Publications by authors named "Peiying Yang"

126 Publications

Optimal management of oligometastatic nasopharyngeal carcinoma.

Eur Arch Otorhinolaryngol 2021 Jun 5. Epub 2021 Jun 5.

Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300000, People's Republic of China.

Purpose: Oligometastatic nasopharyngeal carcinoma (NPC) is a distinctive subset of metastatic NPC. Imaging examinations and biomarkers can screen out NPC patients with limited number of sites showing metastasis. Past studies have demonstrated the survival advantages of oligometastatic NPC over multiple metastatic NPC. The treatment strategies of de-novo oligometastatic NPC differ owing to the heterogeneity of this disease. This study aims to systematically review the characteristics and treatments of oligometastatic NPC.

Methods: PubMed, EMBASE, the Web of Science, and the Cochrane Library were used to search for publications with an emphasis on oligometastatic NPC.

Results: We have presented the current advances on the management of oligometastatic NPC, including the definition, diagnosis, biomarkers, classification, prognosis, subtype, especially systematic therapy, locoregional radiotherapy to the primary tumor, and treatments of the metastatic lesions.

Conclusions: More well-designed prospective clinical trials that are exclusive for oligometastatic NPC are warranted to determine the best treatment paradigm.
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http://dx.doi.org/10.1007/s00405-021-06918-yDOI Listing
June 2021

Neonatal screening and genotype-phenotype correlation of hyperphenylalaninemia in the Chinese population.

Orphanet J Rare Dis 2021 May 12;16(1):214. Epub 2021 May 12.

Genetic Medicine Center, Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, 123 Tianfei St., Qinhuai District, Nanjing, 210004, People's Republic of China.

Background: Hyperphenylalaninemia (HPA) is the most common amino acid metabolic disease involving phenylalanine hydroxylase (PAH, OMIM*612,349) deficiency or coenzyme tetrahydrobiopterin (BH4) deficiency. Patients with severe HPA often have a difficult life. Early diagnosis of HPA before the development of symptoms is possible via neonatal screening, facilitating appropriate treatment and reducing mortality and disability rates. This study revealed the prevalence, mutational and phenotypic spectrum, and prognosis of HPA by neonatal screening from January 2001 to September 2020 in Nanjing, Jiangsu Province, China.

Methods: Through a retrospective analysis of the information available in the neonatal screening database, the clinical presentations, laboratory data, molecular characteristics and treatment follow-up data of HPA patients detected by neonatal screening were evaluated.

Results: We diagnosed 181 patients with HPA from 1 to 957 newborns, giving an incidence of 1:6873. Among these patients, 177 were identified as PAH deficient and four patients were BH4 deficient. The average current age of the patients was 6.38 years old. The most common mutations of PAH were c.728 C > A/ p.Arg243Gln (13.83 %), c.158G > A/ p.Arg53His (9.57 %), c.611 A > G/ p.Tyr204Cys (7.44 %), and c.721 C > T/ p.Arg241Cys (6.38 %).

Conclusions: This study revealed the prevalence, phenotype-genotype, and prognosis of HPA in China and contributes to the updating of PAHD data for China and worldwide. Our study not only expanded the spectrum of phenotypes and genotype but also provided a valuable tool for improved genetic counseling and management of future cases.
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http://dx.doi.org/10.1186/s13023-021-01846-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114530PMC
May 2021

Mistletoe Extract Viscum Fraxini-2 for Treatment of Advanced Hepatocellular Carcinoma: A Case Series.

Case Rep Oncol 2021 Jan-Apr;14(1):224-231. Epub 2021 Mar 1.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of death from cancer worldwide, and for advanced HCC the prognosis is poor. Preliminary studies indicate mistletoe extracts may have anticancer activity for HCC.

Methods: A prospective observational case series of advanced HCC patients that chose to take a mistletoe extract called viscum fraxini-2 (VF-2) alone for treatment. Time on treatment, imaging, and laboratory values were collected for descriptive analyses.

Results: A total of 12 patients with advanced HCC enrolled onto the protocol, and 10 patients had data available for evaluation. The majority were male (10/12) with a median age of 64 (SD 11). Most patients had received sorafenib therapy (9/12) and had varying Child-Pugh classes (A-4, B-6, C-2). Treatment with VF-2 ranged from 1 to 36 weeks with a mean of 12.3 weeks (SD 12). Six patients received 8 weeks of treatment, and 3 patients received 12 or more weeks of treatment. For patients that received at least 4 weeks of treatment, the average AFP value stabilized during the first 4 weeks of treatment. Two patients experienced an AFP decrease of >30%, approximately 37 and 40% decreases at the nadir. One patient had stable disease of 9 months. Major side effects were fever, fatigue, rash, and local injection site reaction of swelling, redness, and tenderness.

Conclusion: This case series of advanced HCC indicates that mistletoe extract VF-2 may have potential biological activity against HCC for selected patients. Research is needed to identify the active compound and predictive markers of response.
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http://dx.doi.org/10.1159/000511566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983630PMC
March 2021

Neonatal Screening and Genotype-Phenotype Correlation of 21-Hydroxylase Deficiency in the Chinese Population.

Front Genet 2020 22;11:623125. Epub 2021 Jan 22.

Genetic Medicine Center, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway that leads to impaired cortisol biosynthesis. 21-hydroxylase deficiency (21-OHD) is the most common type of CAH. Severe cases of 21-OHD may result in death during the neonatal or infancy periods or sterility in later life. The early detection and timely treatment of 21-OHD are essential. This study aimed to summarize the clinical and genotype characteristics of 21-OHD patients detected by neonatal screening in Nanjing, Jiangsu province of China from 2000 to 2019. Through a retrospective analysis of medical records, the clinical presentations, laboratory data, and molecular characteristics of 21-OHD patients detected by neonatal screening were evaluated. Of the 1,211,322 newborns who were screened, 62 cases were diagnosed with 21-OHD with an incidence of 1:19858. 58 patients were identified with the classical salt-wasting type (SW) 21-OHD and four patients were identified with simple virilizing type (SV) 21-OHD. Amongst these patients, 19 cases patients accepted genetic analysis, and another 40 cases were received from other cities in Eastern China. Eighteen different variants were found in the gene. The most frequent variants was c.293-13A/C>G (36.29%). The most severe clinical manifestations were caused by large deletions or conversions of . This study suggested that neonatal screening effectively leads to the early diagnosis of 21-OHD and reduces fatal adrenal crisis. Our data provide additional information on the occurrence and genotype-phenotype correlation of 21-OHD in the Chinese population which can be used to better inform treatment and improve prognosis.
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http://dx.doi.org/10.3389/fgene.2020.623125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862715PMC
January 2021

Molecular mechanisms of astragaloside‑IV in cancer therapy (Review).

Int J Mol Med 2021 03 15;47(3). Epub 2021 Jan 15.

Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300380, P.R. China.

Radix Astragali (RA) is widely used in traditional Chinese medicine (TCM), and astragaloside IV (AS‑IV) is the most critical component of RA. Previous studies have demonstrated that AS‑IV exerts effects on the myocardium, nervous system and endocrine system, among others. In the present review article, data from studies conducted over the past 20 years were collated, which have evaluated the effects of AS‑IV on tumors. The mechanisms of action of AS‑IV on malignant cells both and were summarized and it was demonstrated that AS‑IV plays a vital role, particularly in inhibiting tumor growth and metastasis, promoting the apoptosis of tumor cells, enhancing immune function and preventing drug resistance. Moreover, AS‑IV controls several epithelial‑mesenchymal transformation (EMT)‑related and autophagy‑related pathways, such as the phosphoinositide‑3‑kinase (PI3K)/protein kinase B (AKT), Wnt/β‑catenin, mitogen‑activated protein kinase (MAPK)/extracellular regulated protein kinase (ERK) and transforming growth factor‑β (TGF‑β)/SMAD signaling pathways, which are commonly affected in the majority of tumors. The present review provides new perspectives on the functions of AS‑IV and its role as an adjuvant treatment in cancer chemotherapy.
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http://dx.doi.org/10.3892/ijmm.2021.4846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834967PMC
March 2021

The Botanical Drug PBI-05204, a Supercritical CO Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties.

Front Pharmacol 2020 11;11:552428. Epub 2020 Sep 11.

Laboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.

Glioblastoma multiform (GBM) is the most common primary glial tumor resulting in very low patient survival despite current extensive therapeutic efforts. Emerging evidence suggests that more effective treatments are required to overcome tumor heterogeneity, drug resistance and a complex tumor-supporting microenvironment. PBI-05204 is a specifically formulated botanical drug consisting of a modified supercritical C0 extract of that has undergone both phase I and phase II clinical trials in the United States for treatment of patients with a variety of advanced cancers. The present study was designed to investigate the antitumor efficacy of this botanical drug against glioblastoma using both and cancer models as well as exploring efficacy against glioblastoma stem cells. All three human GBM cell lines, U87MG, U251, and T98G, were inhibited by PBI-05204 in a concentration dependent manner that was characterized by induction of apoptosis as evidenced by increased ANNEXIN V staining and caspase activities. The expression of proteins associated with both Akt and mTOR pathway was suppressed by PBI-05240 in all treated human GBM cell lines. PBI-05204 significantly suppressed U87 spheroid formation and the expression of important stem cell markers such as SOX2, CD44, and CXCR4. Oral administration of PBI-05204 resulted in a dose-dependent inhibition of U87MG, U251, and T98G xenograft growth. Additionally, PBI-05204-treated mice carrying U87-Luc cells as an orthotropic model exhibited significantly delayed onset of tumor proliferation and significantly increased overall survival. Immunohistochemical staining of xenograft derived tumor sections revealed dose-dependent declines in expression of Ki67 and CD31 positive stained cells but increased TUNEL staining. PBI-05204 represents a novel therapeutic botanical drug approach for treatment of glioblastoma as demonstrated by significant responses with tumor models. Both cell culture and immunohistochemical studies of tumor tissue suggest drug induction of tumor cell apoptosis and inhibition of PI3k/mTOR pathways as well as cancer stemness. Given the fact that PBI-05204 has already been examined in phase I and II clinical trials for cancer patients, its efficacy when combined with standard of care chemotherapy and radiotherapy should be explored in future clinical trials of this difficult to treat brain cancer.
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http://dx.doi.org/10.3389/fphar.2020.552428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516200PMC
September 2020

Human Biofield Therapy Modulates Tumor Microenvironment and Cancer Stemness in Mouse Lung Carcinoma.

Integr Cancer Ther 2020 Jan-Dec;19:1534735420940398

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Studies have demonstrated that purported biofield therapy emitted from humans can inhibit the proliferation of cancer cells and suppress tumor growth in various cancers. We explored the effects of biofield therapy on tumor growth in the Lewis lung carcinoma and expanded mechanistic outcomes. We found biofield therapy did not inhibit tumor growth. However, the experimental (Ex) condition exposed tumors had a significantly higher percentage of necrosis (24.4 ± 6.8%) compared with that of the Control condition (6.5 ± 2.7%; < .02) and cleaved caspase-3 positive cells were almost 2.3-fold higher ( < .05). Similarly, tumor-infiltrating lymphocytes profiling showed that CD8+/CD45+ immune cell population was significantly increased by 2.7-fold in Ex condition ( < .01) whereas the number of intratumoral FoxP3+/CD4+ (T-reg cells) was 30.4% lower than that of the Control group ( = .01), leading to a significant 3.1-fold increase in the ratio of CD8+/T-reg cells ( < .01). Additionally, there was a 51% lower level of strongly stained CD68+ cells ( < .01), 57.9% lower level of F4/80high/CD206+ (M2 macrophages; < .02) and a significant 1.8-fold increase of the ratio of M1/M2 macrophages ( < .02). Furthermore, Ex exposure resulted in a 15% reduction of stem cell marker CD44 and a significant 33% reduction of SOX2 compared with that of the Controls ( < .02). The Ex group also engaged in almost 50% less movement throughout the session than the Controls. These findings suggest that exposure to purported biofields from a human is capable of enhancing cancer cell death, in part mediated through modification of the tumor microenvironment and stemness of tumor cells in mouse Lewis lung carcinoma model. Future research should focus on defining the optimal treatment duration, replication with different biofield therapists, and exploring the mechanisms of action.
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http://dx.doi.org/10.1177/1534735420940398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522816PMC
September 2020

Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development.

BMC Cancer 2020 Sep 10;20(1):871. Epub 2020 Sep 10.

Departments of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid.

Methods: As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apc mice with the NSAID sulindac, with and without phosphatidylcholine (PC) for 3-weeks. At the end of the treatment period, we evaluated polyp burden, gastric toxicity, urinary prostaglandins (as a marker of sulindac target engagement), and blood chemistries.

Results: Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone.

Conclusions: Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.
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http://dx.doi.org/10.1186/s12885-020-07311-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488444PMC
September 2020

Suppression of Membranous LRP5 Recycling, Wnt/β-Catenin Signaling, and Colon Carcinogenesis by 15-LOX-1 Peroxidation of Linoleic Acid in PI3P.

Cell Rep 2020 08;32(7):108049

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

APC mutation activation of Wnt/β-catenin drives initiation of colorectal carcinogenesis (CRC). Additional factors potentiate β-catenin activation to promote CRC. Western diets are enriched in linoleic acid (LA); LA-enriched diets promote chemically induced CRC in rodents. 15-Lipoxygenase-1 (15-LOX-1), the main LA-metabolizing enzyme, is transcriptionally silenced during CRC. Whether LA and 15-LOX-1 affect Wnt/β-catenin signaling is unclear. We report that high dietary LA promotes CRC in mice treated with azoxymethane or with an intestinally targeted Apc mutation (Apc) by upregulating Wnt receptor LRP5 protein expression and β-catenin activation. 15-LOX-1 transgenic expression in mouse intestinal epithelial cells suppresses LRP5 protein expression, β-catenin activation, and CRC. 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) leads to PI3P_13-HODE formation, which decreases PI3P binding to SNX17 and LRP5 and inhibits LRP5 recycling from endosomes to the plasma membrane, thereby increasing LRP5 lysosomal degradation. This regulatory mechanism of LRP5/Wnt/β-catenin signaling could be therapeutically targeted to suppress CRC.
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http://dx.doi.org/10.1016/j.celrep.2020.108049DOI Listing
August 2020

Ring finger protein 180 is associated with biological behavior and prognosis in patients with non-small cell lung cancer.

Oncol Lett 2020 Oct 22;20(4):35. Epub 2020 Jul 22.

Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300000, P.R. China.

There are few studies on the role of ring finger protein (RNF)180 in non-small cell lung cancer (NSCLC). The present study investigated the expression of RNF180 in NSCLC and its associations with the clinical factors and prognosis of NSCLC. The mRNA and protein expression levels of RNF180 were detected via reverse transcription-quantitative PCR and western blotting. Methylation-specific PCR (MSP) analysis was utilized to detect the methylation of RNF180. RNF180 expression levels were analyzed via immunohistochemistry. The protein and mRNA expression levels of RNF180 were lower in NSCLC cell lines compared with in the non-tumor cell line. Immunohistochemistry revealed that 64 patients that were negative for RNF180, while MSP detection analysis demonstrated that 60 patients exhibited RNF180 promoter methylation. The methylation status of RNF180 was significantly associated with RNF180 expression level. Among all factors evaluated, logistic regression analysis indicated that only T stage was significantly associated with RNF180 expression. Cox multivariate analysis demonstrated that RNF180 expression was an independent predictor of overall survival in patients with NSCLC. Methylation in the promoter of RNF180 was shown to reduce its expression levels. In summary, low RNF180 expression levels were associated with poor biological behaviors, thus RNF180 expression level may be used as a clinical marker to predict the prognosis of patients with NSCLC.
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http://dx.doi.org/10.3892/ol.2020.11898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412726PMC
October 2020

Clinical research linking Traditional Chinese Medicine constitution types with diseases: a literature review of 1639 observational studies.

J Tradit Chin Med 2020 08;40(4):690-702

Center for Studies in Constitution Research and Reproductive Sciences of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.

Objective: To analyze clinical studies on correlations between Traditional Chinese Medicine (TCM) body constitution types and diseases published in the past 10 years, and to provide an evidence base to support the use of such correlations for health maintenance and disease prevention.

Methods: We searched five databases for the period April 2009 to December 2019: China National Knowledge Infrastructure Database, Wanfang Database, China Science and Technology Journal Database, PubMed and Embase. Three types of observational studies on correlation between constitution types and diseases were included: cross-sectional, case-control and cohort studies. Descriptive statistical methods were employed for data analysis.

Results: A total of 1639 clinical studies were identified: 1452 (88.59%) cross-sectional studies, 115 (7.02%) case-control studies and 72 (4.39%) cohort studies covering 30 regions of China and five other countries (Malaysia, South Korea, Singapore, Thailand and France). The collection of studies comprised 19 disease categories and 333 different diseases. The 10 most commonly studied diseases were hypertension, diabetes, stroke, coronary atherosclerotic heart disease (CAHD), sleep disorders, neoplasm of the breast, dysmenorrhea, fatty liver disease, chronic viral hepatitis B and dyslipidemia. We found high distributions for each biased constitution type in different patient populations as follows: Qi-deficiency constitution in stroke, diabetes, chronic obstructive pulmonary disease, acquired immunodeficiency syndrome and hypertension; Yang-deficiency constitution in female infertility, osteoporosis, irritable bowel syndrome, gonarthrosis and dysmenorrhea; Yin-deficiency constitution in hypertension, diabetes, constipation, female climacteric states and osteoporosis; phlegm- dampness constitution in hypertension, stroke, fatty liver disease, diabetes and metabolic syndrome; damp-heat constitution in acne, chronic gastritis, chronic viral hepatitis B, human papillomavirus infection and hyperuricemia; blood-stasis constitution in CAHD, endometriosis and stroke; Qi-stagnation constitution in hyperplasia and neoplasms of the breast, insomnia, depression and thyroid nodules; and inherited-special constitution in asthma and allergic rhinitis.

Conclusion: Eight biased TCM constitutions were closely related to specific diseases, and could be used to guide individualized prevention and treatment. More rigorously designed studies are recommended to further verify the constitution-disease relationship.
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http://dx.doi.org/10.19852/j.cnki.jtcm.2020.04.019DOI Listing
August 2020

magnetic resonance imaging of orthotopic prostate cancer.

Biotechniques 2020 07 2;69(1):395-403. Epub 2020 May 2.

Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030, USA.

Methods for imaging orthotopic prostate tumors within the prostate or small tumors with extension outside the prostate are needed to more closely model human prostate tumors, which are most commonly located within the gland or may extend just through the gland. By comparing MR sequences, we found that the T2-based Dixon 'water only' sequence best visualized tumors within the prostate of mouse models in both young and old mice and that tumor weight derived from this sequence correlated highly with tumor weight (r = 0.98, p < 0.001, n = 12). This should aid tumor detection, margin delineation and evaluation of tumor burden to enable studies including, but not limited to, evaluating the natural history of the disease, the mechanisms of action and the efficacy of therapeutic interventions.
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http://dx.doi.org/10.2144/btn-2020-0021DOI Listing
July 2020

Low expression of RGL4 is associated with a poor prognosis and immune infiltration in lung adenocarcinoma patients.

Int Immunopharmacol 2020 Jun 4;83:106454. Epub 2020 Apr 4.

Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China. Electronic address:

Lung adenocarcinoma (LUAD) is a frequently diagnosed histologic subtype with increasing morbidity and mortality. RalGDS-Like 4 (RGL4) has not been reported to be associated with cancer risk, prognosis, immunotherapy or any other treatments. We perform a bioinformatics analysis on data downloaded from the Cancer Genome Atlas (TCGA)-LUAD, and we find that low expression of RGL4 is accompanied by worse outcomes and prognosis in LUAD patients. As a promising predictor, the potential influence and mechanisms of RGL4 on overall survival are worth exploring. Moreover, RGL4 expression is significantly associated with a variety of tumor-infiltrating immune cells (TIICs), particularly memory B cells, CD8T cells and neutrophils. Subsequently, we evaluated the most notable KEGG pathways, including glycolysis gluconeogenesis, the P53 signaling pathway, RNA degradation, and the B cell receptor signaling pathway, among others. Our findings provide evidence that the decreased expression of RGL4 is significantly associated with poor prognosis and immune cell infiltration in patients with LUAD and highlight the use of RGL4 as a novel predictive biomarker for the prognosis of LUAD and other cancers. RGL4 may also be used in combination with immune checkpoints to identify the benefits of immunotherapy. Subjects: Bioinformatics, Genomics, Oncology, Thoracic surgery.
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http://dx.doi.org/10.1016/j.intimp.2020.106454DOI Listing
June 2020

Carrier Screening and Prenatal Diagnosis for Spinal Muscular Atrophy in 13,069 Chinese Pregnant Women.

J Mol Diagn 2020 06 20;22(6):817-822. Epub 2020 Mar 20.

Department of Prenatal Diagnosis, Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, People's Republic of China.

Spinal muscular atrophy (SMA) is a relatively common, life-shortening, autosomal recessive neuromuscular disease. The carrier frequency of SMA ranges from approximately 0.98% to 2.02%, depending on ethnicity. The American College of Medical Genetics has therefore recommended population screening for SMA carrier status, regardless of race or ethnicity. We performed the largest-scale carrier screening for SMA carriers in mainland China. Carrier screening was offered to 36,470 pregnant women between July 2017 and June 2019, of whom 13,069 women accepted the screening program [35.83%; 95% credibility interval (CI), 35.34%-36.33%]. Copy numbers of exons 7 and 8 in the SMN1 gene were detected by real-time quantitative PCR, and the results were confirmed by multiplex ligation-dependent probe amplification. A total of 231 women were identified as carriers (1.77%; 95% CI, 1.56%-2.01%), indicating a carrier prevalence of approximately 1:56 in the population. After detailed genetic counseling, 207 paternal partners were recalled and tested. Both partners were carriers in 10 couples, of whom prenatal diagnosis was implemented in seven, and one fetus was diagnosed with SMA. Carrier screening could provide couples with informed reproductive choices. Our workflow and experience of carrier screening may facilitate the popularization of SMA carrier screening in mainland China.
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http://dx.doi.org/10.1016/j.jmoldx.2020.03.001DOI Listing
June 2020

Effect of True and Sham Acupuncture on Radiation-Induced Xerostomia Among Patients With Head and Neck Cancer: A Randomized Clinical Trial.

JAMA Netw Open 2019 12 2;2(12):e1916910. Epub 2019 Dec 2.

Department of Palliative, Rehabilitation, and Integrative Medicine, University of Texas MD Anderson Cancer Center, Houston.

Importance: Radiation-induced xerostomia (RIX) is a common, often debilitating, adverse effect of radiation therapy among patients with head and neck cancer. Quality of life can be severely affected, and current treatments have limited benefit.

Objective: To determine if acupuncture can prevent RIX in patients with head and neck cancer undergoing radiation therapy.

Design, Setting, And Participants: This 2-center, phase 3, randomized clinical trial compared a standard care control (SCC) with true acupuncture (TA) and sham acupuncture (SA) among patients with oropharyngeal or nasopharyngeal carcinoma who were undergoing radiation therapy in comprehensive cancer centers in the United States and China. Patients were enrolled between December 16, 2011, and July 7, 2015. Final follow-up was August 15, 2016. Analyses were conducted February 1 through 28, 2019.

Intervention: Either TA or SA using a validated acupuncture placebo device was performed 3 times per week during a 6- to 7-week course of radiation therapy.

Main Outcomes And Measures: The primary end point was RIX, as determined by the Xerostomia Questionnaire in which a higher score indicates worse RIX, for combined institutions 1 year after radiation therapy ended. Secondary outcomes included incidence of clinically significant xerostomia (score >30), salivary flow, quality of life, salivary constituents, and role of baseline expectancy related to acupuncture on outcomes.

Results: Of 399 patients randomized, 339 were included in the final analysis (mean [SD] age, 51.3 [11.7] years; age range, 21-79 years; 258 [77.6%] men), including 112 patients in the TA group, 115 patients in the SA group, and 112 patients in the SCC group. For the primary aim, the adjusted least square mean (SD) xerostomia score in the TA group (26.6 [17.7]) was significantly lower than in the SCC group (34.8 [18.7]) (P = .001; effect size = -0.44) and marginally lower but not statistically significant different from the SA group (31.3 [18.6]) (P = .06; effect size = -0.26). Incidence of clinically significant xerostomia 1 year after radiation therapy ended followed a similar pattern, with 38 patients in the TA group (34.6%), 54 patients in the SA group (47.8%), and 60 patients in the SCC group (55.1%) experiencing clinically significant xerostomia (P = .009). Post hoc comparisons revealed a significant difference between the TA and SCC groups at both institutions, but TA was significantly different from SA only at Fudan University Cancer Center, Shanghai, China (estimated difference [SE]: TA vs SCC, -9.9 [2.5]; P < .001; SA vs SCC, -1.7 [2.5]; P = .50; TA vs SA, -8.2 [2.5]; P = .001), and SA was significantly different from SCC only at the University of Texas MD Anderson Cancer Center, Houston, Texas (estimated difference [SE]: TA vs SCC, -8.1 [3.4]; P = .016; SA vs SCC, -10.5 [3.3]; P = .002; TA vs SA, 2.4 [3.2]; P = .45).

Conclusions And Relevance: This randomized clinical trial found that TA resulted in significantly fewer and less severe RIX symptoms 1 year after treatment vs SCC. However, further studies are needed to confirm clinical relevance and generalizability of this finding and to evaluate inconsistencies in response to sham acupuncture between patients in the United States and China.

Trial Registration: ClinicalTrials.gov identifier: NCT01266044.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.16910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902763PMC
December 2019

[Analysis of AGR1 gene variants in an infant with early-onset argininemia].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Oct;36(10):996-998

Genetic Medicine Center, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University (Nanjing Maternal and Child Health Hospital), Nanjing, Jiangsu 210004, China.

Objective: To explore the genetic basis for an infant with early-onset argininemia.

Methods: Potential variant was detected with an Ion Torrent semiconductor sequencer using a gene panel for inherited diseases. Suspected variants were verified by Sanger sequencing.

Results: Genetic testing indicated that he has carried c.560+2T>C and c.811T>C compound heterozygous variant of the AGR1 gene, which were inherited from his father and mother, respectively. Among these, c.560+2T>C was suspected to be pathogenic, while c.811T>C was of unknown clinical significance, and both were not reported previously.

Conclusion: The c.560+2T>C and c.811T>C compound heterozygous variants of the AGR1 gene probably underlies the argininemia in this child. Above finding has enriched the variant spectrum of the AGR1 gene.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.10.011DOI Listing
October 2019

Furanoic Lipid F-6, A Novel Anti-Cancer Compound that Kills Cancer Cells by Suppressing Proliferation and Inducing Apoptosis.

Cancers (Basel) 2019 Jul 9;11(7). Epub 2019 Jul 9.

Program in Translational Medicine, Peter Gilgan Centre for Research and Learning (PGCRL), The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Identifying novel anti-cancer drugs is important for devising better cancer treatment options. In a series of studies designed to identify novel therapeutic compounds, we recently showed that a C-20 fatty acid (12,15-epoxy-13,14-dimethyleicosa-12,14-dienoic acid, a furanoic acid or F-6) present in the lipid fraction of the secretions of the Arabian Gulf catfish skin (; AGCS) robustly induces neutrophil extracellular trap formation. Here, we demonstrate that a lipid mix (Ft-3) extracted from AGCS and F-6, a component of Ft-3, dose dependently kill two cancer cell lines (leukemic K-562 and breast MDA MB-231). Pure F-6 is approximately 3.5 to 16 times more effective than Ft-3 in killing these cancer cells, respectively. Multiplex assays and network analyses show that F-6 promotes the activation of MAPKs such as Erk, JNK, and p38, and specifically suppresses JNK-mediated c-Jun activation necessary for AP-1-mediated cell survival pathways. In both cell lines, F-6 suppresses PI3K-Akt-mTOR pathway specific proteins, indicating that cell proliferation and Akt-mediated protection of mitochondrial stability are compromised by this treatment. Western blot analyses of cleaved caspase 3 (cCasp3) and poly ADP ribose polymerase (PARP) confirmed that F-6 dose-dependently induced apoptosis in both of these cell lines. In 14-day cell recovery experiments, cells treated with increasing doses of F-6 and Ft-3 fail to recover after subsequent drug washout. In summary, this study demonstrates that C-20 furanoic acid F-6, suppresses cancer cell proliferation and promotes apoptotic cell death in leukemic and breast cancer cells, and prevents cell recovery. Therefore, F-6 is a potential anti-cancer drug candidate.
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http://dx.doi.org/10.3390/cancers11070960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678287PMC
July 2019

Quxie Capsule Inhibits Colon Tumor Growth Partially Through Foxo1-Mediated Apoptosis and Immune Modulation.

Integr Cancer Ther 2019 Jan-Dec;18:1534735419846377

2 The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Quxie capsule (QX), a herbal remedy used in traditional Chinese medicine, is routinely used in advanced colorectal cancer treatment in Xiyuan Hospital in Beijing, China. However, the mechanism(s) underlying the effect of QX in colorectal cancer remain unclear, which hampers the optimal use of QX for the treatment of the disease. The transcription factor forkhead box O1 (Foxo1) plays important roles in regulation of cell cycle, apoptosis, and immune response in various cancers. In this study, we examined the antitumor efficacy of QX in a mouse model of colorectal cancer and further investigated the mechanism by which QX regulated Foxo1 protein-mediated pathways. QX administered via gavage daily for 2 weeks in mice carrying CT26 mouse colon tumors resulted in significantly lower mean tumor weight (0.93 ± 0.32 g) compared with that in vehicle control-treated mice (1.57 ± 0.57 g, P <.05). Foxo1 protein expression in tumors was also higher in the QX group than that in the vehicle control group. Furthermore, QX treatment upregulated apoptotic proteins such as Fas, Bim, and cleaved caspase-3 in tumor tissue compared with those in the vehicle control group. Intriguingly, the ratios of Th1/Th2 and Th17/Treg cells and levels of T-bet protein (the key regulator of Th1 and Th2 cells) were higher while the level of Foxp3 (the key regulator of Treg cells) was lower in QX-treated mice compared to vehicle control mice, revealing that Foxo1 upregulated T-bet and downregulated Foxp3 and induced a shift in immune balance. This shift could be critical in the antitumor efficacy of QX. Furthermore, knocking down Foxo1 in human colon cancer HCT116 cells partially blocked the effect of QX-elicited antiproliferative activity. Together, these results suggest that QX exerts antitumor activity in CT26 mouse colon cancer model partially mediated by Foxo1-induced apoptosis and antitumor immune response.
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http://dx.doi.org/10.1177/1534735419846377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488785PMC
December 2019

Mistletoe extract Fraxini inhibits the proliferation of liver cancer by down-regulating c-Myc expression.

Sci Rep 2019 04 23;9(1):6428. Epub 2019 Apr 23.

Department of Medicine, Case Western Reserve University & University Hospitals, Cleveland, Ohio, USA.

Mistletoe (Viscum album) is a type of parasitic plant reported to have anticancer activity including in hepatocellular carcinoma (HCC). However, the mechanism of mistletoe's anticancer activity, and its effectiveness in treating HCC are not fully understood. We report here that mistletoe extracts, including Fraxini (grown on ash trees) and Iscador Q and M (grown on oak and maple trees), exert strong antiproliferative activity in Hep3B cells, with median inhibitory concentrations (IC) of 0.5 µg/mL, 7.49 µg/mL, and 7.51 µg/mL, respectively. Results of Reversed Phase Proteomic Array analysis (RPPA) suggests that Fraxini substantially down-regulates c-Myc expression in Hep3B cells. Fraxini-induced growth inhibition (at a concentration of 1.25 μg/ml) was less pronounced in c-Myc knockdown Hep3B cells than in control cells. Furthermore, in the Hep3B xenograft model, Fraxini-treated (8 mg/kg body weight) mice had significantly smaller tumors (34.6 ± 11.9 mm) than control mice (161.6 ± 79.4 mm, p < 0.036). Similarly, c-Myc protein expression was reduced in Fraxini treated Hep3B cell xenografts compared to that of control mice. The reduction of c-Myc protein levels in vitro Hep3B cells appears to be mediated by the ubiquitin-proteasome system. Our results suggest the importance of c-Myc in Fraxini's antiproliferative activity, which warrants further investigation.
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http://dx.doi.org/10.1038/s41598-019-41444-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478697PMC
April 2019

Human Biofield Therapy and the Growth of Mouse Lung Carcinoma.

Integr Cancer Ther 2019 Jan-Dec;18:1534735419840797

1 The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Biofield therapies have gained popularity and are being explored as possible treatments for cancer. In some cases, devices have been developed that mimic the electromagnetic fields that are emitted from people delivering biofield therapies. However, there is limited research examining if humans could potentially inhibit the proliferation of cancer cells and suppress tumor growth through modification of inflammation and the immune system. We found that human NSCLC A549 lung cancer cells exposed to Sean L. Harribance, a purported healer, showed reduced viability and downregulation of pAkt. We further observed that the experimental exposure slowed growth of mouse Lewis lung carcinoma evidenced by significantly smaller tumor volume in the experimental mice (274.3 ± 188.9 mm) than that of control mice (740.5 ± 460.2 mm; P < .05). Exposure to the experimental condition markedly reduced tumoral expression of pS6, a cytosolic marker of cell proliferation, by 45% compared with that of the control group. Results of reversed phase proteomic array suggested that the experimental exposure downregulated the PD-L1 expression in the tumor tissues. Similarly, the serum levels of cytokines, especially MCP-1, were significantly reduced in the experimental group ( P < .05). Furthermore, TILs profiling showed that CD8/CD4 immune cell population was increased by almost 2-fold in the experimental condition whereas the number of intratumoral CD25/CD4 (T-reg cells) and CD68 macrophages were 84% and 33%, respectively, lower than that of the control group. Together, these findings suggest that exposure to purported biofields from a human is capable of suppressing tumor growth, which might be in part mediated through modification of the tumor microenvironment, immune function, and anti-inflammatory activity in our mouse lung tumor model.
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http://dx.doi.org/10.1177/1534735419840797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475842PMC
December 2019

Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux.

Oncogene 2019 03 20;38(12):2135-2150. Epub 2018 Nov 20.

Section of Translational Breast Cancer Research and Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, currently lacks effective targeted therapy options. Eicosapentaenoic acid (EPA), an omega-3 fatty acid and constituent of fish oil, is a common supplement with anti-inflammatory properties. Although it is not a mainstream treatment, several preclinical studies have demonstrated that EPA exerts anti-tumor activity in breast cancer. However, against solid tumors, EPA as a monotherapy is clinically ineffective; thus, we sought to develop a novel targeted drug combination to bolster its therapeutic action against TNBC. Using a high-throughput functional siRNA screen, we identified Ephrin type-A receptor 2 (EPHA2), an oncogenic cell-surface receptor tyrosine kinase, as a therapeutic target that sensitizes TNBC cells to EPA. EPHA2 expression was uniquely elevated in TNBC cell lines and patient tumors. In independent functional expression studies in TNBC models, EPHA2 gene-silencing combined with EPA significantly reduced cell growth and enhanced apoptosis compared with monotherapies, both in vitro and in vivo. EPHA2-specific inhibitors similarly enhanced the therapeutic action of EPA. Finally, we identified that therapy-mediated apoptosis was attributed to a lethal increase in cancer cell membrane polarity due to ABCA1 inhibition and subsequent dysregulation of cholesterol homeostasis. This study provides new molecular and preclinical evidence to support a clinical evaluation of EPA combined with EPHA2 inhibition in patients with TNBC.
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http://dx.doi.org/10.1038/s41388-018-0569-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430703PMC
March 2019

Anticancer effects of curcumin on nude mice bearing lung cancer A549 cell subsets SP and NSP cells.

Oncol Lett 2018 Nov 24;16(5):6756-6762. Epub 2018 Sep 24.

Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China.

Curcumin is a key polyphenolic curcuminoid extracted from the root of turmeric rhizome Curcuma longa Linn, which is a frequently used Chinese herb for the treatment of cancer. The aim of the present study was to investigate the mechanism of the inhibitory effects of curcumin on nude mice with lung cancer A549 cell subsets side population (SP) and non-SP (NSP) cells. BALB/c mice were subcutaneously injected with the tumor cells of A549 SP or NSP subsets consisting of 1×10 cells/l (0.2 ml in total). After 16 days of inoculation with A549, the mice were intraperitoneally injected with curcumin (100 mg/kg, 0.2 ml) once every other day, eight times in total. A series of assays were performed to detect the effects of curcumin on: i) Tumor weight and size; ii) Notch and hypoxia inducible factor 1 (HIF-1) mRNA expression by quantitative polymerase chain reaction; and iii) vascular endothelial growth factor (VEGF) and nuclear factor-κB (NF-κB) by immunohistochemistry. It was determined that curcumin decreased the tumor weight and size, downregulated the expression of Notch and HIF-1 mRNA and suppressed the VEGF and NF-κB expression. These results indicated that curcumin inhibited lung cancer growth through the regulation of angiogenesis mediated by VEGF signaling.
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http://dx.doi.org/10.3892/ol.2018.9488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202465PMC
November 2018

Colonoscopic-Guided Pinch Biopsies in Mice as a Useful Model for Evaluating the Roles of Host and Luminal Factors in Colonic Inflammation.

Am J Pathol 2018 12 28;188(12):2811-2825. Epub 2018 Sep 28.

Department of Medicine, Weill Cornell Medicine, New York, New York. Electronic address:

Colonic inflammation, a hallmark of inflammatory bowel disease, can be influenced by host intrinsic and extrinsic factors. There continues to be a need for models of colonic inflammation that can both provide insights into disease pathogenesis and be used to investigate potential therapies. Herein, we tested the utility of colonoscopic-guided pinch biopsies in mice for studying colonic inflammation and its treatment. Gene expression profiling of colonic wound beds after injury showed marked changes, including increased expression of genes important for the inflammatory response. Interestingly, many of these gene expression changes mimicked those alterations found in inflammatory bowel disease patients. Biopsy-induced inflammation was associated with increases in neutrophils, macrophages, and natural killer cells. Injury also led to elevated levels of sphingosine-1-phosphate (S1P), a bioactive lipid that is an important mediator of inflammation mainly through its receptor, S1P. Genetic deletion of S1P in the endothelium did not alter the inflammatory response but led to increased colonic bleeding. Bacteria invaded into the wound beds, raising the possibility that microbes contributed to the observed changes in mucosal gene expression. In support of this, reducing bacterial abundance markedly attenuated the inflammatory response to wounding. Taken together, this study demonstrates the utility of the pinch biopsy model of colonic injury to elucidate the molecular underpinnings of colonic inflammation and its treatment.
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http://dx.doi.org/10.1016/j.ajpath.2018.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334259PMC
December 2018

Stress, inflammation, and eicosanoids: an emerging perspective.

Cancer Metastasis Rev 2018 09;37(2-3):203-211

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1515 Holcombe Blvd., Houston, TX, 77030, USA.

Clinical and experimental studies support the notion that adrenergic stimulation and chronic stress affect inflammation, metabolism, and tumor growth. Eicosanoids are also known to heavily influence inflammation while regulating certain stress responses. However, additional work is needed to understand the full extent of interactions between the stress-related pathways and eicosanoids. Here, we review the potential influences that stress, inflammation, and metabolic pathways have on each other, in the context of eicosanoids. Understanding the intricacies of such interactions could provide insights on how systemic metabolic effects mediated by the stress pathways can be translated into therapies for cancer and other diseases.
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http://dx.doi.org/10.1007/s10555-018-9741-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237279PMC
September 2018

Accreditation Standard Guideline Initiative for Tai Chi and Qigong Instructors and Training Institutions.

Medicines (Basel) 2018 Jun 8;5(2). Epub 2018 Jun 8.

Dana-Farber Cancer Institute; Brigham and Women's Hospital; Harvard Medical School, Boston, MA 02115, USA.

Evidence of the health and wellbeing benefits of (TQ) have emerged in the past two decades, but TQ is underutilized in modern health care in Western countries due to lack of promotion and the availability of professionally qualified TQ instructors. To date, there are no government regulations for TQ instructors or for training institutions in China and Western countries, even though TQ is considered to be a part of Traditional Chinese medicine that has the potential to manage many chronic diseases. Based on an integrative health care approach, the accreditation standard guideline initiative for TQ instructors and training institutions was developed in collaboration with health professionals, integrative medicine academics, Tai Chi and Qigong master instructors and consumers including public safety officers from several countries, such as Australia, Canada, China, Germany, Italy, Korea, Sweden and USA. In this paper, the rationale for organizing the (MTQA) is discussed and the accreditation standard guideline for TQ instructors and training institutions developed by the committee members of MTQA is presented. The MTQA acknowledges that the proposed guidelines are broad, so that the diversity of TQ instructors and training institutions can be integrated with recognition that these guidelines can be developed with further refinement. Additionally, these guidelines face challenges in understanding the complexity of TQ associated with different principles, philosophies and schools of thought. Nonetheless, these guidelines represent a necessary first step as primary resource to serve and guide health care professionals and consumers, as well as the TQ community.
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http://dx.doi.org/10.3390/medicines5020051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023434PMC
June 2018

Tumor cell-released autophagosomes (TRAP) enhance apoptosis and immunosuppressive functions of neutrophils.

Oncoimmunology 2018;7(6):e1438108. Epub 2018 Mar 6.

Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu Province, China.

Our previous studies have confirmed that tumor cell-released autophagosomes (TRAP) could induce the differentiation of B cells into IL-10 regulatory B cells (Bregs) with suppressive activities on T lymphocytes. However, the mechanism of TRAP-mediated immune suppression is still largely unclear. Herein, we sought to assess the immunomodulatory effect of TRAPs on human neutrophils, a major immune cell type that infiltrates human tumor tissues. We found that TRAPs enriched from malignant effusions or ascites of cancer patients and tumor cell lines were rapidly and effectively phagocytized by neutrophils through macropinocytosis and promoted neutrophil apoptosis via reactive oxygen species (ROS) generation and caspase-3 activation. Moreover, the apoptotic neutrophils that have phagocytized TRAPs inhibited the proliferation and activation of CD4 T and CD8 T cells in a cell contact- and ROS-dependent manner. These findings define a novel TRAP-mediated mechanism in neutrophils that potentially suppresses the anti-tumor T cell immunity and highlight TRAPs as an important target for future tumor immunotherapy.
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http://dx.doi.org/10.1080/2162402X.2018.1438108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980412PMC
March 2018

Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy.

Cell Metab 2018 May 5;27(5):977-987.e4. Epub 2018 Apr 5.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis-related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo. Moreover, glycolysis-related gene expression was higher in melanoma tissues from ACT-refractory patients, and tumor cells derived from these patients exhibited higher glycolytic activity. We identified reduced levels of IRF1 and CXCL10 immunostimulatory molecules in highly glycolytic melanoma cells. Our findings demonstrate that tumor glycolysis is associated with the efficacy of ACT and identify the glycolysis pathway as a candidate target for combinatorial therapeutic intervention.
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http://dx.doi.org/10.1016/j.cmet.2018.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932208PMC
May 2018

KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.

Nature 2017 12 6;552(7684):273-277. Epub 2017 Dec 6.

Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Histone modifications, such as the frequently occurring lysine succinylation, are central to the regulation of chromatin-based processes. However, the mechanism and functional consequences of histone succinylation are unknown. Here we show that the α-ketoglutarate dehydrogenase (α-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. We show that succinyl-coenzyme A (succinyl-CoA) binds to KAT2A. The crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA at 2.3 Å resolution shows that succinyl-CoA binds to a deep cleft of KAT2A with the succinyl moiety pointing towards the end of a flexible loop 3, which adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Site-directed mutagenesis indicates that tyrosine 645 in this loop has an important role in the selective binding of succinyl-CoA over acetyl-CoA. KAT2A acts as a succinyltransferase and succinylates histone H3 on lysine 79, with a maximum frequency around the transcription start sites of genes. Preventing the α-KGDH complex from entering the nucleus, or expression of KAT2A(Tyr645Ala), reduces gene expression and inhibits tumour cell proliferation and tumour growth. These findings reveal an important mechanism of histone modification and demonstrate that local generation of succinyl-CoA by the nuclear α-KGDH complex coupled with the succinyltransferase activity of KAT2A is instrumental in histone succinylation, tumour cell proliferation, and tumour development.
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http://dx.doi.org/10.1038/nature25003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841452PMC
December 2017

Resveratrol inhibits obesity-associated adipose tissue dysfunction and tumor growth in a mouse model of postmenopausal claudin-low breast cancer.

Mol Carcinog 2018 03 1;57(3):393-407. Epub 2017 Dec 1.

Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina.

Adipose tissue dysregulation, a hallmark of obesity, contributes to a chronic state of low-grade inflammation and is associated with increased risk and progression of several breast cancer subtypes, including claudin-low breast tumors. Unfortunately, mechanistic targets for breaking the links between obesity-associated adipose tissue dysfunction, inflammation, and claudin-low breast cancer growth have not been elucidated. Ovariectomized female C57BL/6 mice were randomized (n = 15/group) to receive a control diet, a diet-induced obesity (DIO) diet, or a DIO + resveratrol (0.5% wt/wt) diet. Mice consumed these diets ad libitum throughout study and after 6 weeks were orthotopically injected with M-Wnt murine mammary tumor cells, a model of estrogen receptor (ER)-negative claudin-low breast cancer. Compared with controls, DIO mice displayed adipose dysregulation and metabolic perturbations including increased mammary adipocyte size, cyclooxygenase-2 (COX-2) expression, inflammatory eicosanoid levels, macrophage infiltration, and prevalence of crown-like structures (CLS). DIO mice (relative to controls) also had increased systemic inflammatory cytokines and decreased adipocyte expression of peroxisome proliferator-activated receptor gamma (PPARγ) and other adipogenesis-regulating genes. Supplementing the DIO diet with resveratrol prevented obesity-associated increases in mammary tumor growth, mammary adipocyte hypertrophy, COX-2 expression, macrophage infiltration, CLS prevalence, and serum cytokines. Resveratrol also offset the obesity-associated downregulation of adipocyte PPARγ and other adipogenesis genes in DIO mice. Our findings suggest that resveratrol may inhibit obesity-associated inflammation and claudin-low breast cancer growth by inhibiting adipocyte hypertrophy and associated adipose tissue dysregulation that typically accompanies obesity.
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http://dx.doi.org/10.1002/mc.22763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053655PMC
March 2018

EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer.

Oncotarget 2017 Sep 4;8(40):67904-67917. Epub 2017 Jul 4.

Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Inflammatory breast cancer (IBC) is the most lethal and aggressive type of breast cancer, with a strong proclivity to metastasize, and IBC-specific targeted therapies have not yet been developed. Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in IBC. However, the mechanism behind the therapeutic effect of EGFR targeted therapy is not well defined. Here, we report that EGFR regulates the IBC cell population that expresses cancer stem-like cell (CSC) markers through COX-2, a key mediator of inflammation whose expression correlates with worse outcome in IBC. The COX-2 pathway promoted IBC cell migration and invasion and the CSC marker-bearing population , and the inhibition of this pathway reduced IBC tumor growth . Mechanistically, we identified Nodal, a member of the TGFβ superfamily, as a potential driver of COX-2-regulated invasive capacity and the CSC phenotype of IBC cells. Our data indicate that the EGFR pathway regulates the expression of COX-2, which in turn regulates the expression of Nodal and the activation of Nodal signaling. Together, our findings demonstrate a novel connection between the EGFR/COX-2/Nodal signaling axis and CSC regulation in IBC, which has potential implications for new combination approaches with EGFR targeted therapy for patients with IBC.
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http://dx.doi.org/10.18632/oncotarget.18958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620223PMC
September 2017