Patients with suspected OSA were examined using PSG.They were divided into two groups based on the presence of nocturia.Nocturia was defined as a patient who needed to void at least once.Apneaehypopnea index(AHI)was e...Patients with suspected OSA were examined using PSG.They were divided into two groups based on the presence of nocturia.Nocturia was defined as a patient who needed to void at least once.Apneaehypopnea index(AHI)was employed to classify patients according to degrees of severity:AHI<5 events/h,5 events/hAHI<15 events/h,15 events/hAHI<30 events/h,and AHI30 events/h,defined as normal,mild OSA,moderate OSA,and severe OSA,respectively.Demographic variables,PSG parameters,International Prostate Symptom Scores(IPSSs),and quality of life scores due to urinary symptoms were analyzed.Results:In total 140 patients,114 patients had OSA(48 had mild OSA;34 had moderate OSA;and 32 had severe OSA)and 107 patients had nocturia.The total IPSS was significantly higher in nocturia patients in all groups except the group of severe OSA patients.With the increasing severity of OSA,more correlated factors related to nocturia were determined.In mild OSA patients,nocturia related to increased age(p=0.025),minimum arterial blood oxygenation saturation(p=0.046),and decreased AHI of non-rapid eye movement(p=0.047),AHI of total sleep time(p=0.010),and desaturation index(p=0.012).In moderate OSA patients,nocturia related to increased age(p<0.001),awake time(p=0.025),stage 1 sleep(p=0.033),and sleep latency(p=0.033),and decreased height(p=0.044),weight(p=0.025),and sleep efficiency(p=0.003).In severe OSA patients,nocturia related to increased weight(p=0.011),body mass index(p=0.009),awake time(p=0.008),stage 1 sleep(p=0.040),arousal number(p=0.030),arousal index(p=0.013),periodic limb movement number(p=0.013),and periodic limb movement index(p=0.004),and decreased baseline arterial blood oxygenation saturation(p=0.046).Conclusion:Our study revealed that there were more correlated factors related to nocturia with increasing severity of OSA.This study helps in clinical education and treatment for OSA patients with different severity.展开更多
Hepatitis B virus X protein(HBx) plays an important role in the development of hepatocellular carcinoma(HCC). In addition, hepatoma upregulated protein(HURP) is a cellular oncogene that is upregulated in a majority of...Hepatitis B virus X protein(HBx) plays an important role in the development of hepatocellular carcinoma(HCC). In addition, hepatoma upregulated protein(HURP) is a cellular oncogene that is upregulated in a majority of HCC cases. We highlight here recent findings demonstrating a link between HBx, HURP and anti-apoptosis effects observed in cisplatin-treated HCC cells. We observed that Hep3B cells overexpressing HBx display increased HURP mRNA and protein levels, and show resistance to cisplatin-induced apoptosis. Knockdown of HURP in HBx-expressing cells reverses this effect, and sensitizes cells to cisplatin. The anti-apoptotic effect of HBx requires activation of the p38/MAPK pathway as well as expression of SATB1, survivin and HURP. Furthermore, silencing of HURP using short-hairpin RNA promotes accumulation of p53 and reduces cell proliferation in SK-Hep-1 cells(p53^(+/–)), whereas these effects are not observed in p53-mutant Mahlavu cells. Similarly, HURP silencing does not affect the proliferation of H1299 lung carcinoma cells or Hep3 B HCC cells which lack p53. Silencing of HURP sensitizes SK-Hep-1 cells to cisplatin. While HURP overexpression promotes p53 ubiquitination and degradation by the proteasome, HURP silencing reverses these effects. Inoculation of SK-Hep-1 cancer cells in which HURP has been silenced produces smaller tumors than control in nude mice. Besides, gankyrin, a positive regulator of the E3 ubiquitin ligase MDM2, is upregulated following HURP expression, and silencing of gankyrin reduces HURP-mediated downregulation of p53. In addition, we observed a positive correlation between HURP and gankyrin protein levels in HCC patients(r^2 = 0.778; n = 9). These findings suggest a role for the viral protein HBx and the host protein HURP in preventing p53-mediated apoptosis during cancer progression and establishment of chemoresistance.展开更多
AIM To test whether a simple animal, Caenorhabditis elegans(C. elegans), can be used as an alternative model to study the interaction between hepatitis B virus antigens(HBs Ag) and host factors. METHODS Three plasmids...AIM To test whether a simple animal, Caenorhabditis elegans(C. elegans), can be used as an alternative model to study the interaction between hepatitis B virus antigens(HBs Ag) and host factors. METHODS Three plasmids that were able to express the large, middle and small forms of HBs Ags(LHBs Ag, MHBs Ag, and SHBs Ag, respectively) driven by a ubiquitous promoter(fib-1) and three that were able to express SHBs Ag driven by different tissue-specific promoters were constructed and microinjected into worms. The brood size, egglaying rate, and gonad development of transgenic worms were analyzed using microscopy. Levels of m RNA related to endoplasmic reticulum stress, enpl-1, hsp-4, pdi-3 and xbp-1, were determined using reverse transcription polymerase reaction(RT-PCRs) in three lines of transgenic worms and dithiothreitol(DTT)-treated wild-type worms. RESULTS Severe defects in egg-laying, decreases in brood size, and gonad retardation were observed in transgenic worms expressing SHBs Ag whereas moderate defects were observed in transgenic worms expressing LHBs Ag and MHBs Ag. RT-PCR analysis revealed that enpl-1, hsp-4 and pdi-3 transcripts were significantly elevated in worms expressing LHBs Ag and MHBs Ag and in wild-type worms pretreated with DTT. By contrast, only pdi-3 was increased in worms expressing SHBs Ag. To further determine which tissue expressing SHBs Ag could induce gonad retardation, we substituted the fib-1 promoter with three tissue-specific promoters(myo-2 for the pharynx, est-1 for the intestines and mec-7 for the neurons) and generated corresponding transgenic animals. Moderate defective phenotypes were observed in worms expressing SHBs Ag in the pharynx and intestines but not in worms expressing SHBs Ag in the neurons, suggesting that the secreted SHBs Ag may trigger a cross-talk signal between the digestive track and the gonad resulting in defective phenotypes. CONCLUSION Ectopic expression of three forms of HBs Ag that causes recognizable phenotypes in transgenic worms suggests that C. elegans can be used as an alternative model for studying virus-host interactions because the resulting phenotype is easily detected through microscopy.展开更多
MicroRNA-22 (miR-22), a short non-coding RNA that post-transcriptionally regulates mRNA stability and protein synthesis, has been shown to enhance metastatic potential and to suppress HER-3, an important mRNA marker f...MicroRNA-22 (miR-22), a short non-coding RNA that post-transcriptionally regulates mRNA stability and protein synthesis, has been shown to enhance metastatic potential and to suppress HER-3, an important mRNA marker for non-small cell lung cancer (NSCLC). However, the effect of miR-22 has not been investigated in lung adenocarcinoma (LADC), the most common type of NSCLC in the Far East. In this study, we analyzed the role of miR-22 expression in LADC patients. Expression of miR-22 was detected by reverse-transcription polymerase chain reaction (RT-PCR), and confirmed by cDNA sequencing. Signals of miR-22 in LADC sections were identified using in situ hybridization (ISH). The association between miR-22 expression and survival was evaluated by the log-rank test. Induction of miR-22 expression and the effect on HER-3 levels, as well as the subsequent cell behavior were also investigated In vitro. Two types of miR-22: miR-22 and miR-22H, were detected by RT-PCR. The miR-22H had extra 13 bases, 5’-TGTGTTCAGTGGT-3’, at the 3’-end, and this segment was named miR-22E. Using ISH, miR-22E overexpression was detected in 225 (83.0%) of 271 LADC patients. A significant difference was found in cumulative survival between patients with high miR-22E levels and those with low miR-22E levels (p In vitro, epidermal growth factor induced miR-22, but reduced HER-3 expression. Expression of miR-22 increased cell movement ability. In conclusion, expression of miR-22 is closely associated with tumor recurrence, metastasis and overall survival in LADC patients by suppressing HER-3 protein expression to enhance epithelial-mesenchymal transition and metastasis.展开更多
The persistence and performance (growth promoting potential) of green fluorescent protein (gfp) marked Azotobacter chroococcum strain ABR 4G were studied in sterilized and unsterilized wheat rhizospheric soil. The gfp...The persistence and performance (growth promoting potential) of green fluorescent protein (gfp) marked Azotobacter chroococcum strain ABR 4G were studied in sterilized and unsterilized wheat rhizospheric soil. The gfp was integrated via Tn 5 transposition into A. chroococcum chromosome and the resultant gfp marked colonies were identified by green fluorescent emission under UV light. The gfp was stably maintained in A. chroococcum and the gfp insertion had no apparent adverse effect on the growth promoting properties of the marked soil isolate ABR 4G. The growth promoting properties (nitrogen fixation, ammonia excretion, phosphate solubilization and IAA production) of the parent soil isolate and the gfp marked strain were found to be almost the same. All the quantitative wheat plant traits were significantly influenced by inoculation of A. chroococcum ABR 4G strain in sterilized and unsterilized soil. Inoculated bacterial counts increased gradually in wheat rhizosphere, reached maximum on 60 th d and declined on 80 th d. Fertility levels also affected survival of marked strain and the survival was comparable in sterilized and unsterilized soil. The growth promoting properties were also determined from the marked strain reisolated from wheat rhizosphere in both types of soil. Fig 1, Tab 2, Ref展开更多
Colorectal cancer (CRC) is an important health issue in Taiwan. There were over ten thousand newly diagnosed CRC patients each year. The outcome of late stage CRC still remains to be improved, and tumor markers are ex...Colorectal cancer (CRC) is an important health issue in Taiwan. There were over ten thousand newly diagnosed CRC patients each year. The outcome of late stage CRC still remains to be improved, and tumor markers are expected to improve CRC detection and management. From a colorectal cancer cell secretome database, we chose four proteins as candidates for clinical verification, including tumor-associated calcium signal transducer 2 (TROP2, TACSTD2), transmembrane 9 superfamily member 2 (TM9SF2), and tetraspanin-6 (TSPAN6), and tumor necrosis factor receptor superfamily member 16 (NGFR). Different groups of 30 CRC patients’ tissue samples collected from Chang Gung Memorial Hospital were analyzed by immunohistochemistry (IHC) for the four proteins, and the results were scored by pathologist. For all the four candidate proteins, marked differences of IHC score existed between tumor and adjacent non-tumor counterpart. However, there were only trends between higher protein expression levels and worse outcome. Three proteins (TROP2, TM9SF2 and NGFR) had trends between higher tissue expression and tumor stage or lymph node metastasis. Our study revealed that tissue expression of four proteins (TROP2, TM9SF2, TSPAN6, and NGFR) was markedly different between tumor and adjacent non-tumor counterparts. Overexpression of all these four proteins showed some trends with poorer survival.展开更多
Autophagy is a lysosome-associated,degradative process that catabolizes cytosolic components to recycle nutrients for further use and maintain cell homeostasis.Hepatitis C virus(HCV)is a major cause of chronic hepatit...Autophagy is a lysosome-associated,degradative process that catabolizes cytosolic components to recycle nutrients for further use and maintain cell homeostasis.Hepatitis C virus(HCV)is a major cause of chronic hepatitis,which often leads to end-stage liverassociated diseases and is a significant burden on worldwide public health.Emerging lines of evidence indicate that autophagy plays an important role in promoting the HCV life cycle in host cells.Moreover,the diverse impacts of autophagy on a variety of signaling pathways in HCV-infected cells suggest that the autophagic process is required for balancing HCVhost cell interactions and involved in the pathogenesis of HCV-related liver diseases.However,the detailed molecular mechanism underlying how HCV activates autophagy to benefit viral growth is still enigmatic.Additionally,how the autophagic response contributes to disease progression in HCV-infected cells remains largely unknown.Hence,in this review,we overview the interplay between autophagy and the HCV life cycle and propose possible mechanisms by which autophagy may promote the pathogenesis of HCVassociated chronic liver diseases.Moreover,we outline the related studies on how autophagy interplays with HCV replication and discuss the possible implications of autophagy and viral replication in the progression of HCV-induced liver diseases,e.g.,steatosis and hepatocellular carcinoma.Finally,we explore the potential therapeutics that target autophagy to cure HCV infection and its related liver diseases.展开更多
AIM: To test for the association between genome-wide methylation and myopia in human and mice. METHODS: Long interspersed nucleotide element 1(LINE-1) methylation levels were used to surrogate genome-wide methylation...AIM: To test for the association between genome-wide methylation and myopia in human and mice. METHODS: Long interspersed nucleotide element 1(LINE-1) methylation levels were used to surrogate genome-wide methylation level. We first tested for the association between high myopia(<-6 D) and LINE-1 methylation in leukocytes in 220 cases and 220 control subjects. Secondly, we validated the results of LINE-1 methylation in eyes from the form deprivation myopia(FDM) mice. Furthermore,we calculated the correlation of LINE-1 methylation levels between leukocyte DNA and ocular DNA in the mice. We also tested whether dopamine can alter LINE-1 methylation levels. RESULTS: The LINE-1 methylation level was significantly higher in the myopic human subjects than controls. The upper and middle tertiles of the methylation levels increased an approximately 2-fold(P≤0.002) risk for myopia than the lower tertile. Similarly, FDM mice had high LINE-1 methylation levels in the leukocyte, retina and sclera, and furthermore the methylation levels detected from these three tissues were significantly correlated. Immunohistochemical staining revealed higher levels of homocysteine and methionine in the rodent myopic eyes than normal eyes. Dopamine treatment to the cells reduced both LINE-1 methylation and DNA methyltransferase levels. CONCLUSION: LINE-1 hypermethylation may be associated with high myopia in human and mice. Homocysteine and methionine are accumulated in myopic eyes, which may provide excess methyl group for genome-wide methylation.展开更多
Viral hepatitis remains a worldwide public health problem.The hepatitis D virus(HDV)must either coinfect or superinfect with the hepatitis B virus(HBV).HDV contains a small RNA genome(approximately 1.7 kb)with a singl...Viral hepatitis remains a worldwide public health problem.The hepatitis D virus(HDV)must either coinfect or superinfect with the hepatitis B virus(HBV).HDV contains a small RNA genome(approximately 1.7 kb)with a single open reading frame(ORF)and requires HBV supplying surface antigens(HBsAgs)to assemble a new HDV virion.During HDV replication,two isoforms of a delta antigen,a small delta antigen(SDAg)and a large delta antigen(LDAg),are produced from the same ORF of the HDV genome.The SDAg is required for HDV replication,whereas the interaction of LDAg with HBsAgs is crucial for packaging of HDV RNA.Various clinical outcomes of HBV/HDV dual infection have been reported,but the molecular interaction between HBV and HDV is poorly understood,especially regarding howHBV and HDV compete with HBsAgs for assembling virions.In this paper,we review the role of endoplasmic reticulum stress induced by HBsAgs and the molecular pathway involved in their promotion of LDAg nuclear export.Because the nuclear sublocalization and export of LDAg is regulated by posttranslational modifications(PTMs),including acetylation,phosphorylation,and isoprenylation,we also summarize the relationship among HBsAg-induced endoplasmic reticulum stress signaling,LDAg PTMs,and nuclear export mechanisms in this review.展开更多
Cancer treatment in the past few years has been transformed by a new kind of therapy that targets the immune system instead of the cancer itself to reinvigorate antitumor immunity with astonishing results. However, pr...Cancer treatment in the past few years has been transformed by a new kind of therapy that targets the immune system instead of the cancer itself to reinvigorate antitumor immunity with astonishing results. However, primary and acquired resistance to this type of treatment, namely immune checkpoint blockade(ICB), continue to counter treatment efficacy. In many cases, resistance has been attributed to defective or chronically enhanced interferon signaling and/or upregulation of alternative immune checkpoints,including T-cell immunoglobulin mucin-3(Tim-3) and its ligand galactin-9(Gal-9). In this article, we briefly describe the current knowledge of common checkpoint resistance mechanisms, focusing on the Tim-3/Gal-9 pathway as an alternative checkpoint that holds great promise as another target for ICB.展开更多
Objective： To investigate the inhibitory activities of norcantharidin （NCTD）, a demethylated analogue of cantharidin, on Hep3B cells （a human hepatoma cell line） with deficiency of p53. Methods： The survival rat...Objective： To investigate the inhibitory activities of norcantharidin （NCTD）, a demethylated analogue of cantharidin, on Hep3B cells （a human hepatoma cell line） with deficiency of p53. Methods： The survival rate of the Hep3B cells after treating with NCTD was measured by MTT assay. Cell cycle of treated cells was analyzed by flow cytometry, and DNA fragmentation was observed by electrophoresis. The influence of inhibitors for various caspases and anti-death receptors antibodies on the NCTD-induced apoptosis in the cells was determined. Results： NCTD treatment resulted in growth inhibition of Hep3B cells in a dose- and time-dependent manner. Cell cycle analysis of the cells after treatment with NCTD for 48 h shows that NCTD induced G2M phase arrest occursat low concentration （≤25 μ mol/L） but G0G1 phase arrest at high concentration （50 μ mol/L）. The addition of both caspase-3 and caspase-10 inhibitors completely inhibited DNA fragmentation. Addition of anti-TRAIL/DR5 antibody significantly inhibited DNA fragmentation. Conclusion： NCTD may inhibit the proliferation of Hep3B cells by arresting cell cycle at G2M or G0G1 phase, and induce cells apoptosis via TRAIL/DR5 signal transduction through activation of caspase-3 and caspase-10 by a p53-independent pathway,展开更多
Melanoma is the most serious type of skin cancer and one of the most common cancers in the world.Advanced melanoma is often resistant to conventional therapies and has high potential for metastasis and low survival ra...Melanoma is the most serious type of skin cancer and one of the most common cancers in the world.Advanced melanoma is often resistant to conventional therapies and has high potential for metastasis and low survival rates.Vemurafenib is a small molecule inhibitor of the BRAF serine-threonine kinase recently approved by the United States Food and Drug Administration to treat patients with metastatic and unresectable melanomas that carry an activating BRAF(V600E)mutation.Many clinical trials evaluating other therapeutic uses of vemurafenib are still ongoing.The ATP-binding cassette(ABC)transporters are membrane proteins with important physiological and pharmacological roles.Collectively,they transport and regulate levels of physiological substrates such as lipids,porphyrins and sterols.Some of them also remove xenobiotics and limit the oral bioavailability and distribution of many chemotherapeutics.The overexpression of three major ABC drug transporters is the most common mechanism for acquired resistance to anticancer drugs.In this review,we highlight some of the recent findings related to the effect of ABC drug transporters such as ABCB1 and ABCG2 on the oral bioavailability of vemurafenib,problems associated with treating melanoma brain metastases and the development of acquired resistance to vemurafenib in cancers harboring the BRAF(V600E)mutation.展开更多
Objective： To study whether the ethanol extract of Phellinus merrillii（EPM） has chemopreventive potential against liver carcinogenesis. Methods： Thirty male Spraque-Dawley rats were randomly divided into control g...Objective： To study whether the ethanol extract of Phellinus merrillii（EPM） has chemopreventive potential against liver carcinogenesis. Methods： Thirty male Spraque-Dawley rats were randomly divided into control group, EPM control group, hepatocarcinoma control group, low-dose EPM group and high-dose EPM group, 6 in each group. Using the Solt and Farber protocol in a rat model of hepatocarcinogenesis, the chemopreventive effect of EPM on diethylnitrosamine（DEN）-initiated, 2-acetylaminofluorene（2-AAF） and partial hepatectomy（PH）-promoted liver carcinogenesis in rats was evaluated. Basic pathophysiological and histological examinations, together with the serum levels of glutamic oxaloacetic transaminase（s GOT）, glutamic pyruvic transaminase（s GPT） and gamma-glutamyl transpeptidase（γ-GT） were measured. Results： Treatment of EPM at the concentration of 2 g/kg body weight in the diet for 8 weeks clearly prevented the development of carcinogenesis and reduced the levels of s GOT, s GPT, and serum γ-GT of rats as compared with the hepatocarcinoma control group（P〈0.05 or P〈0.01）. These phenotypes were accompanied by a significant increase in natural killer cell activity. Conclusion： EPM showed a strong liver preventive effect against DEN＋2-AAF＋PH-induced hepatocarcinogenesis in a rat model.展开更多
“In the practice of tolerance,one’s enemy is the best teacher”.-Sayings of Buddhism.To survive an infection,two evolutionarily conserved defense strategies are required for infected host survival.One strategy in vo...“In the practice of tolerance,one’s enemy is the best teacher”.-Sayings of Buddhism.To survive an infection,two evolutionarily conserved defense strategies are required for infected host survival.One strategy in volves acquiri ng resista nee by reduci ng pathogen load via pathoge n recog nition,signaling tran sducti on pathways,and effector mechanisms.Another strategy involves increasing disease tolerance by eliciting tissue damage control mechanisms,which adjust the metabolic output of host tissue in response to different forms of stress and damage.Hence,in recent research,disease tolera nee is regarded as an in here nt comp onent of immunity,which does not exert a direct impact on pathogens but is essential to limit the health and fitness costs of infection;however,its molecular bases remain poorly understood.展开更多
Objective:To extract,characterize and quantify glycosaminoglycans(GAGs)from the body of cuttlefish,tennis-ball sea cucumber,shrimp,seabass and fresh water fish Nile tilapia.Methods:The extracted crude powder was evalu...Objective:To extract,characterize and quantify glycosaminoglycans(GAGs)from the body of cuttlefish,tennis-ball sea cucumber,shrimp,seabass and fresh water fish Nile tilapia.Methods:The extracted crude powder was evaluated for the content of GAGs.The qualitative analysis of sulfated pattern and other important functional groups related with GAGs were explained in the form of Fourier transform infra-red spectroscopy data.Proteins and nucleic acid in the crude extract were determined by the ultraviolet spectrophotometer,while the quantification of total sulfated GAGs and estimation of N-sulfated and O-sulfated GAGs in the crude mixture were performed by using Blyscan kit.Results:The sulfated pattern and other important functional groups related with GAGs were intercepted in Fourier transform infrared analysis.Blyscan quantification method reported that a rare variety of sea cucumber(tennis-ball sea cucumber)emerged as a rich source of GAGs with high values of both N-sulfated and O-sulfated GAGs in comparison to its other counterparts.Conclusions:Findings in this study point out the potential of tennis-ball sea cucumber,a rare variety of sea cucumber to act as an alternative source for GAG extraction for commercial purpose.展开更多
Foxp3＋ regulatory T cells （Tregs） are unique in their immunosuppressive abilities and contribution to immune regulation. However, the homeostatic processes and survival programs that maintain the Treg population re...Foxp3＋ regulatory T cells （Tregs） are unique in their immunosuppressive abilities and contribution to immune regulation. However, the homeostatic processes and survival programs that maintain the Treg population remain unclear. Here, we highlight the recent study by Pierson et al.,1 which dissected the regulatory mechanisms of Treg home- ostasis and survival.展开更多
"Practice is the hardest part of learning,and training is the essence of transformation."Ann Voskamp,One Thousand Gifts:A Dare to Live Fully Right Where YouAre Early-life exposure to environmental allergens ..."Practice is the hardest part of learning,and training is the essence of transformation."Ann Voskamp,One Thousand Gifts:A Dare to Live Fully Right Where YouAre Early-life exposure to environmental allergens and viral infections can lead to trained immunity and macrophage polarization resulting in an augmented type 2 immune response in allergic disorders.However,the detailed mechanism is unknown.展开更多
Melanoma,a type of skin malignancy with a high incidence and poor prognosis,is a global public health issue.The tumorigenesis and pathogenesis of melanoma involve genetic mutations,metabolic disruption,and immune evas...Melanoma,a type of skin malignancy with a high incidence and poor prognosis,is a global public health issue.The tumorigenesis and pathogenesis of melanoma involve genetic mutations,metabolic disruption,and immune evasion.Tumors undergo immune editing to escape immune surveillance,and immune escape has been identified as a critical factor in the development and progression of melanoma.展开更多
Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironm...Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironment(TME),but their role in immunotherapy is unclear.We performed integrative analyses including bioinformatics analysis,functional study,and clinical validation to investigate the role of SPHK1 in tumor immunity.Functionally,we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures.A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1.Preclinically,we found that anti-PD-1 monoclonal antibody(mAb)treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion.Significantly,we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients.Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis,identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment,and provided a therapeutic possibility for the treatment of melanoma patients.展开更多
The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood...The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood.In this study,vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation(CBMT)or vascularized bone marrow(VBM)transplantation from Balb/c(H2d)to C57BL/6(H2b)mice were compared.Either high-or low-dose CBMT(1.5×10^(8)or 3×10^(7)bone marrow cells,respectively)was applied.In addition,recipients were treated with costimulation blockade(1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2,respectively)and short-term rapamycin(3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks).Similar to high-dose conventional bone marrow transplantation,5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival(>120 days).In contrast,significantly shorter median survival was noted in the low-dose CBMT group(~64 days).Consistently high chimerism levels were observed in the VBM transplantation group.Notably,low levels of circulating CD4^(+)and CD8^(+)T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients(>30 days)but not in low-dose VBM transplant recipients.Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro.Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.展开更多
基金support from Tungs’Taichung Metroharbor Hospital(grant number#TTMHH-109R0048 to Stella Chin-Shaw Tsai).
文摘Patients with suspected OSA were examined using PSG.They were divided into two groups based on the presence of nocturia.Nocturia was defined as a patient who needed to void at least once.Apneaehypopnea index(AHI)was employed to classify patients according to degrees of severity:AHI<5 events/h,5 events/hAHI<15 events/h,15 events/hAHI<30 events/h,and AHI30 events/h,defined as normal,mild OSA,moderate OSA,and severe OSA,respectively.Demographic variables,PSG parameters,International Prostate Symptom Scores(IPSSs),and quality of life scores due to urinary symptoms were analyzed.Results:In total 140 patients,114 patients had OSA(48 had mild OSA;34 had moderate OSA;and 32 had severe OSA)and 107 patients had nocturia.The total IPSS was significantly higher in nocturia patients in all groups except the group of severe OSA patients.With the increasing severity of OSA,more correlated factors related to nocturia were determined.In mild OSA patients,nocturia related to increased age(p=0.025),minimum arterial blood oxygenation saturation(p=0.046),and decreased AHI of non-rapid eye movement(p=0.047),AHI of total sleep time(p=0.010),and desaturation index(p=0.012).In moderate OSA patients,nocturia related to increased age(p<0.001),awake time(p=0.025),stage 1 sleep(p=0.033),and sleep latency(p=0.033),and decreased height(p=0.044),weight(p=0.025),and sleep efficiency(p=0.003).In severe OSA patients,nocturia related to increased weight(p=0.011),body mass index(p=0.009),awake time(p=0.008),stage 1 sleep(p=0.040),arousal number(p=0.030),arousal index(p=0.013),periodic limb movement number(p=0.013),and periodic limb movement index(p=0.004),and decreased baseline arterial blood oxygenation saturation(p=0.046).Conclusion:Our study revealed that there were more correlated factors related to nocturia with increasing severity of OSA.This study helps in clinical education and treatment for OSA patients with different severity.
文摘Hepatitis B virus X protein(HBx) plays an important role in the development of hepatocellular carcinoma(HCC). In addition, hepatoma upregulated protein(HURP) is a cellular oncogene that is upregulated in a majority of HCC cases. We highlight here recent findings demonstrating a link between HBx, HURP and anti-apoptosis effects observed in cisplatin-treated HCC cells. We observed that Hep3B cells overexpressing HBx display increased HURP mRNA and protein levels, and show resistance to cisplatin-induced apoptosis. Knockdown of HURP in HBx-expressing cells reverses this effect, and sensitizes cells to cisplatin. The anti-apoptotic effect of HBx requires activation of the p38/MAPK pathway as well as expression of SATB1, survivin and HURP. Furthermore, silencing of HURP using short-hairpin RNA promotes accumulation of p53 and reduces cell proliferation in SK-Hep-1 cells(p53^(+/–)), whereas these effects are not observed in p53-mutant Mahlavu cells. Similarly, HURP silencing does not affect the proliferation of H1299 lung carcinoma cells or Hep3 B HCC cells which lack p53. Silencing of HURP sensitizes SK-Hep-1 cells to cisplatin. While HURP overexpression promotes p53 ubiquitination and degradation by the proteasome, HURP silencing reverses these effects. Inoculation of SK-Hep-1 cancer cells in which HURP has been silenced produces smaller tumors than control in nude mice. Besides, gankyrin, a positive regulator of the E3 ubiquitin ligase MDM2, is upregulated following HURP expression, and silencing of gankyrin reduces HURP-mediated downregulation of p53. In addition, we observed a positive correlation between HURP and gankyrin protein levels in HCC patients(r^2 = 0.778; n = 9). These findings suggest a role for the viral protein HBx and the host protein HURP in preventing p53-mediated apoptosis during cancer progression and establishment of chemoresistance.
基金Supported by Chang Gung Memorial Hospital,grants Nos.CMRPD1C0812,CMRPD1C0813 and BMRP742(to Lo SJ)
文摘AIM To test whether a simple animal, Caenorhabditis elegans(C. elegans), can be used as an alternative model to study the interaction between hepatitis B virus antigens(HBs Ag) and host factors. METHODS Three plasmids that were able to express the large, middle and small forms of HBs Ags(LHBs Ag, MHBs Ag, and SHBs Ag, respectively) driven by a ubiquitous promoter(fib-1) and three that were able to express SHBs Ag driven by different tissue-specific promoters were constructed and microinjected into worms. The brood size, egglaying rate, and gonad development of transgenic worms were analyzed using microscopy. Levels of m RNA related to endoplasmic reticulum stress, enpl-1, hsp-4, pdi-3 and xbp-1, were determined using reverse transcription polymerase reaction(RT-PCRs) in three lines of transgenic worms and dithiothreitol(DTT)-treated wild-type worms. RESULTS Severe defects in egg-laying, decreases in brood size, and gonad retardation were observed in transgenic worms expressing SHBs Ag whereas moderate defects were observed in transgenic worms expressing LHBs Ag and MHBs Ag. RT-PCR analysis revealed that enpl-1, hsp-4 and pdi-3 transcripts were significantly elevated in worms expressing LHBs Ag and MHBs Ag and in wild-type worms pretreated with DTT. By contrast, only pdi-3 was increased in worms expressing SHBs Ag. To further determine which tissue expressing SHBs Ag could induce gonad retardation, we substituted the fib-1 promoter with three tissue-specific promoters(myo-2 for the pharynx, est-1 for the intestines and mec-7 for the neurons) and generated corresponding transgenic animals. Moderate defective phenotypes were observed in worms expressing SHBs Ag in the pharynx and intestines but not in worms expressing SHBs Ag in the neurons, suggesting that the secreted SHBs Ag may trigger a cross-talk signal between the digestive track and the gonad resulting in defective phenotypes. CONCLUSION Ectopic expression of three forms of HBs Ag that causes recognizable phenotypes in transgenic worms suggests that C. elegans can be used as an alternative model for studying virus-host interactions because the resulting phenotype is easily detected through microscopy.
文摘MicroRNA-22 (miR-22), a short non-coding RNA that post-transcriptionally regulates mRNA stability and protein synthesis, has been shown to enhance metastatic potential and to suppress HER-3, an important mRNA marker for non-small cell lung cancer (NSCLC). However, the effect of miR-22 has not been investigated in lung adenocarcinoma (LADC), the most common type of NSCLC in the Far East. In this study, we analyzed the role of miR-22 expression in LADC patients. Expression of miR-22 was detected by reverse-transcription polymerase chain reaction (RT-PCR), and confirmed by cDNA sequencing. Signals of miR-22 in LADC sections were identified using in situ hybridization (ISH). The association between miR-22 expression and survival was evaluated by the log-rank test. Induction of miR-22 expression and the effect on HER-3 levels, as well as the subsequent cell behavior were also investigated In vitro. Two types of miR-22: miR-22 and miR-22H, were detected by RT-PCR. The miR-22H had extra 13 bases, 5’-TGTGTTCAGTGGT-3’, at the 3’-end, and this segment was named miR-22E. Using ISH, miR-22E overexpression was detected in 225 (83.0%) of 271 LADC patients. A significant difference was found in cumulative survival between patients with high miR-22E levels and those with low miR-22E levels (p In vitro, epidermal growth factor induced miR-22, but reduced HER-3 expression. Expression of miR-22 increased cell movement ability. In conclusion, expression of miR-22 is closely associated with tumor recurrence, metastasis and overall survival in LADC patients by suppressing HER-3 protein expression to enhance epithelial-mesenchymal transition and metastasis.
文摘The persistence and performance (growth promoting potential) of green fluorescent protein (gfp) marked Azotobacter chroococcum strain ABR 4G were studied in sterilized and unsterilized wheat rhizospheric soil. The gfp was integrated via Tn 5 transposition into A. chroococcum chromosome and the resultant gfp marked colonies were identified by green fluorescent emission under UV light. The gfp was stably maintained in A. chroococcum and the gfp insertion had no apparent adverse effect on the growth promoting properties of the marked soil isolate ABR 4G. The growth promoting properties (nitrogen fixation, ammonia excretion, phosphate solubilization and IAA production) of the parent soil isolate and the gfp marked strain were found to be almost the same. All the quantitative wheat plant traits were significantly influenced by inoculation of A. chroococcum ABR 4G strain in sterilized and unsterilized soil. Inoculated bacterial counts increased gradually in wheat rhizosphere, reached maximum on 60 th d and declined on 80 th d. Fertility levels also affected survival of marked strain and the survival was comparable in sterilized and unsterilized soil. The growth promoting properties were also determined from the marked strain reisolated from wheat rhizosphere in both types of soil. Fig 1, Tab 2, Ref
文摘Colorectal cancer (CRC) is an important health issue in Taiwan. There were over ten thousand newly diagnosed CRC patients each year. The outcome of late stage CRC still remains to be improved, and tumor markers are expected to improve CRC detection and management. From a colorectal cancer cell secretome database, we chose four proteins as candidates for clinical verification, including tumor-associated calcium signal transducer 2 (TROP2, TACSTD2), transmembrane 9 superfamily member 2 (TM9SF2), and tetraspanin-6 (TSPAN6), and tumor necrosis factor receptor superfamily member 16 (NGFR). Different groups of 30 CRC patients’ tissue samples collected from Chang Gung Memorial Hospital were analyzed by immunohistochemistry (IHC) for the four proteins, and the results were scored by pathologist. For all the four candidate proteins, marked differences of IHC score existed between tumor and adjacent non-tumor counterpart. However, there were only trends between higher protein expression levels and worse outcome. Three proteins (TROP2, TM9SF2 and NGFR) had trends between higher tissue expression and tumor stage or lymph node metastasis. Our study revealed that tissue expression of four proteins (TROP2, TM9SF2, TSPAN6, and NGFR) was markedly different between tumor and adjacent non-tumor counterparts. Overexpression of all these four proteins showed some trends with poorer survival.
文摘Autophagy is a lysosome-associated,degradative process that catabolizes cytosolic components to recycle nutrients for further use and maintain cell homeostasis.Hepatitis C virus(HCV)is a major cause of chronic hepatitis,which often leads to end-stage liverassociated diseases and is a significant burden on worldwide public health.Emerging lines of evidence indicate that autophagy plays an important role in promoting the HCV life cycle in host cells.Moreover,the diverse impacts of autophagy on a variety of signaling pathways in HCV-infected cells suggest that the autophagic process is required for balancing HCVhost cell interactions and involved in the pathogenesis of HCV-related liver diseases.However,the detailed molecular mechanism underlying how HCV activates autophagy to benefit viral growth is still enigmatic.Additionally,how the autophagic response contributes to disease progression in HCV-infected cells remains largely unknown.Hence,in this review,we overview the interplay between autophagy and the HCV life cycle and propose possible mechanisms by which autophagy may promote the pathogenesis of HCVassociated chronic liver diseases.Moreover,we outline the related studies on how autophagy interplays with HCV replication and discuss the possible implications of autophagy and viral replication in the progression of HCV-induced liver diseases,e.g.,steatosis and hepatocellular carcinoma.Finally,we explore the potential therapeutics that target autophagy to cure HCV infection and its related liver diseases.
基金Supported by the grants from the Taiwan Ministry of Science and Technology(MOST 104-2622-B-037-005)Taiwan Ministry of Health and Welfare Clinical Trial Centre(MOHW107-TDU-B-212-123004)Drug Development Center,China Medical University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education(MOE)in Taiwan
文摘AIM: To test for the association between genome-wide methylation and myopia in human and mice. METHODS: Long interspersed nucleotide element 1(LINE-1) methylation levels were used to surrogate genome-wide methylation level. We first tested for the association between high myopia(<-6 D) and LINE-1 methylation in leukocytes in 220 cases and 220 control subjects. Secondly, we validated the results of LINE-1 methylation in eyes from the form deprivation myopia(FDM) mice. Furthermore,we calculated the correlation of LINE-1 methylation levels between leukocyte DNA and ocular DNA in the mice. We also tested whether dopamine can alter LINE-1 methylation levels. RESULTS: The LINE-1 methylation level was significantly higher in the myopic human subjects than controls. The upper and middle tertiles of the methylation levels increased an approximately 2-fold(P≤0.002) risk for myopia than the lower tertile. Similarly, FDM mice had high LINE-1 methylation levels in the leukocyte, retina and sclera, and furthermore the methylation levels detected from these three tissues were significantly correlated. Immunohistochemical staining revealed higher levels of homocysteine and methionine in the rodent myopic eyes than normal eyes. Dopamine treatment to the cells reduced both LINE-1 methylation and DNA methyltransferase levels. CONCLUSION: LINE-1 hypermethylation may be associated with high myopia in human and mice. Homocysteine and methionine are accumulated in myopic eyes, which may provide excess methyl group for genome-wide methylation.
基金Supported by Grants(CMRPD-1C0811)from Chang Gung Memorial Hospital,the National Science Council and the National Health Research Institute to Lo SJ
文摘Viral hepatitis remains a worldwide public health problem.The hepatitis D virus(HDV)must either coinfect or superinfect with the hepatitis B virus(HBV).HDV contains a small RNA genome(approximately 1.7 kb)with a single open reading frame(ORF)and requires HBV supplying surface antigens(HBsAgs)to assemble a new HDV virion.During HDV replication,two isoforms of a delta antigen,a small delta antigen(SDAg)and a large delta antigen(LDAg),are produced from the same ORF of the HDV genome.The SDAg is required for HDV replication,whereas the interaction of LDAg with HBsAgs is crucial for packaging of HDV RNA.Various clinical outcomes of HBV/HDV dual infection have been reported,but the molecular interaction between HBV and HDV is poorly understood,especially regarding howHBV and HDV compete with HBsAgs for assembling virions.In this paper,we review the role of endoplasmic reticulum stress induced by HBsAgs and the molecular pathway involved in their promotion of LDAg nuclear export.Because the nuclear sublocalization and export of LDAg is regulated by posttranslational modifications(PTMs),including acetylation,phosphorylation,and isoprenylation,we also summarize the relationship among HBsAg-induced endoplasmic reticulum stress signaling,LDAg PTMs,and nuclear export mechanisms in this review.
基金National Institutes of Health (CCSG CA16672)Cancer Prevention & Research Institutes of Texas (DP150052 and RP160710)+7 种基金National Breast Cancer Foundation, Inc.Breast Cancer Research Foundation (BCRF-17-069)Patel Memorial Breast Cancer Endowment FundThe University of Texas MD Anderson-China Medical University and Hospital Sister Institution FundMinistry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE MOST 105-2911-I-002-302)Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW106-TDU-B-212-144003)Center for Biological Pathways
文摘Cancer treatment in the past few years has been transformed by a new kind of therapy that targets the immune system instead of the cancer itself to reinvigorate antitumor immunity with astonishing results. However, primary and acquired resistance to this type of treatment, namely immune checkpoint blockade(ICB), continue to counter treatment efficacy. In many cases, resistance has been attributed to defective or chronically enhanced interferon signaling and/or upregulation of alternative immune checkpoints,including T-cell immunoglobulin mucin-3(Tim-3) and its ligand galactin-9(Gal-9). In this article, we briefly describe the current knowledge of common checkpoint resistance mechanisms, focusing on the Tim-3/Gal-9 pathway as an alternative checkpoint that holds great promise as another target for ICB.
文摘Objective： To investigate the inhibitory activities of norcantharidin （NCTD）, a demethylated analogue of cantharidin, on Hep3B cells （a human hepatoma cell line） with deficiency of p53. Methods： The survival rate of the Hep3B cells after treating with NCTD was measured by MTT assay. Cell cycle of treated cells was analyzed by flow cytometry, and DNA fragmentation was observed by electrophoresis. The influence of inhibitors for various caspases and anti-death receptors antibodies on the NCTD-induced apoptosis in the cells was determined. Results： NCTD treatment resulted in growth inhibition of Hep3B cells in a dose- and time-dependent manner. Cell cycle analysis of the cells after treatment with NCTD for 48 h shows that NCTD induced G2M phase arrest occursat low concentration （≤25 μ mol/L） but G0G1 phase arrest at high concentration （50 μ mol/L）. The addition of both caspase-3 and caspase-10 inhibitors completely inhibited DNA fragmentation. Addition of anti-TRAIL/DR5 antibody significantly inhibited DNA fragmentation. Conclusion： NCTD may inhibit the proliferation of Hep3B cells by arresting cell cycle at G2M or G0G1 phase, and induce cells apoptosis via TRAIL/DR5 signal transduction through activation of caspase-3 and caspase-10 by a p53-independent pathway,
基金CP Wu was supported by funds from National Science Council of Taiwan(Grant No.NSC102-2320-B-182-036)S.V.Ambudkar was supported by the Intramural Research Program of the National Institutes of Health,National Cancer Institute.National Cancer Institute,NIH,Center for Cancer Research.
文摘Melanoma is the most serious type of skin cancer and one of the most common cancers in the world.Advanced melanoma is often resistant to conventional therapies and has high potential for metastasis and low survival rates.Vemurafenib is a small molecule inhibitor of the BRAF serine-threonine kinase recently approved by the United States Food and Drug Administration to treat patients with metastatic and unresectable melanomas that carry an activating BRAF(V600E)mutation.Many clinical trials evaluating other therapeutic uses of vemurafenib are still ongoing.The ATP-binding cassette(ABC)transporters are membrane proteins with important physiological and pharmacological roles.Collectively,they transport and regulate levels of physiological substrates such as lipids,porphyrins and sterols.Some of them also remove xenobiotics and limit the oral bioavailability and distribution of many chemotherapeutics.The overexpression of three major ABC drug transporters is the most common mechanism for acquired resistance to anticancer drugs.In this review,we highlight some of the recent findings related to the effect of ABC drug transporters such as ABCB1 and ABCG2 on the oral bioavailability of vemurafenib,problems associated with treating melanoma brain metastases and the development of acquired resistance to vemurafenib in cancers harboring the BRAF(V600E)mutation.
基金Supported by China Medical University Tsuzuki Institute for Traditional Medicine(No.CMU95-PH-11 and No.CMU97-232)the National Science Council(No.NSC 95-2320-B-182-059-MY3)Chang Gung University(No.CMRPD160271),Taiwan,China
文摘Objective： To study whether the ethanol extract of Phellinus merrillii（EPM） has chemopreventive potential against liver carcinogenesis. Methods： Thirty male Spraque-Dawley rats were randomly divided into control group, EPM control group, hepatocarcinoma control group, low-dose EPM group and high-dose EPM group, 6 in each group. Using the Solt and Farber protocol in a rat model of hepatocarcinogenesis, the chemopreventive effect of EPM on diethylnitrosamine（DEN）-initiated, 2-acetylaminofluorene（2-AAF） and partial hepatectomy（PH）-promoted liver carcinogenesis in rats was evaluated. Basic pathophysiological and histological examinations, together with the serum levels of glutamic oxaloacetic transaminase（s GOT）, glutamic pyruvic transaminase（s GPT） and gamma-glutamyl transpeptidase（γ-GT） were measured. Results： Treatment of EPM at the concentration of 2 g/kg body weight in the diet for 8 weeks clearly prevented the development of carcinogenesis and reduced the levels of s GOT, s GPT, and serum γ-GT of rats as compared with the hepatocarcinoma control group（P〈0.05 or P〈0.01）. These phenotypes were accompanied by a significant increase in natural killer cell activity. Conclusion： EPM showed a strong liver preventive effect against DEN＋2-AAF＋PH-induced hepatocarcinogenesis in a rat model.
文摘“In the practice of tolerance,one’s enemy is the best teacher”.-Sayings of Buddhism.To survive an infection,two evolutionarily conserved defense strategies are required for infected host survival.One strategy in volves acquiri ng resista nee by reduci ng pathogen load via pathoge n recog nition,signaling tran sducti on pathways,and effector mechanisms.Another strategy involves increasing disease tolerance by eliciting tissue damage control mechanisms,which adjust the metabolic output of host tissue in response to different forms of stress and damage.Hence,in recent research,disease tolera nee is regarded as an in here nt comp onent of immunity,which does not exert a direct impact on pathogens but is essential to limit the health and fitness costs of infection;however,its molecular bases remain poorly understood.
文摘Objective:To extract,characterize and quantify glycosaminoglycans(GAGs)from the body of cuttlefish,tennis-ball sea cucumber,shrimp,seabass and fresh water fish Nile tilapia.Methods:The extracted crude powder was evaluated for the content of GAGs.The qualitative analysis of sulfated pattern and other important functional groups related with GAGs were explained in the form of Fourier transform infra-red spectroscopy data.Proteins and nucleic acid in the crude extract were determined by the ultraviolet spectrophotometer,while the quantification of total sulfated GAGs and estimation of N-sulfated and O-sulfated GAGs in the crude mixture were performed by using Blyscan kit.Results:The sulfated pattern and other important functional groups related with GAGs were intercepted in Fourier transform infrared analysis.Blyscan quantification method reported that a rare variety of sea cucumber(tennis-ball sea cucumber)emerged as a rich source of GAGs with high values of both N-sulfated and O-sulfated GAGs in comparison to its other counterparts.Conclusions:Findings in this study point out the potential of tennis-ball sea cucumber,a rare variety of sea cucumber to act as an alternative source for GAG extraction for commercial purpose.
文摘Foxp3＋ regulatory T cells （Tregs） are unique in their immunosuppressive abilities and contribution to immune regulation. However, the homeostatic processes and survival programs that maintain the Treg population remain unclear. Here, we highlight the recent study by Pierson et al.,1 which dissected the regulatory mechanisms of Treg home- ostasis and survival.
文摘"Practice is the hardest part of learning,and training is the essence of transformation."Ann Voskamp,One Thousand Gifts:A Dare to Live Fully Right Where YouAre Early-life exposure to environmental allergens and viral infections can lead to trained immunity and macrophage polarization resulting in an augmented type 2 immune response in allergic disorders.However,the detailed mechanism is unknown.
基金supported by the National Key Research and Development Program of China(2019YFE0120800 and 2019YFA0111600)the National Natural Science Foundation of China for Innovative Research Group Project(82221002,82130090,81874242,31800979,and 82073145)+2 种基金the Natural Science Foundation of China for Outstanding Young Scholars(82022060)the Natural Science Foundation of Hunan Province for Outstanding Young Scholars(2019JJ30040)Talent Young Scholars of Hunan Province(2019RS2009)。
文摘Melanoma,a type of skin malignancy with a high incidence and poor prognosis,is a global public health issue.The tumorigenesis and pathogenesis of melanoma involve genetic mutations,metabolic disruption,and immune evasion.Tumors undergo immune editing to escape immune surveillance,and immune escape has been identified as a critical factor in the development and progression of melanoma.
基金This work was supported by the National Key Research and Development Program of China(No.2019YFA0111600,No.2019YFE0120800)the Natural Science Foundation of China for Outstanding Young Scholars(No.82022060)+3 种基金the National Natural Science Foundation of China(No.81874242,No.31800979,No.62102455)the Natural Science Foundation of Hunan Province for Outstanding Young Scholars(No.2019JJ30040)China Postdoctoral Science Foundation(No.2020M682587)Hunan Outstanding Postdoctoral Innovative Talents Program(No.2021RC2035).
文摘Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironment(TME),but their role in immunotherapy is unclear.We performed integrative analyses including bioinformatics analysis,functional study,and clinical validation to investigate the role of SPHK1 in tumor immunity.Functionally,we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures.A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1.Preclinically,we found that anti-PD-1 monoclonal antibody(mAb)treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion.Significantly,we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients.Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis,identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment,and provided a therapeutic possibility for the treatment of melanoma patients.
基金This work was supported by grants from the Ministry of Science and Technology of Taiwan,China(MOST 106-2314-B-182A-048-MY3)Chang Gung Medical Foundation(CMRPG3B0261,CMRPG6F0601-3,and CMRPG3C121-3).
文摘The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood.In this study,vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation(CBMT)or vascularized bone marrow(VBM)transplantation from Balb/c(H2d)to C57BL/6(H2b)mice were compared.Either high-or low-dose CBMT(1.5×10^(8)or 3×10^(7)bone marrow cells,respectively)was applied.In addition,recipients were treated with costimulation blockade(1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2,respectively)and short-term rapamycin(3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks).Similar to high-dose conventional bone marrow transplantation,5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival(>120 days).In contrast,significantly shorter median survival was noted in the low-dose CBMT group(~64 days).Consistently high chimerism levels were observed in the VBM transplantation group.Notably,low levels of circulating CD4^(+)and CD8^(+)T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients(>30 days)but not in low-dose VBM transplant recipients.Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro.Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.
