Identifying the characteristics of patients with stroke who have difficulty benefiting from gait training with the hybrid assistive limb: a retrospective cohort study.

Robot-assisted gait training is effective for walking independence in stroke rehabilitation, the hybrid assistive limb (HAL) is an example. However, gait training with HAL may not be effective for everyone, and it is not clear who is not expected to benefit. Therefore, we aimed to identify the characteristics of stroke patients who have difficulty gaining benefits from gait training with HAL. We conducted a single-institutional retrospective cohort study. The participants were 82 stroke patients who had received gait training with HAL during hospitalization. The dependent variable was the functional ambulation category (FAC) that a measure of gait independence in stroke patients, and five independent [age, National Institutes of Health Stroke Scale, Brunnstrom recovery stage (BRS), days from stroke onset, and functional independence measure total score (cognitive items)] variables were selected from previous studies and analyzed by logistic regression analysis. We evaluated the validity of logistic regression analysis by using several indicators, such as the area under the curve (AUC), and a confusion matrix. Age, days from stroke onset to HAL initiation, and BRS were identified as factors that significantly influenced walking independence through gait training with HAL. The AUC was 0.86. Furthermore, after building a confusion matrix, the calculated binary accuracy, sensitivity (recall), and specificity were 0.80, 0.80, and 0.81, respectively, indicated high accuracy. Our findings confirmed that older age, greater degree of paralysis, and delayed initiation of HAL-assisted training after stroke onset were associated with increased likelihood of walking dependence upon hospital discharge.

THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer.

Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.

Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis.

RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast-like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.

Simultaneous activation of Kras-Akt and Notch pathways induces extrahepatic biliary cancer via the mTORC1 pathway.

Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. Therefore, we investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct (EHBD) and GB. Activation of Notch signaling and oncogenic Kras resulted in the development of biliary intraepithelial neoplasia (BilINs) in the EHBD and GB, which were premalignant lesions that progressed to adenocarcinoma in mice. The expression of genes involved in the mTORC1 pathway was increased in biliary spheroids from Hnf1b-CreERT2; KrasLSL-G12D ; Rosa26LSL-NotchIC mice and inhibition of the mTORC1 pathway suppressed spheroid growth. Additionally, simultaneous activation of the PI3K-AKT and Notch pathways in EHBD and GB induced biliary cancer development in mice. Consistent with this, we observed a significant correlation between activated NOTCH1 and phosphorylated Ribosomal Protein S6 (p-S6) expression in human eCCA. Furthermore, inhibition of the mTORC1 pathway suppressed the growth of Notch-activated human biliary cancer cells in vitro and in vivo. Mechanistically, the Kras/Notch-Myc axis activated mTORC1 through TSC2 phosphorylation in mutant biliary spheroids. These data indicate that inhibition of the mTORC1 pathway could be an effective treatment strategy for Notch-activated human eCCA. © 2023 The Pathological Society of Great Britain and Ireland.

Brg1 controls stemness and metastasis of pancreatic cancer through regulating hypoxia pathway.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. We previously reported that chromatin remodeler Brg1 is essential for acinar cell-derived PDAC formation in mice. However, the functional role of Brg1 in established PDAC and its metastasis remains unknown. Here, we investigated the importance of Brg1 for established PDAC by using a mouse model with a dual recombinase system. We discovered that Brg1 was a critical player for the cell survival and growth of spontaneously developed PDAC in mice. In addition, Brg1 was essential for metastasis of PDAC cells by inhibiting apoptosis in splenic injection and peritoneal dissemination models. Moreover, cancer stem-like property was compromised in PDAC cells by Brg1 ablation. Mechanistically, the hypoxia pathway was downregulated in Brg1-deleted mouse PDAC and BRG1-low human PDAC. Brg1 was essential for HIF-1α to bind to its target genes to augment the hypoxia pathway, which was important for PDAC cells to maintain their stem-like properties and to metastasize to the liver. Human PDAC cells with high BRG1 expression were more susceptible to BRG1 suppression. In conclusion, Brg1 plays a critical role for cell survival, stem-like property and metastasis of PDAC through the regulation of hypoxia pathway, and thus could be a novel therapeutic target for PDAC.

Theta phase coherence in visual mismatch responses involved in access processing to visual awareness.

Introduction: The electroencephalographic brain response to a deviation from the preceding sequential regularity of visual events, called visual mismatch negativity (vMMN), is well known to reflect automatic visual change detection. Our preliminary study showed a significant correlation between the enhancement of the vMMN amplitude and facilitation of perceptual alternation in binocular rivalry when the deviant stimulus was presented unconsciously. This implies that the vMMN is relevant to access processing, in which the unconscious stimulus is consciously perceived. Recent studies have reported that theta band oscillation evoked by a deviant stimulus is involved in evoking vMMN. However, it has not been clarified whether theta band oscillation associated with vMMN is also relevant to access processing. Methods: We analyzed the correlations between event-related spectral perturbation (ERSP) and inter-trial phase coherence (ITPC) in the theta band and the proportion of perceptual alternation from before to after the presentation of deviation in the same experimental paradigm as in our previous study. Results: We found that an increase in ITPC in the theta band tended to correlate with facilitation of perceptual alternation in binocular rivalry when the deviant was presented unconsciously, but there was no significant correlation in ERSP. Discussion: The results suggest that theta phase coherence underlying the visual mismatch process is relevant to the access processing.

Early Initiation of Exoskeletal Robotic Gait Training Improves Functional Outcomes in the Patients with Stroke: A Retrospective Observational Study.

INTRODUCTION: The effect of early initiation of gait training using hybrid assistive limb (HAL) remains unclear. This observational study aimed to investigate whether early initiation of gait training using HAL improves functional outcomes in patients with stroke. METHODS: We retrospectively analyzed patients with acute stroke admitted to our facility. HAL was used for exoskeletal robotic gait training. Study participants were median split into an early group and a late group based on the days from stroke onset to initiation of gait training using HAL. The functional outcomes, defined by the Brunnstrom recovery stage (BRS), modified Rankin Scale (mRS), and Functional Independence Measure (FIM) at discharge, were compared using propensity score-matched analysis. RESULTS: We performed a propensity score-matched analysis in 63 patients with stroke (31 from the early group and 32 from the late group), and 17 pairs were matched. There were no significant differences in discharge in the BRS of the upper limb and finger in the post-matched cohort. On the other hand, the BRS of the lower limb in the early group was significantly higher than that in the late group. In addition, the mRS, but not FIM scores, was significantly better in the early group than that in the late group. CONCLUSIONS: In conclusion, early initiation of gait training using HAL might improve the motor function of the paralyzed lower limb and disability in patients with stroke.

Does frequent use of an exoskeletal upper limb robot improve motor function in stroke patients?

PURPOSE: To determine how differences in frequency of the single-joint hybrid assistive limb (HAL-SJ) use affect the improvement of upper limb motor function and activities of daily living (ADL) in stroke patients. MATERIALS AND METHODS: Subacute stroke patients were divided into the high or low frequency of HAL-SJ use groups. The two groups were matched by propensity score, and the degree of changes 30 days after initiating HAL-SJ use was compared. A logistic regression analysis was performed to examine whether frequent use would increase the number of subjects experiencing the efficacy of more than the minimal clinically important difference (MCID) of Fugl-Meyer assessment (FMA). RESULTS: Twenty-five stroke patients were matched by propensity score, and nine pairs were matched. The high-frequency group showed a significantly superior increase to total FMA shoulder, elbow, forearm, and Barthel index compared with the low-frequency group. Logistic regression analysis revealed no significant associations between frequent use and MCID. CONCLUSIONS: The frequency of HAL-SJ use may affect the improvement of motor function and ADL ability of the upper limb with exception of the fingers and wrist. However, the frequency of intervention was not effective enough to further increase the number of subjects with clinically meaningful changes in upper limb motor function.IMPLICATIONS FOR REHABILITATIONThe current study aimed to clarify how differences in the frequency of single-joint hybrid assistive limb (HAL-SJ) use can affect the improvement of upper-limb motor functions and ADL in subacute stroke patients.Our results implied that the frequency of HAL-SJ use may influence the recovery of upper limb function.However, even if HAL-SJ is used frequently, it does not mean that more patients will achieve clinically meaningful recovery.

Age-Related Sex Differences in Glucose Tolerance by 75 g Oral Glucose Tolerance Test in Japanese.

To elucidate the age-related sex difference in glucose tolerance, we conducted 75 g oral glucose tolerance tests in 1156 participants. Participants were divided into four groups, namely, young (22−29) males, young females, middle-aged (>50) males, and middle-aged females. According to the Japanese Clinical Practice Guideline for Diabetes 2019, the prevalence of normal glucose tolerance (NGT) was significantly lower in middle-aged than in young participants. The prevalence of high-normal fasting plasma glucose (FPG) was higher, and NGT was lower in young males (high-normal FPG 15.2%, NGT 82.0%) than young females (high-FPG 3.9%, NGT 94.3%). Combined glucose intolerance (CGI) was higher and NGT was lower in middle-aged males (CGI 10.2%, NGT 25.2%) than in middle-aged females (CGI 3.3%, NGT 39.8%). FPG and body mass index (BMI) were the lowest and Homeostatic model assessment beta cell function (HOMA-ß) was the highest in young females, followed by young males, middle-aged females, and middle-aged males. Multiple linear regression analysis revealed that BMI weakly correlated with HOMA-ß and Matsuda index in all subjects except young females. The superior glucose tolerance in females was apparent in young, but attenuated in middle-aged females. The differences are due to the higher insulin secretion potential and lower BMI in young females.

JNK pathway plays a critical role for expansion of human colorectal cancer in the context of BRG1 suppression.

Tumor stem cells (TSCs), capable of self-renewal and continuous production of progeny cells, could be potential therapeutic targets. We have recently reported that chromatin remodeling regulator Brg1 is required for maintenance of murine intestinal TSCs and stemness feature of human colorectal cancer (CRC) cells by inhibiting apoptosis. However, it is still unclear how BRG1 suppression changes the underlying intracellular mechanisms of human CRC cells. We found that Brg1 suppression resulted in upregulation of the JNK signaling pathway in human CRC cells and murine intestinal TSCs. Simultaneous suppression of BRG1 and the JNK pathway, either by pharmacological inhibition or silencing of c-JUN, resulted in even stronger inhibition of the expansion of human CRC cells compared to Brg1 suppression alone. Consistently, high c-JUN expression correlated with worse prognosis for survival in human CRC patients with low BRG1 expression. Therefore, the JNK pathway plays a critical role for expansion and stemness of human CRC cells in the context of BRG1 suppression, and thus a combined blockade of BRG1 and the JNK pathway could be a novel therapeutic approach against human CRC.

Left-to-right rotated single lung transplant.

We successfully performed left-to-right rotated single lung transplants in 2 patients. For this procedure, the left pulmonary artery of the donor undergoes a U-shaped turn with A3 at the bottom to anastomose with the recipient's right pulmonary artery in front of the bronchus. It is extremely important to avoid kinking the pulmonary artery at the site of the U-shaped turn.

Clinical Prediction Rule for Identifying the Stroke Patients who will Obtain Clinically Important Improvement of Upper Limb Motor Function by Robot-Assisted Upper Limb.

BACKGROUND: The number of studies on the characteristics of patients with stroke who would benefit from robot-assisted upper limb rehabilitation is limited, and there are no clear criteria for determining which individuals should receive such treatment. The current study aimed to develop a clinical prediction rule using machine learning to identify the characteristics of patients with stroke who can the achieve minimal clinically important difference of the Fugl-Meyer Upper Extremity Evaluation (FMA-UE) after single-joint hybrid assistive limb (HAL-SJ) rehabilitation. METHODS: This study included 71 patients with subacute stroke who received HAL-SJ rehabilitation. The chi-square automatic interaction detector (CHAID) model was applied to predict improvement in upper limb motor function. Based the analysis using CHAID, age, sex, days from stroke onset to the initiation of HAL-SJ rehabilitation, and upper limb motor and cognitive functions were used as independent variables. Improvement in upper limb motor function was determined based on the minimal clinically important difference of the FMA-UE, which was used as a dependent variable. RESULTS: According to the CHAID model, the FMA-UE score during the initiation of HAL-SJ rehabilitation was the most significant predictive factor for patients who are likely to respond to the intervention. Interestingly, this therapy was more effective in patients with moderate upper limb motor dysfunction and early initiation of HAL-SJ rehabilitation. The accuracy of the CHAID model was 0.89 (95% confidence interval: 0.81-0.96). CONCLUSION: We developed a clinical prediction rule for identifying the characteristics of patients with stroke whose upper limb motor function can improve with HAL-SJ rehabilitation.

Involvement of the Rostromedial Prefrontal Cortex in Human-Robot Interaction: fNIRS Evidence From a Robot-Assisted Motor Task.

Assistive exoskeleton robots are being widely applied in neurorehabilitation to improve upper-limb motor and somatosensory functions. During robot-assisted exercises, the central nervous system appears to highly attend to external information-processing (IP) to efficiently interact with robotic assistance. However, the neural mechanisms underlying this process remain unclear. The rostromedial prefrontal cortex (rmPFC) may be the core of the executive resource allocation that generates biases in the allocation of processing resources toward an external IP according to current behavioral demands. Here, we used functional near-infrared spectroscopy to investigate the cortical activation associated with executive resource allocation during a robot-assisted motor task. During data acquisition, participants performed a right-arm motor task using elbow flexion-extension movements in three different loading conditions: robotic assistive loading (ROB), resistive loading (RES), and non-loading (NON). Participants were asked to strive for kinematic consistency in their movements. A one-way repeated measures analysis of variance and general linear model-based methods were employed to examine task-related activity. We demonstrated that hemodynamic responses in the ventral and dorsal rmPFC were higher during ROB than during NON. Moreover, greater hemodynamic responses in the ventral rmPFC were observed during ROB than during RES. Increased activation in ventral and dorsal rmPFC subregions may be involved in the executive resource allocation that prioritizes external IP during human-robot interactions. In conclusion, these findings provide novel insights regarding the involvement of executive control during a robot-assisted motor task.

Loss of Arid1a and Pten in Pancreatic Ductal Cells Induces Intraductal Tubulopapillary Neoplasm via the YAP/TAZ Pathway.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) arises from several types of premalignant lesions, including intraductal tubulopapillary neoplasm (ITPN); however, the molecular pathogenesis of ITPN remains unknown. METHODS: We performed studies with Hnf1b-CreERT2; Ptenf/f; Arid1af/f mice to investigate the consequence of genetic deletion of Arid1a in adult pancreatic ductal cells in the context of oncogenic PI3K/Akt pathway activation. RESULTS: Simultaneous deletion of Arid1a and Pten in pancreatic ductal cells resulted in the development of ITPN, which progressed to PDAC, in mice. Simultaneous loss of Arid1a and Pten induced dedifferentiation of pancreatic ductal cells and Yes-associated protein 1/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) pathway activation. Consistent with the mouse data, TAZ expression was found elevated in human ITPNs and ITPN-derived PDACs but not in human intraductal papillary mucinous neoplasms, indicating that activation of the TAZ pathway is a distinctive feature of ITPN. Furthermore, pharmacological inhibition of the YAP/TAZ pathway suppressed the dedifferentiation of pancreatic ductal cells and development of ITPN in Arid1a and Pten double-knockout mice. CONCLUSION: Concurrent loss of Arid1a and Pten in adult pancreatic ductal cells induced ITPN and ITPN-derived PDAC in mice through aberrant activation of the YAP/TAZ pathway, and inhibition of the YAP/TAZ pathway prevented the development of ITPN. These findings provide novel insights into the pathogenesis of ITPN-derived PDAC and highlight the YAP/TAZ pathway as a potential therapeutic target.

[Lung Transplantation at a Low Volume Center].

The number of lung transplantation performed in Japan is extremely low compared to other countries, whereas we have 10 facilities certified as cadaveric lung transplantation in Japan, meaning that there are low volume centers. By August 2021, we performed lung transplantation in 21 cases for 12 years, therefore, our facility should be considered as low volume center. Surgical outcomes at low volume centers are generally considered poor. However, the overall five-year survival rate of total cases was 84.8%, and that of cadaveric cases was 94.4% in our hospital. It was better than the average of about 73% of all facilities in Japan. These data suggested that the accreditation system in Japan is functioning well. On the other hand, there may be a disparity between facilities. At our facility, we are actively performing inverted lung transplantation so as not to lose the opportunity for transplantation, and we have performed it in three cases so far and have achieved good results.

Concurrent Activation of Kras and Canonical Wnt Signaling Induces Premalignant Lesions That Progress to Extrahepatic Biliary Cancer in Mice.

Biliary cancer has long been known to carry a poor prognosis, yet the molecular pathogenesis of carcinoma of the extrahepatic biliary system and its precursor lesions remains elusive. Here we investigated the role of Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic bile duct (EHBD) and gall bladder (GB). In mice, concurrent activation of Kras and Wnt pathways induced biliary neoplasms that resembled human intracholecystic papillary-tubular neoplasm (ICPN) and biliary intraepithelial neoplasia (BilIN), putative precursors to invasive biliary cancer. At a low frequency, these lesions progressed to adenocarcinoma in a xenograft model, establishing them as precancerous lesions. Global gene expression analysis revealed increased expression of genes associated with c-Myc and TGFß pathways in mutant biliary spheroids. Silencing or pharmacologic inhibition of c-Myc suppressed proliferation of mutant biliary spheroids, whereas silencing of Smad4/Tgfbr2 or pharmacologic inhibition of TGFß signaling increased proliferation of mutant biliary spheroids and cancer formation in vivo. Human ICPNs displayed activated Kras and Wnt signals and c-Myc and TGFß pathways. Thus, these data provide direct evidence that concurrent activation of the Kras and canonical Wnt pathways results in formation of ICPN and BilIN, which could develop into biliary cancer. SIGNIFICANCE: This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression.

Association Between Insulin Resistance and Cardinal Rheological Parameters in Young Healthy Japanese Individuals During 75g Oral Glucose Tolerance Test.

BACKGROUND: Insulin resistance is a well-known predictor and risk factor for type 2 diabetes mellitus (T2DM). Higher hematocrit induced by higher insulin resistance affects blood rheology. OBJECTIVE: This study intended to reveal the association between indices of insulin resistance and hemorheological parameters during a 75 g oral glucose tolerance test (75-g OGTT). METHODS: A total of 575 healthy young Japanese participants took 75-g OGTT. We then analyzed the association between insulin resistance indices and hematological parameters. RESULTS: The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was significantly correlated with hematocrit (Ht), hemoglobin (Hb), red blood cell (RBC), white blood cell (WBC), platelet count, lipid parameters and body mass index (BMI). The Matsuda index was negatively correlated with RBC count, WBC count, platelet count, total cholesterol (TC), low-density lipoprotein- cholesterol (LDL-C), triglyceride (TG), and positively correlated with high-density lipoprotein- cholesterol (HDL-C). The disposition index was negatively correlated with Hb, RBC count, LDL-C and BMI, and positively correlated with HDL-C. The Homeostasis Model Assessment of beta cell (HOMA-ß) was positively correlated with WBC count, platelet count, TC, LDL-C and TG. The insulinogenic index was positively correlated with WBC count, platelet count and TC. Multiple regression analysis revealed that HOMA-IR was independently associated with TG, and the Matsuda index was independently associated with TG, WBC count, and platelet count. The insulinogenic index was independently associated with WBC count. CONCLUSION: Cardinal rheological parameters reflected insulin resistance and release even in young healthy Japanese individuals within the physiological range of glycemic control.

Spatial synaptic modulation through IP3 diffusion triggered by ECB: a computational study with an astrocyte-neurons model.

Recently, functional interactions between neurons and astrocytes have been steadily clarified. In particular, the effects of presynaptic depolarization-induced suppression of excitation (DSE) through endocannabinoid (ECB) and endocannabinoids-mediated synaptic potentiation (eSP) by an astrocyte have been used as an evidence of global heterosynaptic modulation. However, the mechanism of occurrence of spatial modulation in a neural network remains unknown. Although the Ca2+ density in astrocytes is strongly related to eSP through ECB, the mechanism of the rise in the ECB receptor in Ca2+ remains unclear. Since Ca2+ is closely related to inositol-1,4,5-trisphosphate (IP3), it is believed that the released IP3 affects Ca2+ in astrocytes that receive ECB. Therefore, this study approximately showed the spatial distribution of DSE or eSP with astrocyte-neuron computational models, assuming that the IP3 caused by ECB is transmitted in an astrocyte. The results showed doughnut-shaped DSE, eSP, and DSE regions from the central ECB released points to the surroundings. They suggested that IP3 diffusion plays an important role in mediating this synaptic modulation.

Involvement of Visual Mismatch Negativity in Access Processing to Visual Awareness.

Psychophysiological studies with electroencephalography, focusing on the dynamical aspect of neural correlate of consciousness, reported that visual awareness negativity and P3 enhancement are observed at a latency, 200-300 ms after the visual stimulus onset, when the visual stimulus is consciously perceived. However, access processing to visual awareness (APVA) immediately before conscious perception still remains at the earlier stage of visual sensory processing, though there is little known regarding this subject. The present study hypothesized that visual mismatch negativity (vMMN), which reflects automatic change detection at a latency of 130-250 ms, might be involved in the APVA. In a previous study, vMMN was reported to be evoked by the deviant stimulus that is not consciously perceived in binocular rivalry. To clarify whether the visual change detection affects APVA, we conducted a modified experiment of oddball paradigm on binocular rivalry. The results showed a significant correlation between enhancement of vMMN amplitude and facilitation of perceptual alternation when the unconscious deviant was presented. This implies that vMMN is relevant to the APVA, which is a novel role of vMMN. In early visual processing, the attentional mechanism associated with vMMN is suggested to play an important role in unconscious neural processing at an earlier stage of visual awareness.

Brg1 is required to maintain colorectal cancer stem cells.

Tumor cells capable of self-renewal and continuous production of progeny cells are called tumor stem cells (TSCs) and are considered to be potential therapeutic targets. However, the mechanisms underlying the survival and function of TSCs are not fully understood. We previously reported that chromatin remodeling regulator Brg1 is essential for intestinal stem cells in mice and Dclk1 is an intestinal TSC marker. In this study, we investigated the role of Brg1 in Dclk1+ intestinal tumor cells for the maintenance of intestinal tumors in mice. Specific ablation of Brg1 in Dclk1+ intestinal tumor cells reduced intestinal tumors in ApcMin mice, and continuous ablation of Brg1 maintained the reduction of intestinal tumors. Lineage tracing in the context of Brg1 ablation in Dclk1+ intestinal tumor cells revealed that Brg1-null Dclk1+ intestinal tumor cells did not give rise to their descendent tumor cells, indicating that Brg1 is essential for the self-renewal of Dclk1+ intestinal tumor cells. Five days after Brg1 ablation, we observed increased apoptosis in Dclk1+ tumor cells. Furthermore, Brg1 was crucial for the stemness of intestinal tumor cells in a spheroid culture system. BRG1 knockdown also impaired cell proliferation and increased apoptosis in human colorectal cancer (CRC) cells. Microarray analysis revealed that apoptosis-related genes were upregulated and stem cell-related genes were downregulated in human CRC cells by BRG1 suppression. Consistently, high BRG1 expression correlated with poor disease-specific survival in human CRC patients. These data indicate that Brg1 plays a crucial role in intestinal TSCs in mice by inhibiting apoptosis and is critical for cell survival and stem cell features in human CRC cells. Thus, BRG1 represents a new therapeutic target for human CRC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.