STAG2 mutations regulate 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme.

Inactivating mutations of genes encoding the cohesin complex are common in a wide range of human cancers. STAG2 is the most commonly mutated subunit. Here we report the impact of stable correction of endogenous, naturally occurring STAG2 mutations on gene expression, 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme (GBM). In two GBM cell lines, correction of their STAG2 mutations significantly altered the expression of ∼10% of all expressed genes. Virtually all the most highly regulated genes were negatively regulated by STAG2 (i.e., expressed higher in STAG2-mutant cells), and one of them-HEPH-was regulated by STAG2 in uncultured GBM tumors as well. While STAG2 correction had little effect on large-scale features of 3D genome organization (A/B compartments, TADs), STAG2 correction did alter thousands of individual chromatin loops, some of which controlled the expression of adjacent genes. Loops specific to STAG2-mutant cells, which were regulated by STAG1-containing cohesin complexes, were very large, supporting prior findings that STAG1-containing cohesin complexes have greater loop extrusion processivity than STAG2-containing cohesin complexes and suggesting that long loops may be a general feature of STAG2-mutant cancers. Finally, STAG2 mutation activated Polycomb activity leading to increased H3K27me3 marks, identifying Polycomb signaling as a potential target for therapeutic intervention in STAG2-mutant GBM tumors. Together, these findings illuminate the landscape of STAG2-regulated genes, A/B compartments, chromatin loops, and pathways in GBM, providing important clues into the largely still unknown mechanism of STAG2 tumor suppression.

Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea.

Background: Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans. Methods: A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness. Conclusion: A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.

The effect of cognitive behavioral therapy on depression of people with epilepsy.

BACKGROUND: Depression, a common mental problem frequently detected in people with epilepsy (PWE), is a major factor that decreases the quality of life of PWE. The cognitive behavioral therapy (CBT) is the most commonly used non-pharmacological treatment for depressive disorders. The CBT for PWE with depression has not yet been studied in Korea. This study aimed to evaluate the effects of the CBT on depression in PWE in Korea. METHOD: This study included 16 PWE with depression who received CBT and 30 control PWE with depression who did not receive CBT. The mean number of CBT sessions per patient was 7.2 in the CBT group. The Beck Depression Inventory-II (BDI-II) and Patient Health Questionnaire-9 (PHQ-9) were administered before and after CBT sessions in the CBT group, whereas PHQ-9 was performed at baseline and follow-up in the control group. The difference in PHQ-9 and BDI-II scores were analyzed between the pre- and post-CBT periods in the CBT group. The difference between baseline and follow-up PHQ-9 scores was compared in the control group. RESULTS: There was no significant difference in baseline variables between the CBT and control groups. The PHQ-9 score significantly decreased after the CBT sessions in the CBT group (pre-CBT PHQ-9 = 13.56 vs. post-CBT PHQ-9 = 8.56) but it did not change in the control group (Baseline PHQ-9 = 13.83 vs. follow-up PHQ-9 = 14.67). Twelve PWE had undergone four or more CBT sessions with pre-CBT and post-CBT BDI-II. The BDI-II score significantly decreased after CBT sessions (pre-CBT BDI-II = 30.75 vs. post-CBT BDI-II = 21.5). The CBT decreased the sub-field scores of cognitive and physical-emotional factors as well as suicidal ideation, but the score of sleep problems did not significantly improve. The CBT did not significantly change the seizure frequency. CONCLUSION: The CBT significantly improved depression in Korean PWE. Therefore, it can be considered a treatment tool for depression in PWE. However, a study with more patients and a fixed number of CBT sessions is recommended to generalize this effect.

Identification of STAG2-Mutant Bladder Cancers by Immunohistochemistry.

Bladder cancer is the fifth most common cancer in the United States. Most bladder cancers are early-stage lesions confined to the mucosa or submucosa and are therefore classified as non-muscle-invasive bladder cancer (NMIBC). A minority of tumors are diagnosed after they have invaded the underlying detrusor muscle and are classified as muscle-invasive bladder cancer (MIBC). Mutational inactivation of the STAG2 tumor suppressor gene is common in bladder cancer, and we and others have recently demonstrated that STAG2 mutation status can be used as an independent prognostic biomarker to predict whether NMIBC will recur and/or progress to MIBC. Here we describe an immunohistochemistry-based assay for identifying the STAG2 mutational status of bladder tumors.

Long-term oncologic outcome of D3 lymph node dissection for clinical stage 2/3 right-sided colon cancer.

PURPOSE: To investigate oncologic outcomes including overall survival and disease-free survival depending on the extent of lymphadenectomy (D3 versus D2) by comparing D3 and D2 lymphadenectomy in patients with clinical stage 2/3 right colon cancer. METHODS: Consecutive series of patients who underwent radical resection for right colon cancer at our three hospitals between January 2015 and June 2018 were retrospectively analyzed. Study cohorts were divided into two groups: D3 group and D2 group. Oncologic, pathologic, and perioperative outcomes of the two groups were compared. RESULTS: A total of 295 patients (167 in the D2 group and 128 in the D3 group) were included in this study. Patients' characteristics showed no significant difference between the two groups. The median number of harvested lymph nodes was significantly higher in the D3 group than in the D2 group. The rate of complications was not significantly different between the two groups except for chyle leakage, which was more frequent in the D3 group. Five-year disease-free survival was 90.2% (95% CI: 84.8-95.9%) in the D3 group, which was significantly (p = 0.028) higher than that (80.5%, 95% CI: 74-87.5%) in the D2 group. There was no significant difference in overall survival between the two groups. CONCLUSION: Our results indicate that D3 lymphadenectomy is associated with more favorable 5-year disease-free survival than D2 lymphadenectomy for patients with stage 2/3 right-sided colon cancer. D3 lymphadenectomy might improve oncologic outcomes in consideration of the recurrence rate.

Tuning La2O3 to high ionic conductivity by Ni-doping.

Ni-doped La2O3 was developed as an ionic conducting membrane corresponding to a conductivity of 0.187 S cm-1 at 550 °C. A peak power density of 970 mW cm-2 with an open circuit voltage of 1.05 V was achieved using 10 mol% Ni-doped La2O3 (10NLO). XPS and Raman investigations reveal that the performance enhancement is due to the high concentration of oxygen vacancies. Density functional theory calculations verify that Ni doping can tune the band structure of La2O3 to enhance its electrochemical performance. A Schottky junction barrier is formed at the anode to avoid short circuit problems and facilitate the ionic transportation at the anode/electrolyte interface. This study indicates that wide-band gap semiconductors with suitable element-doping can be tuned to be promising ionic conductors for advanced fuel cell applications.

Surface-Engineered Homostructure for Enhancing Proton Transport.

Ultra-wide bandgap semiconductor samarium oxide attracts great interest because of its high stability and electronic properties. However, the ionic transport properties of Sm2 O3 have rarely been studied. In this work, Ni doping is proposed to be used for electronic structure engineering of Sm2 O3 . The formation of Ni-doping defects lowers the Fermi level to induce a local electric field, which greatly enhances the proton transport at the surface. Furthermore, ascribed to surface modification, the high concentration of vacancies and lattice disorder on the surface layer promote proton transport. A high-performance of 1438 mW cm-2 and ionic conductivity of 0.34 S cm-1 at 550 °C have been achieved using 3% mol Ni doped Sm2 O3 as electrolyte for fuel cells. The well-dispersed Ni doped surface in Sm2 O3 builds up continuous surfaces as proton channels for high-speed transport. In this work, a new methodology is presented to develop high-performance, low-temperature ceramic fuel cells.

Acetyl-CoA carboxylase-1/2 blockade locks dendritic cells in the semimature state associated with FA deprivation by favoring FAO.

Immunometabolism is rising as an intriguing topic that reveals the connection between immune cell function and metabolic processes. Especially, fatty acid metabolism plays an essential role in the dendritic cells (DCs) during the differentiation and maturation period. We questioned whether regulation of acetyl-CoA carboxylases 1 and 2-(ACC1/2), the core enzymes of fatty acid synthesis (FAS), would control DC function. Here, we report that blocking ACC1/2 to prevent FAS during DC maturation switched their cellular metabolism into fatty acid oxidation to fuel oxidative phosphorylation. This action turned DCs to utilize exogenous fatty acids to sustain their basal energy demand and maintain a stable cellular respiration rate. Coincidentally, under the ACC1/2 inhibitor treatment, LPS-treated DCs exhibited a semimaturation phenotype with a maturation-resistance feature, with decreased expression of costimulatory molecules including CD86 and CD40, along with the reduction of IL-12 and IL-6. The migratory capability of DCs has been known to relate to the glycolysis pathway, and here we showed that the ACC1/2 blockade did not affect the expression of CCR7 and DC migration. Furthermore, we found that under the ACC1/2 blocking condition, DCs pulsed with OVA failed to activate OVA-specific CD4+ T cell proliferation even though their antigen uptake capacity was intact. Together, our data suggest ACC1/2 as a promising target to control DC fate.

Generation of scalable cancer models by combining AAV-intron-trap, CRISPR/Cas9, and inducible Cre-recombinase.

Scalable isogenic models of cancer-associated mutations are critical to studying dysregulated gene function. Nonsynonymous mutations of splicing factors, which typically affect one allele, are common in many cancers, but paradoxically confer growth disadvantage to cell lines, making their generation and expansion challenging. Here, we combine AAV-intron trap, CRISPR/Cas9, and inducible Cre-recombinase systems to achieve >90% efficiency to introduce the oncogenic K700E mutation in SF3B1, a splicing factor commonly mutated in multiple cancers. The intron-trap design of AAV vector limits editing to one allele. CRISPR/Cas9-induced double stranded DNA breaks direct homologous recombination to the desired genomic locus. Inducible Cre-recombinase allows for the expansion of cells prior to loxp excision and expression of the mutant allele.  Importantly, AAV or CRISPR/Cas9 alone results in much lower editing efficiency and the edited cells do not expand due to toxicity of SF3B1-K700E. Our approach can be readily adapted to generate scalable isogenic systems where mutant oncogenes confer a growth disadvantage.

Multimaterial Self-Aligned Nanopatterning by Simultaneous Adjacent Thin Film Deposition and Etching.

Printed component sizes in electronic circuits are approaching 10 nm, but inherent variability in feature alignment during photolithography poses a fundamental barrier for continued device scaling. Deposition-based self-aligned patterning is being introduced, but nuclei defects remain an overarching problem. This work introduces low-temperature chemically self-aligned film growth via simultaneous thin film deposition and etching in adjacent regions on a nanopatterned surface. During deposition, nucleation defects are avoided in nongrowth regions because deposition reactants are locally consumed via sacrificial etching. For a range of materials and process conditions, thermodynamic modeling confirms that deposition and etching are both energetically favorable. We demonstrate nanoscale patterning of tungsten at 220 °C with simultaneous etching of TiO2. Area selective deposition (ASD) of the sacrificial TiO2 layer produces an orthogonal sequence for self-aligned patterning of two materials on one starting pattern, i.e., TiO2 ASD on SiO2 followed by W ASD on Si-H. Experiments also show capacity for self-aligned dielectric patterning via favorable deposition of AlF3 on Al2O3 at 240 °C with simultaneous atomic layer etching of sacrificial ZnO. Simultaneous deposition and etching provides opportunities for low-temperature bottom-up self-aligned patterning for electronic and other nanoscale systems.

Photocatalytic Reaction Properties of TiO2-Supported on the Long Lasting Phosphor: Sr4Al14O25:Eu2+,Dy3.

The TiO2/Sr4Al14O25:Eu2+,Dy3+ photocatalytic composite was prepared by depositing the nano-crystalline titanium dioxide layer on the long-lasting phosphor substrate of strontium aluminate, using a low-pressure chemical vapor deposition (LP-CVD). The photocatalysis characteristic was studied by examining the photodegradation of benzene (C6H6) gas under UV, visible light illumination, and in the darkness. The photocatalytic composite of TiO2-deposited Sr4Al14O25:Eu2+,Dy3+ showed an active photocatalytic reactivity under UV-light as well as visible-light illumination. The mechanism of the photocatalysis reaction for the TiO2-deposited strontium aluminate phosphor composite was interpreted in point of the energy band structure and phosphorescent emission. The coupling of nanocrystalline TiO2 with the strontium aluminate phosphor might result in an energy band bending at the interface of TiO2/Sr4Al14O25:Eu2+,Dy3+, making the titanium dioxide at the junction to be photo-reactive even in a visible wavelength region. In addition, the depth profile of Auger electron spectroscopy (AES) confirmed a possible formation of oxygen vacancies at the interface between TiO2 and Sr4Al14O25:Eu2+,Dy3+. Then, oxygen defects create extra electrons which may excited subsequently to the conduction band and participate in a photocatalytic reaction, resulting in an enhancement of the photodecomposition of benzene. The LP-CVD TiO2-strontium aluminate phosphor was also photoactive in the darkness because of light emission from the long lasting phosphor. Also, the TiO2-deposited Sr4Al14O25:Eu2+,Dy3+ long lasting phosphor was analyzed by a XRD (X-ray diffraction), TEM (transmission electron microscopy), UV/visible spectroscopy and AES.

STAG2 as a prognostic biomarker in low-grade non-muscle invasive bladder cancer.

OBJECTIVE: Improvements to bladder cancer risk stratification guidelines are needed to better tailor post-operative surveillance and adjuvant therapy to individual patients. We previously identified STAG2 as a commonly mutated tumor suppressor gene in bladder cancer and an independent predictor of progression in NMIBC. Here we test the value of combining STAG2 immunostaining with other risk stratification biomarkers in NMIBC, and as an individual biomarker in MIBC. MATERIALS AND METHODS: STAG2 immunohistochemistry was performed on a progressor-enriched cohort of tumors from 297 patients with NMIBC, and on tumors from 406 patients with MIBC from Aarhus University Hospital in Denmark. Survival analysis was performed using Kaplan-Meier survival analysis, the log rank test, and Cox proportional hazards models. RESULTS: STAG2-negative low-grade NMIBC tumors were 2.5 times less likely to progress to muscle invasion than STAG2-positive low-grade NMIBC tumors (Log-rank test, P = 0.008). In a composite group of patients with AUA intermediate and high-risk NMIBC tumors, STAG2-negative tumors were less likely to progress (Log-rank test, P = 0.02). In contrast to NMIBC, we show that STAG2 is not useful as a prognostic biomarker in MIBC. CONCLUSIONS: STAG2 immunostaining can be used to subdivide low-grade NMIBC tumors into two groups with substantially different risks of disease progression. Furthermore, STAG2 immunostaining may be useful to enhance NMIBC risk stratification guidelines, though larger cohorts are needed to solidify this conclusion in individual risk groups. STAG2 is not useful as a biomarker in MIBC. Further study of the use of STAG2 immunostaining as a biomarker for predicting the clinical behavior in NMIBC is warranted.

Impact of D3 lymph node dissection on upstaging and short-term survival in clinical stage I right-sided colon cancer.

BACKGROUND: D3 lymph node dissection is becoming the standard procedure for the treatment of advanced right colon cancer and has shown increasing evidence of its oncologic benefit. However, a clear indication for its application is lacking and data on this topic is unsatisfactory. Thus, the necessity for D3 lymph node dissection in clinical stage I right colon cancer remains controversial. METHODS: We retrospectively analyzed data from clinical stage I right colon cancer patients who underwent radical surgery at three hospitals of Korea university medical center between January 2015 and June 2018. We compared surgical complications and short-term oncologic outcomes between D2 and D3 lymph node dissections in these patients. RESULTS: Among 512 patients, 122 (23.8%) were clinical stage I. Of these, 88 and 34 patients received D2 and D3 lymph node dissection, respectively. There were no statistically significant differences in clinicopathologic variables and surgical outcomes between the two groups. Upstaging occurred in 16 patients (47.1%) in the D3 group and 23 patients (26.1%) in the D2 group. There were four recurrences in the D2 group but no recurrence in the D3 group. Log-rank tests showed no statistically significant difference in disease-free survival rates between the two groups (p = 0.210). CONCLUSION: There was no significant difference in disease-free survival rates between D2 and D3 lymph node dissection in clinical stage I right colon cancer patients. However, recurrence occurred in the D2 group. Efforts to improve the accuracy of clinical staging are required and more studies with better quality are needed.

Junction and energy band on novel semiconductor-based fuel cells.

Fuel cells are highly efficient and green power sources. The typical membrane electrode assembly is necessary for common electrochemical devices. Recent research and development in solid oxide fuel cells have opened up many new opportunities based on the semiconductor or its heterostructure materials. Semiconductor-based fuel cells (SBFCs) realize the fuel cell functionality in a much more straightforward way. This work aims to discuss new strategies and scientific principles of SBFCs by reviewing various novel junction types/interfaces, i.e., bulk and planar p-n junction, Schottky junction, and n-i type interface contact. New designing methodologies of SBFCs from energy band/alignment and built-in electric field (BIEF), which block the internal electronic transport while assisting interfacial superionic transport and subsequently enhance device performance, are comprehensively reviewed. This work highlights the recent advances of SBFCs and provides new methodology and understanding with significant importance for both fundamental and applied R&D on new-generation fuel cell materials and technologies.

USP13 interacts with cohesin and regulates its ubiquitination in human cells.

Cohesin is a multiprotein ring complex that regulates 3D genome organization, sister chromatid cohesion, gene expression, and DNA repair. Cohesin is known to be ubiquitinated, although the mechanism, regulation, and effects of cohesin ubiquitination remain poorly defined. We previously used gene editing to introduce a dual epitope tag into the endogenous allele of each of 11 known components of cohesin in human HCT116 cells. Here we report that mass spectrometry analysis of dual-affinity purifications identified the USP13 deubiquitinase as a novel cohesin-interacting protein. Subsequent immunoprecipitation/Western blots confirmed the endogenous interaction in HCT116, 293T, HeLa, and RPE-hTERT cells; demonstrated that the interaction occurs specifically in the soluble nuclear fraction (not in the chromatin); requires the ubiquitin-binding domains (UBA1/2) of USP13; and occurs preferentially during DNA replication. Reciprocal dual-affinity purification of endogenous USP13 followed by mass spectrometry demonstrated that cohesin is its primary interactor in the nucleus. Ectopic expression and CRISPR knockout of USP13 showed that USP13 is paradoxically required for both deubiquitination and ubiquitination of cohesin subunits in human cells. USP13 was dispensable for sister chromatid cohesion in HCT116 and HeLa cells, whereas it was required for the dissociation of cohesin from chromatin as cells transit through mitosis. Together these results identify USP13 as a new cohesin-interacting protein that regulates the ubiquitination of cohesin and its cell cycle regulated interaction with chromatin.

Effect of Coupling Indium Tin Oxide with the TiO2-NaYF4:(Gd, Si) Composite for Photocatalytic Properties.

Indium tin oxide (ITO) nanoparticles were coupled with NaYF4:(Gd, Si) using a TiO2-solution impregnation method. Scanning electron microscopy confirmed that TiO2 and ITO nanoparticles were loaded on the surface of the NaYF4:(Gd, Si) upconversion phosphor. The ultraviolet/visible spectra of the 20 wt.% ITO-NaYF4:(Gd, Si)/TiO2 composites were extended at the absorption edges towards the UV-visible region. The 20 wt.% ITO-coupled NaYF4:(Gd, Si)/TiO2 composites exhibited superior photocatalytic efficiency compared to only NaYF4:(Gd, Si)/TiO2 under near-infrared (NIR) irradiation. Multi-wavelength NIR photons of γ > 760 nm from a Xe solar simulator source induced photo-activation through the NaYF4:(Gd, Si) activator centers. The three-cycle photocatalytic reusability performance of the 20 wt.% ITO-impregnated NaYF4:(Gd, Si)/TiO2 composite was positively enhanced by up to 20% more than that of NaYF4:(Gd, Si)/TiO2.

Development of a Novel Multi-Channel Thermocouple Array Sensor for In-Situ Monitoring of Ice Accretion.

A test was performed to determine the efficacy of a novel multi-channel thermocouple temperature sensor employing "N+1" array architecture for the in-situ detection of icing in cold climates. T-type thermoelements were used to fabricate a sensor with six independent temperature sensing points, capable of two-dimensional temperature mapping. The sensor was intended to detect the high latent heat of fusion of water (334 J/g) which is released to the environment during ice formation. The sensor was embedded on a plywood board and an aluminium plate, respectively by an epoxy resin. Three different ice accretion cases were considered. Ice accretion for all cases was achieved on the surface of the resin layer. In order to analyse the temperature variation for all three cases, the first 20 s response for each case was averaged between three cases. A temperature increase of (1.0 ± 0.1) °C and (0.9 ± 0.1) °C was detected by the sensors 20 s after the onset of icing, attributed to the latent heat of fusion of water. The results indicate that the sensor design is well-suited to cold temperature applications and that detection of the latent heat of fusion could provide a rapid and robust means of icing detection.

CD4+ /CD8+ T-cell ratio correlates with the graft fate in pig-to-non-human primate islet xenotransplantation.

BACKGROUND: Xenogeneic islet transplantation using porcine pancreata has been a promising option for substituting human islet transplantation. Moreover, recent advances in pre-clinical results have put islet xenotransplantation closer to the possibility of clinical application. While preparing for the era of clinical xenotransplantation, developing non-invasive immune monitoring method which could predict the graft fate could benefit the patient. However, there are few reports showing predictive immune parameters associated with the fate of the graft in islet xenotransplantation. METHODS: The absolute number and ratio of T-cell subsets have been measured via flow cytometry from the peripheral blood of 16 rhesus monkeys before and after porcine islet xenotransplantation. The correlation between the graft survival and the absolute number or ratio of T cells was retrospectively analyzed. RESULTS: The ratio of CD4+ versus CD8+ T cells was significantly reduced due to CD8+ effector memory cells' increase. Correlation analyses revealed that CD4+ /CD8+ , CD4+ /CD8+ naïve, CD4+ naïve/CD8+ naïve, and CD4+ central memory/CD8+ naïve cell ratios negatively correlated with the duration of graft survival. Conversely, further analyses discovered strong, positive correlation of CD4+ /CD8+ cell ratios within the early graft-rejected monkeys (≤60 days). CONCLUSIONS: This retrospective study demonstrated that CD4+ /CD8+ ratios correlated with graft survival, especially in recipients which rejected the graft in early post-transplantation periods. CD4+ /CD8+ ratios could be used as a surrogate marker to predict the graft fate in pig-to-NHP islet xenotransplantation.

Bioinformatic analysis of peripheral blood RNA-sequencing sensitively detects the cause of late graft loss following overt hyperglycemia in pig-to-nonhuman primate islet xenotransplantation.

Clinical islet transplantation has recently been a promising treatment option for intractable type 1 diabetes patients. Although early graft loss has been well studied and controlled, the mechanisms of late graft loss largely remains obscure. Since long-term islet graft survival had not been achieved in islet xenotransplantation, it has been impossible to explore the mechanism of late islet graft loss. Fortunately, recent advances where consistent long-term survival (≥6 months) of adult porcine islet grafts was achieved in five independent, diabetic nonhuman primates (NHPs) enabled us to investigate on the late graft loss. Regardless of the conventional immune monitoring methods applied in the post-transplant period, the initiation of late graft loss could rarely be detected before the overt graft loss observed via uncontrolled blood glucose level. Thus, we retrospectively analyzed the gene expression profiles in 2 rhesus monkey recipients using peripheral blood RNA-sequencing (RNA-seq) data to find out the potential cause(s) of late graft loss. Bioinformatic analyses showed that highly relevant immunological pathways were activated in the animal which experienced late graft failure. Further connectivity analyses revealed that the activation of T cell signaling pathways was the most prominent, suggesting that T cell-mediated graft rejection could be the cause of the late-phase islet loss. Indeed, the porcine islets in the biopsied monkey liver samples were heavily infiltrated with CD3+ T cells. Furthermore, hypothesis test using a computational experiment reinforced our conclusion. Taken together, we suggest that bioinformatics analyses with peripheral blood RNA-seq could unveil the cause of insidious late islet graft loss.

Non-clinical pharmacokinetic behavior of ginsenosides.

Ginsenosides, the major active ingredients of ginseng and other plants of the genus Panax, have been used as natural medicines in the East for a long time; in addition, their popularity in the West has increased owing to their various beneficial pharmacological effects. There is therefore a wealth of literature regarding the pharmacological effects of ginsenosides. In contrast, there are few comprehensive studies that investigate their pharmacokinetic behaviors. This is because ginseng contains the complicated mixture of herbal materials as well as thousands of constituents with complex chemical properties, and ginsenosides undergo multiple biotransformation processes after administration. This is a significant issue as pharmacokinetic studies provide crucial data regarding the efficacy and safety of compounds. Moreover, there have been many difficulties in the development of the optimal dosage regimens of ginsenosides and the evaluation of their interactions with other drugs. Therefore, this review details the pharmacokinetic properties and profiles of ginsenosides determined in various animal models administered through different routes of administration. Such information is valuable for designing specialized delivery systems and determining optimal dosing strategies for ginsenosides.