Mesenchymal Stem Cell Therapy in Acute Intracerebral Hemorrhage: A Dose-Escalation Safety and Tolerability Trial.

BACKGROUND: We conducted a preliminary phase I, dose-escalating, safety, and tolerability trial in the population of patients with acute intracerebral hemorrhage (ICH) by using human allogeneic bone marrow-derived mesenchymal stem/stromal cells. METHODS: Eligibility criteria included nontraumatic supratentorial hematoma less than 60 mL and Glasgow Coma Scale score greater than 5. All patients were monitored in the neurosciences intensive care unit for safety and tolerability of mesenchymal stem/stromal cell infusion and adverse events. We also explored the use of cytokines as biomarkers to assess responsiveness to the cell therapy. We screened 140 patients, enrolling 9 who met eligibility criteria into three dose groups: 0.5 million cells/kg, 1 million cells/kg, and 2 million cells/kg. RESULTS: Intravenous administration of allogeneic bone marrow-derived mesenchymal stem/stromal cells to treat patients with acute ICH is feasible and safe. CONCLUSIONS: Future larger randomized, placebo-controlled ICH studies are necessary to validate this study and establish the effectiveness of this therapeutic approach in the treatment of patients with ICH.

Probiotic effects of mixture of Groenewaldozyma salmanticensis and Gluconacetobacter liquefaciens on growth and immune responses in Paralichthys olivaceus.

This study was performed to evaluate the effects of dietary probiotics on growth, non-specific immune responses and disease resistance in olive flounder, Paralichthys olivaceus. During 8 weeks, the fish were fed the five experimental diets such as a basal commercial diet (CON), oxytetracycline (OTC) and three basal diets containing Bacillus subtilis (BS), a commercial microbial product (CES) and a mixture of yeast and bacterium (PI), respectively. Fish fed all the probiotics diets and OTC showed a significantly higher growth than fish-fed CON (P < 0·05). Fish-fed PI had a significantly higher nitroblue tetrazolium activity, whereas fish-fed CES showed a higher lysozyme level (P < 0·05). A 7-day challenge test also showed that fish-fed PI had a cumulative survival rate equivalent to that of fish-fed OTC (P < 0·05). Moreover, the diet (PI) appeared to increase the diversity of microbial community in the fish. All these results suggest that the probiotics diet could function as a potential antibiotic replacer in the olive flounder. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is unique in revealing that a diet mixture of yeast, Groenewaldozyma salmanticensis and bacterium Gluconacetobacter liquefaciens can enhance growth, innate immunity and diversity of microbial community including dominant species in the olive flounder. All these indicate that the diet mixture could function as a potential antibiotic replacer in one of the most commercially important fisheries in South Korea.

A genome-wide DNA methylation signature for SETD1B-related syndrome.

SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients.

Evaluating Tissue Contrast and Detecting White Matter Injury in the Infant Brain: A Comparison Study of Synthetic Phase-Sensitive Inversion Recovery.

BACKGROUND AND PURPOSE: Synthetic MR imaging enables the acquisition of phase-sensitive inversion recovery images. The aim of this study was to compare the image quality of synthetic phase-sensitive inversion recovery with that of other sequences in infants. MATERIALS AND METHODS: Brain MR imaging with 3D T1-weighted fast-spoiled gradient recalled, synthetic T1WI, and synthetic phase-sensitive inversion recovery of 91 infants was compared. Contrast between unmyelinated WM and myelinated WM and between unmyelinated WM and cortical GM was calculated. Qualitative evaluation of image quality and myelination degree was performed. In infants with punctate white matter injuries, the number of lesions was compared. RESULTS: The contrast between unmyelinated WM and myelinated WM was higher in synthetic phase-sensitive inversion recovery compared with fast-spoiled gradient recalled or synthetic T1WI (P < .001). Compared with synthetic T1WI, synthetic phase-sensitive inversion recovery showed higher gray-white matter differentiation (P < .001) and myelination degree in the cerebellar peduncle (P < .001). The number of detected punctate white matter injuries decreased with synthetic phase-sensitive inversion recovery compared with fast-spoiled gradient recalled sequences (1.2 ± 3.2 versus 3.4 ± 3.6, P = .001). CONCLUSIONS: Synthetic phase-sensitive inversion recovery has the potential to improve tissue contrast and image quality in the brain MR imaging of infants. However, we have to be aware that synthetic phase-sensitive inversion recovery has limited value when assessing punctate white matter injuries compared with 3D fast-spoiled gradient recalled imaging.

Multidelay Arterial Spin-Labeling MRI in Neonates and Infants: Cerebral Perfusion Changes during Brain Maturation.

BACKGROUND AND PURPOSE: Arterial spin-labeling with multiple postlabeling delays can correct transit times. We tried to evaluate CBF in neonates and infants using multidelay arterial spin-labeling. MATERIALS AND METHODS: Multidelay arterial spin-labeling was applied to 13 preterm neonates (mean postmenstrual age, 34.9 weeks), 13 term-equivalent-age neonates (mean postmenstrual age, 39.2 weeks), and 6 infants (mean postmenstrual age, 57.8 weeks). Transit time-corrected CBF in the caudate, thalamus, frontal GM, occipital GM, frontal WM, and occipital WM was measured, and relative CBF compared with the whole-brain CBF was calculated. Inter- and intragroup comparisons were performed among the 3 age groups. A correlation and nonlinear regression analysis were performed between postmenstrual age and CBF. RESULTS: Intergroup comparisons showed significantly higher whole-brain CBF in infants (38.3 mL/100 g/min) compared with preterm (15.5 mL/100 g/min) and term-equivalent-age (18.3 mL/100 g/min) neonates (P < .001). In the intragroup comparison, all 3 groups showed significantly higher relative CBF values in the occipital WM (63.6%-90.3%) compared with the frontal WM (46.3%-73.9%). In term-equivalent-age neonates, the occipital GM (120.8%) had significantly higher relative CBF values than the frontal GM (103.5%). There was a significant negative correlation between postmenstrual age and the relative CBF of the thalamus (r = - 0.449, P = .010). There were significant positive relationships between postmenstrual age and the relative CBF of the frontal WM (R 2 = 0.298, P = .001) and occipital WM (R 2 = 0.452, P < .001). CONCLUSIONS: Multidelay arterial spin-labeling with transit time-corrected CBF showed developmental changes and regional differences of CBF in neonates and infants.

Differential diagnosis of jaw pain using informatics technology.

This study aimed to deduce evidence-based clinical clues that differentiate temporomandibular disorders (TMD)-mimicking conditions from genuine TMD by text mining using natural language processing (NLP) and recursive partitioning. We compared the medical records of 29 patients diagnosed with TMD-mimicking conditions and 290 patients diagnosed with genuine TMD. Chief complaints and medical histories were preprocessed via NLP to compare the frequency of word usage. In addition, recursive partitioning was used to deduce the optimal size of mouth opening, which could differentiate TMD-mimicking from genuine TMD groups. The prevalence of TMD-mimicking conditions was more evenly distributed across all age groups and showed a nearly equal gender ratio, which was significantly different from genuine TMD. TMD-mimicking conditions were caused by inflammation, infection, hereditary disease and neoplasm. Patients with TMD-mimicking conditions frequently used "mouth opening limitation" (P < .001), but less commonly used words such as "noise" (P < .001) and "temporomandibular joint" (P < .001) than patients with genuine TMD. A diagnostic classification tree on the basis of recursive partitioning suggested that 12.0 mm of comfortable mouth opening and 26.5 mm of maximum mouth opening were deduced as the most optimal mouth-opening cutoff sizes. When the combined analyses were performed based on both the text mining and clinical examination data, the predictive performance of the model was 96.6% with 69.0% sensitivity and 99.3% specificity in predicting TMD-mimicking conditions. In conclusion, this study showed that AI technology-based methods could be applied in the field of differential diagnosis of orofacial pain disorders.

Evolving affinity between Coulombic reversibility and hysteretic phase transformations in nano-structured silicon-based lithium-ion batteries.

Nano-structured silicon is an attractive alternative anode material to conventional graphite in lithium-ion batteries. However, the anode designs with higher silicon concentrations remain to be commercialized despite recent remarkable progress. One of the most critical issues is the fundamental understanding of the lithium-silicon Coulombic efficiency. Particularly, this is the key to resolve subtle yet accumulatively significant alterations of Coulombic efficiency by various paths of lithium-silicon processes over cycles. Here, we provide quantitative and qualitative insight into how the irreversible behaviors are altered by the processes under amorphous volume changes and hysteretic amorphous-crystalline phase transformations. Repeated latter transformations over cycles, typically featured as a degradation factor, can govern the reversibility behaviors, improving the irreversibility and eventually minimizing cumulative irreversible lithium consumption. This is clearly different from repeated amorphous volume changes with different lithiation depths. The mechanism behind the correlations is elucidated by electrochemical and structural probing.

Comparison of image quality between conventional VIBE and radial VIBE in free-breathing paediatric abdominal MRI.

AIM: To compare the image quality between conventional volume interpolated breath-hold examination (VIBE) and radial VIBE in contrast-enhanced fat-suppressed T1-weighted images of paediatric abdominal magnetic resonance imaging (MRI) during free-breathing. MATERIALS AND METHODS: Images from paediatric patients who underwent contrast-enhanced abdominal MRI with a 3 T magnet using conventional VIBE (conventional group) and radial VIBE (radial group) while freely breathing were reviewed retrospectively. For objective analysis, the mean values of noise and signal-to-noise ratio (SNR) in the liver on contrast-enhanced fat-suppressed T1-weighted images were compared. For subjective analysis, overall image quality, respiratory motion, portal vein clarity, and hepatic margin sharpness were assessed using four-point scales. RESULTS: Nine patients (mean age of 2.8±2.3 years) in the conventional and 17 patients (mean age of 2.4±2.8 years) in the radial groups were included. According to the objective analysis, the noise was significantly lower and the SNR was significantly higher in the radial group than those in the conventional group (all, p<0.001). In the subjective analysis, overall image quality, respiratory motion, portal vein clarity, and hepatic margin sharpness were all significantly higher in the radial group (all, p<0.001). CONCLUSION: Paediatric abdominal MRI images with radial VIBE showed lower noise with higher SNR in objective analysis and higher image quality in subjective analysis, compared to conventional VIBE.

A simulation study on angular and micro pattern effects in GEM detectors.

A useful approach for the enhancement of thermal neutrons detection has been reported here. This technique, based on the angular and micro pattern effects, has been developed and applied to the boron-coated ((10)B) Gas Electron multiplier (GEM) detector. In the angular effect case, as a general rule, the detector device is turned at an angle which improves the device response per unit area of the detector. While for the latter case, a regular pattern in the form of micrometer deep grooves is fabricated onto the converter coating, consequently it enhances the capture probability of the detector. For the current study, both of these techniques using a (10)B-coated GEM detector have been simulated for low energy neutrons. For the evaluation of detector response thermal neutrons in the energy ranges from 25meV to 100meV were transported onto the detector surface. For this work, FLUKA MC code has been utilized. The output in both cases has been estimated as a function of incident thermal neutron energies. By employing both techniques, the angle and the micro pattern dependent efficiencies for (10)B-coated GEM detectors are presented, which indicate an improved efficiency response of the device. We anticipate that by using these modifications can lead a further forward step in the development and improvement of thermal neutron detection technology.

Therapeutic targeting of tetraspanin8 in epithelial ovarian cancer invasion and metastasis.

Epithelial ovarian cancer (EOC) invasion and metastasis are complex phenomena that result from the coordinated action of many metastatic regulators and must be overcome to improve clinical outcomes for patients with these cancers. The identification of novel therapeutic targets is critical because of the limited success of current treatment regimens, particularly in advanced-stage ovarian cancers. In this study, we found that tetraspanin 8 (TSPAN8) is overexpressed in about 52% (14/27) of EOC tissues and correlates with poor survival. Using small interfering RNA-mediated TSPAN8 knockdown and a competition assay with purified TSPAN8 large extracellular loop (TSPAN8-LEL) protein, we identified TSPAN8-LEL as a key regulator of EOC cell invasion. Furthermore, monotherapy with TSPAN8-blocking antibody we developed shows that antibody-based modulation of TSPAN8-LEL can significantly reduce the incidence of EOC metastasis without severe toxicity in vivo. Finally, we demonstrated that the TSPAN8-blocking antibody promotes the internalization and concomitant downregulation of cell surface TSPAN8. Collectively, our data suggest TSPAN8 as a potential novel therapeutic target in EOCs and antibody targeting of TSPAN8 as an effective strategy for inhibiting invasion and metastasis of TSPAN8-expressing EOCs.

Bioavailability of the Nano-Unit 14C-Agrochemicals Under Various Water Potential.

The study was conducted to investigate the effects of water potential on bioavailability of the nano-unit 14C-cafenstrole, 14C-pretilachlor, 14C-benfuresate, 14C-simetryn and 14C-oxyfluorfen applied with or without dimepiperate or daimuron under various water potential conditions. The highest bioavailable concentration in soil solution (BCSS) was found at 60% soil moisture, while the lowest occurred at 50% soil moisture for soil-applied alone or in combination. All water potential conditions differed significantly from each other with variations in total bioavailable amount in soil solution (TBSS) when either dimepiperate or daimuron were added to the soil, and changes were directly proportional to variations in water potential. Across all treatments, TBSS at 80% soil moisture was three to four times greater than that at 50% soil moisture when applied alone or in combination with dimepiperate or daimuron. Cafenstrole and simetryn had distribution coefficient (Kd) values <64 ml g-1 and a TBSS ranging from 10 to 44 ng g-1 soil, regardless of water potential conditions applied alone or in combination. Pretilachlor and benfuresate had Kd values <15 ml g-1 and a TBSS range of 38 to 255 ng g-1 soil when applied with or without dimepiperate or daimuron.

Thermal neutron response of a boron-coated GEM detector via GEANT4 Monte Carlo code.

In this work, we report the design configuration and the performance of the hybrid Gas Electron Multiplier (GEM) detector. In order to make the detector sensitive to thermal neutrons, the forward electrode of the GEM has been coated with the enriched boron-10 material, which works as a neutron converter. A total of 5×5cm2 configuration of GEM has been used for thermal neutron studies. The response of the detector has been estimated via using GEANT4 MC code with two different physics lists. Using the QGSP_BIC_HP physics list, the neutron detection efficiency was determined to be about 3%, while with QGSP_BERT_HP physics list the efficiency was around 2.5%, at the incident thermal neutron energies of 25meV. The higher response of the detector proves that GEM-coated with boron converter improves the efficiency for thermal neutrons detection.

Is histologic differentiation a prognostic indicator for gastric carcinoma patients with curative resection?

BACKGROUND: The prognostic relevance of histologic differentiation in gastric carcinoma patients with curative resection is unclear. We analyzed the clinicopathologic features of gastric carcinoma patients with curative resection according to the histologic differentiation and evaluated surgical outcome. MATERIALS AND METHODS: Of 1198 gastric carcinoma patients with curative resection (American joint committee on cancer, Stages I-III), 274 (22.9%) had well-differentiated, 331 (27.6%) had moderately differentiated and 593 (49.5%) had poorly differentiated gastric carcinomas. RESULTS: Patients with the poorly differentiated type had more prominent serosal invasion, much more lymph node involvement and more advanced stage than patients with the well-differentiated type. The overall survival rate was higher for patients with a well-differentiated gastric carcinoma than for patients with a poorly differentiated type. Using Cox's proportional hazard regression model, histologic differentiation was found to be a statistically significant prognostic parameter (risk ratio, 1.41; 95% confidence interval, 1.028-1.922; P < 0.05). CONCLUSION: Our results suggest that patients with a well-differentiated gastric carcinoma have a good prognosis compared with those with a poorly differentiated type. Therefore, histologic differentiation can be used as a prognostic indicator in gastric carcinoma patients with curative resection.

Staging accuracy of endoscopic ultrasound performed by nonexpert endosonographers in patients with resectable esophageal squamous cell carcinoma: is it possible?

The accuracy of endoscopic ultrasound (EUS) is operator-dependent. According to learning curve study, the accuracy of EUS T-staging for esophageal cancer has been reported to be greater in an investigator who had performed at least 100 EUS examinations. We determined comparative study regarding T-staging accuracy of EUS for esophageal squamous cell carcinoma between expert and nonexpert endoscopic ultrasonographers. We retrospectively identified 73 consecutive patients with esophageal squamous cell carcinoma who underwent EUS and endoscopic mucosal resection, endoscopic submucosal dissection, or surgery. EUS was performed by expert (Group 1) and nonexpert (Group 2) endoscopic ultrasonographers in multitertiary hospitals. Groups 1 and 2 were 37 and 36 patients during 2005-2011, respectively. Forty-two patients (57.5%) of the overall patients underwent surgical exploration. Correct endoscopic ultrasonographic T-staging of Group 1 was observed in 34 (91.9%) patients, while that of Group 2 was observed in 26 (72.2%) patients. And there was significant difference in correct endoscopic ultrasonographic T-staging between Group 1 and Group 2 (P = 0.035). The incorrect endoscopic ultrasonographic T-staging of Group 1 were three cases that were overstaging (8.1%), but in Group 2 there were seven overstaging (19.4%) and three understaging (8.3%). There was no significant difference in overstaging or understaging of incorrect endoscopic ultrasonographic T-staging between Group 1 and Group 2 (P = 0.528). This study first provides evidence that endoscopic ultrasonographic T-staging of nonexpert endoscopic ultrasonographers was inferior to be correct, compared with that of expert endoscopic ultrasonographers. EUS staging for esophageal cancer should be performed by expert endoscopic ultrasonographers to provide appropriate management strategy.

LKB1 reduces ROS-mediated cell damage via activation of p38.

Liver kinase B1 (LKB1, also known as serine/threonine kinase 11, STK11) is a tumor suppressor mutated in Peutz-Jeghers syndrome and in a variety of sporadic cancers. Herein, we demonstrate that LKB1 controls the levels of intracellular reactive oxygen species (ROS) and protects the genome from oxidative damage. Cells lacking LKB1 exhibit markedly increased intracellular ROS levels, excessive oxidation of DNA, increased mutation rates and accumulation of DNA damage, which are effectively prevented by ectopic expression of LKB1 and by incubation with antioxidant N-acetylcysteine. The role of LKB1 in suppressing ROS is independent of AMP-activated protein kinase, a canonical substrate of LKB1. Instead, under the elevated ROS, LKB1 binds to and maintains the activity of the cdc42-PAK1 (p21-activated kinase 1) complex, which triggers the activation of p38 and its downstream signaling targets, such as ATF-2, thereby enhancing the activity of superoxide dismutase-2 and catalase, two antioxidant enzymes that protect the cells from ROS accumulation, DNA damage and loss of viability. Our results provide a new paradigm for a non-canonical tumor suppressor function of LKB1 and highlight the importance of targeting ROS signaling as a potential therapeutic strategy for cancer cells lacking LKB1.

Neuritin can normalize neural deficits of Alzheimer's disease.

Reductions in hippocampal neurite complexity and synaptic plasticity are believed to contribute to the progressive impairment in episodic memory and the mild cognitive decline that occur particularly in the early stages of Alzheimer's disease (AD). Despite the functional and therapeutic importance for patients with AD, intervention to rescue or normalize dendritic elaboration and synaptic plasticity is scarcely provided. Here we show that overexpression of neuritin, an activity-dependent protein, promoted neurite outgrowth and maturation of synapses in parallel with enhanced basal synaptic transmission in cultured hippocampal neurons. Importantly, exogenous application of recombinant neuritin fully restored dendritic complexity as well as spine density in hippocampal neurons prepared from Tg2576 mice, whereas it did not affect neurite branching of neurons from their wild-type littermates. We also showed that soluble recombinant neuritin, when chronically infused into the brains of Tg2576 mice, normalized synaptic plasticity in acute hippocampal slices, leading to intact long-term potentiation. By revealing the protective actions of soluble neuritin against AD-related neural defects, we provide a potential therapeutic approach for patients with AD.

Walnuts (seeds of Juglandis sinensis L.) protect human epidermal keratinocytes against UVB-induced mitochondria-mediated apoptosis through upregulation of ROS elimination pathways.

PURPOSE: Ultraviolet (UV) light from sunlight is an important environmental factor causing hazardous health effects, including various skin disorders. UV irradiation downregulates reactive oxygen species (ROS) elimination pathways, thereby promoting the production of ROS, which are implicated in mitochondria-mediated apoptosis. Walnuts, the seeds of Juglandis sinensis L., are a highly nutritious food and have been shown to have a number of pharmacological activities. To our knowledge, no study on the protective effects of walnuts on human epidermal keratinocytes has been reported previously. Here, we investigated the protective effects of walnuts against UVB (50 mJ/cm(2)) -induced mitochondria-mediated apoptosis. PROCEDURES AND RESULTS: Walnuts significantly and dose-dependently reduced UVB-induced apoptotic toxicity by lactate dehydrogenase assay kit. Walnuts decreased mitochondrial dysfunction, B-cell lymphoma 2 (Bcl-2)-associated X (Bax) protein levels, and cytochrome c release from mitochondria, while increasing Bcl-2 protein levels using immunofluorescence, Western blot, or kit analysis. Moreover, walnuts inhibited caspase-3 activity, indicating an inhibition of the apoptotic cascade, and induced the expression of heme oxygenase and NAD(P)H dehydrogenase via NF-E2-related factor-2 activation using immunofluorescence or Western blot analysis. CONCLUSION: Together, these results demonstrate that walnuts can protect human epidermal keratinocytes against UVB-induced mitochondria-mediated apoptosis by regulating ROS elimination pathways.

Antioxidants decrease the apoptotic effect of 5-Fu in colon cancer by regulating Src-dependent caspase-7 phosphorylation.

Although the rate of development of drug resistance remains very high, 5-fluorouracil (5-Fu) is still the most common chemotherapeutic drug used for the treatment of colon cancer. A better understanding of the mechanism of why cancers develop resistance to 5-Fu could improve its therapeutic effect. Sometimes, antioxidants are used simultaneously with 5-Fu treatment. However, a recent clinical trial showed no advantage or even a harmful effect of combining antioxidants with 5-Fu compared with administration of 5-Fu alone. The mechanism explaining this phenomenon is still poorly understood. In this study, we show that 5-Fu can induce reactive oxygen species-dependent Src activation in colon cancer cells. Mouse embryonic fibroblasts that are deficient in Src showed a clear resistance to 5-Fu, and knocking down Src protein expression in colon cancer cells also decreased 5-Fu-induced apoptosis. We found that Src could interact with and phosphorylate caspase-7 at multiple tyrosine sites. Functionally, the tyrosine phosphorylation of caspase-7 increases its activity, thereby enhancing cellular apoptosis. When using 5-Fu and antioxidants together, Src activation was blocked, resulting in decreased 5-Fu-induced apoptosis. Our results provide a novel explanation as to why 5-Fu is not effective in combination with some antioxidants in colon cancer patients, which is important for clinical chemotherapy.