Publications by authors named "Philip R Taylor"

355 Publications

Colorectal cancer in the Linxian China Nutrition Intervention Trial: Risk factors and intervention results.

PLoS One 2021 15;16(9):e0255322. Epub 2021 Sep 15.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.

Background: Colorectal cancer (CRC) is among the most common cancers in economically developed countries and developing world. While dietary factors are associated with risk of CRC in the West and urban China, little is known about risk or protective factors in rural China.

Methods: The Linxian General Population Nutrition Intervention Trial (NIT) cohort was established over 30 years ago to test whether daily multivitamin/mineral supplements could reduce the incidence and mortality of esophageal/gastric cardia cancer. The cohort included a total of 29,553 healthy participants 40-69 years old who were randomly assigned to supplements or placebos via a 24 fractional factorial study design. We examined risk factors for the development of CRC as well as the effects of four different nutritional factors (Factor A: retinol, zinc; B: riboflavin, niacin; C: ascorbic acid, molybdenum; D: selenium, alpha-tocopherol, beta-carotene,) on CRC incidence following 5.25 years of supplementation in this randomized, placebo-controlled intervention trial.

Results: CRC risk increased with age and height as well as piped water usage, family history of CRC, and consumption of foods cooked in oil, eggs, and fresh fruits. No effect on CRC was seen for any of these four intervention factors tested in both genders, but CRC was reduced 37% in females who received Factor D (selenium/alpha-tocopherol/beta-carotene) (RR = 0.63, 95% CI = 0.43-0.92, P = 0.016) compared to females who did not receive Factor D.

Conclusions: In this undernourished rural Chinese population, CRC risk factors in this Chinese cohort showed both similarities and differences compared to Western and urban Asian Chinese populations. Intervention results suggested a potential benefit for women supplemented with selenium/alpha-tocopherol/beta-carotene.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255322PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443060PMC
September 2021

Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer's disease.

Sci Rep 2021 07 22;11(1):14935. Epub 2021 Jul 22.

Division of Infection and Immunity, Cardiff University, Cardiff, UK.

Genetic association studies have identified multiple variants at the SPI1 locus that modify risk and age of onset for Alzheimer's Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higher SPI1 expression are likely to have an earlier AD onset, and several other AD risk genes contain PU.1 binding sites in the promoter region. Overall, this suggests the level of SPI1 may alter microglial phenotype potentially impacting AD. This study determined how the microglial transcriptome was altered following modest changes to Spi1 expression in primary mouse microglia. RNA-sequencing was performed on microglia with reduced or increased Spi1/PU.1 expression to provide an unbiased approach to determine transcriptomic changes affected by Spi1. In summary, a reduction in microglial Spi1 resulted in the dysregulation of transcripts encoding proteins involved in DNA replication pathways while an increased Spi1 results in an upregulation of genes associated with immune response pathways. Additionally, a subset of 194 Spi1 dose-sensitive genes was identified and pathway analysis suggests that several innate immune and interferon response pathways are impacted by the concentration of Spi1. Together these results suggest Spi1 levels can alter the microglial transcriptome and suggests interferon pathways may be altered in individuals with AD related Spi1 risk SNPs.
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http://dx.doi.org/10.1038/s41598-021-94324-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298495PMC
July 2021

PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522.

EMBO J 2021 Sep 13;40(17):e105603. Epub 2021 Jul 13.

UK Dementia Research Institute at Cardiff, Cardiff, UK.

Variants identified in genome-wide association studies have implicated immune pathways in the development of Alzheimer's disease (AD). Here, we investigated the mechanistic basis for protection from AD associated with PLCγ2 R522, a rare coding variant of the PLCG2 gene. We studied the variant's role in macrophages and microglia of newly generated PLCG2-R522-expressing human induced pluripotent cell lines (hiPSC) and knockin mice, which exhibit normal endogenous PLCG2 expression. In all models, cells expressing the R522 mutation show a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This manifests as enhanced release of cellular calcium ion stores in response to physiologically relevant stimuli like Fc-receptor ligation or exposure to Aβ oligomers. Expression of the PLCγ2-R522 variant resulted in increased stimulus-dependent PIP depletion and reduced basal PIP levels in vivo. Furthermore, it was associated with impaired phagocytosis and enhanced endocytosis. PLCγ2 acts downstream of other AD-related factors, such as TREM2 and CSF1R, and alterations in its activity directly impact cell function. The inherent druggability of enzymes such as PLCγ2 raises the prospect of PLCγ2 manipulation as a future therapeutic approach in AD.
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http://dx.doi.org/10.15252/embj.2020105603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408593PMC
September 2021

Single-Nucleus RNA Sequencing Identifies New Classes of Proximal Tubular Epithelial Cells in Kidney Fibrosis.

J Am Soc Nephrol 2021 Oct 21;32(10):2501-2516. Epub 2021 Jun 21.

Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom

Background: Proximal tubular cells (PTCs) are the most abundant cell type in the kidney. PTCs are central to normal kidney function and to regeneration versus organ fibrosis following injury. This study used single-nucleus RNA sequencing (snRNAseq) to describe the phenotype of PTCs in renal fibrosis.

Methods: Kidneys were harvested from naïve mice and from mice with renal fibrosis induced by chronic aristolochic acid administration. Nuclei were isolated using Nuclei EZ Lysis buffer. Libraries were prepared on the 10× platform, and snRNAseq was completed using the Illumina NextSeq 550 System. Genome mapping was carried out with high-performance computing.

Results: A total of 23,885 nuclei were analyzed. PTCs were found in five abundant clusters, mapping to S1, S1-S2, S2, S2-cortical S3, and medullary S3 segments. Additional cell clusters ("new PTC clusters") were at low abundance in normal kidney and in increased number in kidneys undergoing regeneration/fibrosis following injury. These clusters exhibited clear molecular phenotypes, permitting labeling as proliferating, New-PT1, New-PT2, and (present only following injury) New-PT3. Each cluster exhibited a unique gene expression signature, including multiple genes previously associated with renal injury response and fibrosis progression. Comprehensive pathway analyses revealed metabolic reprogramming, enrichment of cellular communication and cell motility, and various immune activations in new PTC clusters. In ligand-receptor analysis, new PTC clusters promoted fibrotic signaling to fibroblasts and inflammatory activation to macrophages.

Conclusions: These data identify unrecognized PTC phenotype heterogeneity and reveal novel PTCs associated with kidney fibrosis.
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http://dx.doi.org/10.1681/ASN.2020081143DOI Listing
October 2021

Family History and Risk of Upper Gastrointestinal Cancer in the Linxian General Population.

Front Oncol 2021 28;11:605106. Epub 2021 May 28.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Objective: The objective of this study was to investigate family history (FH) of upper gastrointestinal (UGI) cancer and risk of esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC), and gastric non-cardia carcinoma (GNCC) in the Linxian General Population Nutrition Intervention Trial (NIT) cohort. Methods: This prospective analysis was conducted using the Linxian NIT cohort data. Subjects with FH of UGI cancer was treated as an exposed group while the remainders were considered as a comparison group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between FH of UGI cancer and risk of UGI cancer incidence and mortality were estimated using Cox proportional hazards models.

Results: There were 5,680 newly diagnosed UGI cancer cases during the follow-up period, with a total of 4,573 UGI cancer deaths occurred, including 2,603 ESCC, 1,410 GCC, and 560 GNCC deaths. A positive FH of UGI cancer was associated with a significantly increased risk of ESCC and GCC (Incidence: HR = 1.45, 95%CI: 1.35-1.56; HR = 1.27, 95%CI: 1.15-1.40; Mortality: HR = 1.40, 95%CI: 1.30-1.52; HR = 1.27, 95%CI: 1.14-1.42) after adjusting for age at baseline, gender, smoking status, alcohol drinking, education level, and frequency of fresh fruit and vegetable consumption. Subjects with FH in both parents had the highest risk of ESCC and GCC incidence (HR = 1.65, 95%CI: 1.40-1.95; HR = 1.42, 95%CI: 1.12-1.81) and deaths (HR = 1.65, 95%CI: 1.38-1.97; HR = 1.42, 95%CI: 1.09-1.85). Spouse diagnosed with UGI cancer did not increase the risk of any UGI cancers of the subjects. In subgroup analysis, FH of UGI cancer was shown to significantly increase the risk of GCC in non-drinkers (Incidence: HR = 1.31, 95%CI: 1.17-1.47; Mortality: HR = 1.33, 95%CI: 1.17-1.50). No associations were observed for risk of GNCC. Sensitivity analysis by excluding subjects who were followed up less than three years did not materially alter our results.

Conclusion: Our data point to the role of the FH of UGI cancer to the risk of ESCC and GCC incidence and mortality. The influence of family history on the risk of UGI cancer varies from different types of family members.
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http://dx.doi.org/10.3389/fonc.2021.605106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193945PMC
May 2021

Association between serum ferritin, incident primary liver cancer, and chronic liver disease mortality in the Linxian Nutrition Intervention Trials: A nested case-control study.

J Gastroenterol Hepatol 2021 Jun 9. Epub 2021 Jun 9.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Background And Aim: Previous studies suggest that serum ferritin may be associated with higher risk of liver cancer. However, additional studies of the association are needed. It is also not clear whether serum ferritin is associated with mortality from chronic liver disease (CLD).

Methods: We performed a nested case-control study in the Linxian Nutrition Intervention Trials. Baseline serum ferritin was measured for 226 incident primary liver cancer cases, 281 CLD mortalities diagnosed, and 1061 age-matched, gender-matched, and trial-matched controls. We used multivariable logistic regression models to calculate odds ratios and 95% confidence intervals. Subgroup analysis and interaction tests were performed by age, gender, alcohol drinking, hepatitis B virus seropositivity (HBV+)/hepatitis C virus seropositivity (HCV+), and trial.

Results: Participants with serum ferritin in the highest quartile, as compared with those in the lowest quartile, had an increased risk of CLD mortality (odds ratio = 1.72, 95% confidence interval = 1.12, 2.64, P-trend < 0.01). Moreover, the association with higher serum ferritin was stronger among alcohol drinkers and those who were HCV+ (P-interaction < 0.05). For incident liver cancer, risk estimates were above one but were not statistically significant.

Conclusion: In this study, higher levels of serum ferritin at baseline were associated with subsequent mortality from CLD, particularly if combined with alcohol drinking or viral hepatitis. Further work is warranted to confirm our findings.
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http://dx.doi.org/10.1111/jgh.15571DOI Listing
June 2021

ABO genotypes and the risk of esophageal and gastric cancers.

BMC Cancer 2021 May 22;21(1):589. Epub 2021 May 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr. 6E3280, Rockville, MD, 20850, USA.

Background: Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC).

Methods: We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer.

Results: Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07-1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P < 0.001) with risk significantly elevated in type A (1.37, 1.14-1.65) and AB (1.44, 1.10-1.89) compared to type O. Blood type was not associated with gastric cardia adenocarcinoma (P = 0.13).

Conclusions: This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.
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http://dx.doi.org/10.1186/s12885-021-08334-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141232PMC
May 2021

Selenium Kinetics in Humans Change Following 2 Years of Supplementation With Selenomethionine.

Front Endocrinol (Lausanne) 2021 29;12:621687. Epub 2021 Mar 29.

Metabolic Modeling Services, West Lafayette, IN, United States.

Background: Selenium (Se) is a nutritionally essential trace element and health may be improved by increased Se intake. Previous kinetic studies have shown differences in metabolism of organic inorganic forms of Se [e.g., higher absorption of selenomethionine (SeMet) than selenite (Sel), and more recycling of Se from SeMet than Sel]. However, the effects on Se metabolism after prolonged Se supplementation are not known.

Objective: To determine how the metabolism and transport of Se changes in the whole-body in response to Se-supplementation by measuring Se kinetics before and after 2 years of Se supplementation with SeMet.

Methods: We compared Se kinetics in humans [n = 31, aged 40 ± 3 y (mean ± SEM)] studied twice after oral tracer administration; initially (PK1), then after supplementation for 2 y with 200 µg/d of Se as selenomethionine (SeMet) (PK2). On each occasion, we administered two stable isotope tracers of Se orally: SeMet, the predominant food form, and selenite (Na SeO or Sel), an inorganic form. Plasma and RBC were sampled for 4 mo; urine and feces were collected for the initial 12 d of each period. Samples were analyzed for tracers and total Se by isotope dilution GC-MS. Data were analyzed using a compartmental model, we published previously, to estimate fractional transfer between pools and pool masses in PK2.

Results: We report that fractional absorption of SeMet or Sel do not change with SeMet supplementation and the amount of Se absorbed increased. The amount of Se excreted in urine increases but does not account for all the Se absorbed. As a result, there is a net incorporation of SeMet into various body pools. Nine of the 11 plasma pools doubled in PK2; two did not change. Differences in metabolism were observed for SeMet and Sel; RBC uptake increased 247% for SeMet, urinary excretion increased from two plasma pools for Sel and from two different pools for SeMet, and recycling to liver/tissues increased from one plasma pool for Sel and from two others for SeMet. One plasma pool increased more in males than females in PK2.

Conclusions: Of 11 Se pools identified kinetically in human plasma, two did not increase in size after SeMet supplementation. These pools may be regulated and important during low Se intake.
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http://dx.doi.org/10.3389/fendo.2021.621687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043082PMC
March 2021

Serum Levels of Androgens, Estrogens, and Sex Hormone Binding Globulin and Risk of Primary Gastric Cancer in Chinese Men: A Nested Case-Control Study.

Cancer Prev Res (Phila) 2021 Jun 25;14(6):659-666. Epub 2021 Mar 25.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Gastric cancer shows a strong male predominance, and sex steroid hormones have been hypothesized to explain this sex disparity. Previous studies examining the associations between sex hormones and sex hormone binding globulin (SHBG) and risk of gastric cancer come primarily from western populations and additional studies in diverse populations will help us better understand the association. We performed a nested case-control study in Linxian Nutrition Intervention Trials cohorts to evaluate the associations among Chinese men, where we had sufficient cases to perform a well-powered study. Using radioimmunoassays and immunoassays, we quantitated androgens, estrogens, and SHBG in baseline serum from 328 men that developed noncardia gastric cancer and matched controls. We used multivariable unconditional logistic regression to calculate ORs and 95% confidence intervals (CI) and explored interactions with body mass index (BMI), age, alcohol drinking, smoking, and follow-up time. Subjects with SHBG in the highest quartile, as compared with those in the lowest quartile, had a significantly increased risk of gastric cancer (OR = 1.87; 95% CI, 1.01-3.44). We found some evidence for associations of sex steroid hormones in men with lower BMI. Our study found a novel association suggesting that higher serum concentrations of SHBG may be associated with risk of gastric cancer in men. We found no overall associations with sex hormones themselves, but future studies should expand the scope of these studies to include women and further explore whether BMI modifies a potential association. PREVENTION RELEVANCE: It was the first study to investigate the association of gastric cancer with prediagnostic sex steroid hormones and SHBG in an Asian male population. Although there were no overall associations for sex steroid hormone concentrations, higher concentrations of SHBG was associated with increased risk of noncardia gastric cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225565PMC
June 2021

A Human Dectin-2 Deficiency Associated With Invasive Aspergillosis.

J Infect Dis 2021 Oct;224(7):1219-1224

Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom.

Immunocompromised patients are highly susceptible to invasive aspergillosis. Herein, we identified a homozygous deletion mutation (507 del C) resulting in a frameshift (N170I) and early stop codon in the fungal binding Dectin-2 receptor, in an immunocompromised patient. The mutated form of Dectin-2 was weakly expressed, did not form clusters at/near the cell surface and was functionally defective. Peripheral blood mononuclear cells from this patient were unable to mount a cytokine (tumor necrosis factor, interleukin 6) response to Aspergillus fumigatus, and this first identified Dectin-2-deficient patient died of complications of invasive aspergillosis.
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http://dx.doi.org/10.1093/infdis/jiab145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514184PMC
October 2021

Dependence on Mincle and Dectin-2 Varies With Multiple Species During Systemic Infection.

Front Microbiol 2021 25;12:633229. Epub 2021 Feb 25.

Division of Infection and Immunity, Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom.

More than 95% of invasive infections are caused by four spp. (). C-type lectin-like receptors (CLRs), such as Dectin-1, Dectin-2, and Mincle mediate immune responses to . Dectin-1 promotes clearance of , and , however, dependence on Dectin-1 for specific immune responses varies with the different spp. Dectin-2 is important for host immunity to and , and Mincle is important for the immune response to However, whether Dectin-2 drives host immunity to or , and whether Mincle mediates host immunity to or is unknown. Therefore, we compared the roles of Dectin-2 and Mincle in response to these four spp. We demonstrate that these four spp. cell walls have differential mannan contents. Mincle and Dectin-2 play a key role in regulating cytokine production in response to these four spp. and Dectin-2 is also important for clearance of all four spp. during systemic infection. However, Mincle was only important for clearance of during systemic infection. Our data indicate that multiple spp. have different mannan contents, and dependence on the mannan-detecting CLRs, Mincle, and Dectin-2 varies between different spp. during systemic infection.
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http://dx.doi.org/10.3389/fmicb.2021.633229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951061PMC
February 2021

Macrophage reprogramming for therapy.

Immunology 2021 06 25;163(2):128-144. Epub 2021 Jan 25.

Systems Immunity Research Institute, Cardiff University, Cardiff, UK.

Dysfunction of the immune system underlies a plethora of human diseases, requiring the development of immunomodulatory therapeutic intervention. To date, most strategies employed have been focusing on the modification of T lymphocytes, and although remarkable improvement has been obtained, results often fall short of the intended outcome. Recent cutting-edge technologies have highlighted macrophages as potential targets for disease control. Macrophages play central roles in development, homeostasis and host defence, and their dysfunction and dysregulation have been implicated in the onset and pathogenesis of multiple disorders including cancer, neurodegeneration, autoimmunity and metabolic diseases. Recent advancements have led to a greater understanding of macrophage origin, diversity and function, in both health and disease. Over the last few years, a variety of strategies targeting macrophages have been developed and these open new therapeutic opportunities. Here, we review the progress in macrophage reprogramming in various disorders and discuss the potential implications and challenges for macrophage-targeted approaches in human disease.
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http://dx.doi.org/10.1111/imm.13300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114216PMC
June 2021

Methylated DNA Markers of Esophageal Squamous Cancer and Dysplasia: An International Study.

Cancer Epidemiol Biomarkers Prev 2020 12 18;29(12):2642-2650. Epub 2020 Sep 18.

Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Background: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices.

Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons.

Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia ( < 0.004).

Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results.

Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710574PMC
December 2020

Independent and Joint Associations between Serum Calcium, 25-Hydroxy Vitamin D, and the Risk of Primary Liver Cancer: A Prospective Nested Case-Control Study.

Cancer Epidemiol Biomarkers Prev 2020 10 20;29(10):2057-2064. Epub 2020 Aug 20.

Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Accumulating evidence has shown that serum calcium and vitamin D may be associated with or influence various cancer risks. However, no prospective studies have evaluated the independent and joint associations between prediagnostic levels of serum calcium and vitamin D and future risk of incident primary liver cancer.

Methods: We used a nested case-control design to evaluate subjects over 22 years of follow-up. Serum calcium, 25-hydroxy vitamin D [25(OH)D], and three markers of hepatitis B virus and hepatitis C virus were measured in baseline serum from 226 incident primary liver cancer cases and 1,061 matched controls. We calculated ORs and 95% confidence intervals (CI) using logistic regression to estimate the associations between calcium, 25(OH)D, and primary liver cancer risk.

Results: Multivariable adjusted models showed that subjects with both low (OR = 1.48, 95% CI = 1.01-2.17) or high (OR = 1.92, 95% CI = 1.34-2.76) calcium had an increased primary liver cancer risk, while those with high 25(OH)D had a decreased risk of primary liver cancer (OR = 0.54, 95% CI = 0.35-0.82). In joint analyses, when compared with subjects with medium calcium and 25(OH)D, subjects with high calcium and medium 25(OH)D had elevated odds of developing primary liver cancer (OR = 1.89, 95% CI = 1.17-3.05); those with medium calcium and high 25(OH)D had reduced odds of developing primary liver cancer (OR = 0.34, 95% CI = 0.17-0.67); and subjects in other classifications of calcium and serum 25(OH)D levels had no change in the odds of developing primary liver cancer (all > 0.05).

Conclusions: In a nutrient-deficient population, we found that serum calcium and serum 25(OH)D could potentially be modifiable risk or protective factors.

Impact: Our findings provide potential targets for primary liver cancer prevention and control.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0417DOI Listing
October 2020

Oral leukoplakia and the long-term risk of upper gastrointestinal cancer deaths in the Linxian dysplasia population.

Thorac Cancer 2020 10 18;11(10):2804-2811. Epub 2020 Aug 18.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: To investigate oral leukoplakia (OL) and risk of upper gastrointestinal (UGI) cancer deaths in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort.

Methods: A total of 3318 subjects with esophageal squamous dysplasia enrolled on 1 May 1985, and were followed up until 30 September 2015. Participants with OL at baseline were treated as an exposed group, while the remainder was selected as a control group. All subjects were followed monthly and reviewed quarterly by the Linxian Cancer Registry. Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs).

Results: During the 30-year follow-up, a total of 902 UGI cancer deaths occurred, including 541 esophageal squamous cell carcinoma (ESCC) related, 284 gastric cardia carcinoma (GCC) related, and 77 gastric noncardia carcinoma (GNCC) related deaths. Relative to subjects without OL, the long-term risk of ESCC mortality in participants with OL increased by 26.1% (HR = 1.26, 95% CI: 1.05-1.52). In the subgroup analyses, adverse effects of OL on ESCC mortality were observed especially in younger subjects (HR = 1.48, 95% CI: 1.11-1.97), females (HR = 1.44, 95% CI: 1.11-1.89), non-smokers (HR = 1.44, 95% CI: 1.15-1.81), nondrinkers (HR = 1.28, 95% CI: 1.04-1.57), and individuals with a family history of cancer (HR = 1.37, 95% CI: 1.05-1.79). No associations were observed between OL and risk of GCC and GNCC mortality.

Conclusions: OL may increase the long-term risk of ESCC mortality, especially in younger subjects, females, nondrinkers, non-smokers, and subjects with a family cancer history. Future studies are needed to explore the potentially etiological mechanism.
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http://dx.doi.org/10.1111/1759-7714.13595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529544PMC
October 2020

Esophageal Histological Precursor Lesions and Subsequent 8.5-Year Cancer Risk in a Population-Based Prospective Study in China.

Am J Gastroenterol 2020 07;115(7):1036-1044

Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Introduction: Data on the associations between esophageal histological lesions and risk of esophageal squamous cell carcinoma (ESCC) in general populations are limited. We aimed to investigate these associations in a large Chinese general population to inform future Chinese ESCC screening guidelines.

Methods: We performed endoscopic screening of 21,111 participants aged 40-69 years from 3 high-risk areas of China in 2005-2009, and followed the cohort through 2016. Cumulative incidence and mortality rates of ESCC were calculated by baseline histological diagnosis, and hazard ratios of ESCC, overall and by age and sex, were assessed using the Cox proportional hazards models.

Results: We identified 143 new ESCC cases (0.68%) and 62 ESCC deaths (0.29%) during a median follow-up of 8.5 years. Increasing grades of squamous dysplasia were associated with the increasing risk of ESCC incidence and mortality. The cumulative ESCC incidence rates for severe dysplasia/carcinoma in situ, moderate dysplasia (MD), and mild dysplasia were 15.5%, 4.5%, and 1.4%, respectively. Older individuals (50-69 years) had 3.1 times higher ESCC incidence than younger individuals (40-49 years), and men had 2.4 times higher ESCC incidence than women.

Discussion: This study confirmed that increasing grades of squamous dysplasia are associated with increasing risk of ESCC and that severe dysplasia and carcinoma in situ require clinical treatment. This study suggests that in high-risk areas of China, patients with endoscopically worrisome MD should also receive therapy, the first screening can be postponed to 50 years, and endoscopic surveillance intervals for unremarkable MD and mild dysplasia can be lengthened to 3 and 5 years, respectively.
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http://dx.doi.org/10.14309/ajg.0000000000000640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477846PMC
July 2020

Tissue-resident macrophages actively suppress IL-1beta release via a reactive prostanoid/IL-10 pathway.

EMBO J 2020 07 2;39(14):e103454. Epub 2020 Jun 2.

Systems Immunity Research Institute, Heath Park, Cardiff University, Cardiff, UK.

The alarm cytokine interleukin-1β (IL-1β) is a potent activator of the inflammatory cascade following pathogen recognition. IL-1β production typically requires two signals: first, priming by recognition of pathogen-associated molecular patterns leads to the production of immature pro-IL-1β; subsequently, inflammasome activation by a secondary signal allows cleavage and maturation of IL-1β from its pro-form. However, despite the important role of IL-1β in controlling local and systemic inflammation, its overall regulation is still not fully understood. Here we demonstrate that peritoneal tissue-resident macrophages use an active inhibitory pathway, to suppress IL-1β processing, which can otherwise occur in the absence of a second signal. Programming by the transcription factor Gata6 controls the expression of prostacyclin synthase, which is required for prostacyclin production after lipopolysaccharide stimulation and optimal induction of IL-10. In the absence of secondary signal, IL-10 potently inhibits IL-1β processing, providing a previously unrecognized control of IL-1β in tissue-resident macrophages.
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http://dx.doi.org/10.15252/embj.2019103454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360975PMC
July 2020

Fresh fruit consumption may decrease the long-term risk of esophageal cancer mortality: A 30-year follow-up study in the Linxian Dysplasia Nutrition Intervention trial (NIT).

Thorac Cancer 2020 07 29;11(7):1918-1926. Epub 2020 May 29.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: The objective of this study was to explore the association between fresh fruit consumption and long-term risk of upper gastrointestinal cancer (UGI) in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort.

Methods: A cohort of 3318 subjects with esophageal squamous dysplasia participated in the Linxian Dysplasia NIT in May 1985 and were followed up until 30 September 2015. Demographic characteristics, lifestyle, and history of diseases were collected at the baseline. The primary endpoint was death from esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC), and gastric noncardia carcinoma (GNCC). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard model.

Results: In the 30-year follow-up, a total of 541 ESCC, 284 GCC, and 77 GNCC deaths occurred. Relative to those who never or rarely consumed fresh fruit, the risk of ESCC mortality in participants who consumed fresh fruit more than 12 times/year were significantly decreased by 37.3% (HR = 0.63, 95% CI: 0.49-0.81). In the subgroup analyses, significantly protective effects on ESCC mortality were observed especially in females (HR = 0.59, 95% CI: 0.40-0.89), non-smokers (HR = 0.67, 95% CI: 0.48-0.94), and nondrinkers (HR = 0.69, 95% CI: 0.51-0.93).

Conclusions: Consuming fresh fruit more than 12 times/year may reduce the long-term risk of ESCC mortality in this dysplasia population, particularly in females, non-smokers, and nondrinkers. Future studies are needed to confirm these findings.
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http://dx.doi.org/10.1111/1759-7714.13482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327702PMC
July 2020

Integrated analysis of genome-wide miRNAs and targeted gene expression in esophageal squamous cell carcinoma (ESCC) and relation to prognosis.

BMC Cancer 2020 May 6;20(1):388. Epub 2020 May 6.

Division of Cancer Epidemiology and Genetics, NCI, Bethesda, MD, 20892, USA.

Background: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide and in China. We know miRNAs influence gene expression in tumorigenesis, but it is unclear how miRNAs affect gene expression or influence survival at the genome-wide level in ESCC.

Methods: We performed miRNA and mRNA expression arrays in 113 ESCC cases with tumor/normal matched tissues to identify dysregulated miRNAs, to correlate miRNA and mRNA expressions, and to relate miRNA and mRNA expression changes to survival and clinical characteristics.

Results: Thirty-nine miRNAs were identified whose tumor/normal tissue expression ratios showed dysregulation (28 down- and 11 up-regulated by at least two-fold with P < 1.92E-04), including several not previously reported in ESCC (miR-885-5p, miR-140-3p, miR-708, miR-639, miR-596). Expressions of 16 miRNAs were highly correlated with expressions of 195 genes (P < 8.42E-09; absolute rho values 0.51-0.64). Increased expressions of miRNA in tumor tissue for both miR-30e* and miR-124 were associated with increased survival (P < 0.05). Similarly, nine probes in eight of 818 dysregulated genes had RNA expression levels that were nominally associated with survival, including NF1, ASXL1, HSPA4, TGOLN2, BAIAP2, EZH2, CHAF1A, SUPT7L.

Conclusions: Our characterization and integrated analysis of genome-wide miRNA and gene expression in ESCC provides insights into the expression of miRNAs and their relation to regulation of RNA targets in ESCC tumorigenesis, and suggest opportunities for the future development of miRs and mRNAs as biomarkers for early detection, diagnosis, and prognosis in ESCC.
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http://dx.doi.org/10.1186/s12885-020-06901-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201714PMC
May 2020

Low Epstein-Barr Virus Prevalence in Cardia Gastric Cancer Among a High-Incidence Chinese Population.

Dig Dis Sci 2021 04 4;66(4):1220-1226. Epub 2020 May 4.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Room 6E110, 9609 Medical Center Drive, Rockville, MD, 20892-9776, USA.

Background: Epstein-Barr virus (EBV) positivity is associated with better gastric cancer prognosis and is found in a relatively fixed 9% of tumors worldwide.

Aim: We aimed to examine the EBV status of gastric adenocarcinomas in a very high-incidence population and to compare prevalence between cardia and non-cardia anatomic subsites.

Methods: We evaluated 1035 adult gastric adenocarcinoma cases presenting during 1997-2005 to the Shanxi Cancer Hospital in Taiyuan, Shanxi Province, China. EBV-encoded RNA was detected in alcohol-fixed paraffin-embedded tumor specimens by in situ hybridization. Associations were assessed in case-case comparisons using the Chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables, with p values < 0.05 considered statistically significant. Adjusted odds ratios were calculated using logistic regression, and mortality hazard ratios (HRs) were estimated by Cox proportional hazards regression.

Results: Sixty-four percent of the evaluated cancers were found in the cardia. Cardia tumor localization was associated with male sex, advanced primary tumor stage, better differentiated histology, and intestinal-type Lauren classification. Four percent of the non-cardia and only 0.9% of cardia cancers were EBV-positive. EBV positivity was associated with better overall survival (adjusted HR 0.30, 95% CI 0.14-0.63).

Conclusions: Our study highlights unusually low EBV prevalence in gastric adenocarcinoma among a high-incidence population, particularly for cardia cancers. These findings suggest a unique risk factor profile for the high incidence of gastric cancer in this population.
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http://dx.doi.org/10.1007/s10620-020-06288-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685001PMC
April 2021

Body mass index and risk of upper gastrointestinal cancer: A 30-year follow-up of the Linxian dysplasia nutrition intervention trial cohort.

Cancer Epidemiol 2020 04 9;65:101683. Epub 2020 Feb 9.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Although a number of previous studies have noted the association between body mass index (BMI) and upper gastrointestinal (UGI) cancer risk, little evidence exists in the Chinese esophageal squamous dysplasia population. This prospective study investigated the association between BMI and UGI cancer risk in the Linxian Dysplasia Nutrition Intervention Trial (NIT) cohort.

Methods: A total of 3298 participants were included in the final analysis. Asian-specific BMI cut-offs were used to define BMI subgroups: underweight <18.5 kg/m, normal ≥18.5 to <24 kg/m and overweight or obese ≥24 kg/m. Hazard ratios (HRs) and 95 % confidence intervals (95 %CIs) were estimated using the Cox proportional hazard model.

Results: During over 30 years of follow-up we identified 654 incident esophageal squamous-cell carcinoma (ESCC) cases and 434 gastric cancer cases which included 88 gastric non-cardia carcinoma (GNCC) and 346 gastric cardia carcinoma (GCC) cases. Relative to normal weight, overweight or obesity were associated with a significantly reduced risk of ESCC (HR 0.69, 95 %CI 0.48-0.98) after multivariate adjustment, including age at baseline, gender, smoking, drinking, family history of cancer, education and consumption of fresh fruit. Subgroup analyses found that clear effects were evident in women and subjects with a family history of cancer. No association with gastric cancer was observed in any subjects or subgroups.

Conclusion: Overweight/obesity was associated with decreased risk of ESCC in this dysplasia population, particularly in women and persons who had a family history of cancer. Future studies are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.canep.2020.101683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276490PMC
April 2020

The U-shaped association between body mass index and gastric cancer risk in the Helicobacter pylori Biomarker Cohort Consortium: A nested case-control study from eight East Asian cohort studies.

Int J Cancer 2020 08 12;147(3):777-784. Epub 2019 Dec 12.

Cancer Control and Population Sciences Program, Duke Cancer Institute, Durham, NC.

The association between body mass index (BMI) and noncardia gastric cancer (NCGC) risk remains controversial. The purpose of our study was to examine the association of BMI with NCGC risk with consideration of Helicobacter pylori (HP) biomarkers. This international nested case-control study, composed of 1,591 incident NCGC cases and 1,953 matched controls, was established from eight cohorts in China, Japan and Korea, where the majority of NCGCs are diagnosed worldwide. HP antibody biomarkers were measured in blood collected at cohort enrollment by multiplex serology. The NCGC risk according to baseline BMI was estimated using logistic regression to produce odds ratios (ORs) and 95% confidence intervals (CIs). We found a U-shaped association between BMI category and NCGC risk. Compared to those with reference BMI (22.6-25.0 kg/m ), those with lower and higher BMI had an increased NCGC risk (BMI <18.5 kg/m , OR = 1.56, 95% CI = 1.04-2.34; BMI >27.5 kg/m , OR = 1.48, 95% CI = 1.15-1.91; adjusted for age, sex and smoking). The U-shaped association was persistent among subjects with HP infection and high-risk biomarkers (HP+ CagA+: BMI <18.5 kg/m , OR = 1.60, 95% CI = 1.00-2.55; BMI >27.5 kg/m , OR = 1.59, 95% CI = 1.21-2.11; and Omp+ HP0305+: BMI <18.5 kg/m , OR = 1.88, 95% CI = 1.04-3.42; BMI >27.5 kg/m , OR = 1.70, 95% CI = 1.20-2.42, respectively). Our study provides evidence of significantly increased NCGC risk among individuals with low or high BMI, including in subjects with high-risk HP biomarkers (HP+ CagA+, Omp+ HP0305+) in the high-risk area of East Asia.
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http://dx.doi.org/10.1002/ijc.32790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234914PMC
August 2020

Effective Gene Modification in Mouse Tissue-Resident Peritoneal Macrophages by Intraperitoneal Delivery of Lentiviral Vectors.

Mol Ther Methods Clin Dev 2020 Mar 18;16:21-31. Epub 2019 Oct 18.

Systems Immunity Research Institute, Cardiff University School of Medicine, Tenovus Building, Heath Park, Cardiff CF14 4XN, UK.

Tissue-resident macrophages exhibit specialized phenotypes dependent on their physiological niche. Investigation of their function often relies upon complex whole mouse transgenic studies. While some appropriate lineage-associated promoters exist, there are no options for tissue-specific targeting of macrophages. We have developed full protocols for productive infection (defined by stable transgene expression) of tissue-resident macrophages with lentiviral vectors, enabling RNA and protein overexpression, including expression of small RNA species such as shRNA, to knock down and modulate gene expression. These approaches allow robust infection of peritoneal tissue-resident macrophages without significant infection of other cell populations. They permit rapid functional study of macrophages in homeostatic and inflammatory settings, such as thioglycolate-induced peritonitis, while maintaining the cells in their physiological context. Here we provide detailed protocols for the whole workflow: viral production, purification, and quality control; safety considerations for administration of the virus to mice; and assessment of transduction efficiency and the low background levels of inflammation induced by the virus. In summary, we present a quick and accessible protocol for the rapid assessment of gene function in peritoneal tissue-resident macrophages .
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http://dx.doi.org/10.1016/j.omtm.2019.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838965PMC
March 2020

Serologic Profile of Antiparietal Cell Antibodies, Pepsinogens, and and Risk of Upper Gastrointestinal Cancer: A Nested Case-Control Study in China.

Cancer Epidemiol Biomarkers Prev 2019 12 9;28(12):2022-2029. Epub 2019 Sep 9.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Background: Autoimmune gastritis is understudied and possibly associated with gastric noncardia adenocarcinoma (GNCA) and esophageal squamous cell carcinoma (ESCC) in Western populations when it presents as pernicious anemia.

Methods: A nested case-control study within a Chinese cohort included 100 ESCC, 200 gastric cardia adenocarcinoma (GCA), and 200 GNCA cases diagnosed between 1986 and 2001 and 400 controls. Serostatus of antiparietal cell antibodies (APCA), antibodies, and pepsinogens were measured using commercial kits and serum collected at baseline. We used logistic regression to calculate odds ratios (OR) and 95% confidence interval (CI) for associations between serologic biomarkers and cancer risk adjusted for numerous potential confounders.

Results: There was an average interval of 8 years between baseline blood draw and cancer diagnosis. The baseline prevalence of APCA seropositivity was 10.0% and 14.5% in subjects who developed GCA and GNCA, respectively. APCA seropositivity was inversely associated with later development of GCA (OR = 0.42; 95% CI, 0.24-0.75), but not significantly associated with later development of GNCA (OR = 0.82; 95% CI, 0.50-1.36) or ESCC (OR = 1.05; 95% CI, 0.58-1.88). APCA seropositivity was significantly associated with low pepsinogen I/II ratios (OR = 3.69; 95% CI, 1.66-8.21), and individuals with low pepsinogen I/II ratios who were seronegative for APCA had the highest risk of both GCA and GNCA.

Conclusions: APCA seropositivity measured years prior to diagnosis was associated with prevalent atrophic gastritis but inversely associated with incident GCA in this Chinese population.

Impact: APCA may contribute to a growing list of serologic markers that can improve risk stratification for gastric cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891191PMC
December 2019

Dependence on Dectin-1 Varies With Multiple Species.

Front Microbiol 2019 6;10:1800. Epub 2019 Aug 6.

Division of Infection and Immunity and Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Four spp. (, , , ) cause >95% of invasive infections. elicits immune responses via pathogen recognition receptors including C-type lectin-like receptors (CLRs). The CLR, Dectin-1 is important for host immunity to and , however, whether Dectin-1 is important for host defense against or is unknown. Therefore, we compared the involvement of Dectin-1 in response to these four diverse spp. We found that Dectin-1 mediates innate cytokine responses to these spp. in a species- and cell-dependent manner. Dectin-1 KO mice succumbed to infection with highly virulent while they mostly survived infection with less virulent spp. However, Dectin-1 KO mice displayed increased fungal burden following infection with each spp. Additionally, T cells from Dectin-1 KO mice displayed enhanced effector functions likely due to the inability of Dectin-1 KO mice to clear the infections. Together, these data indicate that Dectin-1 is important for host defense to multiple spp., although the specific roles for Dectin-1 varies with different spp.
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http://dx.doi.org/10.3389/fmicb.2019.01800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691182PMC
August 2019

The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors.

PLoS Pathog 2019 06 26;15(6):e1007850. Epub 2019 Jun 26.

Division of Infection and Immunity and Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, Wales.

Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection.
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http://dx.doi.org/10.1371/journal.ppat.1007850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594653PMC
June 2019

Development and characterization of novel anti-C5 monoclonal antibodies capable of inhibiting complement in multiple species.

Immunology 2019 08 17;157(4):283-295. Epub 2019 Jun 17.

Division of Infection and Immunity, School of Medicine, Systems Immunity Research Institute, Cardiff University, Wales, UK.

Over the last decade there has been an explosion in complement therapies; one-third of the drugs in the clinic or in development target C5 protein. Eculizumab, a monoclonal antibody (mAb) that binds C5 and blocks its cleavage by the convertase, is the current reference standard treatment for atypical haemolytic uraemic syndrome (aHUS) and paroxysmal nocturnal haemoglobinuria (PNH) and in clinical trials for many other diseases. Here we describe a panel of novel anti-C5 mAb, including mAb that, like Eculizumab, are efficient inhibitors of complement but, unlike Eculizumab, inhibit across species, including human, rat, rabbit and guinea pig. Several inhibitory anti-C5 mAb were identified and characterized for C5 binding and lytic inhibitory capacity in comparison to current therapeutic anti-C5 mAb; three clones, 4G2, 7D4 and 10B6, were selected and further characterized for ligand specificity and affinity and cross-species inhibitory activity. The mAb 10B6 was human-specific whereas mAb 4G2 and 7D4 efficiently inhibited lysis by human, rabbit and rat serum, and weakly inhibited guinea pig complement; 7D4 also weakly inhibited mouse complement in vitro The rat C5-cross-reactive mAb 4G2, when administered intraperitoneally in a rat model of myasthenia gravis, effectively blocked the disease and protected muscle endplates from destruction. To our knowledge this is the first report of an anti-C5 function blocking mAb that permits preclinical studies in rats.
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http://dx.doi.org/10.1111/imm.13083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620185PMC
August 2019

Activation of naïve CD4 T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4 T cells.

Nat Immunol 2019 04 19;20(4):458-470. Epub 2019 Mar 19.

Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK.

The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4 T cells, prior activation via the T cell antigen receptor limits IL-6's control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4 T cells. Transcriptomics and chromatin immunoprecipitation-sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4 T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4 T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4 T cells sense and interpret cytokine signals.
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http://dx.doi.org/10.1038/s41590-019-0350-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610646PMC
April 2019

Association between tooth loss and upper gastrointestinal cancer: A 30-year follow-up of the Linxian Dysplasia Nutrition Intervention Trial Cohort.

Thorac Cancer 2019 04 18;10(4):966-974. Epub 2019 Mar 18.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: This prospective study investigated the association between tooth loss and upper gastrointestinal (UGI) cancer mortality in the Linxian Dysplasia Nutrition Intervention Trial Cohort.

Methods: Subjects were categorized into three groups according to age at baseline. No missing teeth and less or greater than median tooth loss in each group was defined as none, moderate, and severe, respectively. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using the Cox proportional hazard model.

Results: Through 30 September 2015, 541 esophageal squamous cell carcinoma (ESCC), 284 gastric cardia carcinoma (GCC), and 77 gastric non-cardia carcinoma (GNCC) deaths occurred. In the six-year follow-up, severe tooth loss was associated with an increased risk of GCC mortality (HR 1.55, 95% CI 1.06-2.18). In the 15-year follow-up, moderate tooth loss increased the ESCC mortality risk by 58% (HR 1.58, 95% CI 1.06-2.35), while severe loss increased the GCC mortality risk by 30% (HR 1.30, 95% CI 1.03-1.64). In the 30-year follow-up, moderate tooth loss increased the risk of ESCC mortality (HR 1.34, 95% CI 1.01-1.76). In subjects aged < 55 at baseline and men, moderate tooth loss had 53% and 52% higher risks of ESCC mortality (HR 1.53, 95% CI 1.06-2.05; HRmen 1.52, 95% CI 1.01-2.28). No significant association was observed for GNCC in any subjects or subgroups.

Conclusion: Moderate tooth loss increased the risk of ESCC mortality, particularly in younger subjects and men. Severe tooth loss increased the risk of GCC mortality. Future studies are needed to confirm these findings.
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http://dx.doi.org/10.1111/1759-7714.13037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449253PMC
April 2019
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