly involved in the processing of high-frequency vibrotactile information with contralateral dominance.

Feature optimization method for machine learning-based diagnosis of schizophrenia using magnetoencephalography.

BACKGROUND: When many features and a small number of clinical data exist, previous studies have used a few top-ranked features from the Fisher's discriminant ratio (FDR) for feature selection. However, there are many similarities between selected features. New method: To reduce the redundant features, we applied a technique employing FDR in conjunction with feature correlation. We performed an attention network test on schizophrenic patients and normal subjects with a 152-channel magnetoencephalograph. P300m amplitudes of event-related fields (ERFs) were used as features at the sensor level and P300m amplitudes of ERFs for 500 nodes on the cortex surface were used as features at the source level. Features were ranked using FDR criterion and cross-correlation measure, and then the highest ranked 10 features were selected and an exhaustive search was used to find combination having the maximum accuracy. RESULTS: At the sensor level, we found a single channel of the occipital region that distinguished the two groups with an accuracy of 89.7 %. At source level, we obtained an accuracy of 96.2 % using two features, the left superior frontal region and the left inferior temporal region. COMPARISON WITH EXISTING METHOD: At source level, we obtained a higher accuracy than traditional method using only FDR criterion (accuracy = 88.5 %). We used only the P300 m amplitude (not latency) on a single channel and two brain regions at a fairly high rate.

Sad faces increase the heartbeat-associated interoceptive information flow within the salience network: a MEG study.

The somatic marker hypothesis proposes that the cortical representation of visceral signals is a crucial component of emotional processing. No previous study has investigated the information flow among brain regions that process visceral information during emotional perception. In this magnetoencephalography study of 32 healthy subjects of either sex, heartbeat-evoked responses (HERs), which reflect the cortical processing of heartbeats, were modulated by the perception of a sad face. The modulation effect was localized to the prefrontal cortices, the globus pallidus, and an interoceptive network including the right anterior insula (RAI) and dorsal anterior cingulate cortex (RdACC). Importantly, our Granger causality analysis provides the first evidence for the increased flow of heartbeat information from the RAI to the RdACC during sad face perception. Moreover, using a surrogate R-peak analysis, we have shown that this HER modulation effect was time-locked to heartbeats. These findings advance the understanding of brain-body interactions during emotional processing.

Dynamic pattern decoding of source-reconstructed MEG or EEG data: Perspective of multivariate pattern analysis and signal leakage.

Recently, an increasing number of studies have employed multivariate pattern analysis (MVPA) rather than univariate analysis for the dynamic pattern decoding of event-related responses recorded with a MEG/EEG sensor. The use of the MVPA approach for source-reconstructed MEG/EEG data is uncommon. For these data, we need to consider the source orientation information and the signal leakage among brain regions. In the present study, we evaluate the perspective of the MVPA approach in the context of source orientation information and signal leakage in source-reconstructed MEG data. We perform face vs. tool object category decoding (FvsT-OCD) of event-related responses from single or multiple voxels from a brain region using a univariate analysis approach and/or the MVPA approach. We also propose and perform symmetric signal leakage correction of source-reconstructed data using an independent component analysis-based approach. FvsT-OCD using single voxel information shows higher sensitivity for the MVPA approach than univariate analysis, as the MVPA approach efficiently utilizes information on all three dipole orientations and is less affected by inter-subject variability. The MVPA approach shows higher sensitivity for FvsT-OCD when considering information from multiple voxels than for a single voxel in a brain region. This finding suggests that the MVPA approach captures the latent multivoxel distributed pattern. However, the results may be partly or entirely attributable to signal leakage between brain regions, as the sensitivity is substantially reduced after signal leakage correction. A consideration of signal leakage is therefore essential during the evaluation of MVPA outcomes.

Magnetoencephalographic study of event-related fields and cortical oscillatory changes during cutaneous warmth processing.

Thermoreception is an important cutaneous sense, which plays a role in the maintenance of our body temperature and in the detection of potential noxious heat stimulation. In this study, we investigated event-related fields (ERFs) and neural oscillatory activities, which were modulated by warmth stimulation. We developed a warmth stimulator that could elicit a warmth sensation, without pain or tactile sensation, by using a deep-penetrating 980-nm diode laser. The index finger of each participant (n = 24) was irradiated with the laser warmth stimulus, and the cortical responses were measured using magnetoencephalography (MEG). The ERFs and oscillatory responses had late latencies (∼1.3 s and 1.0-1.5 s for ERFs and oscillatory responses, respectively), which could be explained by a slow conduction velocity of warmth-specific C-fibers. Cortical sources of warmth-related ERFs were seen in the bilateral primary and secondary somatosensory cortices (SI and SII), posterior part of the anterior cingulate cortex (pACC), ipsilateral primary motor, and premotor cortex. Thus, we suggested that SI, SII, and pACC play a role in processing the warmth sensation. Time-frequency analysis demonstrated the suppression of the alpha (8-13 Hz) and beta (18-23 Hz) band power in the bilateral sensorimotor cortex. We proposed that the suppressions in alpha and beta band power are involved in the automatic response to the input of warmth stimulation and sensorimotor interactions. The delta band power (1-4 Hz) increased in the frontal, temporal, and cingulate cortices. The power changes in delta band might be related with the attentional processes during the warmth stimulation.

Interbrain phase synchronization during turn-taking verbal interaction-a hyperscanning study using simultaneous EEG/MEG.

Recently, neurophysiological findings about social interaction have been investigated widely, and hardware has been developed that can measure multiple subjects' brain activities simultaneously. These hyperscanning studies have enabled us to discover new and important evidences of interbrain interactions. Yet, very little is known about verbal interaction without any visual input. Therefore, we conducted a new hyperscanning study based on verbal, interbrain turn-taking interaction using simultaneous EEG/MEG, which measures rapidly changing brain activities. To establish turn-taking verbal interactions between a pair of subjects, we set up two EEG/MEG systems (19 and 146 channels of EEG and MEG, respectively) located ∼100 miles apart. Subjects engaged in verbal communication via condenser microphones and magnetic-compatible earphones, and a network time protocol synchronized the two systems. Ten subjects participated in this experiment and performed verbal interaction and noninteraction tasks separately. We found significant oscillations in EEG alpha and MEG alpha/gamma bands in several brain regions for all subjects. Furthermore, we estimated phase synchronization between two brains using the weighted phase lag index and found statistically significant synchronization in EEG and MEG data. Our novel paradigm and neurophysiological findings may foster a basic understanding of the functional mechanisms involved in human social interactions. Hum Brain Mapp 39:171-188, 2018. © 2017 Wiley Periodicals, Inc.

Approximate Subject Specific Pseudo MRI from an Available MRI Dataset for MEG Source Imaging.

Computation of headmodel and sourcemodel from the subject's MRI scan is an essential step for source localization of magnetoencephalography (MEG) (or EEG) sensor signals. In the absence of a real MRI scan, pseudo MRI (i.e., associated headmodel and sourcemodel) is often approximated from an available standard MRI template or pool of MRI scans considering the subject's digitized head surface. In the present study, we approximated two types of pseudo MRI (i.e., associated headmodel and sourcemodel) using an available pool of MRI scans with the focus on MEG source imaging. The first was the first rank pseudo MRI; that is, the MRI scan in the dataset having the lowest objective registration error (ORE) after being registered (rigid body transformation with isotropic scaling) to the subject's digitized head surface. The second was the averaged rank pseudo MRI that is generated by averaging of headmodels and sourcemodels from multiple MRI scans respectively, after being registered to the subject's digitized head surface. Subject level analysis showed that the mean upper bound of source location error for the approximated sourcemodel in reference to the real one was 10 ± 3 mm for the averaged rank pseudo MRI, which was significantly lower than the first rank pseudo MRI approach. Functional group source response in the brain to visual stimulation in the form of event-related power (ERP) at the time latency of peak amplitude showed noticeably identical source distribution for first rank pseudo MRI, averaged rank pseudo MRI, and real MRI. The source localization error for functional peak response was significantly lower for averaged rank pseudo MRI compared to first rank pseudo MRI. We conclude that it is feasible to use approximated pseudo MRI, particularly the averaged rank pseudo MRI, as a substitute for real MRI without losing the generality of the functional group source response.

Scientific rationale for extrapolation of biosimilar data across cancer indications: case study of CT-P10.

For a biosimilar to gain regulatory approval, a comprehensive comparability exercise must demonstrate that it is highly similar to its originator biologic, or reference product. Once biosimilarity has been shown, it is possible to approve the biosimilar for additional indications held by the reference product, without clinical trials in these indications. Extrapolation of clinical data is permitted by regulatory agencies as long as it is scientifically justified. CT-P10, a biosimilar of rituximab, was recently approved in Europe for all indications held by its reference product, incorporating both autoimmune diseases and hematological cancers. Here, we review the scientific rationale for extrapolation in biosimilar development using the example of CT-P10 as a case study.

Clinical development of CT-P10 and other biosimilar cancer therapeutics.

Biosimilars are highly similar versions of approved biologic drugs that may confer equivalent efficacy at a reduced cost. Patents for several biological cancer therapeutics are past or approaching expiry, presenting an opportunity to increase affordability and global accessibility of key drugs through the development of biosimilars. To receive approval, a biosimilar must show no clinically meaningful differences from the reference product in terms of efficacy or safety. The first monoclonal antibody biosimilar cancer therapeutic to gain approval was CT-P10, a biosimilar of rituximab. Here, we review the oncology clinical development program for CT-P10, providing insights into the rationale for, and design of, CT-P10 clinical trials in patients with cancer. Trials of biosimilar cancer therapeutics in development are also discussed.

Looking to the future and learning lessons from the recent past: changing stakeholder perceptions of biosimilars in cancer.

As the patents for many biologic anticancer drugs expire, significant growth in the use of biosimilars is predicted, offering an opportunity to help combat the rising costs of treatment and increase patient access to biologic therapy. Attainment of regulatory approval, involving numerous nonclinical and clinical comparative studies versus each reference product, is only one of several barriers to realize the potential gains offered by biosimilars. It is important to understand the current perceptions and informational needs of different stakeholders if biosimilars are to be accepted and widely used in the clinic. We discuss these considerations and refer to recent experiences with CT-P13, a biosimilar of the TNF inhibitor infliximab used to treat rheumatoid arthritis and other inflammatory disorders.

An introduction to biosimilar cancer therapeutics: definitions, rationale for development and regulatory requirements.

Monoclonal antibodies and other biologic drugs play important roles in the treatment of various hematological malignancies and solid tumors. However, such drugs are intrinsically more expensive to develop than small molecules and their clinical benefits are often accompanied by challenges relating to affordability and access. Patent expiry for 'originator' biologics is providing opportunities for a new generation of biosimilar drugs, potentially capable of relieving pressure on healthcare budgets. This article discusses key characteristics of biosimilars, distinguishes them from generics and noncomparable biologics and outlines the robust regulatory requirements that must be followed to establish biosimilarity with a reference product. The path to approval is discussed with reference to the rituximab biosimilar CT-P10, the first licensed monoclonal antibody biosimilar cancer therapeutic.

Development of a bio-magnetic measurement system and sensor configuration analysis for rats.

Magnetoencephalography (MEG) based on superconducting quantum interference devices enables the measurement of very weak magnetic fields (10-1000 fT) generated from the human or animal brain. In this article, we introduce a small MEG system that we developed specifically for use with rats. Our system has the following characteristics: (1) variable distance between the pick-up coil and outer Dewar bottom (∼5 mm), (2) small pick-up coil (4 mm) for high spatial resolution, (3) good field sensitivity (45∼ 80fT/cm/Hz), (4) the sensor interval satisfies the Nyquist spatial sampling theorem, and (5) small source localization error for the region to be investigated. To reduce source localization error, it is necessary to establish an optimal sensor layout. To this end, we simulated confidence volumes at each point on a grid on the surface of a virtual rat head. In this simulation, we used locally fitted spheres as model rat heads. This enabled us to consider more realistic volume currents. We constrained the model such that the dipoles could have only four possible orientations: the x- and y-axes from the original coordinates, and two tangentially layered dipoles (local x- and y-axes) in the locally fitted spheres. We considered the confidence volumes according to the sensor layout and dipole orientation and positions. We then conducted a preliminary test with a 4-channel MEG system prior to manufacturing the multi-channel system. Using the 4-channel MEG system, we measured rat magnetocardiograms. We obtained well defined P-, QRS-, and T-waves in rats with a maximum value of 15 pT/cm. Finally, we measured auditory evoked fields and steady state auditory evoked fields with maximum values 400 fT/cm and 250 fT/cm, respectively.

Gene expression profiling of hematologic malignant cell lines resistant to oncolytic virus treatment.

Pexa-Vec (pexastimogene devacirpvec; JX-594) has emerged as an attractive tool in oncolytic virotherapy. Pexa-Vec demonstrates oncolytic and immunotherapeutic mechanisms of action. But the determinants of resistance to Pexa-Vec are mostly unknown. We treated hemoatologic malignant cells with Pexa-Vec and examined the gene-expression pattern of sensitive and resistant cells. Human myeloid malignant cell lines (RPMI-8226, IM-9, K562, THP-1) and lymphoid cancer cell lines (MOLT4, CCRF-CEM, Ramos, U937) were treated with Pexa-Vec. Pexa-Vec was cytotoxic on myeloid cell lines in a dose-dependent manner, and fluorescent imaging and qPCR revealed that Pexa-Vec expression was low in RAMOS than IM-9 after 24 hrs and 48 hrs of infection. Gene expression profiles between two groups were analyzed by microarray. Genes with at least 2-fold increase or decrease in their expression were identified. A total of 660 genes were up-regulated and 776 genes were down-regulated in lymphoid cancer cell lines. The up- and down-regulated genes were categorized into 319 functional gene clusters. We identified the top 10 up-regulated genes in lymphoid cells. Among them three human genes (LEF1, STAMBPL1, and SLFN11) strongly correlated with viral replication. Up-regulation of PVRIG, LPP, CECR1, Arhgef6, IRX3, IGFBP2, CD1d were related to resistant to Pexa-Vec. In conclusion, lymphoid malignant cells are resistant to Pexa-Vec and displayed up-regulated genes associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for further clinical trials with Pexa-Vec.

Evaluation of Phase-Amplitude Coupling in Resting State Magnetoencephalographic Signals: Effect of Surrogates and Evaluation Approach.

Phase-amplitude coupling (PAC) plays an important role in neural communication and computation. Interestingly, recent studies have indicated the presence of ubiquitous PAC phenomenon even during the resting state. Despite the importance of PAC phenomenon, estimation of significant physiological PAC is challenging because of the lack of appropriate surrogate measures to control false positives caused by non-physiological PAC. Therefore, in the present study, we evaluated PAC phenomenon during resting-state magnetoencephalography (MEG) signal and considered various surrogate measures and computational approaches widely used in the literature in addition to proposing new ones. We evaluated PAC phenomenon over the entire length of the MEG signal and for multiple shorter time segments. The results indicate that the extent of PAC phenomenon mainly depends on the surrogate measures and PAC computational methods used, as well as the evaluation approach. After a careful and critical evaluation, we found that resting-state MEG signals failed to exhibit ubiquitous PAC phenomenon, contrary to what has been suggested previously.

Repolarization Heterogeneity of Magnetocardiography Predicts Long-Term Prognosis in Patients with Acute Myocardial Infarction.

PURPOSE: Magnetocardiography (MCG) has been proposed as a noninvasive, diagnostic tool for risk-stratifying patients with acute myocardial infarction (AMI). This study evaluated whether MCG predicts long-term prognosis in AMI. MATERIALS AND METHODS: In 124 AMI patients (95 males, mean age 60±11 years), including 39 with ST-elevation myocardial infarction, a 64-channel MCG was performed within 2 days after AMI. During a mean follow-up period of 6.1 years, major adverse cardiac events (MACE) were evaluated. RESULTS: MACE occurred in 31 (25%) patients, including 20 revascularizations, 8 deaths, and 3 re-infarctions. Non-dipole patterns were observed at the end of the T wave in every patients. However, they were observed at T-peak in 77% (24/31) and 54% (50/93) of patients with and without MACE, respectively (p=0.03). Maximum current, field map angles, and distance dynamics were not different between groups. In the multivariate analysis, patients with non-dipole patterns at T-peak had increased age- and gender-adjusted hazard ratios for MACE (hazard ratio 2.89, 95% confidence interval 1.20-6.97, p=0.02) and lower cumulative MACE-free survival than those with dipole patterns (p=0.02). CONCLUSION: Non-dipole patterns at T-peak were more frequently observed in patients with MACE and were related to poor long-term prognosis. Thus, repolarization heterogeneity measured by MCG may be a useful predictor for AMI prognosis.

Relationship between insulin-like growth factor axis gene polymorphisms and clinical outcome in advanced gastric cancer patients treated with FOLFOX.

The insulin-like growth factor (IGF) axis plays a crucial role in proliferation, differentiation, migration, angiogenesis, and apoptosis. The present study evaluated the associations between IGF axis single-nucleotide polymorphisms (SNPs) and clinical outcomes in advanced gastric cancer (AGC) patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). A total of 190 patients undergoing FOLFOX chemotherapy for AGC were considered eligible for this study. Forty-four SNPs of 10 IGF axis genes were genotyped. Levels of serum IGF1 were measured using enzyme-linked immunoassays. SNPs of the IGF1R (rs12423791), and IGF1 (rs2162679, rs5742612, rs35767) genes were significantly associated with tumor response to FOLFOX. SNPs of rs4619 and rs17847203 were significantly associated with PFS (hazard ratio [HR] 0.575, 95% CI 0.385-0.858, P = 0.007; and HR 2.530, 95% CI 1.289-4.966, P = 0.007; respectively). SNPs of rs2872060 were significantly associated with OS-OS was shorter in patients carrying the TT variant than in those with the GG/GT genotypes (HR, 1.708, 95% CI 1.024-2.850, P = 0.040). The GT genotype of rs12847203 was also identified as an independent prognostic factor (HR 2.087, 95% CI 1.070-4.069, P = 0.031). These results suggest that IGF axis-pathway SNPs could be used as prognostic biomarkers of the outcome of FOLFOX chemotherapy in AGC patients. This information may facilitate identification of population subgroups that could benefit from IGF1R-targeted agents.

Estimating functional connectivity using 2D tangential components in MEG sensor space.

BACKGROUND: Connectivity analysis in magnetoencephalography (MEG) sensor space is commonly used for the preliminary estimation of the functional relationship between cortical areas, but the results are difficult to interpret due to the field spread effect. To improve the interpretability of sensor-level connectivity analysis, we introduce and test a new connectivity measure based on imaginary coherence in this study. NEW METHOD: MEG signals from axial gradiometers are subjected to a wavelet transform at a frequency of interest, and are used to reconstruct 2D tangential magnetometer signals. The Euclidean norm of imaginary coherence values obtained from four available pairs between 2D tangential components at two locations is then used to estimate functional connectivity between sensor locations. The use of this new connectivity measure can be extended to 2D planar gradiometer signals or 3D source signals, where the functional relationship between multi-dimensional signals at different locations needs to be quantified as scalar variables. RESULTS: The proposed method was applied to measured and simulated auditory evoked MEG data. The Euclidean norm of imaginary coherence reliably eliminated the field spread effect and showed increased inter-hemispheric coherence between sensors above the left and the right auditory cortex. The significance of the results was tested by introducing variability in spontaneous brain activities in multi-trial evoked data simulations. COMPARISON WITH EXISTING METHOD: The distribution of imaginary coherence among axial gradiometer signals shows peaks not at the sensors directly above the neuronal current sources, but at sensors with field extreme.