Posttransplant-Alloantibodies Against MICA Antigens Associated With Decreased Long-Term Allograft Survival of Kidney Transplant Recipients.

BACKGROUND: Previous evidence showed that antibodies against major histocompatibility complex class I-related chain A (MICA) could lead to antibody-mediated rejection in kidney transplantation in case where the patients had no alloantibodies against HLA. However, the effects of posttransplant anti-MICA antibodies on long-term renal allograft survival and function remained unsettled. We tested the posttransplant anti-MICA antibodies in 150 kidney transplant patients. The aim of this study was to compare the long-term graft survival and function between patients who were MICA positive and those who were negative. METHODS: The posttransplant serum samples from 150 patients receiving kidney transplantation in our center from 2012 to 2013 were tested for MICA antibodies and HLA antibodies by Luminex single antigen array technology. Graft survival and function were followed up for a mean time of 74.2 months. The research was conducted in accordance with the Helsinki Congress and the Declaration of Istanbul. RESULTS: Of the 150 patients, 38 (25.3%) were sensitized against MICA after transplantation. The anti-MICA antibodies-positive (anti-MICA+) group had a worse long-term renal allograft survival than that of anti-MICA-negative (anti-MICA-) group (P = .029), even when stratified by posttransplant HLA sensitization status or donor source. Anti-MICA antibodies also had a detrimental impact on renal allograft function, but only at 1 year posttransplantation (estimated glomerular filtration rates at 1 year: anti-MICA+ 66.6 mL/min/1.73 m2 vs anti-MICA- 78.7 mL/min/1.73 m2; P = .023). CONCLUSION: Posttransplant anti-MICA antibodies were associated with decreased long-term renal allograft survival and short-term renal allograft function.

Marijuana smoking and asthma: a protocol for a meta-analysis.

INTRODUCTION: Recent studies have raised the concern on the risk of asthma in marijuana smokers; however, the results remain controversial and warrant further investigation. With a growing number of marijuana smokers, examining the association between marijuana smoking and asthma and quantifying such association through meta-analysis have important implications for public health and clinical decision-making. In view of this, the present protocol aims to detail a comprehensive plan of meta-analysis on the association aforementioned. The findings are expected to strengthen the current knowledge base pertaining to the potential adverse effects of marijuana smoking on pulmonary health and to facilitate the development of prevention strategies for asthma. METHODS AND ANALYSIS: The MEDLINE/PubMed, Web of Science and EMBASE databases will be searched systematically from inception to 1 September 2021 to retrieve the relevant observational studies focusing on the association between marijuana smoking and asthma. Both unadjusted and adjusted effect sizes, such as OR, relative risk, HR and the corresponding 95% CIs will be extracted for pooled analyses. Heterogeneity and publication bias across the included studies will be examined. The Newcastle-Ottawa Quality Scale will be used to assess the quality and risk of bias. Statistical software Review Manager V.5.3 and Stata V.11.0 will be used for statistical analyses. ETHICS AND DISSEMINATION: Since no private and confidential patient data will be included in the reporting, approval from an ethics committee is not required. The results will be published in a peer-reviewed journal or disseminated in the relevant conferences. The study raises no ethical issue. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/UPTXC.

Activation of RSK2 upregulates SOX8 to promote methotrexate resistance in gestational trophoblastic neoplasia.

Resistance to chemotherapy is frequently driven by aberrantly activated kinases in cancer. Herein, we characterized the global phosphoproteomic alterations associated with methotrexate (MTX) resistance in gestational trophoblastic neoplastic (GTN) cells. A total of 1111 phosphosites on 713 proteins were significantly changed, with highly elevated Ribosomal S6 Kinase 2 (RSK2) phosphorylation (pS227) observed in MTX-resistant GTN cells. Activation of RSK2 promoted cell proliferation and survival after MTX treatment in GTN cell models. Interestingly, RSK2 might play an important role in the regulation of reactive oxygen species (ROS) homeostasis, as manipulation of RSK2 activation affected ROS accumulation and SOX8 expression in GTN cells. In addition, overexpression of SOX8 partly rescued cell proliferation and survival in RSK2-depleted MTX-resistant GTN cells, suggesting that SOX8 might serve as a downstream effector of RSK2 to promote MTX resistance in GTN cells. Highly activated RSK2/SOX8 signaling was observed in MTX-resistant GTN specimens. Further, the RSK2 inhibitor BIX02565 effectively reduced SOX8 expression, induced ROS accumulation, and enhanced MTX-induced cytotoxicity in vitro and in vivo. Collectively, our findings suggested that RSK2 activation could promote MTX resistance via upregulating SOX8 and attenuating MTX-induced ROS in GTN cells, which may help to develop experimental therapeutics to treat MTX-resistant GTN.

LED Light Quality of Continuous Light before Harvest Affects Growth and AsA Metabolism of Hydroponic Lettuce Grown under Increasing Doses of Nitrogen.

To study the effects of light quality of continuous light before harvest on the growth and ascorbic acid (AsA) metabolism of lettuce (Lactuca sativa L.) grown under relative high nitrogen level, lettuce plants grown under different nitrogen levels (8, 10 and 12 mmol·L-1) were subjected to continuous light with different red: blue light ratios (2R:1B and 4R:1B) before harvest. The results showed that the shoot fresh weight of lettuce under 12 mmol·L-1 nitrogen level was significantly higher than that under other treatments. There were no significant differences in shoot dry weight, root fresh weight, root dry weight, soluble sugar content, nitrate content and AsA content in leaves among the treatments at different nitrogen levels. The content of AsA in leaves was significantly higher than that in petioles before and after continuous light. Under the same nitrogen level, the fresh weight of lettuce under continuous light quality 4R:1B was significantly higher than that under other treatments. The content of AsA in lettuce leaves increased in different degrees after continuous light before harvest. High yield and AsA content could be obtained by 72 h continuous light with red and blue light 4R:1B at 12 mmol·L-1 nitrogen level. After continuous light, the content of AsA increased significantly due to the increase of the ratio of red light and nitrogen level, which increased the activities of L-galactono-1,4-lactone dehydrogenase (GalLDH) and dehydroascorbic acid reductase (DHAR) involved in AsA synthesis and in the recycling of DHAR to AsA respectively.

Light Quality Affected the Growth and Root Organic Carbon and Autotoxin Secretions of Hydroponic Lettuce.

Light is a crucial environmental signal and photosynthetic energy for plant growth, development, and primary and secondary metabolism. To explore the effects of light quality on the growth and root exudates of hydroponic lettuce (Lactuca sativa L.), white LED (W, control) and four the mixtures of red (R) and blue (B) LED with different R/B light intensity ratios (R/B = 2, 2R1B; R/B = 3, 3R1B; R/B = 4, 4R1B; and R/B = 8, 8R1B) were designed. The results showed that the biomass of lettuce under 8R1B and W treatments was higher than that under other light quality treatments. The photosynthetic rate (Pn) under red and blue light was significantly higher than that of white light. Total root length, root surface area, and root volume were the highest under 8R1B. 4R1B treatment significant increased root activity by 68.6% compared with W. In addition, total organic carbon (TOC) content, TOC content/shoot dry weight, TOC content/root dry weight, and TOC content/root surface area were the highest under 4R1B. Moreover, 8R1B treatment reduced the concentration of benzoic acid and salicylic acid, and the secretion ability of benzoic acid and salicylic acid by per unit root surface area and accumulation by per unit shoot dry weight. In addition, 2R1B and 3R1B reduced the secretion ability of gallic acid and tannic acid by per unit root surface area and accumulation by per unit shoot dry weight. In conclusion, this study showed that the secretion of autotoxins could be reduced through the mediation of red and blue light composition of LEDs in a plant factory. In terms of autotoxin secretion reduction efficiency and yield performance of lettuce, 8R1B light regime is recommended for practical use.

The botanical origin and antioxidant, anti-BACE1 and antiproliferative properties of bee pollen from different regions of South Korea.

BACKGROUND: Bee pollen (BP) has been used as a traditional medicine and food diet additive due to its nutritional and biological properties. The potential biological properties of bee pollen vary greatly with the botanical and geographical origin of the pollen grains. This study was conducted to characterize the botanical origin and assess the antioxidant effects of ethanol extracts of 18 different bee pollen (EBP) samples from 16 locations in South Korea and their inhibitory activities on human ß-amyloid precursor cleavage enzyme (BACE1), acetylcholinesterase (AChE), human intestinal bacteria, and 5 cancer cell lines. METHODS: The botanical origin and classification of each BP sample was evaluated using palynological analysis by observing microscope slides. We measured the biological properties, including antioxidant capacity, inhibitory activities against human BACE1, and AChE, and antiproliferative activities toward five cancer cell lines, of the 18 EBPs. In addition, the growth inhibitory activities on four harmful intestinal bacteria, six lactic acid-producing bacteria, two nonpathogenic bacteria, and an acidulating bacterium were also assessed. RESULTS: Four samples (BP3, BP4, BP13 and BP15) were found to be monofloral and presented four dominant pollen types: Quercus palustris, Actinidia arguta, Robinia pseudoacacia, and Amygdalus persica. One sample (BP12) was found to be bifloral, and the remaining samples were considered to be heterofloral. Sixteen samples showed potent antioxidant activities with EC50 from 292.0 to 673.9 µg mL- 1. Fourteen samples presented potent inhibitory activity against human BACE1 with EC50 from 236.0 to 881.1 µg mL- 1. All samples showed antiproliferative activity toward the cancer cell lines PC-3, MCF-7, A549, NCI-H727 and AGS with IC50 from 2.7 to 14.4 mg mL- 1, 0.9 to 12.7 mg mL- 1, 5.0 to > 25 mg mL- 1, 2.7 to 17.7 mg mL- 1, and 2.4 to 8.7 mg mL- 1, respectively. In addition, total phenol and flavonoid contents had no direct correlation with antioxidant, anti-human BACE1, or antiproliferative activities. CONCLUSION: Fundamentally, Korean bee pollen-derived preparations could be considered a nutritional addition to food to prevent various diseases related to free radicals, neurodegenerative problems, and cancers. The botanical and geographical origins of pollen grains could help to establish quality control standards for bee pollen consumption and industrial production.

Regulation of Ascorbate Accumulation and Metabolism in Lettuce by the Red:Blue Ratio of Continuous Light Using LEDs.

Ascorbate (AsA), an antioxidant that cannot be synthesized and stored by the human body, plays an essential role in the proper functioning of both plants and humans. With the goal of increasing the AsA level in lettuce, the effects of different ratios of red (R) to blue (B) light (75R:25B, 50R:50B, and 25R:75B) on AsA pool sizes as well as the transcript levels and activities of key enzymes involved in AsA metabolism were constantly monitored for 12 days under continuous light (200 µmol⋅m-2⋅s-1) from LEDs. The results showed that lettuce biomass was positively correlated with the ratio of red light, while the AsA pool size had a positive correlation with the ratio of blue light during the whole experiment. The 25R:75B treatment increased the expression of genes involved in AsA biosynthesis (GMP, GME, GGP, GPP, GLDH) and regeneration (APX, MDHAR, DHAR, and GR) on day 3 but only significantly elevated the activities of enzymes involved in AsA regeneration (APX, MDHAR, DHAR, and GR) subsequently. AsA regeneration enzymes (MDHAR, DHAR and GR) had greater correlations with the AsA level than the AsA synthesis enzyme (GLDH). Thus, it is concluded that a high ratio of blue light elevated the AsA level mainly by promoting AsA regeneration rather than biosynthesis. Taken together, altering the red:blue ratio of continuous light from high to low before harvest is recommended for lettuce cultivation to achieve both high yield and high quality.

Non-Mitogenic Fibroblast Growth Factor 1 Enhanced Angiogenesis Following Ischemic Stroke by Regulating the Sphingosine-1-Phosphate 1 Pathway.

Ischemic strokes account for about 80% of all strokes and are associated with a high risk of mortality. Angiogenesis of brain microvascular endothelial cells may contribute to functional restoration following ischemia. Fibroblast growth factor 1 (FGF1), a member of FGF superfamily, involved in embryonic development, angiogenesis, wound healing, and neuron survival. However, the mitogenic activity of FGF1 is known to contribute to several human pathologies, thereby questioning the safety of its clinical applications. Here, we explored the effects and mechanism of action of non-mitogenic FGF1 (nmFGF1) on angiogenesis in mice after ischemia stroke and an oxygen-glucose deprivation (OGD)-induced human brain microvascular endothelial cells (HBMECs) injury model. We found that intranasal administration nmFGF1 significantly promoted angiogenesis in mice after stroke, and significantly increased the formation of matrigel tube and promoted scratch migration in a dose-dependent manner in OGD-induced HBMECs in vitro. However, the co-administration of an FGF receptor 1 (FGFR1)-specific inhibitor PD173074 significantly reversed the effects of nmFGF1 in vitro, suggesting that nmFGF1 functions via FGFR1 activation. Moreover, nmFGF1 activated sphingosine-1-phosphate receptor 1 (S1PR1, S1P1) in mice after stroke in vivo. S1P1 protein antagonist VPC23019 and agonist FTY720 were used to confirm that nmFGF1 promotes angiogenesis in vitro partially through the S1P1 pathway. OGD induced downregulation of S1P1 expression. The S1P1 antagonist VPC23019 blocked the stimulatory effects of nmFGF1, whereas the S1P1 agonist FTY720 exerted effects comparable with those of nmFGF1. Furthermore, PD173074 reversed the effect of nmFGF1 on upregulating S1P1 signaling. In conclusion, nmFGF1 enhanced angiogenesis in mice following stroke and OGD-induced HBMECs through S1P1 pathway regulation mediated via FGFR1 activation. This new discovery suggests the potential therapeutic role of nmFGF1 for the treatment of ischemic strokes.

Morphological and Physiological Stress Responses of Lettuce to Different Intensities of Continuous Light.

In this study, specific dynamic changes in growth, oxidative stress, ascorbate metabolism, and chlorophyll fluorescence were monitored during 12 days in lettuce plants exposed to continuous light (CL) of different intensities: low light (LL, 100 µmol·m-2·s-1), medium light (ML, 200 µmol·m-2·s-1), and high light (HL, 300 µmol·m-2·s-1). Lettuce plants grown under CL of higher light intensity gained greater biomass, dry weight ratio, root/shoot ratio, and specific leaf FW, but not leaf area. Both the reactive oxygen species (ROS) production and the lipid peroxidation degree, measured in terms of the malondialdehyde (MDA) levels, were progressively enhanced by increasing the light intensity of CL. Overall, the pool sizes of ascorbate (AsA) and glutathione, as well as the activities of enzymes involved in AsA metabolism, had positive correlations with light intensity under CL. Ascorbate peroxidase and dehydroascorbate reductase presented the maximal and minimal responses to light intensity, respectively, among all the studied enzymes. After 6 days under CL, ML and HL intensity caused reversible photoinhibition, represented by lower values of maximum quantum efficiency (F v /F m), effective quantum yield (ΦPSII), and photochemical quenching (qP) and a higher value of non-photochemical quenching (qN). However, this photoinhibition recovered on day 12 with increasing of F v /F m, ΦPSII, and qP. Taken together, under ML and HL conditions, greater AsA level could help maintain photosynthetic efficiency by elevating excess excitation energy dissipation, though ROS accumulation and lipid peroxidation could not be prevented in the long-term. Likewise, there was no dark period under LL condition, but no photooxidative stress was observed in lettuce. Thus, it is concluded that photooxidative stress induced by CL can be attributed to excessive daily light integral instead of circadian asynchrony.

Fibroblast growth factor 21 enhances angiogenesis and wound healing of human brain microvascular endothelial cells by activating PPARγ.

Angiogenesis of brain microvascular endothelial cells (BMECs) is required in the functional restoration of brain injury, such as traumatic brain injury (TBI) and ischemic stroke. Fibroblast growth factor 21 (FGF21) is an angiogenic molecule that functions through the formation of the FGF21/FGFR1/ß-klotho complex but does not cause carcinogenic events. The current study was to determine whether recombinant human FGF21 (rhFGF21) could promote angiogenesis and scratch wound healing of human brain microvascular endothelial cells (HBMECs) and the possible underlying mechanism. rhFGF21 promoted angiogenesis and migration of HBMECs. The FGFR1 inhibitor PD173074 was applied to demonstrate that rhFGF21 functions through the formation of FGF21/FGFR1/ß-klotho complexes. In addition, the specific PPARγ inhibitor GW9662 and PPARγ activator rosiglitazone were applied to determine that the role of rhFGF21 in increasing angiogenesis is through the PPARγ pathway. In addition, we revealed that the effect of rhFGF21 acts partially through upregulating eNOS expression. In conclusion, our study provides novel evidence that rhFGF21 can enhance the angiogenesis and migration of HBMECs through the formation of the FGF21/FGFR1/ß-klotho complex via PPARγ activation and eNOS upregulation, indicating that FGF21 is a potential therapeutic angiogenic agent for the treatment of human brain injury.

Poly(amine-co-ester) nanoparticles for effective Nogo-B knockdown in the liver.

Degradable poly(amine-co-ester) (PACE) terpolymers hold tremendous promise for siRNA delivery because these materials can be formulated into delivery vehicles with highly efficient siRNA encapsulation, providing effective knockdown with low toxicity. Here, we demonstrate that PACE nanoparticles (NPs) provide substantial protein knockdown in human embryonic kidney cells (HEK293) and hard-to-transfect primary human umbilical vein endothelial cells (HUVECs). After intravenous administration, NPs of solid PACE (sPACE)-synthesized with high monomer content of a hydrophobic lactone-accumulated in the liver and, to a lesser extent, in other tissues. Within the liver, a substantial fraction of sPACE NPs were phagocytosed by liver macrophages, while a smaller fraction of NPs accumulated in hepatic stellate cells and liver sinusoidal endothelial cells, suggesting that sPACE NPs could deliver siRNA to diverse cell populations within the liver. To test this hypothesis, we loaded sPACE NPs with siRNA designed to knockdown Nogo-B, a protein that has been implicated in the progression of alcoholic liver disease and liver fibrosis. These sPACE:siRNA NPs produced up to 60% Nogo-B protein suppression in the liver after systemic administration. We demonstrate that sPACE NPs can effectively deliver siRNA therapeutics to the liver to mediate protein knockdown in vivo.

Incorporation of Gene-Environment Interaction Terms Improved the Predictive Accuracy of Tacrolimus Stable Dose Algorithms in Chinese Adult Renal Transplant Recipients.

The narrow therapeutic window of tacrolimus necessitates daily monitoring and predictive algorithms based on genetic and nongenetic factors. In this study, we constructed predictive algorithms for tacrolimus stable dose in a retrospective cohort of 1045 Chinese renal transplant recipients. All patients were genotyped for CYP3A4 20230T>C (rs2242480), CYP3A4 T>C (rs4646437), CYP3A5*3 6898A>G (rs776746), ABCB1 129T>C (rs3213619); ABCB1 c.1236C>T (rs01128503), ABCB1 c.2677G>T/A (rs2032582) and ABCB1 c.3435C>T (rs1045642) polymorphisms, and the effects of gene-gene and gene-environment interactions on the predictive accuracy of algorithm were evaluated. In wild-type CYP3A4 rs2242480 (TT) carriers, patients who took calcium channel blockers had lower tacrolimus stable doses than those without the concomitant medications (P < 1 × 10-4 ). In contrast, there was no significant difference in mutant type patients. Similarly, the tacrolimus stable doses in wild-type CYP3A5 rs776746 carriers who had hypertension were higher than those without hypertension (P = 4.10 × 10-3 ). More importantly, dose-predictive algorithms with interaction terms showed higher accuracy and better performance than those without interaction terms. Our finding suggested that wild-type CYP3A4 rs2242480 (TT) carriers should be more cautious to take tacrolimus when they are coadministrated with calcium channel blockers, and CYP3A5 rs776746 (AA) carriers may need higher tacrolimus dosage when they are in combination with hypertension.

Potential Prognostic and Diagnostic Values of CDC6, CDC45, ORC6 and SNHG7 in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is a common human malignancy. The aims of this study are to investigate the gene expression profile of CRC and to explore potential strategy for CRC diagnosis, therapy and prognosis. METHODS: We use affy and Limma package of Bioconductor R to do differential expression genes (DEGs) and differential expression lncRNAs (DELs) analysis from the gene datasets (GSE8671, GSE21510, GSE32323, GSE39582 and TCGA) respectively. Then, DEGs were analyzed by GO and KEGG pathway and Kaplan-Meier survival curve and Cox regression analyses were used to find aberrantly expressed genes associated with survival outcome of CRC patients. Real-time PCR assay was used to verify the aberrantly expressed genes expression in CRC samples. RESULTS: 306 up-regulation and 213 down-regulation common DEGs were found. A total of 485 DELs were identified, of which 241 up-regulated and 244 down-regulated. Then, GO and KEGG pathway analyses showed that DEGs were involved in cell cycle, mineral absorption, DNA replication, and Nitrogen metabolism. Among them, Kaplan-Meier survival curve and Cox regression analyses revealed that CDC6, CDC45, ORC6 and SNHG7 levels were significantly associated with survival outcome of CRC patients. Finally, real-time PCR assay was used to verify that the CDC6, CDC45, ORC6 and SNHG7 expression were up-regulated in 198 CRC samples compared with the expression levels in individual-matched adjacent mucosa samples. CONCLUSION: CDC6, CDC45, ORC6 and SNHG7 are implicated in CRC initiation and progression and could be explored as potential diagnosis, therapy and prognosis targets for CRC.

FGF21 Protects the Blood-Brain Barrier by Upregulating PPARγ via FGFR1/ß-klotho after Traumatic Brain Injury.

Blood-brain barrier (BBB) disruption and dysfunction result in brain edema, which is responsible for more than half of all deaths after severe traumatic brain injury (TBI). Fibroblast growth factor 21 (FGF21) has a potential neuroprotective function in the brain. However, the effects and underlying possible mechanism of action on BBB integrity following TBI remain unknown. The purpose of the current study was to determine the effects of FGF21 on BBB protection and TBI treatment. The effects of recombinant human FGF21 (rhFGF21) on BBB integrity and on tight junction (TJ) and adhesion junction (AJ) proteins were investigated both in a TBI mouse model and an in vitro BBB disruption model established with tumor necrosis factor alpha (TNF-α)-induced human brain microvascular endothelial cells (HBMECs). The ability of rhFGF21 to form an FGF21/FGFR1/ß-klotho complex was confirmed by in vitro ß-klotho small interfering RNA (siRNA) transfection and FGFR1 co-immunoprecipitation. In addition, the specific FGFR1 and peroxisome proliferator-activated receptor gamma (PPARγ) inhibitors PD173074 and GW9662, respectively, were applied to further explore the possible mechanism of rhFGF21 in BBB maintenance after TBI. rhFGF21 markedly reduced neurofunctional behavior deficits and cerebral edema degree, preserved BBB integrity, and recued brain tissue loss and neuron apoptosis in the mouse model after TBI. Both in vivo and in vitro, rhFGF21 upregulated TJ and AJ proteins, thereby preserving the BBB. Moreover, rhFGF21 activated PPARγ in TNF-α-induced HBMECs through formation of an FGF21/FGFR1/ß-klotho complex. rhFGF21 protected the BBB through FGF21/FGFR1/ß-klotho complex formation and PPARγ activation, which upregulated TJ and AJ proteins.

Corrigendum: Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients.

This corrects the article DOI: 10.1038/srep42192.

Comparative efficacy and safety of antibody induction therapy for the treatment of kidney: a network meta-analysis.

To evaluate the efficacy and safety of antibody induction therapies in kidney transplantation. Systematic literature searches were undertaken using MEDLINE, Embase, and Cochrane Library database from 1980 to 2016. Randomized controlled trials (RCTs) comparing three antibody induction therapies (alemtuzumab, interleukin-2 receptor antibodies and antithymocyte globulin) between each other were identified. Bayesian network meta-analysis was used to combine both the direct and indirect evidence on treatment efficacy and its safety. Antibody induction therapy studies, comprising of 18 RCTs (3444 kidney transplant recipients), were included. Overall, alemtuzumab treatment was superior to the ATG group (OR: 0.49, 95% CI: 0.32 to 0.71) and IL-2RAs group (OR: 0.36, 95% CI: 0.25 to 0.52) for reducing the 1-year acute rejection in kidney transplant recipients. Although alemtuzumab treatment was nearly same with ATG group and IL-2RAs group in improving patient survival and renal function, it can reduce the adverse effects of cytomegalovirus infection more efficiently than ATG group (OR: 0.59, 95% CI: 0.32 to 0.95) and IL-2RAs group (OR: 1.08, 95% CI: 0.61 to 1.73). Alemtuzumab was not associated with increased other adverse effects. Alemtuzumab treatment is safe and effective for kidney transplant recipients. No serious adverse effects were observed in trials or in general populations.

The origin and evolution of Basigin(BSG) gene: A comparative genomic and phylogenetic analysis.

Basigin (BSG), also known as extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147), plays various fundamental roles in the intercellular recognition involved in immunologic phenomena, differentiation, and development. In this study, we aimed to compare the similarities and differences of BSG among organisms and explore possible evolutionary relationships based on the comparison result. We used the extensive BLAST tool to search the metazoan genomes, N-glycosylation sites, the transmembrane region and other functional sites. We then identified BSG homologs from genomic sequences and analyzed their phylogenetic relationships. We identified that BSG genes exist not only in the vertebrate metazoans but also in the invertebrate metazoans such as Amphioxus B. floridae, D. melanogaster, A. mellifera, S. japonicum, C. gigas, and T. patagoniensis. After sequence analysis, we confirmed that only vertebrate metazoans and Cephalochordate (amphioxus B. floridae) have the classic structure (a signal peptide, two Ig-like domains (IgC2 and IgI), a transmembrane region, and an intracellular domain). The invertebrate metazoans (excluding amphioxus B. floridae) lack the N-terminal signal peptides and IgC2 domain. We then generated a phylogenetic tree, genome organization comparison, and chromosomal disposition analysis based on the biological information obtained from the NCBI and Ensembl databases. Finally, we established the possible evolutionary scenario of the BSG gene, which showed the restricted exon rearrangement that has occurred during evolution, forming the present-day BSG gene.

Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients.

Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the "derivation cohort" to develop dose-prediction algorithm, while the remaining 20% constituted the "validation cohort" to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.

An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization.

Nogo-B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Because ER stress is known to induce M2 macrophage polarization, we examined whether Nogo-B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). M1 and M2 phenotypes were assessed in relation to Nogo-B expression and disease severity in liver specimens from ALD patients (NCT01875211). Liver specimens from wild-type (WT) and Nogo-B knockout (KO) mice fed a control or Lieber-DeCarli ethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis. Kupffer cells isolated from WT and Nogo-B KO mice were assessed for M1 and M2 activation. A significant positive correlation was observed between Nogo-B positive Kupffer cells and disease severity in ALD patients (n = 30, r = 0.66, P = 0.048). Furthermore, Nogo-B-positive Kupffer cells were correlated with M1 activation (inducible nitric oxide synthase) (r = 0.50, P = 0.05) and negatively with markers of M2 status (CD163) (r = -0.48, P = 0.07) in these patients. WT mice exhibited significantly increased liver injury (P < 0.05) and higher hepatic triglyceride levels (P < 0.01) compared with Nogo-B KO mice in response to chronic ethanol feeding. Nogo-B in Kupffer cells promoted M1 polarization, whereas absence of Nogo-B increased ER stress and M2 polarization in Kupffer cells. CONCLUSION: Nogo-B is permissive of M1 polarization of Kupffer cells, thereby accentuating liver injury in ALD in humans and mice. Nogo-B in Kupffer cells may represent a new therapeutic target for ALD. (Hepatology 2017;65:1720-1734).

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients.

The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P =0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P =0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.