Tumor suppressor let-7 acts as a key regulator for pluripotency gene expression in Muse cells.

In embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), the expression of an RNA-binding pluripotency-relevant protein, LIN28, and the absence of its antagonist, the tumor-suppressor microRNA (miRNA) let-7, play a key role in maintaining pluripotency. Muse cells are non-tumorigenic pluripotent-like stem cells residing in the bone marrow, peripheral blood, and organ connective tissues as pluripotent surface marker SSEA-3(+). They express pluripotency genes, differentiate into triploblastic-lineage cells, and self-renew at the single cell level. Muse cells do not express LIN28 but do express let-7 at higher levels than in iPSCs. In Muse cells, we demonstrated that let-7 inhibited the PI3K-AKT pathway, leading to sustainable expression of the key pluripotency regulator KLF4 as well as its downstream genes, POU5F1, SOX2, and NANOG. Let-7 also suppressed proliferation and glycolysis by inhibiting the PI3K-AKT pathway, suggesting its involvement in non-tumorigenicity. Furthermore, the MEK/ERK pathway is not controlled by let-7 and may have a pivotal role in maintaining self-renewal and suppression of senescence. The system found in Muse cells, in which the tumor suppressor let-7, but not LIN28, tunes the expression of pluripotency genes, might be a rational cell system conferring both pluripotency-like properties and a low risk for tumorigenicity.

Human post-implantation blastocyst-like characteristics of Muse cells isolated from human umbilical cord.

Muse cells, identified as cells positive for the pluripotent surface marker SSEA-3, are pluripotent-like endogenous stem cells located in the bone marrow (BM), peripheral blood, and organ connective tissues. The detailed characteristics of SSEA-3(+) cells in extraembryonic tissue, however, are unknown. Here, we demonstrated that similar to human-adult tissue-Muse cells collected from the BM, adipose tissue, and dermis as SSEA-3(+), human-umbilical cord (UC)-SSEA-3(+) cells express pluripotency markers, differentiate into triploblastic-lineage cells at a single cell level, migrate to damaged tissue, and exhibit low telomerase activity and non-tumorigenicity. Notably, ~ 20% of human-UC-SSEA-3(+) cells were negative for X-inactive specific transcript (XIST), a naïve pluripotent stem cell characteristic, whereas all human adult tissue-Muse cells are XIST-positive. Single-cell RNA sequencing revealed that the gene expression profile of human-UC-SSEA-3(+) cells was more similar to that of human post-implantation blastocysts than human-adult tissue-Muse cells. The DNA methylation level showed the same trend, and notably, the methylation levels in genes particularly related to differentiation were lower in human-UC-SSEA-3(+) cells than in human-adult tissue-Muse cells. Furthermore, human-UC-SSEA-3(+) cells newly express markers specific to extraembryonic-, germline-, and hematopoietic-lineages after differentiation induction in vitro whereas human-adult tissue-Muse cells respond only partially to the induction. Among various stem/progenitor cells in living bodies, those that exhibit properties similar to post-implantation blastocysts in a naïve state have not yet been found in humans. Easily accessible human-UC-SSEA-3(+) cells may be a valuable tool for studying early-stage human development and human reproductive medicine.

Characterization of CM-Dil-labeled Muse cells in culture and in skin wounds in rats.

To investigate the characteristics of multilineage-differentiating stress-enduring (Muse) cells labeled with chloromethyl dialkylcarbocyanine (CM-Dil) in culture and in skin wounds of rats. Normal human dermal fibroblasts (NHDFs) were obtained from foreskins and were confirmed by immunocytochemistry with vimentin. Muse cells were derived from NHDFs using long-term trypsinization (LTT), were confirmed using immunocytochemistry with antibodies against stage specific embryonic antigen-3 (SSEA-3) and CD105 and were expanded in suspension cultures. The Muse cells were labeled with CM-Dil and were further evaluated with respect to their biological properties using CCK-8 assays and scratch tests. One hundred µl CM-Dil-labeled Muse cells at a concentration of 5 × 103/µl were injected subcutaneously at the edges of skin wounds in adult male SD rats. At weeks 1, 3 and 5 after the injection, the distribution of CM-Dil-labeled Muse cells in skin tissues was observed using immunofluorescence microscopy. Muse cells were double-positive for CD105 and SSEA-3. ALP staining of the M-clusters were positive and they displayed orange-red fluorescence after labelling with CM-Dil, which had no adverse effects on their viability, migration or differentiation capacity. One week after the subcutaneous injection of CM-Dil-labeled Muse cells, many cells with orange-red fluorescence were observed at the edges of the skin injuries; those fluorescent spots gradually decreased over time, and only a few Muse cells with fluorescence could be detected by week 5. CM-Dil can be used to label Muse cells without affecting their proliferation, migration or differentiation, and can be used for short-term tracking of Muse cells for the treatment of skin wounds in a rat model.

Water/fat separation for self-navigated diffusion-weighted multishot echo-planar imaging.

The purpose of this study was to develop a self-navigation strategy to improve scan efficiency and image quality of water/fat-separated, diffusion-weighted multishot echo-planar imaging (ms-EPI). This is accomplished by acquiring chemical shift-encoded diffusion-weighted data and using an appropriate water-fat and diffusion-encoded signal model to enable reconstruction directly from k-space data. Multishot EPI provides reduced geometric distortion and improved signal-to-noise ratio in diffusion-weighted imaging compared with single-shot approaches. Multishot acquisitions require corrections for physiological motion-induced shot-to-shot phase errors using either extra navigators or self-navigation principles. In addition, proper fat suppression is important, especially in regions with large B0 inhomogeneity. This makes the use of chemical shift encoding attractive. However, when combined with ms-EPI, shot-to-shot phase navigation can be challenging because of the spatial displacement of fat signals along the phase-encoding direction. In this work, a new model-based, self-navigated water/fat separation reconstruction algorithm is proposed. Experiments in legs and in the head-neck region of 10 subjects were performed to validate the algorithm. The results are compared with an image-based, two-dimensional (2D) navigated water/fat separation approach for ms-EPI and with a conventional fat saturation approach. Compared with the 2D navigated method, the use of self-navigation reduced the shot duration time by 30%-35%. The proposed algorithm provided improved diffusion-weighted water images in both leg and head-neck regions compared with the 2D navigator-based approach. The proposed algorithm also produced better fat suppression compared with the conventional fat saturation technique in the B0 inhomogeneous regions. In conclusion, the proposed self-navigated reconstruction algorithm can produce superior water-only diffusion-weighted EPI images with less artefacts compared with the existing methods.

Homeostasis of Arabidopsis R protein RPS2 is negatively regulated by the RING-type E3 ligase MUSE16.

The homeostasis of resistance (R) proteins in plants must be tightly regulated to ensure precise activation of plant immune responses upon pathogen infection, while avoiding autoimmunity and growth defects when plants are uninfected. It is known that CPR1, an F-box protein in the SCF E3 complex, functions as a negative regulator of plant immunity through targeting the resistance (R) proteins SNC1 and RPS2 for degradation. However, whether these R proteins are also targeted by other E3 ligases is unclear. Here, we isolated Arabidopsis MUSE16, which encodes a RING-type E3 ligase, from a forward genetic screen and suggest that it is a negative regulator of plant immunity. Unlike CPR1, knocking out MUSE16 alone in Arabidopsis is not enough to result in defense-related dwarfism, since only RPS2 out of the tested R proteins accumulated in the muse16 mutants. Thus, our study identifies a novel E3 ligase involved in the degradation of nucleotide-binding and leucine-rich repeat (NLR) R proteins, support the idea that ubiquitin-mediated degradation is a fine-tuned mechanism for regulating the turnover of R proteins in plants, and that the same R protein can be targeted by different E3 ligases for regulation of its homeostasis.

MRI: Evaluating the Application of FOCUS-MUSE Diffusion-Weighted Imaging in the Pancreas in Comparison With FOCUS, MUSE, and Single-Shot DWIs.

BACKGROUND: Diffusion-weighted imaging (DWI) is a useful technique to detect pancreatic lesion. In DWIs, field-of-view optimized and constrained undistorted single-shot (FOCUS) can improve the spatial resolution and multiplexed sensitivity-encoding (MUSE) can gain a high signal-to-noise ratio (SNR). Based on the advantage of FOCUS and MUSE, a new DWI sequence-named FOCUS-MUSE DWI (FOCUS combined with MUSE)-was developed to delineate the pancreas. PURPOSE: To investigate the reliability of FOCUS-MUSE DWI compared to FOCUS, MUSE and single-shot (SS) DWI via the systematical evaluation of the apparent diffusion coefficient (ADC) measurements, SNR and image quality. STUDY TYPE: Prospective. SUBJECTS: A total of 33 healthy volunteers and 9 patients with pancreatic lesion. FIELD STRENGTH/SEQUENCE: A 3.0 T scanner. FOCUS-MUSE DWI, FOCUS DWI, MUSE DWI, SS DWI. ASSESSMENT: For volunteers, ADC and SNR were measured by two readers in the pancreatic head, body, and tail. For all subjects, the diagnostic image quality score was assessed by three other readers on above four DWIs. STATISTICAL TESTS: Paired-sample T-test, intraclass correlation (ICC), Bland-Altman method, Friedman test, Dunn-Bonferroni post hoc test and kappa coefficient. A significance level of 0.05 was used. RESULTS: FOCUS-MUSE DWI had the best intersession repeatability of ADC measurements (head: 59.53, body: 101.64, tail: 42.30) among the four DWIs, and also maintained the significantly highest SNR (reader 1 [head: 19.68 ± 3.23, body: 23.42 ± 5.00, tail: 28.85 ± 4.96], reader 2 [head: 19.93 ± 3.52, body: 23.02 ± 5.69, tail: 29.77 ± 6.33]) except for MUSE DWI. Furthermore, it significantly achieved better image quality in volunteers (median value: 4 score) and 9 patients (most in 4 score). DATA CONCLUSION: FOCUS-MUSE DWI improved the reliability of pancreatic images with the most stable ADC measurement, best image quality score and sufficient SNR among four DWIs. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

High-Dose Photodynamic Therapy Increases Tau Protein Signals in Drosophila.

Amyloid-Detection and imaging of amyloid-ß plaques (Aß) has been a focus in the field of neurodegeneration (ND) due to the high correlation with Parkinson's and Alzheimer's diseases. Here, a novel approach is being proposed and developed to induce and assess those diseases. Photodynamic therapy (PDT) is applied to the fruit fly Drosophila melanogaster as a model of systemic oxidative stress to induce rapid Aß accumulation. Excised brains are evaluated by Brillouin-Raman spectroscopy and microscopy with UV surface emissions (MUSE) to interrogate physical property changes due to fixation and high-dose PDT. MUSE reveals reasonable autofluorescence in the spectral range of Aß, particularly for females, with increased signal once stained. A presence of significant mechanical changes in fresh brains treated with PDT compared to healthy controls is revealed using Brillouin spectroscopy. Aß plaque presence was confirmed with confocal analysis, with female PDT flies yielding nearly four-fold the mean intensity of controls, thus marking PDT as a potential neurodegenerative disease model. MUSE may serve as a viable early screening method for Aß presence and quantification in a research setting. This reduces the time for sample preparation and drastically decreases the cost of Aß quantification.

Phagocytosing differentiated cell-fragments is a novel mechanism for controlling somatic stem cell differentiation within a short time frame.

Stem cells undergo cytokine-driven differentiation, but this process often takes longer than several weeks to complete. A novel mechanism for somatic stem cell differentiation via phagocytosing 'model cells' (apoptotic differentiated cells) was found to require only a short time frame. Pluripotent-like Muse cells, multipotent mesenchymal stem cells (MSCs), and neural stem cells (NSCs) phagocytosed apoptotic differentiated cells via different phagocytic receptor subsets than macrophages. The phagocytosed-differentiated cell-derived contents (e.g., transcription factors) were quickly released into the cytoplasm, translocated into the nucleus, and bound to promoter regions of the stem cell genomes. Within 24 ~ 36 h, the cells expressed lineage-specific markers corresponding to the phagocytosed-differentiated cells, both in vitro and in vivo. At 1 week, the gene expression profiles were similar to those of the authentic differentiated cells and expressed functional markers. Differentiation was limited to the inherent potential of each cell line: triploblastic-, adipogenic-/chondrogenic-, and neural-lineages in Muse cells, MSCs, and NSCs, respectively. Disruption of phagocytosis, either by phagocytic receptor inhibition via small interfering RNA or annexin V treatment, impeded differentiation in vitro and in vivo. Together, our findings uncovered a simple mechanism by which differentiation-directing factors are directly transferred to somatic stem cells by phagocytosing apoptotic differentiated cells to trigger their rapid differentiation into the target cell lineage.

Characteristics of multilineage-differentiating stress-enduring cell clusters in different culture conditions.

OBJECTIVE: To observe the morphological characteristics of clusters of Muse cells from normal human dermal fibroblasts (NHDFs) under different culture conditions. METHODS: Muse cells were sorted by magnetic activated cell sorting (MACS) from NHDFs, and were evaluated by flow cytometry. Muse cells were cultured in suspension and in adherent conditions to obtain Muse cell clusters (M-clusters), which were further characterized by alkaline phosphatase (AP) staining, immunofluorescence (IF) staining and transmission electron microscopy (TEM). The M-clusters were further cultured on Lando artificial dermal regeneration matrix (LADRM) for analysis by scanning electron microscopy (SEM) and IF staining of frozen sections. RESULTS: The proportion of SSEA3 and CD105 double-positive cells obtained by MACS was 87.4%. The sorted cells rapidly formed M-clusters after suspension culture, and showed internal characteristics of stem cells under TEM. After adherent culture, M-clusters stained positively for AP, SSEA-3 and OCT-4. Each M-cluster on the surface of the LADRM displayed an outer membrane of amorphous materials under SEM. Frozen sections and fluorescence staining of LADRM loaded with M-clusters showed an uneven fluorescence intensity of SSEA-3 within the clusters. CONCLUSIONS: Muse cells sorted by MACS from NHDFs could generate M-clusters, which included cells of different stemness and are wrapped in membrane-like structures.

Online Learning for Wearable EEG-Based Emotion Classification.

Giving emotional intelligence to machines can facilitate the early detection and prediction of mental diseases and symptoms. Electroencephalography (EEG)-based emotion recognition is widely applied because it measures electrical correlates directly from the brain rather than indirect measurement of other physiological responses initiated by the brain. Therefore, we used non-invasive and portable EEG sensors to develop a real-time emotion classification pipeline. The pipeline trains different binary classifiers for Valence and Arousal dimensions from an incoming EEG data stream achieving a 23.9% (Arousal) and 25.8% (Valence) higher F1-Score on the state-of-art AMIGOS dataset than previous work. Afterward, the pipeline was applied to the curated dataset from 15 participants using two consumer-grade EEG devices while watching 16 short emotional videos in a controlled environment. Mean F1-Scores of 87% (Arousal) and 82% (Valence) were achieved for an immediate label setting. Additionally, the pipeline proved to be fast enough to achieve predictions in real-time in a live scenario with delayed labels while continuously being updated. The significant discrepancy from the readily available labels on the classification scores leads to future work to include more data. Thereafter, the pipeline is ready to be used for real-time applications of emotion classification.

Adipose tissue-derived Muse cells promote autophagy and oxidative stress tolerance in human epidermal melanocytes.

To investigate the effect of human adipose tissue-derived multilineage-differentiating stress-enduring (Muse) cells on the oxidative stress injury of human epidermal melanocytes (HEMs) in vitro. HEMs were treated with H2O2 to establish an oxidative stress injury model and then were co-cultured with adipose tissue-derived Muse cells. Immunohistochemistry, flow cytometry and Western blotting were used to assess changes in autophagy flux, apoptosis, expression of melanin synthesis related proteins and proliferation of melanocytes. Our findings demonstrate that co-culture with Muse cells significantly increased the tolerance of HEMs to oxidative stress, enhanced autophagy flux and reduced apoptosis. The expression of proteins related to the formation of melanin increased as did cell proliferation. Treatment with the autophagy inhibitor, 3-methyladenine (3MA), partially counteracted the improvement of oxidative stress tolerance in melanocytes elicited by co-culture with Muse cells. Muse cells promote autophagy and oxidative stress tolerance of melanocytes.

Intravenous Administration of Human Muse Cells Ameliorates Deficits in a Rat Model of Subacute Spinal Cord Injury.

Multilineage-differentiating stress-enduring (Muse) cells are newly established pluripotent stem cells. The aim of the present study was to examine the potential of the systemic administration of Muse cells as an effective treatment for subacute SCI. We intravenously administered the clinical product "CL2020" containing Muse cells to a rat model two weeks after mid-thoracic spinal cord contusion. Eight experimental animals received CL2020, and twelve received the vehicle. Behavioral analyses were conducted over 20 weeks. Histological evaluations were performed. After 20 weeks of observation, diphtheria toxin was administered to three CL2020-treated animals to selectively ablate human cell functions. Hindlimb motor functions significantly improved from 6 to 20 weeks after the administration of CL2020. The cystic cavity was smaller in the CL2020 group. Furthermore, larger numbers of descending 5-HT fibers were preserved in the distal spinal cord. Muse cells in CL2020 were considered to have differentiated into neuronal and neural cells in the injured spinal cord. Neuronal and neural cells were identified in the gray and white matter, respectively. Importantly, these effects were reversed by the selective ablation of human cells by diphtheria toxin. Intravenously administered Muse cells facilitated the therapeutic potential of CL2020 for severe subacute spinal cord injury.

The long-term efficacy of transoral incisionless fundoplication with Medigus Ultrasonic Surgical Endostapler (MUSE) for gastroesophageal reflux disease.

BACKGROUND: To evaluate the long-term efficacy of transoral incisionless fundoplication (TIF) with Medigus Ultrasonic Surgical Endostapler (MUSE) for gastroesophageal reflux disease (GERD). METHODS: A total of 16 patients with proton pump inhibitor-dependent gastroesophageal reflux disease had undergone TIF by MUSE in Shanghai General Hospital （Shanghai, China）from March 2017 to December 2018. Patients were followed up at 6 months, and the GERD-health-related quality of life (GERD-HRQL) questionnaire score, the GERD questionnaire (GERD-Q) score, high-resolution esophageal manometry (HREM) and 24 h esophageal pH parameters, the Hill grade of the gastroesophageal flap valve (GEFV) and daily Proton pump inhibitor (PPI) consumption before and after procedure were compared. Patients also were followed up at 3 years and 5 years using a structured questionnaire via phone which evaluated symptoms of reflux, dose of PPI medication and side effects. RESULTS: Follow-up data were collected from 13 patients, ranging from 38 to 63 months, 53 months on average. 10/13 patients reported symptomatic improvement and daily PPI consumption was stopped or halved in 11/13. After procedure, the mean scores of GERD-HRQL and GERD-Q were significantly increased. The mean DeMeester score, the mean acid exposure time percentage and the mean number of acid reflux episodes were significantly lower. The mean rest pressure at lower esophageal sphincter (LES) had no significant difference. CONCLUSION: TIF by MUSE has significant efficacy in the treatment of PPI-dependent GERD, which can improve symptoms and life quality of patients, and reduce the acid exposure time for long-term. Chictr.org.cn. TRIAL REGISTRATION: ChiCTR2000034350.

Transoral incisionless fundoplication with Medigus ultrasonic surgical endostapler (MUSE) for the treatment of gastro-esophageal reflux disease: outcomes up to 3 years.

BACKGROUND: Transoral incisionless fundoplication (TIF) with Medigus Ultrasonic Surgical Endostapler (MUSE) is a new intervention for treatment of gastro-esophageal reflux disease (GERD). We aimed at assessing the clinical, functional, and endoscopic effects of TIF by MUSE. METHODS: Forty-six patients underwent TIF. Proton pump inhibitor (PPI) consumption, GERD-health-related quality of life (HRQL) and reflux symptom index (RSI) questionnaires, upper gastrointestinal (GI) endoscopy, esophageal 24-h pH-impedance recording, and high-resolution manometry (HRM) were done before TIF and scheduled 6 and 12 months later (HRM only at 6-month). PPI consumption and symptoms were then assessed yearly. Data up to 3 years are reported in this study (PP- and ITT-analysis). RESULTS: TIF was successfully performed in 45/46 patients; in one patient esophageal intubation was impossible. Perforation occurred in two cases. One patient required surgery within 6 months. Clinical follow-up was available for 42 patients at 6 months and 1 year, 35 patients at 2 years, and 31 patients at 3 years. At 1, 2, and 3 years, PPI consumption was stopped, respectively, in 64.3%, 62.9%, and 74.2% of cases (ITT-analysis: 58.7%, 56.4%, and 65.7%). GERD-HRQL and RSI scores decreased at least 50%, respectively, in 71.5% and 76.2%, 71.4% and 68.6%, and 67.7% of cases (ITT-analysis: 65.2% and 69.6%, 64.1% and 61.5%, and 60%). A significant improvement of both scores was observed up to 3 years. 6-month and 1-year functional follow-up were possible in 31 and 20 patients. HRM showed significant increase of the median lower esophageal sphincter length and rate of peristaltic waves. Esophageal pH-impedance recording found significantly fewer acid, proximal and total refluxes, and percentage of esophageal pH < 4 total time at 6 months, but not at 1 year. CONCLUSION: TIF by MUSE significantly improved symptoms and PPIs consumption up to 3 years. However, esophagitis still persisted in one-third of cases at 1 year and functional improvement at 6 months was not confirmed at 1 year. Severe complications requiring surgery occurred in two cases. CLINICALTRIALS: GOV: ID: NCT03669874.

Effects of human Muse cells on bladder inflammation, overactivity, and nociception in a chemically induced Hunner-type interstitial cystitis-like rat model.

INTRODUCTION AND HYPOTHESIS: We investigated the effects of locally administered human multilineage-differentiating stress enduring (Muse) cells, nontumorigenic pluripotent-like endogenous stem cells, on bladder tissues, function, and nociceptive behavior in a chemically induced Hunner-type interstitial cystitis (HIC)-like rat model without immunosuppressant. METHODS: Chemical cystitis was induced by intravesical instillation of 0.2 N hydrochloride (HCl) for 15 min in female F344 rats. SSEA-3+ Muse cells, SSEA-3- non-Muse cells or Hanks' balanced salt solution (HBSS; vehicle) were injected into the anterior and posterior bladder wall at each 1×104 cells/10 µl 6 h after HCl application. The sham group received HBSS without HCl instillation. Urinary frequency was assessed using metabolic cages, cystometrograms, nociceptive behavior, and histological analysis of the bladder and L6 spinal cord. RESULTS: Increases in urinary frequency and decreases in bladder capacity compared with the sham group were observed in the vehicle and non-Muse groups, but not in the Muse group, at 1 week. Significant increases in nociceptive behavior compared with the sham group and the expression of TNFα in the bladder and c-Fos in the bilateral dorsal horns of L6 spinal cord were also observed in the vehicle and non-Muse groups, whereas these changes were not seen in the Muse group at 1 week. Histological analysis exhibited a higher proportion of injected Muse cells remaining in the urothelial basal layer and lamina propria of the bladder than non-Muse cells until 4 weeks. CONCLUSIONS: Muse cell therapy could be a promising modality for treating HIC.

Intravenous injection of human multilineage-differentiating stress-enduring cells alleviates mouse severe acute pancreatitis without immunosuppressants.

INTRODUCTION: We examined the effect of intravenously injected human multilineage-differentiating stress-enduring (Muse) cells, non-tumorigenic endogenous reparative stem cells already used in clinical trials, on a severe acute pancreatitis (SAP) mouse model without immunosuppressants. METHODS: Human Muse cells (1.0 × 105 cells) collected from mesenchymal stem cells (MSCs) as SSEA-3(+) were injected into a C57BL/6 mouse model via the jugular vein 6 h after SAP-induction with taurocholate. The control group received saline or the same number of SSEA-3(-)-non-Muse MSCs. RESULTS: Edematous parameters, F4/80(+) macrophage infiltration and terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity was the lowest and the number of proliferating endogenous pancreatic progenitors (CK18(+)/Ki67(+) cells) the highest in the Muse group among the three groups, with statistical significance, at 72 h. An enzyme-linked immunosorbent assay and quantitative polymerase chain reaction demonstrated that in vitro production of VEGF, HGF, IGF-1, and MMP-2, which are relevant to tissue protection, anti-inflammation, and anti-fibrosis, were higher in Muse cells than in non-Muse MSCs, particularly when cells were cultured in SAP mouse serum. Consistently, the pancreas of animals in the Muse group contained higher amounts of those factors according to Western blotting at 18 h than that in the non-Muse MSCs and control groups. CONCLUSIONS: Intravenous injection of human Muse cells was suggested to be effective for attenuating edema, inflammation and apoptosis in the acute phase of SAP.

State of Evidence in Minimally Invasive Management of Gastroesophageal Reflux: Findings of a Scoping Review.

BACKGROUNDS & AIMS: Endoscopic management of gastroesophageal reflux disease (GERD) is being employed increasingly. The aim of this scoping review was to assess the volume of available evidence on the benefits of endoscopic and minimally invasive surgical therapies for GERD. METHODS: criteria were used to perform an extensive literature search of data regarding the reported benefit of endoscopic therapies in GERD. Randomized controlled studies were utilized when available; however, data from observational studies were also reviewed. RESULTS: A formal review of evidence was performed in 22 studies. Inclusion and exclusion criteria and study duration were noted and tabulated. Assessment of outcomes was based on symptoms and objective criteria reported by investigators. Reported outcomes for the interventions were tabulated under the heading of subjective (symptom scores, quality of life metrics, and change in proton pump inhibitor use) and objective metrics (pH parameters, endoscopic signs, and lower esophageal sphincter pressure changes). Adverse events were noted and tabulated. The majority of studies showed symptomatic and objective improvement of GERD with the device therapies. Adverse events were minimal. However, normalization of acid exposure occurred in about 50% of patients and, for some modalities, long-term durability is uncertain. CONCLUSIONS: This scoping review revealed that the endoluminal and minimally invasive surgical devices for GERD therapy are a promising alternative to proton pump inhibitor therapy. Their place in the treatment algorithm for GERD will be better defined when important clinical parameters, especially durability of effect, are better understood.

Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice.

Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Musecells accumulate to the damaged tissue, where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice orally inoculated with 9 × 109 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5 × 104 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection.

The evaluation of the safety and efficacy of intravenously administered allogeneic multilineage-differentiating stress-enduring cells in a swine hepatectomy model.

INTRODUCTION: Multilineage-differentiating stress-enduring (Muse) cells are non-tumorigenic endogenous pluripotent-like cells residing in the bone marrow that exert a tissue reparative effect by replacing damaged/apoptotic cells through spontaneous differentiation into tissue-constituent cells. Post-hepatectomy liver failure (PHLF) is a potentially fatal complication. The main purpose of this study was to evaluate the safety and efficiency of allogeneic Muse cell administration via the portal vein in a swine model of PHLF. METHODS: Swine Muse cells, collected from swine bone marrow-mesenchymal stem cells (MSCs) as SSEA-3(+) cells, were examined for their characteristics. Then, 1 × 107 allogeneic-Muse cells and allogeneic-MSCs and vehicle were injected via the portal vein in a 70% hepatectomy swine model. RESULTS: Swine Muse cells exhibited characteristics comparable to previously reported human Muse cells. Compared to the MSC and vehicle groups, the Muse group showed specific homing of the administered cells into the liver, resulting in improvements in the control of hyperbilirubinemia (P = 0.04), prothrombin international normalized ratio (P = 0.05), and suppression of focal necrosis (P = 0.04). Integrated Muse cells differentiated spontaneously into hepatocyte marker-positive cells. CONCLUSIONS: Allogeneic Muse cell administration may provide a reparative effect and functional recovery in a 70% hepatectomy swine model and thus may contribute to the treatment of PHLF.

Harmonization of large MRI datasets for the analysis of brain imaging patterns throughout the lifespan.

As medical imaging enters its information era and presents rapidly increasing needs for big data analytics, robust pooling and harmonization of imaging data across diverse cohorts with varying acquisition protocols have become critical. We describe a comprehensive effort that merges and harmonizes a large-scale dataset of 10,477 structural brain MRI scans from participants without a known neurological or psychiatric disorder from 18 different studies that represent geographic diversity. We use this dataset and multi-atlas-based image processing methods to obtain a hierarchical partition of the brain from larger anatomical regions to individual cortical and deep structures and derive age trends of brain structure through the lifespan (3-96 years old). Critically, we present and validate a methodology for harmonizing this pooled dataset in the presence of nonlinear age trends. We provide a web-based visualization interface to generate and present the resulting age trends, enabling future studies of brain structure to compare their data with this reference of brain development and aging, and to examine deviations from ranges, potentially related to disease.