Clinical and Biomarker Analysis of a Phase I/II Study of PDR001 Plus Imatinib for Advanced Treatment-Refractory Gastrointestinal Stromal Tumors.

PURPOSE: In this phase Ib/II study, we aimed to evaluate the safety and efficacy of PDR001, an anti-PD1 antibody, in combination with imatinib in patients with treatment-refractory gastrointestinal stromal tumor (GIST). PATIENTS AND METHODS: Patients with advanced GIST whose disease had progressed on imatinib, sunitinib, and regorafenib were enrolled. In phase Ib, the standard 3 + 3 dose escalation scheme was applied. Intravenous administration of PDR001 at 400 mg for every 4 weeks plus imatinib (300 and 400 mg daily for dose levels I and II, respectively) was given. The primary outcome for phase II was the disease control rate at 12 weeks. Exploratory biomarker analysis was performed based on PDL1 IHC, next-generation sequencing, and multiplexed IHC. RESULTS: No dose-limiting toxicity was observed in the phase Ib part (n = 10), and dose level II was selected as the recommended phase II dose. In the phase II part (n = 29), there was no objective response, and the disease control rate at 12 weeks was 37.9%, not meeting the primary efficacy endpoint. For patients in phase Ib-dose level II and phase II (n = 36), the median progression-free survival (PFS) and overall survival were 2.3 and 9.5 months, respectively. The most common grade 3 to 4 adverse event was anemia. Exploratory biomarker analysis indicated that a higher CD8+ T-cell density was associated with a favorable PFS but to a limited degree. Tumor mutational burden and PDL1 were not associated with better PFS. CONCLUSIONS: In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.

Exosomes derived from mesenchymal stem cells primed with disease-condition-serum improved therapeutic efficacy in a mouse rheumatoid arthritis model via enhanced TGF-ß1 production.

BACKGROUNDS: Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by synovial inflammation-mediated progressive destruction of the cartilage and bone, resulting in reduced quality of life. We primed human telomerase reverse transcriptase-overexpressing immortalized human adipose tissue-derived mesenchymal stem cells (iMSCs) with serum derived from a non-human primate RA model and studied the immunomodulatory ability of exosomes obtained from primed iMSCs. METHODS: After immunophenotyping, nanoparticle tracking analysis, and in vitro functional tests, Dulbecco's phosphate-buffered saline (dPBS, Group C), exosomes derived from the supernatant of iMSCs (Exo-FBS, Group E), exosomes derived from the supernatant of iMSCs primed with RA serum (Exo-RA, Group F), and methotrexate (Group M) were administered in collagen-induced arthritis (CIA) model mice. dPBS was administered to the normal (N) group for comparison (n = 10/group). RESULTS: Exo-RA had a significantly higher number of exosomes compared to Exo-FBS when measured with nanoparticle tracking analysis or exosome marker CD81, and Transforming growth factor-ß1 amounts were significantly higher in Exo-RA than in Exo-FBS. When Exo-FBS or Exo-RA was administered to the collagen-induced arthritis model, serum interleukin (IL)-4 and the proportion of Th2 (CD4+CD25+GATA3+) and M2 (CD11c - CD206+ of CD45+CD64+) cells were significantly increased compared to the control group. Furthermore, Exo-RA could alleviate cartilage damage by significantly lowering the concentrations of proinflammatory cytokines such as tumor necrosis factor-α, keratinocyte chemoattractant, and IL-12p70. CONCLUSION: Exosomes derived from disease-condition-serum-primed iMSCs ameliorated cartilage damage in a RA model by enhancing TGF-ß1 production, inducing Th2 and M2 polarization and lowering proinflammatory cytokines, TNF-α, KC, and IL-12p70 in the host. Patient-derived serum can be used as an iMSC priming strategy in iMSC-derived exosome treatment of RA.

Application of microphysiologic system to assess neutrophil extracellular trap in xenotransplantation.

Transplantation of organs, cells, or tissues from one species to another, known as xenotransplantation, has the potential to alleviate organ donor shortages and enhance the success of organ transplantation. However, the possibility of immunological rejection by the recipient is one of the biggest difficulties associated with xenotransplantation. The creation of neutrophil extracellular traps (NETs), also known as NETosis, is hypothesized as a mechanism of rejection. Innovations in microfluidics and co-culturing techniques have provided access to several classes of microengineered model systems in experimental models, connecting animal research and traditional in vitro methods such as organoids, microphysiological systems, and organs-on-chip. To achieve this goal, we established a perfusable 3D Xeno vessel chip using a porcine aortic endothelial cell line and examined how NETs grow when isolated human and primate neutrophils were used. Neutrophils from both humans and monkeys displayed the usual NETosis phases, including nuclear decondensation, enlargement, and rounding of DNA, occupying the entire cytoplasm, and discharge of fragmented DNA after cell membrane rupture. Using confocal fluorescence imaging of DNA and citrullinated histone colocalization and DNA histone complex formation in supernatants from xeno vessel chips, we confirmed NETs generation by human and monkey neutrophils when cocultured in a xeno-vessel chip.

Systematic review of challenging issues in pathology of intraductal papillary mucinous neoplasms.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are a cystic precursor to pancreatic cancer. IPMNs deemed clinically to be at high-risk for malignant progression are frequently treated with surgical resection, and pathological examination of the pancreatectomy specimen is a key component of the clinical care of IPMN patients. METHODS: Systematic literature reviews were conducted around eight topics of clinical relevance in the examination of pathological specimens in patients undergoing resection of IPMN. RESULTS: This review provides updated perspectives on morphological subtyping of IPMNs, classification of intraductal oncocytic papillary neoplasms, nomenclature for high-grade dysplasia, assessment of T stage, distinction of carcinoma associated or concomitant with IPMN, role of molecular assessment of IPMN tissue, role of intraoperative assessment by frozen section, and preoperative evaluation of cyst fluid cytology. CONCLUSIONS: This analysis provides the foundation for data-driven approaches to several challenging issues in the pathology of IPMNs.

Grain Boundary-Rich Copper Nanocatalysts Generated from Metal-Organic Framework Nanoparticles for CO2 -to-C2+ Electroconversion.

Due to severe contemporary energy issues, generating C2+ products from electrochemical carbon dioxide reduction reactions (eCO2 RRs) gains much interest. It is known that the catalyst morphology and active surface structures are critical for product distributions and current densities. Herein, a synthetic protocol of nanoparticle morphology on copper metal-organic frameworks (n-Cu MOFs) is developed by adjusting growth kinetics with termination ligands. Nanoscale copper oxide aggregates composed of small particulates are yielded via calcining the Cu-MOF nanoparticles at a specific temperature. The resulting nanosized MOF-derived catalyst (n-MDC) exhibits Faradaic efficiencies toward ethylene and C2+ products of 63% and 81% at -1.01 V versus reversible hydrogen electrode (RHE) in neutral electrolytes. The catalyst also shows prolonged stability for up to 10 h. A partial current density toward C2+ products is significantly boosted to -255 mA cm-2 in an alkaline flow cell system. Comprehensive analyses reveal that the nanoparticle morphology of pristine Cu MOFs induces homogeneous decomposition of organic frameworks at a lower calcination temperature. It leads to evolving grain boundaries in a high density and preventing severe agglomeration of copper domains, the primary factors for improving eCO2 RR activity toward C2+ production.

Overexpression of Replication-Dependent Histone Signifies a Subset of Dedifferentiated Liposarcoma with Increased Aggressiveness.

Liposarcoma (LPS) is an adult soft tissue malignancy that arises from fat tissue, where well-differentiated (WD) and dedifferentiated (DD) forms are the most common. DDLPS represents the progression of WDLPS into a more aggressive high-grade and metastatic form. Although a few DNA copy-number amplifications are known to be specifically found in WD- or DDLPS, systematic genetic differences that signify subtype determination between WDLPS and DDLPS remain unclear. Here, we profiled the genome and transcriptome of 38 LPS tumors to uncover the genetic signatures of subtype differences. Replication-dependent histone (RD-HIST) mRNAs were highly elevated and their regulation was disrupted in a subset of DDLPS, increasing cellular histone molecule levels, as measured using RNA-seq (the averaged fold change of 53 RD-HIST genes between the DD and WD samples was 10.9) and immunohistochemistry. The change was not observed in normal tissues. Integrated whole-exome sequencing, RNA-seq, and methylation analyses revealed that the overexpressed HMGA2 (the fold change between DD and WD samples was 7.3) was responsible for the increased RD-HIST level, leading to aberrant cell proliferation. Therefore, HMGA2-mediated elevation of RD-HISTs were crucial events in determining the aggressiveness of DDLPS, which may serve as a biomarker for prognosis prediction for liposarcoma patients.

Soluble Spike DNA Vaccine Provides Long-Term Protective Immunity against SARS-CoV-2 in Mice and Nonhuman Primates.

The unprecedented and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has motivated the need for a rapidly producible and scalable vaccine. Here, we developed a synthetic soluble SARS-CoV-2 spike (S) DNA-based vaccine candidate, GX-19. In mice, immunization with GX-19 elicited not only S-specific systemic and pulmonary antibody responses but also Th1-biased T cell responses in a dose-dependent manner. GX-19-vaccinated nonhuman primates seroconverted rapidly and exhibited a detectable neutralizing antibody response as well as multifunctional CD4+ and CD8+ T cell responses. Notably, when the immunized nonhuman primates were challenged at 10 weeks after the last vaccination with GX-19, they had reduced viral loads in contrast to non-vaccinated primates as a control. These findings indicate that GX-19 vaccination provides a durable protective immune response and also support further development of GX-19 as a vaccine candidate for SARS-CoV-2.

Extracellular Vesicles from Thapsigargin-Treated Mesenchymal Stem Cells Ameliorated Experimental Colitis via Enhanced Immunomodulatory Properties.

Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton's jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-ß1 (TGFß), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis.

Air Pollution and Atopic Dermatitis (AD): The Impact of Particulate Matter (PM10) on an AD Mouse-Model.

Air pollution reportedly contributes to the development and exacerbation of atopic dermatitis (AD). However, the exact mechanism underlying this remains unclear. To examine the relationship between air pollution and AD, a clinical, histological, and genetic analysis was performed on particulate matter (PM)-exposed mice. Five-week-old BALB/c mice were randomly divided into four groups (control group, ovalbumin (OVA) group, PM group, OVA + PM group; n = 6) and treated with OVA or PM10, alone or together. Cutaneous exposure to OVA and PM10 alone resulted in a significant increase in skin severity scores, trans-epidermal water loss (TEWL) and epidermal thickness compared to the control group at Week 6. The findings were further accentuated in the OVA + PM group showing statistical significance over the OVA group. A total of 635, 501, and 2149 genes were found to be differentially expressed following OVA, PM10, and OVA + PM10 exposure, respectively. Strongly upregulated genes included RNASE2A, S100A9, SPRR2D, THRSP, SPRR2A1 (OVA vs. control), SPRR2D, S100A9, STFA3, CHIL1, DBP, IL1B (PM vs. control) and S100A9, SPRR2D, SPRR2B, S100A8, SPRR2A3 (OVA + PM vs. control). In comparing the groups OVA + PM with OVA, 818 genes were differentially expressed with S100A9, SPRR2B, SAA3, S100A8, SPRR2D being the most highly upregulated in the OVA + PM group. Taken together, our study demonstrates that PM10 exposure induces/aggravates skin inflammation via the differential expression of genes controlling skin barrier integrity and immune response. We provide evidence on the importance of public awareness in PM-associated skin inflammation. Vigilant attention should be paid to all individuals, especially to those with AD.

Pre-Transplant Angiotensin II Type 1 Receptor Antibodies and Anti-Endothelial Cell Antibodies Predict Graft Function and Allograft Rejection in a Low-Risk Kidney Transplantation Setting.

BACKGROUND: Non-HLA antibodies, anti-angiotensin II type 1 receptor antibodies (anti-AT1R) and anti-endothelial cell antibodies (AECA), are known to play a role in allograft rejection. We evaluated the role of both antibodies in predicting post-transplant outcomes in low-risk living donor kidney transplantation (LDKT) recipients. METHODS: In 94 consecutive LDKT recipients who were ABO compatible and negative for pre-transplant HLA donor-specific antibodies, we determined the levels of anti-AT1Rs using an enzyme-linked immunosorbent assay and the presence of AECAs using a flow cytometric endothelial cell crossmatch (ECXM) assay with pre-transplant sera. Hazard ratio (HR) was calculated to predict post-transplant outcomes. RESULTS: Pre-transplant anti-AT1Rs (≥11.5 U/mL) and AECAs were observed in 36 (38.3%) and 22 recipients (23.4%), respectively; 11 recipients had both. Pre-transplant anti-AT1Rs were a significant risk factor for the development of acute rejection (AR) (HR 2.09; P=0.018), while a positive AECA status was associated with AR or microvascular inflammation only (HR 2.47; P=0.004) throughout the follow-up period. In particular, AECA (+) recipients with ≥11.5 U/mL anti-AT1Rs exhibited a significant effect on creatinine and estimated glomerular filtration rate (P<0.001; P=0.028), although the risk of AR was not significant. CONCLUSIONS: Pre-transplant anti-AT1Rs and AECAs have independent negative effects on post-transplant outcomes in low-risk LDKT recipients. Assessment of both antibodies would be helpful in stratifying the pre-transplant immunological risk, even in low-risk LDKT recipients.

Subwavelength-scale nanorods implemented hexagonal pyramids structure as efficient light-extraction in Light-emitting diodes.

Subwavelength-scale nanorods were implemented on the hexagonal pyramid of photochemically etched light-emitting diodes (LEDs) to improve light extraction efficiency (LEE). Sequential processes of Ag deposition and inductively coupled plasma etching successfully produce nanorods on both locally unetched flat surface and sidewall of hexagonal pyramids. The subwavelength-scale structures on flat surface offer gradually changed refractive index, and the structures on side wall of hexagonal pyramid reduce backward reflection, thereby enhancing further enhancement of the light extraction efficiency. Consequently, the nanorods implemented LED shows a remarkable enhancement in the light output power by 14% compared with that of the photochemically etched LEDs which is known to exhibit the highest light output power. Theoretical calculations using a rigorous coupled wave analysis method reveal that the subwavelength-scale nanorods are very effective in the elimination of TIR as well as backward reflections, thereby further enhancing LEE of the LEDs.

Characterization and Analysis of the Skin Microbiota in Acne: Impact of Systemic Antibiotics.

Systemic antibiotics are extensively used to control moderate to severe acne. Hence, it is crucial to understand their impact on the skin microbiota, which is supposedly perturbed. The purpose of this study was to compare the makeup and diversity of the skin microbiota in acne patients before and after taking oral antibiotics. A longitudinal cohort study was performed on 20 participants with moderate to severe facial acne with no recent use of oral and topical antibiotics/retinoids. Patients were prescribed oral doxycycline, 100 mg, twice daily for six weeks. Skin areas on the cheek were sampled for 16S ribosomal RNA gene sequencing at baseline, and after six weeks of doxycycline treatment. Ten males and 10 females aged 11 to 44 years with a median Investigator's Global Assessment score of 3 (moderate) were enrolled. At baseline, Cutibacterium acnes (formerly Propionibacterium acnes) was the most dominant species followed by Staphylococcus epidermidis. Acne severity showed a positive correlation with the abundance of Cutibacterium acnes. Across all subjects, antibiotic treatment reduced clinical acne grades and was associated with a 1.96-fold reduction in the relative abundance of Cutibacterium acnes (p = 0.01, 95% CI -22% to -3%). Marked changes were also identified in other bacterial species, such as Cutibacterium granulosum (formerly Propionibacterium granulosum), which increased by 4.46-fold (p = 0.02, 95% CI 0.004% to 0.9%) in the treated samples. In general, antibiotics administration was associated with an increase in bacterial diversity (alpha diversity). Principal coordinates analysis showed mild clustering of samples by patient (analysis of similarity, R = 0.135, p = 0.04) whereas there was scant clustering with treatment (ANOSIM, R = 0.005; p = 0.29). In conclusion, we found individuals with acne to have a unique microbial signature. Acne treatment with systemic antibiotics was associated with changes in the composition and diversity of skin microbiota, especially Cutibacterium acnes, which correlates with acne severity. Our study provides insight into the skin microbiota in acne and how it is modulated by systemic antibiotics.

Improvement of medication adherence with simplified once-daily immunosuppressive regimen in stable kidney transplant recipients: A prospective cohort study.

BACKGROUND: Many immunosuppressive drugs are prescribed as twice-daily dosing. A simplified once-daily dosing of immunosuppressive drug regimen may improve medication adherence. We investigated medication adherence of simplified once-daily immunosuppressive regimen consisting of extended-release tacrolimus, sirolimus, and corticosteroids along with the efficacy and safety of this regimen. METHODS: This study was a prospective, multicenter, controlled and cohort trial. Stable kidney transplant recipients who had received transplantation at least 3 months before the study enrollment were eligible for the study. Participants were required to fill-out the self-reported immunosuppressant therapy barrier scale (ITBS) questionnaire before and after the conversion. Other clinical laboratory parameters and adverse events were evaluated until 6 months post-conversion. RESULTS: A total of 160 kidney recipients comprised the intention-to-treat population. The mean total ITBS score was 19.5 ± 4.0 at pre-conversion and 6 months after converting, the mean total ITBS score was 16.6 ± 3.6 (p < 0.001). Particularly, the ITBS scores of 4 questions related to the frequency of medication dosing were significantly different between pre-conversion and post-conversion. Only 1 patient (0.62%) was diagnosed as biopsy-confirmed acute rejection in the study period. There was no significant change in the mean estimated glomerular filtration rate after the conversion. Overall 95 patients (59.4%) had an adverse event and 28 patients (17.5%) had a serious adverse event. No graft loss and 1 death were reported. CONCLUSION: Medication adherence after the conversion to the once-daily immunosuppressive regimen was significantly improved with no additional risks of efficacy failure or adverse events.

Immunogenicity and Safety of the Adjuvanted Recombinant Zoster Vaccine in Chronically Immunosuppressed Adults Following Renal Transplant: A Phase 3, Randomized Clinical Trial.

BACKGROUND: The incidence of herpes zoster is up to 9 times higher in immunosuppressed solid organ transplant recipients than in the general population. We investigated the immunogenicity and safety of an adjuvanted recombinant zoster vaccine (RZV) in renal transplant (RT) recipients ≥18 years of age receiving daily immunosuppressive therapy. METHODS: In this phase 3, randomized (1:1), observer-blind, multicenter trial, RT recipients were enrolled and received 2 doses of RZV or placebo 1-2 months (M) apart 4-18M posttransplant. Anti-glycoprotein E (gE) antibody concentrations, gE-specific CD4 T-cell frequencies, and vaccine response rates were assessed at 1M post-dose 1, and 1M and 12M post-dose 2. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Solicited general symptoms and unsolicited AEs were also collected 7 days before first vaccination. Serious AEs (including biopsy-proven allograft rejections) and potential immune-mediated diseases (pIMDs) were recorded up to 12M post-dose 2. RESULTS: Two hundred sixty-four participants (RZV: 132; placebo: 132) were enrolled between March 2014 and April 2017. gE-specific humoral and cell-mediated immune responses were higher in RZV than placebo recipients across postvaccination time points and persisted above prevaccination baseline 12M post-dose 2. Local AEs were reported more frequently by RZV than placebo recipients. Overall occurrences of renal function changes, rejections, unsolicited AEs, serious AEs, and pIMDs were similar between groups. CONCLUSIONS: RZV was immunogenic in chronically immunosuppressed RT recipients. Immunogenicity persisted through 12M postvaccination. No safety concerns arose. CLINICAL TRIALS REGISTRATION: NCT02058589.

TOMM20 as a potential therapeutic target of colorectal cancer.

Translocase of outer mitochondrial membrane 20 (TOMM20) plays an essential role as a receptor for proteins targeted to mitochondria. TOMM20 was shown to be overexpressed in various cancers. However, the oncological function and therapeutic potential for TOMM20 in cancer remains largely unexplored. The purpose of this study was to elucidate the underlying molecular mechanism of TOMM20's contribution to tumorigenesis and to explore the possibility of its therapeutic potential using colorectal cancer as a model. The results show that TOMM20 overexpression resulted in an increase in cell proliferation, migration, and invasion of colorectal cancer (CRC) cells, while siRNA-mediated inhibition of TOMM20 resulted in significant decreases in cell proliferation, migration, and invasion. TOMM20 expression directly impacted the mitochondrial function including ATP production and maintenance of membrane potential, which contributed to tumorigenic cellular activities including regulation of S phase cell cycle and apoptosis. TOMM20 was overexpressed in CRC compared to the normal tissues and increased expression of TOMM20 to be associated with malignant characteristics including a higher number of lymph nodes and perineural invasion in CRC. Notably, knockdown of TOMM20 in the xenograft mouse model resulted in a significant reduction of tumor growth. This is the first report demonstrating a relationship between TOMM20 and tumorigenesis in colorectal cancer and providing promising evidence for the potential for TOMM20 to serve as a new therapeutic target of colorectal cancer. [BMB Reports 2019; 52(12): 712-717].

Virtual Loudspeaker Effect of Graphene-Based Hybrid Material To Improve Low-Frequency Acoustic Performance.

Closed-box loudspeaker systems (CBLSSs) are compact and simple air-suspension loudspeaker systems, and their low-frequency responses are determined by two fundamental parameters: resonance frequency and total damping. Recently, electronic devices have come to require more compact designs, so the volumes of loudspeaker should be reduced. However, a small loudspeaker cannot retain sufficient acoustic space, resulting in poor low-frequency acoustic performance. Herein, we investigated acoustic characterization of the CBLSS with different filling materials such as thermally expanded graphene oxide (TEGO), activated carbon, graphene platelets, and melamine foam (MF). Upon the powder-based test, the resonance frequency of the loudspeaker decreased and resulted in a volume increasing effect inside of the loudspeaker. The TEGO shows almost double volume increase rate, compared to other particle-based filling materials. Employing hybrid filling material that consists of TEGO in an MF cage (TEGO@MF), the volume increase rate of the novel loudspeaker was over 24% at 300 cc. Because of the high adsorptive characteristics and thermal properties of TEGO, the acoustic performance in the low-frequency domain was clearly enhanced, despite the reduced mass loading. Furthermore, these properties were observed to be highly effective for enhancing the low-frequency acoustic performance of the larger loudspeaker, achieving a volume increase rate of 49.5% in a 700 cc enclosure.

Ultrafast and Chemically Stable Transfer of Au Nanomembrane Using a Water-Soluble NaCl Sacrificial Layer for Flexible Solar Cells.

Large-scale industrial application of flexible device has called for development of transfer methods that deliver high yield and stability. Here, we show an ultrafast and chemically stable transfer method by using a water-soluble NaCl sacrificial layer. Extremely thin (10 nm) and large-area (4 in. wafer) free-standing Au nanomembranes (NMs) prepared on silicon substrate were successfully transferred to flexible PDMS substrate by dissolving the NaCl sacrificial layer. This transfer method enables highly transparent and electrically conductive Au NMs on PDMS substrate. To transfer a multilayered optoelectronic device, we fabricated flexible hydrogenated amorphous silicon (a-Si:H) solar cell on a glass substrate and transferred it to a PDMS substrate. There was no degradation of the electrical characteristic of the solar cell after the transfer. This approach enables the integration of high-temperature-processed a-Si:H solar cell onto low-temperature tolerant flexible polymer substrate without chemical contamination or damage.

Relationships between Cytokine Levels and Disease Parameters during the Development of a Collagen-induced Arthritis Model in Cynomolgus Macaques (Macaca fascicularis).

In rheumatoid arthritis research, NHP models of collagen-induced arthritis are important because these species share many immunologic and pathologic features with humans. In addition, serum levels of various cytokines in patients with rheumatoid arthritis have been studied as immune markers for disease prediction, early diagnosis, and effective therapeutic management. The purpose of this study was to identify changes in cytokine levels that occur during the development of collagen-induced arthritis in female cynomolgus macaques (n = 8) and to assess the relationships between these changes and various disease parameters. Blood samples were collected weekly before (week 0) and after (weeks 1 through 7) immunization with type II collagen; clinicopathologic and cytokine data from those samples and other clinical parameters were used in correlation analysis. Serum levels of IFN γ, chemokine (C-C motif) ligand 2 (CCL2), and IL6 showed significant changes after generation of collagen-induced arthritis. IFNγ levels showed a strong negative correlation with body weight (an indicator of general body condition), and CCL2 and IL6 showed moderate negative correlation with body weight. Serum IL6 levels showed moderate positive correlation with the soft tissue swelling score and strong positive correlation with serum C-reactive protein levels in our NHP model of collagen-induced arthritis. In addition, serum levels of matrix metalloproteinase 3 increased significantly after inoculation with type II collagen and showed a moderate positive correlation with serum levels of C-reactive protein, IL6, and IL15. These results suggest close correlations between various cytokines and disease parameters in NHP models of rheumatoid arthritis. These cytokines therefore potentially could be used as markers for monitoring the efficacy of novel treatments in NHP models of rheumatoid arthritis.

The E3 ubiquitin ligase MARCH2 regulates ERGIC3-dependent trafficking of secretory proteins.

The E3 ubiquitin ligase membrane-associated ring-CH-type finger 2 (MARCH2) is known to be involved in intracellular vesicular trafficking, but its role in the early secretory pathway between the endoplasmic reticulum (ER) and Golgi compartments is largely unknown. Human ER-Golgi intermediate compartment protein 2 (ERGIC2) and ERGIC3 are orthologs of Erv41 and Erv46 in yeast, proteins that form a heteromeric complex, cycle between the ER and Golgi, and function as cargo receptors in both anterograde and retrograde protein trafficking. Here, we report that MARCH2 directs ubiquitination and subsequent degradation of ERGIC3 and that MARCH2 depletion increases endogenous ERGIC3 levels. We provide evidence that the lysine residues at positions 6 and 8 of ERGIC3 are the major sites of MARCH2-mediated ubiquitination. Of note, MARCH2 did not significantly decrease the levels of an ERGIC3 variant with lysine-to-arginine substitutions at residues 6 and 8. We also show that ERGIC3 binds to itself or to ERGIC2, whereas ERGIC2 is unable to interact with itself. Our results indicate that α1-antitrypsin and haptoglobin are likely to be cargo proteins of ERGIC3. We further observed that α1-antitrypsin and haptoglobin specifically bind to ERGIC3 and that ERGIC3 depletion decreases their secretion. Moreover, MARCH2 reduced secretion of α1-antitrypsin and haptoglobin, and coexpression of the ubiquitination-resistant ERGIC3 variant largely restored their secretion, suggesting that MARCH2-mediated ERGIC3 ubiquitination is the major cause of the decrease in trafficking of ERGIC3-binding secretory proteins. Our findings provide detailed insights into the regulation of the early secretory pathway by MARCH2 and into ERGIC3 function.

Safety and Efficacy of Reduced Prolonged-release Tacrolimus Exposure in De Novo Kidney Transplantation: A Randomized, Open-label, Pilot Study in Asia-OPTIMIZE Study.

BACKGROUND: A multicenter, randomized, open-label, parallel group, pilot, 52-week study in Asian countries that assessed the renal function, efficacy, and safety of reduced-exposure versus standard-exposure prolonged-release tacrolimus (PR-T) in adult kidney transplant recipients (KTRs). METHODS: Posttransplantation, KTRs received PR-T from weeks 0 to 4 (initial dose, 0.2-0.3 mg/kg; target trough level, 6-10 ng/mL). At week 4, KTRs were randomized (1:1) to receive reduced-exposure PR-T (target 4-6 ng/mL, weeks 4-12; 3-5 ng/mL, weeks 12-52) or standard-exposure PR-T (target: 6-10 ng/mL, weeks 4-52). Primary end point: estimated glomerular filtration rate (eGFR) over 52 weeks. Secondary end points (week 52) included creatinine clearance, serum creatinine, graft/patient survival, biopsy-confirmed acute rejection (AR), composite of graft loss/patient death/biopsy-confirmed AR, and steroid-resistant AR. Treatment-emergent adverse events were recorded. RESULTS: Sixty-six KTRs received PR-T (reduced-exposure, n = 32; standard-exposure, n = 34) and were analyzed. After per-protocol dose adjustment, mean ± standard deviation tacrolimus trough level was lower with reduced- versus standard-exposure PR-T (week 52, 4.5 ± 1.1 ng/mL vs 8.0 ± 2.2 ng/mL). In the reduced- versus standard-exposure group, eGFR was similar at weeks 8 to 52 (overall least-square mean difference, -2.82; 95% confidence interval, -7.91 to 2.27; P = 0.272). At week 52, there was no significant difference in creatinine clearance (P = 0.375) or serum creatinine (P = 0.547) between groups. All grafts/patients survived, no steroid-resistant AR was reported, and 4 and 3 patients had AR in reduced- and standard-exposure groups, respectively. Drug-related treatment-emergent adverse events were reported in 34.4% and 38.2% of patients, respectively. CONCLUSIONS: Reducing exposure to PR-T resulted in a clinically acceptable short-term safety profile and was generally as effective as standard tacrolimus exposure for Asian patients.