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Fulltext Tryptophan metabolism-related gene expression patterns: unveiling prognostic insights and immune landscapes in uveal melanoma

Wang J, Zhao T, Li B, Wei W

Aging (Albany NY), 2023 Oct 13;15(20):11201-11216.
PMID: 37844995 DOI: 10.18632/aging.205122

Uveal melanoma (UVM) remains the leading intraocular malignancy in adults, with a poor prognosis for those with metastatic disease. Tryptophan metabolism plays a pivotal role in influencing cancerous properties and modifying the tumor's immune microenvironment. In this study, we explore the relationship between tryptophan metabolism-related gene (TRMG) expression and the various features of UVM, including prognosis and tumor microenvironment. Our analysis included 143 patient samples sourced from public databases. Using K-means clustering, we categorized UVM patients into two distinct clusters. Further, we developed a prognostic model based on five essential genes, effectively distinguishing between low-risk and high-risk patients. This distinction underscores the importance of TRMGs in UVM prognostication. Combining TRMG data with gender to create nomograms demonstrated exceptional accuracy in predicting UVM patient outcomes. Moreover, our analysis reveals correlations between risk assessments and immune cell infiltrations. Notably, the low-risk group displayed a heightened potential response to immune checkpoint inhibitors. In conclusion, our findings underscore the dynamic relationship between TRMG expression and various UVM characteristics, presenting a novel prognostic framework centered on TRMGs. The deep connection between TRMGs and UVM's tumor immune microenvironment emphasizes the crucial role of tryptophan metabolism in shaping the immune landscape. Such understanding paves the way for designing targeted immunotherapy strategies for UVM patients.
Fulltext Focal uptake at the rotator interval or inferior capsule of shoulder on18F-FDG PET/CT is associated with adhesive capsulitis

Sridharan R, Engle MP, Garg N, Wei W, Amini B

Skeletal Radiol, 2017 Apr;46(4):533-538.
PMID: 28161721 DOI: 10.1007/s00256-017-2587-8

OBJECTIVE: To determine if focal increased uptake at the rotator interval (RI) and/or inferior capsule (IC) on18F-FDG PET/CT ("positive PET") predicts the presence of adhesive capsulitis (AC).
MATERIALS AND METHODS: Three populations were retrospectively examined. Group 1 included 1,137 consecutive18F-FDG PET/CT studies and was used to determine the prevalence of focal uptake at the RI or IC. Group 2 included 361 cases from a 10-year period with18F-FDG PET/CT and MRI of shoulder performed within 45 days of each other and was used to enrich the study group. Group 3 included 109 randomly selected patients from the same time frame as groups 1 and 2 and was used to generate the control group. The study group consisted of 15 cases from the three groups, which had positive PET findings. PET/CT images were assessed in consensus by two musculoskeletal radiologists. The reference standard for a diagnosis of AC was clinical and was made by review of the medical record by a pain medicine physician.
RESULTS: The prevalence of focal activity at either the RI or IC ("positive PET") was 0.53%. Nine patients had a clinical diagnosis of AC and 15 patients had a positive PET. The sensitivity and specificity of PET for detection of AC was 56% and 87%, respectively. PET/CT had a positive likelihood ratio for AC of 6.3 (95% CI: 2.8-14.6).
CONCLUSIONS: Increased uptake at the RI or IC on PET/CT confers a moderate increase in the likelihood of AC.
Determination of cardiac disease biomarker by plasmonic sandwich ELISA

Wei W, Tang Y, He H, Gopinath SCB, Wang L

Biotechnol Appl Biochem, 2022 Feb;69(1):160-165.
PMID: 33369762 DOI: 10.1002/bab.2092

Acute myocardial infarction (AMI) is the heart attack happening when the blood flow is terminated to the heart muscles. C-reactive protein (CRP) level is raising significantly in AMI patients after the onset of symptom; also, temporal variations of CRP in plasma of AMI patient have also been found. Quantifying the concentration of CRP helps to identify the condition associated with AMI. Plasmonic enzyme-linked immunosorbent assay (ELISA) was utilized here to identify CRP by the sandwich of aptamer and antibody. Bare-eye CRP detection was achieved by plasmonic ELISA through the aggregation (blue color) of gold nanoparticle in the presence of CRP, whereas in the absence of CRP, it retains its red color (dispersion). Depending on the catalase presence on the ELISA surface, hydrogen peroxide (H2 O2 ) controls gold growth and differentiates with color changes. To achieve the lowest detection limit of CRP, H2 O2 (200 µM), gold seed (0.2 µM), and streptavidin-catalase (1:500) were found optimal. The detection limit was reached at 0.25 µg/mL, whereas it was 0.5 µg/mL in the CRP-spiked serum. This method of detection system is easier to detect the levels of CRP and helps diagnosing AMI.
Research on the application effect of cognitive stimulation therapy in patients with Alzheimer's disease based on expert consultation and semistructured interviews

Shuzhen L, Hongyan G, Wei W, Ruiying W, Mulud ZA

J Popul Ther Clin Pharmacol, 2022;29(4):e97-e106.
PMID: 36441056 DOI: 10.47750/jptcp.2022.991

The awareness and utilization of psychological therapies for Alzheimer's disease have increased significantly in recent years. Limitations on the utilization of pharmacological therapy for Alzheimer's disease in China have corresponded with this surge in greater studies in the field. For individuals who have Alzheimer's disease, cognitive stimulation therapy (CST) is a quick self-help that is founded on the theories of quality and cognitive functioning. People with Alzheimer's disease often participate in cognitive behavioral programs; however, their expense has never been studied. Being part of a meta-analysis, we analyze the application effectiveness of a CST program that is based on recent research for Alzheimer's disease patients. A CST group therapy was given to 91 Alzheimer's patients, who resided in healthcare settings or the general public, multiple times per week for 8 weeks; the other 70 people with Alzheimer's disease got a medical therapy. Costs were computed, and resource utilization was tracked for 8 weeks both before and after the therapy. It was determined by a value study. In the value study, cognition and quality of life were the major and tertiary outcomes, respectively. Contours of cost-effectiveness and acceptance were drawn. It was driven based on expert consultation and semistructured interviews. In Alzheimer's disease, CST improves intelligence and standard of living, and there was no difference in implementation expenditures between the categories. Regarding both outcome metrics, there is a significant chance that CST seems to be more expensive than conventional therapy within realistic expectations. The efficacy of CST for Alzheimer's patients is superior to conventional treatment, and it could be the greater value. The outcomes contrast well with pharmacological studies for Alzheimer's. Many people with Alzheimer's disease may benefit significantly from CST groups.
Effects of multidisciplinary collaborative nursing combined with cognitive stimulation therapy on cognitive function, quality of life, and daily activities in patients with Alzheimer's disease

Shuzhen L, Wei W, Hongyan G, Ruiying W, Mulud ZA

J Popul Ther Clin Pharmacol, 2022;29(4):e86-e96.
PMID: 36441055 DOI: 10.47750/jptcp.2022.990

Alzheimer's disease (AD) is a neurodegenerative condition that disrupts neuropsychological activity and hinders the development of mental capacity. Efficient AD therapy is a major challenge in biological studies. Alzheimer's condition cannot be cured with any particular medication. The purpose of this study is to investigate the impact of multidisciplinary collaborative nursing and cognitive stimulation therapy (MCN- CST) on daily activities, quality of life, and cognitive performance in AD patients. The inclusion/exclusion method is initially used to gather information about AD patients. Control and investigative teams were formed with its own set of functions. The control group gets a regular course of treatment, whereas, the investigation group receives MCN-CST. To ensure that our study is as practical and useful, we compare our findings to existing nursing approaches. The ANOVA and Chi-Square tests are used to assess the conditions of Alzheimer's patients. There was a scientifically significant improvement in the overall level of their medical condition after implementing MCN-CST. Nursing protocols developed MCN-CST is beneficial in improving patients' quality of life, cognitive function, and daily activities. It is encouraged to do intensive research using many samples drawn from a wider range of people.
Fulltext The impact of perceived value and affection on Chinese residents' continuous use intention of mobile health science information: An empirical study

Tian K, Hao L, Xuan W, Phongsatha T, Hao R, Wei W

Front Public Health, 2023;11:1034231.
PMID: 36844825 DOI: 10.3389/fpubh.2023.1034231

INTRODUCTION: Disseminating health science information via the internet has become an essential means for improving Chinese residents' health literacy, which has received constant attention from the Chinese government. Therefore, it is important to explore Chinese residents' perceived value and emotional response to mobile health science information for determining Chinese residents' satisfaction and use intention.
METHODS: This study applied the cognition-affect-conation model to evaluate the perceived value, arousal, pleasure, trust, satisfaction, and continuous use intention. A mobile device was used to obtain health science information from 236 Chinese residents via an online survey and the data were analyzed using partial least squares (PLS)-structural equation modeling.
RESULTS: The results showed that Chinese residents' perceived value of health science information obtained using the mobile device directly affect the degree of arousal (β = 0.412, P < 0.001), pleasure (β = 0.215, P < 0.01), and trust (β = 0.339, P < 0.001). The degree of arousal (β = 0.121, P < 0.01), pleasure (β = 0.188, P < 0.01), and trust (β = 0.619, P < 0.001) directly affected Chinese residents' satisfaction, which further affected their continuous use intention (β = 0.513, P < 0.001). Similarly, trust directly affected Chinese residents' continuous use intention (β = 0.323, P < 0.001). The degree of arousal directly affected their degree of pleasure (β = 0.304, P < 0.001), and pleasure also imposed a direct effect on trust (β = 0.293, P < 0.001).
DISCUSSION: The result of this study provided an academic and practical reference to improve mobile health science popularization information. Affective changes have imposed an important effect on Chinese residents' continuous use intention. High-quality, diversified and frequent use of health science information can significantly increase residents' continuous use intention, improving their health literacy as a consequence.
Milk fat globule membrane: composition, production and its potential as encapsulant for bioactives and probiotics

Yao D, Ranadheera CS, Shen C, Wei W, Cheong LZ

Crit Rev Food Sci Nutr, 2023 Aug 26.
PMID: 37632418 DOI: 10.1080/10408398.2023.2249992

Milk fat globule membrane (MFGM) is a complex trilayer structure present in mammalian milk and is mainly composed of phospholipids and proteins (>90%). Many studies revealed MFGM has positive effects on the immune system, brain development, and cognitive function of infants. Probiotics are live microorganisms that have been found to improve mental health and insulin sensitivity, regulate immunity, and prevent allergies. Probiotics are unstable and prone to degradation by environmental, processing, and storage conditions. In this review, the processes used for encapsulation of probiotics particularly the potential of MFGM and its constituents as encapsulating materials for probiotics are described. This study analyzes the importance of MFGM in encapsulating bioactive substances and emphasizes the interaction with probiotics and the gut as well as its resistance to adverse environmental factors in the digestive system when used as a probiotic embedding material. MFGM can enhance the gastric acid resistance and bile resistance of probiotics, mainly manifested in the survival rate of probiotics. Due to the role of digestion, MFGM-coated probiotics can be released in the intestine, and due to the biocompatibility of the membrane, it can promote the binding of probiotics to intestinal epithelial cells, and promote the colonization of some probiotics in the intestine.
[Prevalence of CYP2C19 polymorphisms involved in clopidogrel metabolism in Fujian Han population]

Wei W, Fang L, Wang N, Zhang T, Zeng JB, Lin MT

Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2012 Aug;29(4):420-5.
PMID: 22875498 DOI: 10.3760/cma.j.issn.1003-9406.2012.04.009

To investigate the frequency of CYP2C19 polymorphisms involved in clopidogrel metabolism in Fujian Han population.
Fulltext Interpretation time for screening mammography as a function of the number of computer-aided detection marks

Schwartz TM, Hillis SL, Sridharan R, Lukyanchenko O, Geiser W, Whitman GJ, et al.

J Med Imaging (Bellingham), 2020 Mar;7(2):022408.
PMID: 32042859 DOI: 10.1117/1.JMI.7.2.022408

Purpose: Computer-aided detection (CAD) alerts radiologists to findings potentially associated with breast cancer but is notorious for creating false-positive marks. Although a previous paper found that radiologists took more time to interpret mammograms with more CAD marks, our impression was that this was not true in actual interpretation. We hypothesized that radiologists would selectively disregard these marks when present in larger numbers. Approach: We performed a retrospective review of bilateral digital screening mammograms. We use a mixed linear regression model to assess the relationship between number of CAD marks and ln (interpretation time) after adjustment for covariates. Both readers and mammograms were treated as random sampling units. Results: Ten radiologists, with median experience after residency of 12.5 years (range 6 to 24) interpreted 1832 mammograms. After accounting for number of images, Breast Imaging Reporting and Data System category, and breast density, the number of CAD marks was positively associated with longer interpretation time, with each additional CAD mark proportionally increasing median interpretation time by 4.35% for a typical reader. Conclusions: We found no support for our hypothesis that radiologists will selectively disregard CAD marks when they are present in larger numbers.
An antibacterial metabolite from Lasiodiplodia pseudotheobromae F2

Wei W, Jiang N, Mei YN, Chu YL, Ge HM, Song YC, et al.

Phytochemistry, 2014 Apr;100:103-9.
PMID: 24529576 DOI: 10.1016/j.phytochem.2014.01.003

In searching for symbionts derived from bioactive natural products, six sulfureous diketopiperazines designated as lasiodiplines A-F (1-6) were characterized from the culture of Lasiodiplodia pseudotheobromae F2, previously residing in the apparently normal flower of Illigera rhodantha (Hernandiaceae). Identification of structures was accomplished by a combination of spectroscopic and computational approaches, in conjunction with the low-temperature (100K) single-crystal X-ray diffraction with Cu Kα radiation. Lasiodipline E (5) was demonstrated to be antibacterial against the clinical strains Streptococcus sp., Bacteroides vulgates, Peptostreptococcus sp. and Veillonella parvula, respectively, with an minimum inhibitory concentration (MIC) range of 0.12-0.25 μg/mL. In addition, compounds 4 and 6 exemplify two unusual architectures of natural cyclodipeptides, signifying the unique biochemical characteristics of the producing fungus.
'Candidatus Phytoplasma wodyetiae', a new taxon associated with yellow decline disease of foxtail palm (Wodyetia bifurcata) in Malaysia

Naderali N, Nejat N, Vadamalai G, Davis RE, Wei W, Harrison NA, et al.

Int J Syst Evol Microbiol, 2017 Oct;67(10):3765-3772.
PMID: 28905707 DOI: 10.1099/ijsem.0.002187

Landscape-grown foxtail palm (Wodyetia bifurcata A. K. Irvine) trees displaying symptoms of severe foliar chlorosis, stunting, general decline and mortality reminiscent of coconut yellow decline disease were observed in Bangi, Malaysia, during 2012. DNA samples from foliage tissues of 15 symptomatic palms were analysed by employing a nested PCR assay primed by phytoplasma universal ribosomal RNA operon primer pairs, P1/P7 followed by R16F2n/R2. The assay yielded amplicons of a single band of 1.25 kb from DNA samples of 11 symptomatic palms. Results from cloning and sequence analysis of the PCR-amplified 16S rRNA gene segments revealed that, in three palms, three mutually distinct phytoplasmas comprising strains related to 'Candidatus Phytoplasma asteris' and 'Candidatus Phytoplasma cynodontis', as well as a novel phytoplasma, were present as triple infections. The 16S rRNA gene sequence derived from the novel phytoplasma shared less than 96 % nucleotide sequence identity with that of each previously describedspecies of the provisional genus 'Ca. Phytoplasma', justifying its recognition as the reference strain of a new taxon, 'Candidatus Phytoplasma wodyetiae'. Virtual RFLP profiles of the R16F2n/R2 portion of the 16S rRNA gene and the pattern similarity coefficient value (0.74) supported the delineation of 'Ca. Phytoplasma wodyetiae' as the sole representative subgroup A member of a new phytoplasma ribosomal group, 16SrXXXVI.
Fulltext Methylation profiling and evaluation of demethylating therapy in renal cell carcinoma

Ricketts CJ, Morris MR, Gentle D, Shuib S, Brown M, Clarke N, et al.

Clin Epigenetics, 2013 Sep 13;5(1):16.
PMID: 24034811 DOI: 10.1186/1868-7083-5-16

BACKGROUND: Despite therapeutic advances in targeted therapy, metastatic renal cell carcinoma (RCC) remains incurable for the vast majority of patients. Key molecular events in the pathogenesis of RCC include inactivation of the VHL tumour suppressor gene (TSG), inactivation of chromosome 3p TSGs implicated in chromatin modification and remodelling and de novo tumour-specific promoter methylation of renal TSGs. In the light of these observations it can be proposed that, as in some haematological malignancies, demethylating agents such as azacitidine might be beneficial for the treatment of advanced RCC.
RESULTS: Here we report that the treatment of RCC cell lines with azacitidine suppressed cell proliferation in all 15 lines tested. A marked response to azacitidine therapy (>50% reduction in colony formation assay) was detected in the three cell lines with VHL promoter methylation but some RCC cell lines without VHL TSG methylation also demonstrated a similar response suggesting that multiple methylated TSGs might determine the response to demethylating therapies. To identify novel candidate methylated TSGs implicated in RCC we undertook a combined analysis of copy number and CpG methylation array data. Candidate novel epigenetically inactivated TSGs were further prioritised by expression analysis of RCC cell lines pre and post-azacitidine therapy and comparative expression analysis of tumour/normal pairs. Thus, with subsequent investigation two candidate genes were found to be methylated in more than 25% of our series and in the TCGA methylation dataset for 199 RCC samples: RGS7 (25.6% and 35.2% of tumours respectively) and NEFM in (25.6% and 30.2%). In addition three candidate genes were methylated in >10% of both datasets (TMEM74 (15.4% and 14.6%), GCM2 (41.0% and 14.6%) and AEBP1 (30.8% and 13.1%)). Methylation of GCM2 (P = 0.0324), NEFM (P = 0.0024) and RGS7 (P = 0.0067) was associated with prognosis.
CONCLUSIONS: These findings provide preclinical evidence that treatment with demethylating agents such as azacitidine might be useful for the treatment of advanced RCC and further insights into the role of epigenetic changes in the pathogenesis of RCC.
Correction: S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells

Vrzalikova K, Ibrahim M, Vockerodt M, Perry T, Margielewska S, Lupino L, et al.

Leukemia, 2019 Aug;33(8):2126.
PMID: 31239494 DOI: 10.1038/s41375-019-0511-z

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
[Molecular regulatory mechanisms of hypoxia-inducible factor and interventional effect of Chinese herbal medicine]

Bu-Hui L, Mei-Zi W, Wei S, Yi-Gang W, Wei WU, Qi-Jun F, et al.

Zhongguo Zhong Yao Za Zhi, 2020 Oct;45(20):4805-4811.
PMID: 33350250 DOI: 10.19540/j.cnki.cjcmm.20200630.602

Hypoxia-inducible factors(HIFs)are the key transcription factors that sense and regulate cellular oxygen concentration in vivo. HIF-1 is composed of 2 subunits,α and β,in which,the molecular regulatory mechanism of HIF-1α involves the main processes of its degradation and activation. The degradation of HIF-1α is regulated by oxygen-dependent pathways,including "von hippel-lindau protein(pVHL)-dependent pathway" and "pVHL-independent pathway". The activation of HIF-1α is regulated by oxygen-independent pathways,including mammalian target of rapamycin(mTOR)/eukaryotic initiation factor 4 E-binding protein 1(4 EBP1)/HIF-1α pathway,phosphatidylinositol 3-kinase(PI3 K)/proteirrserinc-threonine kinases(Akt)/HIF-1α pathway and silent information regulator1(Sirt1)/HIF-1α pathway. In recent years,based on the molecular regulatory mechanism of HIFs,Roxadustat,a new drug for the treatment of renal anemia has been developed. Besides, some macromolecular substances with similar pharmacological effect to HIFs have been found in the extracts from Chinese herbal medicine(CHM),such as emodin,notoginseng triterpenes,honokiol and clematichinenoside. These natural macromolecular substances play the regulatory roles in inflammatory response,epigenetic modification and auto-phagy. It is worth noting that,for common hypoxic-related diseases including diabetic kidney disease,HIFs-mediated "pyroptosis" may be a new target of CHMs for clearing dampness and heat and its representative classical prescriptions(Ermiao Pills)in treating inflammatory injury in cells and tissues.
Oncogenic effects of WNT5A in Epstein-Barr virus‑associated nasopharyngeal carcinoma

Yap LF, Ahmad M, Zabidi MM, Chu TL, Chai SJ, Lee HM, et al.

Int J Oncol, 2014 May;44(5):1774-80.
PMID: 24626628 DOI: 10.3892/ijo.2014.2342

The molecular events that drive the progression of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) are still to be elucidated. Here, we report for the first time the pathogenic significance of an NPC-associated gene, wingless-type MMTV integration site family, member 5A (WNT5A) and the contribution of EBV to its expression. WNT5A is a representative Wnt protein that activates non-canonical Wnt signalling. With regard to its role in carcinogenesis, there is conflicting evidence as to whether WNT5A has a tumour-promoting or tumour-suppressive role. We show that WNT5A is upregulated in primary NPC tissue samples. We also demonstrate that WNT5A expression was dramatically increased in NPC cell lines expressing the EBV-encoded LMP2A gene, suggesting that this EBV-encoded latent gene is responsible for upregulating WNT5A in NPC. In addition, in vitro WNT5A overexpression promotes the proliferation, migration and invasion of NPC cells. Our results not only reveal pro-tumorigenic effects of WNT5A in NPC but also suggest that WNT5A could be an important therapeutic target in patients with EBV-associated disease.
Fulltext Oncogenic S1P signalling in EBV-associated nasopharyngeal carcinoma activates AKT and promotes cell migration through S1P receptor 3

Lee HM, Lo KW, Wei W, Tsao SW, Chung GTY, Ibrahim MH, et al.

J Pathol, 2017 05;242(1):62-72.
PMID: 28240350 DOI: 10.1002/path.4879

Undifferentiated nasopharyngeal carcinoma (NPC) is a cancer with high metastatic potential that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the functional contribution of sphingosine-1-phosphate (S1P) signalling to the pathogenesis of NPC. We show that EBV infection or ectopic expression of the EBV-encoded latent genes (EBNA1, LMP1, and LMP2A) can up-regulate sphingosine kinase 1 (SPHK1), the key enzyme that produces S1P, in NPC cell lines. Exogenous addition of S1P promotes the migration of NPC cells through the activation of AKT; shRNA knockdown of SPHK1 resulted in a reduction in the levels of activated AKT and inhibition of cell migration. We also show that S1P receptor 3 (S1PR3) mRNA is overexpressed in EBV-positive NPC patient-derived xenografts and a subset of primary NPC tissues, and that knockdown of S1PR3 suppressed the activation of AKT and the S1P-induced migration of NPC cells. Taken together, our data point to a central role for EBV in mediating the oncogenic effects of S1P in NPC and identify S1P signalling as a potential therapeutic target in this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Fulltext S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells

Vrzalikova K, Ibrahim M, Vockerodt M, Perry T, Margielewska S, Lupino L, et al.

Leukemia, 2018 01;32(1):214-223.
PMID: 28878352 DOI: 10.1038/leu.2017.275

The Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.
Down-regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV-associated nasopharyngeal carcinoma

Yap LF, Velapasamy S, Lee HM, Thavaraj S, Rajadurai P, Wei W, et al.

J Pathol, 2015 Feb;235(3):456-65.
PMID: 25294670 DOI: 10.1002/path.4460

Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of NPC. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines. Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines. Our data point to a central role for EBV in mediating the oncogenic effects of LPA in NPC and identify LPA signalling as a potential therapeutic target in this disease.
Fulltext Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2

Patmanathan SN, Johnson SP, Lai SL, Panja Bernam S, Lopes V, Wei W, et al.

Sci Rep, 2016 05 10;6:25650.
PMID: 27160553 DOI: 10.1038/srep25650

Oral squamous cell carcinoma (OSCC) is a lethal disease with a 5-year mortality rate of around 50%. Molecular targeted therapies are not in routine use and novel therapeutic targets are required. Our previous microarray data indicated sphingosine 1-phosphate (S1P) metabolism and signalling was deregulated in OSCC. In this study, we have investigated the contribution of S1P signalling to the pathogenesis of OSCC. We show that the expression of the two major enzymes that regulate S1P levels were altered in OSCC: SPHK1 was significantly upregulated in OSCC tissues compared to normal oral mucosa and low levels of SGPL1 mRNA correlated with a worse overall survival. In in vitro studies, S1P enhanced the migration/invasion of OSCC cells and attenuated cisplatin-induced death. We also demonstrate that S1P receptor expression is deregulated in primary OSCCs and that S1PR2 is over-expressed in a subset of tumours, which in part mediates S1P-induced migration of OSCC cells. Lastly, we demonstrate that FTY720 induced significantly more apoptosis in OSCC cells compared to non-malignant cells and that FTY720 acted synergistically with cisplatin to induce cell death. Taken together, our data show that S1P signalling promotes tumour aggressiveness in OSCC and identify S1P signalling as a potential therapeutic target.
Fulltext Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC-subtype diffuse large B-cell lymphoma

Vockerodt M, Vrzalikova K, Ibrahim M, Nagy E, Margielewska S, Hollows R, et al.

J Pathol, 2019 06;248(2):142-154.
PMID: 30666658 DOI: 10.1002/path.5237

The Epstein-Barr virus (EBV) is found almost exclusively in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), yet its contribution to this tumour remains poorly understood. We have focused on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCLs and which can disrupt germinal centre (GC) formation and drive lymphomagenesis in mice. Comparison of the transcriptional changes that follow LMP1 expression with those that follow transient CD40 signalling in human GC B cells enabled us to define pathogenic targets of LMP1 aberrantly expressed in ABC-DLBCL. These included the down-regulation of S1PR2, a sphingosine-1-phosphate (S1P) receptor that is transcriptionally down-regulated in ABC-DLBCL, and when genetically ablated leads to DLBCL in mice. Consistent with this, we found that LMP1-expressing primary ABC-DLBCLs were significantly more likely to lack S1PR2 expression than were LMP1-negative tumours. Furthermore, we showed that the down-regulation of S1PR2 by LMP1 drives a signalling loop leading to constitutive activation of the phosphatidylinositol-3-kinase (PI3-K) pathway. Finally, core LMP1-PI3-K targets were enriched for lymphoma-related transcription factors and genes associated with shorter overall survival in patients with ABC-DLBCL. Our data identify a novel function for LMP1 in aggressive DLBCL. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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