Publications by authors named "Zhaoming Wang"

249 Publications

T cells, particularly activated CD4 cells, maintain anti-CD20-mediated NK cell viability and antibody dependent cellular cytotoxicity.

Cancer Immunol Immunother 2021 Jun 10. Epub 2021 Jun 10.

Cancer Biology Graduate Program, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.

Anti-CD20 monoclonal antibody (mAb) therapy is a mainstay of therapy for B cell malignancies, however many patients fail to respond or eventually develop resistance. The current understanding of mechanisms responsible for this resistance is limited. When peripheral blood mononuclear cells of healthy donors were cultured with Raji cells for 7 days, rituximab (RTX) induced NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), enhanced NK cell viability and increased or maintained NK expression of CD56, CD16, CD57 and KIR. T cells, mainly CD4, mediated these changes in a contact-dependent manner, with local T cell production of IL2 playing a central role. Similar findings were found when autologous B cells were used as target cells demonstrating the need for T cell help was not due to allogenic reaction. Results with other anti-CD20 and anti-EGFR antibodies were consistent. Small numbers of T cells activated by anti-CD3/CD28 beads or bispecific antibody enhanced RTX-mediated NK cell ADCC, viability and phenotypical changes. Pathway analysis of bulk NK cell mRNA sequencing after activation by RTX with and without T cells was consistent with T cells maintaining the viability of the activated NK cells. These findings suggest T cell help, mediated in large part by local production of IL2, contributes to NK cell ADCC and viability, and that activating T cells in the tumor microenvironment, such as through the use of anti-CD3 based bispecific antibodies, could enhance the efficacy of anti-CD20 and other mAb therapies where NK-mediated ADCC is a primary mechanism of action.
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http://dx.doi.org/10.1007/s00262-021-02976-7DOI Listing
June 2021

A Pedigree Analysis and Clonal Correlations of the Coexistence of B-Cell Lymphoma and Histiocytic/Dendritic Cell Tumor.

Int J Surg Pathol 2021 May 3:10668969211013402. Epub 2021 May 3.

71069The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

Histiocytic/dendritic cell tumors are rare in clinical practice. It is postulated that they originate from bone marrow stem cells. Accumulating evidence has established the existence of immunoglobulin gene and T-cell receptor gene rearrangements in these tumors. Cases of transdifferentiation across lineages from follicular lymphoma to histiocytic/dendritic cell tumors have also been reported. Herein, we report 2 adult males with histiocytic neoplasms coexisting with B-cell lymphoma. Laser capture microdissection and capillary electrophoresis polymerase chain reaction analysis revealed comparable immunoglobulin gene rearrangement in both patients. In one case, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Langerhans cell sarcoma, and histiocytic sarcoma coexisted in the lymph nodes. 11q22 deletion often present in CLL/SLL and expression of the gene was detected in all the 3 components. In the other case, there diffuse large B-cell lymphoma and histiocytic sarcoma coexisted in the spleen. Forty-seven mutated genes commonly found in B-cell lymphoma were detected by next-generation sequencing. In the same line, , , , , and genes were found to have similar mutation sites. The results of this study will contribute in providing new ideas for targeted treatment of these diseases.
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http://dx.doi.org/10.1177/10668969211013402DOI Listing
May 2021

The Association of Mitochondrial Copy Number with Sarcopenia in Adult Survivors of Childhood Cancer.

J Natl Cancer Inst 2021 Apr 19. Epub 2021 Apr 19.

Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN.

Background: Adult childhood cancer survivors are at risk for frailty, including low muscle mass and weakness (sarcopenia). Using peripheral blood (PB) mitochondrial DNA copy number (mtDNAcn) as a proxy for functional mitochondria, this study describes cross-sectional associations between mtDNAcn and sarcopenia among survivors.

Methods: Among 1,762 adult childhood cancer survivors (51.6% male; median age = 29.4 [IQR = 23.3-36.8] years), with a median of 20.6 years from diagnosis (IQR = 15.2-28.2), mtDNAcn estimates were derived from whole-genome sequencing. A subset was validated by quantitative polymerase chain reaction and evaluated cross-sectionally using multivariable logistic regression for their association with sarcopenia, defined by race-, age-, and sex-specific low lean muscle mass or weak grip strength. All statistical tests were 2-sided.

Results: The prevalence of sarcopenia was 27.0%, higher among females than males (31.5% vs. 22.9%; P < 0.001) and associated with age at diagnosis; 51.7% of survivors with sarcopenia were diagnosed ages 4-13 years (p = 0.01). Sarcopenia was most prevalent (39.0%) among central nervous system tumor survivors. Cranial radiation (OR = 1.84; 95% CI = 1.32-2.59) and alkylating agents (OR = 1.34; 95% CI = 1.04-1.72) increased, while glucocorticoids decreased odds (OR = 0.72; 95% CI = 0.56-0.93) of sarcopenia. mtDNAcn decreased with age (β=-0.81; P = 0.002), was higher among females (β = 9.23; P = 0.01) and among survivors with a C allele at mt.204 (β=-17.9; P = 0.02). In adjusted models, every standard deviation decrease in mtDNAcn increased the odds of sarcopenia 20% (OR = 1.20; 95% CI = 1.07-1.34).

Conclusions: While a growing body of evidence supports PB mtDNAcn as a biomarker for adverse health outcomes, this study is the first to report an association between mtDNAcn and sarcopenia among childhood cancer survivors.
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http://dx.doi.org/10.1093/jnci/djab084DOI Listing
April 2021

Persistent variations of blood DNA methylation associated with treatment exposures and risk for cardiometabolic outcomes in long-term survivors of childhood cancer in the St. Jude Lifetime Cohort.

Genome Med 2021 Apr 6;13(1):53. Epub 2021 Apr 6.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 735, Memphis, TN, 38105, USA.

Background: It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions.

Methods: We included 2052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA.

Results: By performing multiple treatment-specific EWAS, we identified 935 5'-cytosine-phosphate-guanine-3' (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at the epigenome-wide significance level (p < 9 × 10). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (false discovery rate-adjusted p < 0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for the association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for the association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with a 32.9% mediation effect, and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA).

Conclusions: In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.
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http://dx.doi.org/10.1186/s13073-021-00875-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025387PMC
April 2021

Short sleep duration and physical and psychological health outcomes among adult survivors of childhood cancer.

Pediatr Blood Cancer 2021 Jul 6;68(7):e28988. Epub 2021 Apr 6.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: To examine associations between phenotypes of short sleep duration and clinically assessed health conditions in long-term survivors of childhood cancer.

Methods: Survivors recruited from the St. Jude Lifetime Cohort (n = 911; 52% female; mean age 34 years; 26 years postdiagnosis) completed behavioral health surveys and underwent comprehensive physical examinations. Sleep was assessed with the Pittsburgh Sleep Quality Index. Short sleep was defined as ≤6 h per night with phenotypes of short sleep including poor sleep efficiency (<85%), prolonged sleep onset latency (SOL; ≥30 min), and wake after sleep onset (≥3 times per week). Covariates included childhood cancer treatment exposures, demographics, body mass index, and physical inactivity. Separate modified Poisson regression models were computed for each health category to estimate relative risks (RR) and 95% confidence intervals (CI). Multinomial logistic regression models examined associations between sleep and an aggregated burden of chronic health conditions.

Results: Short sleep duration was reported among 44% (95% CI 41%-47%) of survivors. In multivariable models, short sleep duration alone was associated with pulmonary (RR = 1.35, 95% CI 1.08-1.69), endocrine (RR = 1.22, 95% CI 1.06-1.39) and gastrointestinal/hepatic conditions (RR = 1.46, 95% CI 1.18-1.79), and anxiety (RR 3.24, 95% CI 1.64-6.41) and depression (RR = 2.33, 95% CI 1.27-4.27). Short sleep with prolonged SOL was associated with a high/severe burden of health conditions (OR = 2.35, 95% CI 1.12-4.94).

Conclusions: Short sleep duration was associated with multiple clinically ascertained adverse health conditions. Although the temporality of these associations cannot be determined in this cross-sectional study, sleep is modifiable and improving sleep may improve long-term health in survivors.
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http://dx.doi.org/10.1002/pbc.28988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165003PMC
July 2021

Progression of Frailty in Survivors of Childhood Cancer: a St. Jude Lifetime Cohort Report.

J Natl Cancer Inst 2021 Mar 15. Epub 2021 Mar 15.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN.

Background: Some adult survivors of childhood cancers develop frailty at higher rates than expected based on their chronological age. This study examined the incidence of frailty among survivors at ten or more years after diagnosis, frailty prevalence 5 years later, and risk factors for becoming frail.

Methods: Frailty was measured at study entry and five years later. Logistic regression tested the associations of several factors with having frailty at five years for all participants and separately by sex and by study entry frailty status. Cox models evaluated the hazard of death associated with entry frailty considering covariates.

Results: Cancer survivors (range = 0-22 years at diagnosis, median = 7 years) were age 18-45 years (median = 30 years) at study entry. Frailty prevalence increased from 6.2% (95% confidence interval [CI] = 5.0%-7.5%) to 13.6% (95% CI = 11.9%-15.4%) at 5 years. Risk factors for frailty at follow-up among all survivors included chest radiation ≥20 Gy (odds ratio [OR] = 1.98, 95% CI = 1.29-3.05), cardiac (OR = 1.58, 95% CI = 1.02-2.46) and neurological (OR = 2.58, 95% CI = 1.69-3.92) conditions, lack of strength training (OR = 1.74, 95% CI = 1.14-2.66), sedentary lifestyle (OR = 1.75, 95% CI = 1.18-2.59), and frailty at study entry (OR = 11.12, 95% CI = 6.64-18.61). The strongest risk factor for death during follow-up was prior frailty (OR = 3.52, 95% CI = 1.95-6.32).

Conclusions: Prevalent frailty more than doubled at 5 years after study entry among adult childhood cancer survivors. Frailty at entry was the strongest risk factor for death. Because treatment exposures cannot be changed, mitigation of other risk factors for frailty, including lack of strength training and sedentary lifestyle may decrease risk of adverse health events and improve longevity in survivors.
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http://dx.doi.org/10.1093/jnci/djab033DOI Listing
March 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Immune checkpoint markers and anti-CD20-mediated NK cell activation.

J Leukoc Biol 2020 Dec 8. Epub 2020 Dec 8.

Cancer Biology Graduate Program, Carver College of Medicine, the University of Iowa, Iowa City, Iowa, USA.

Anti-CD20 mAb is an effective therapy for most B-cell malignancies. Checkpoint blockade has been used to enhance T-cell-mediated antitumor response. Little is known about the biologic significance of immune checkpoints expressed by NK cells in anti-CD20-based therapy. To investigate the role of checkpoints in anti-CD20-mediated NK cell biology, Raji B-cell lymphoma cells, and PBMCs from normal donors were cocultured with rituximab (RTX), obinutuzumab (OBZ), or trastuzumab as a control mAb for between 20 h and 9 d. RTX and OBZ induced a dose-dependent NK cell up-regulation of T-cell immunoreceptor with Ig and ITIM domain (TIGIT) and T-cell immunoglobulin mucin-3 (TIM3), but not PD1, CTLA4, or LAG3. Resting CD56 NK had higher TIGIT and TIM3 expression than resting CD56 NK although TIGIT and TIM3 were up-regulated on both subsets. NK cells with the CD16 158VV single nucleotide polymorphism had greater TIM3 up-regulation than did NK from VF or FF donors. TIGIT and TIM3 NK cells degranulated, produced cytokines, and expressed activation markers to a greater degree than did TIGIT or TIM3 NK cells. Blockade of TIGIT, TIM3, or both had little impact on RTX-induced NK cell proliferation, degranulation, cytokine production, or activation. Taken together, TIGIT and TIM3 can serve as markers for anti-CD20-mediated NK cell activation, but may not serve well as targets for enhancing the anti-tumor activity of such therapy.
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http://dx.doi.org/10.1002/JLB.5A0620-365RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184884PMC
December 2020

SequencErr: measuring and suppressing sequencer errors in next-generation sequencing data.

Genome Biol 2021 Jan 25;22(1):37. Epub 2021 Jan 25.

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Background: There is currently no method to precisely measure the errors that occur in the sequencing instrument/sequencer, which is critical for next-generation sequencing applications aimed at discovering the genetic makeup of heterogeneous cellular populations.

Results: We propose a novel computational method, SequencErr, to address this challenge by measuring the base correspondence between overlapping regions in forward and reverse reads. An analysis of 3777 public datasets from 75 research institutions in 18 countries revealed the sequencer error rate to be ~ 10 per million (pm) and 1.4% of sequencers and 2.7% of flow cells have error rates > 100 pm. At the flow cell level, error rates are elevated in the bottom surfaces and > 90% of HiSeq and NovaSeq flow cells have at least one outlier error-prone tile. By sequencing a common DNA library on different sequencers, we demonstrate that sequencers with high error rates have reduced overall sequencing accuracy, and removal of outlier error-prone tiles improves sequencing accuracy. We demonstrate that SequencErr can reveal novel insights relative to the popular quality control method FastQC and achieve a 10-fold lower error rate than popular error correction methods including Lighter and Musket.

Conclusions: Our study reveals novel insights into the nature of DNA sequencing errors incurred on DNA sequencers. Our method can be used to assess, calibrate, and monitor sequencer accuracy, and to computationally suppress sequencer errors in existing datasets.
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http://dx.doi.org/10.1186/s13059-020-02254-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829059PMC
January 2021

Hemin from porcine blood effectively stabilized color appearance and odor of prepared pork chops upon repeated freeze-thaw cycles.

Meat Sci 2021 May 6;175:108432. Epub 2021 Jan 6.

School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230601, China; College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, China. Electronic address:

This study was designed to evaluate changes in color following pork chop supplementation with porcine hemin, astaxanthin and paprika red in response to repeated freeze-thaw processes. Surface color analyses revealed that hemin significantly enhanced the appearance of the pork chops (P < 0.05), and the coloring efficiency of 0.10% hemin was similar to that of 0.20% astaxanthin and 0.08% paprika red. Sensory evaluations conducted on both raw and fried chops showed that hemin and astaxanthin significantly enhanced the overall acceptability of the chops before and after cooking. The color stability of the pork chops was also evaluated, and the results suggested that the hemin-colored chops were the most stable among the three, upon repeated freeze-thaw cycles. The electronic nose showed that the odor of the hemin-colored samples after 0, 3, and 7 freeze-thaw cycles was better than that of the other two groups. In conclusion, hemin may be a superior supplement for the large scale preparation of prepared pork chop.
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http://dx.doi.org/10.1016/j.meatsci.2021.108432DOI Listing
May 2021

St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem.

Cancer Discov 2021 May 6;11(5):1082-1099. Epub 2021 Jan 6.

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, and visualizing genomic data from >10,000 pediatric patients with cancer and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes, and 2,202 transcriptomes. The resource is expanding rapidly, with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem-Genomics Platform, Pediatric Cancer Knowledgebase, and Visualization Community-enable simultaneously performing advanced data analysis in the cloud and enhancing the Pediatric Cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes. SIGNIFICANCE: To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing >1.2 petabytes of raw genomic data from >10,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102307PMC
May 2021

Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia.

Environ Int 2021 02 29;147:105975. Epub 2020 Dec 29.

Department of Internal Medicine, Kaohsiung Medical University Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.
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http://dx.doi.org/10.1016/j.envint.2020.105975DOI Listing
February 2021

Genome-wide Association Studies Reveal Novel Locus With Sex-/Therapy-Specific Fracture Risk Effects in Childhood Cancer Survivors.

J Bone Miner Res 2021 Apr 30;36(4):685-695. Epub 2020 Dec 30.

School of Public Health, University of Alberta, Edmonton, Canada.

Childhood cancer survivors treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, understanding of how genetic and clinical susceptibility factors jointly contribute to fracture risk among survivors is limited. To address this gap, we conducted genome-wide association studies of fracture risk after cancer diagnosis in 2453 participants of European ancestry from the Childhood Cancer Survivor Study (CCSS) with 930 incident fractures using Cox regression models (ie, time-to-event analysis) and prioritized sex- and treatment-stratified genetic associations. We performed replication analyses in 1417 survivors of European ancestry with 652 incident fractures from the St. Jude Lifetime Cohort Study (SJLIFE). In discovery, we identified a genome-wide significant (p < 5 × 10 ) fracture risk locus, 16p13.3 (HAGHL), among female CCSS survivors (n = 1289) with strong evidence of sex-specific effects (p  < 7 × 10 ). Combining discovery and replication data, rs1406815 showed the strongest association (hazard ratio [HR] = 1.43, p = 8.2 × 10 ; n = 1935 women) at this locus. In treatment-stratified analyses in the discovery cohort, the association between rs1406815 and fracture risk among female survivors with no RT exposures was weak (HR = 1.22, 95% confidence interval [CI] 0.95-1.57, p = 0.11) but increased substantially among those with greater head/neck RT doses (any RT: HR = 1.88, 95% CI 1.54-2.28, p = 2.4 × 10 ; >36 Gray only: HR = 3.79, 95% CI 1.95-7.34, p = 8.2 × 10 ). These head/neck RT-specific HAGHL single-nucleotide polymorphism (SNP) effects were replicated in female SJLIFE survivors. In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways. Genetic risk profiles integrating this locus may help identify female survivors who would benefit from targeted interventions to reduce fracture risk. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044050PMC
April 2021

Genetic Variants Associated with Therapy-Related Cardiomyopathy among Childhood Cancer Survivors of African Ancestry.

Cancer Res 2021 May 7;81(9):2556-2565. Epub 2020 Dec 7.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.

Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiotherapy; = 246) were compared with cardiotoxic-exposed survivors of European ancestry ( = 1,645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53- and 2.47-fold risks of CTCAE grade 2-4 and grade 3-4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF (rs6689879*C: EF reduction = 4.2%; = 2.8 × 10) in 246 survivors of African ancestry, which was successfully replicated in 1,645 survivors of European ancestry but with attenuated magnitude (EF reduction = 0.4%; = 0.042). In survivors of African ancestry, rs6689879*C showed a 5.43-fold risk of cardiomyopathy and 1.31-fold risk in those of European ancestry. Among survivors of African ancestry with rs6689879*C and CTCAE grade 2-4 cardiomyopathy, the promoter region was hypomethylated. Similar results were observed in survivors of European ancestry, albeit with reduced magnitudes of hypomethylation among those with rs6689879*C and CTCAE grade 2-4 cardiomyopathy. was upregulated in human-induced pluripotent stem cell-derived cardiomyocytes from patients with doxorubicin-induced cardiomyopathy. These findings have potential implications for long-term cardiac surveillance and up-front cancer care for patients of African ancestry. SIGNIFICANCE: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry, and a novel locus at 1p13.2 is associated with therapy-related cardiomyopathy specifically in African-American survivors..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137513PMC
May 2021

Mechanisms of change in gel water-holding capacity of myofibrillar proteins affected by lipid oxidation: The role of protein unfolding and cross-linking.

Food Chem 2021 May 9;344:128587. Epub 2020 Nov 9.

College of Food Science, Southwest University, Chongqing 400715, China. Electronic address:

This work explored the effects of protein unfolding and cross-linking induced by lipid oxidation (linoleic acid, OLA) on the gel water-holding capacity (WHC) of beef myofibrillar proteins (MP). Medium concentration of OLA (≤6 mM) caused the increase of gel WHC from 55.2% to 65.1%, while relative high OLA concentration (>6 mM) decreased the gel WHC. When the OLA concentrations increased from 0 to 10 mM, the population of immobile water of gel decreased from 92.91% to 78.97%, whereas that of free water increased from 6.13% to 19.80%, suggesting that OLA treatment regardless concentration was harmful for gel WHC. However, medium OLA concentrations (≤6 mM) caused the shifting of α-helixes to β-sheets in MP gel, exerting positive effect on gel WHC. Protein unfolding and cross-linking jointly determined the increased gel WHC at moderate oxidative modification. Additionally, the protein aggregation at high OLA concentration resulted in decreased gel WHC.
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http://dx.doi.org/10.1016/j.foodchem.2020.128587DOI Listing
May 2021

The Role of Gallstones in Gallbladder Cancer in India: A Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2021 Feb 13;30(2):396-403. Epub 2020 Nov 13.

Centre for Cancer Epidemiology, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.

Background: Past history of gallstones is associated with increased risk of gallbladder cancer in observational studies. We conducted complementary observational and Mendelian randomization (MR) analyses to determine whether history of gallstones is causally related to development of gallbladder cancer in an Indian population.

Methods: To investigate associations between history of gallstones and gallbladder cancer, we used questionnaire and imaging data from a gallbladder cancer case-control study conducted at Tata Memorial Hospital, Mumbai, Maharashtra, India (cases = 1,170; controls = 2,525). We then used 26 genetic variants identified in a genome-wide association study of 27,174 gallstone cases and 736,838 controls of European ancestry in an MR approach to assess causality. The association of these genetic variants with both gallstones and gallbladder cancer was examined in the gallbladder cancer case-control study. Various complementary MR approaches were used to evaluate the robustness of our results in the presence of pleiotropy and heterogeneity, and to consider the suitability of the selected SNPs as genetic instruments for gallstones in an Indian population.

Results: We found a strong observational association between gallstones and gallbladder cancer using self-reported history of gallstones [OR = 4.5; 95% confidence interval (CI) = 3.5-5.8] and with objective measures of gallstone presence using imaging techniques (OR = 2.0; 95% CI = 1.5-2.7). We found consistent causal estimates across all MR techniques, with ORs for gallbladder cancer in the range of 1.3-1.6.

Conclusions: Our findings indicate a causal relationship between history of gallstones and increased risk of gallbladder cancer, albeit of a smaller magnitude than those found in observational analysis.

Impact: Our findings emphasize the importance of gallstone treatment for preventing gallbladder cancer in high-risk individuals.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0919DOI Listing
February 2021

A comprehensive insight into the effects of microbial spoilage, myoglobin autoxidation, lipid oxidation, and protein oxidation on the discoloration of rabbit meat during retail display.

Meat Sci 2021 Feb 22;172:108359. Epub 2020 Oct 22.

Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, China; School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China. Electronic address:

The effects of the retail display temperature (8 °C, 3 °C and - 1 °C) on the discoloration of the Longissimus thoracis et lumborum of rabbits and the associations among such effects with microbial spoilage, myoglobin autoxidation, lipid oxidation, and protein oxidation were investigated. The total aerobic count, total volatile basic nitrogen content, metmyoglobin content, protein carbonyl content, and contents of thiobarbituric acid-reactive substances steadily increased during retail display. Moreover, the lightness and redness of the rabbit meat significantly (P < 0.05) declined over time, whereas the yellowness increased considerably (P < 0.05) with prolonged retail time. Canonical correlation analysis suggested that microbial spoilage, myoglobin autoxidation, lipid oxidation, and protein oxidation jointly affected rabbit meat color. Linear mixed models further revealed that microbial spoilage, myoglobin autoxidation, lipid oxidation and protein oxidation positively affected yellowness, and they inversely impacted lightness and redness.
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http://dx.doi.org/10.1016/j.meatsci.2020.108359DOI Listing
February 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 Jan 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

Towards a 20 Gbps multi-user bubble turbulent NOMA UOWC system with green and blue polarization multiplexing.

Opt Express 2020 Oct;28(21):31796-31807

We experimentally demonstrated a high-speed multi-user green and blue laser diode based underwater optical wireless communication (UOWC) system using non-orthogonal multiple access (NOMA) with polarization multiplexing. The system affords eight users with a record sum rate of 18.75 Gbps over 2-m underwater plus 0.5-m free-space channel. The modulation bandwidths of four detachable optical paths with different wavelengths and polarization states all exceed 1.5 GHz. The results suggest that the flexible balance according to both user fairness and overall throughput/sum rate can be achieved via an appropriate power allocation strategy. The joint optimization of driving current and user assignment ensures the feasibility of providing stable high-speed UOWC for multiple users. With the proposed OFDMA-NOMA scheme, user scale expands by twice while the sum rate for single path reaches 3.2 Gbps. Finally, the BER performances of NOMA modality in turbulent underwater environment with air bubbles of different flow rates are also discussed in detail.
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http://dx.doi.org/10.1364/OE.405417DOI Listing
October 2020

immunization of a TLR9 agonist virus-like particle enhances anti-PD1 therapy.

J Immunother Cancer 2020 10;8(2)

Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, Iowa, USA

Background: CMP-001 is a novel Toll-like receptor-9 agonist that consists of an unmethylated CpG-A motif-rich G10 oligodeoxynucleotide (ODN) encapsulated in virus-like particles. vaccination of CMP-001 is believed to activate local tumor-associated plasmacytoid dendritic cells (pDCs) leading to type I interferon secretion and tumor antigen presentation to T cells and systemic antitumor T cell responses. This study is designed to investigate if CMP-001 would enhance head and neck squamous cell carcinoma (HNSCC) tumor response to anti-programmed cell death protein-1 (anti-PD-1) therapy in a human papilloma virus-positive (HPV+) tumor mouse model.

Methods: Immune cell activation in response to CMP-001±anti-Qβ was performed using co-cultures of peripheral blood mononuclear cells and HPV+/HPV- HNSCC cells and then analyzed by flow cytometry. vaccination with CMP-001 alone and in combination with anti-PD-1 was investigated in C57BL/6 mice-bearing mEERL HNSCC tumors and analyzed for anti-Qβ development, antitumor response, survival and immune cell recruitment. The role of antitumor immune response due to CMP-001+anti-PD-1 treatment was investigated by the depletion of natural killer (NK), CD4 T, and CD8 T cells.

Results: Results showed that the activity of CMP-001 on immune cell (pDCs, monocytes, CD4+/CD8+ T cells and NK cells) activation depends on the presence of anti-Qβ. A 2-week 'priming' period after subcutaneous administration of CMP-001 was required for robust anti-Qβ development in mice. vaccination of CMP-001 was superior to unencapsulated G10 CpG-A ODN at suppressing both injected and uninjected (distant) tumors. vaccination of CMP-001 in combination with anti-PD-1 therapy induced durable tumor regression at injected and distant tumors and significantly prolonged mouse survival compared with anti-PD-1 therapy alone. The antitumor effect of CMP-001+anti-PD-1 was accompanied by increased interferon gamma (IFNγ) CD4/CD8 T cells compared with control-treated mice. The therapeutic and abscopal effect of CMP-001+ anti-PD-1 therapy was completely abrogated by CD8 T cell depletion.

Conclusions: These results demonstrate that vaccination with CMP-001 can induce both local and abscopal antitumor immune responses. Additionally, the antitumor efficacy of CMP-001 combined with α-PD-1 therapy warrants further study as a novel immunotherapeutic strategy for the treatment of HNSCC.
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http://dx.doi.org/10.1136/jitc-2020-000940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566437PMC
October 2020

The clinicopathological and molecular features of sinusoidal large B-cell lymphoma.

Mod Pathol 2021 May 24;34(5):922-933. Epub 2020 Sep 24.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.

We report 17 cases of sinusoidal large B-cell lymphoma (SLBCL). Clinical, morphologic, immunophenotypic, and molecular features were detected and analyzed. All cases showed an obvious sinusoidal growth pattern, usually associated with residual atrophic lymphoid tissue. All tumors contained large pleomorphic lymphoid cells and one or more prominent nucleoli, with abundant amphophilic cytoplasms; 15/17 cases showed anaplastic morphologic features. The patient age ranged from 43 to 80 years (median 57 years), and 7 males and 10 females were included. Eleven of 15 (73.3%) patients had Ann Arbor stage III or IV disease, and 10/15 (66.6%) patients had an International Prognostic Index (IPI) score ≥3. Immunophenotypically, 16/17 (94.1%) cases displayed a nongerminal center B-cell (non-GCB) immunophenotype. Furthermore, 16/17 (94.1%) cases were positive for CD30, and p53 was expressed in 10/16 (62.5%) cases. In total, 12/14 (85.7%) cases expressed BCL2 and MYC simultaneously (double expression), and 11/14 (78.6%) cases showed PD-L1 positivity (6/11 had a PD-L1 tumor proportion score ≥50%). Cytogenetically, concurrent MYC and BCL2 and/or BCL6 abnormalities (break-apart or extra copy) were detected in 10/15 cases, and 7/13 (53.8%) cases harbored a PD-L1/L2 amplification. TP53 mutation was found in 7/13 (53.8%) cases by Sanger sequencing. Whole-exome and large-panel sequencing results revealed high mutation frequencies of TP53 (4/7), MYD88 (3/7), KMT2D (3/7), CREBBP (3/7), and PIM1 (3/7). Among the 13 patients with SLBCL treated with aggressive chemotherapy regimens, the median overall survival (OS) was 18 months, and the 2-year OS rate was 34.6%. The OS of patients with SLBCL was markedly worse than that of 35 control group patients with common diffuse large B-cell lymphoma (DLBCL) without sinusoidal features (P < 0.001). SLBCL may represent a specific type of DLBCL that has characteristic pathologic features. The cancer is aggressive in most clinical cases, and outcomes are poor. SLBCL and anaplastic DLBCL (A-DLBCL) have many overlapping clinicopathological and molecular features.
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http://dx.doi.org/10.1038/s41379-020-00685-7DOI Listing
May 2021

Epigenetic Age Acceleration and Chronic Health Conditions Among Adult Survivors of Childhood Cancer.

J Natl Cancer Inst 2021 May;113(5):597-605

Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.

Background: Mounting evidence supports the occurrence of accelerating aging among long-term survivors of childhood cancer. We aimed to investigate epigenetic age acceleration (EAA) in survivors and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs).

Methods: Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood-derived DNA from 2139 survivors and 282 frequency matched controls from the St Jude Lifetime Cohort Study. EAAs were estimated as residuals from a linear regression of epigenetic age (Levine's clock) against chronological age. Adjusted least square mean (ALSM) of EAA was calculated and compared between survivors and controls, across treatment exposures and health behaviors. Associations of EAA with 20 clinically assessed CHCs were evaluated with multivariable piecewise-exponential models. All statistical tests for P values below were 2-sided.

Results: EAA was statistically significantly higher in survivors than controls (ALSM = 0.63, 95% confidence interval [CI] = 0.26 to 1.01 vs -3.61, 95% CI = -4.43 to 2.80). In a multivariable model among survivors, statistically significantly higher EAA (P < .05) was observed in those exposed to chest radiotherapy, abdomen or pelvic radiotherapy, alkylating agents, glucocorticoids, or epipodophyllotoxins. Compared with survivors with favorable health behaviors (ALSM = 0.26, 95% CI=-0.36 to 0.87), EAA was statistically significantly higher among survivors with intermediate (ALSM = 1.07, 95% CI = 0.59 to 1.54) or unfavorable health behaviors (ALSM = 1.45, 95% CI = 0.60 to 2.30). In time-to-event analyses, statistically significant associations were identified between EAA tertiles and incidence of 7 CHCs: hypertension (3rd vs 1st tertile, relative rate [RR] = 1.83, 95% CI = 1.17 to 2.83), myocardial infarction (RR = 2.91, 95% CI = 1.27 to 7.21), obesity (RR = 1.39, 95% CI = 1.17 to 1.66), obstructive pulmonary deficit (RR = 1.86, 95% CI = 0.95 to 3.77), peripheral motor neuropathy (RR = 2.89, 95% CI = 1.24 to 6.97), peripheral sensory neuropathy (RR = 2.04, 95% CI = 0.99 to 4.26), and pulmonary diffusion deficits (RR = 2.75, 95% CI = 0.95 to 7.63).

Conclusions: EAA is statistically significantly higher in survivors of childhood cancer than in noncancer controls and is associated with specific treatment exposures, unfavorable health behaviors, and presence of specific CHCs.
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http://dx.doi.org/10.1093/jnci/djaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096366PMC
May 2021

Generalizability of "GWAS Hits" in Clinical Populations: Lessons from Childhood Cancer Survivors.

Am J Hum Genet 2020 10 17;107(4):636-653. Epub 2020 Sep 17.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; School of Public Health, University of Alberta, Edmonton, AB, T6G 1C9, Canada.

With mounting interest in translating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse clinical settings, evaluating their generalizability in target populations is crucial. Here, we consider long-term survivors of childhood cancers from the St. Jude Lifetime Cohort Study, and we show the limited generalizability of 1,376 robust SNP associations reported in the general population across 12 complex anthropometric and cardiometabolic phenotypes (n = 2,231; observed-to-expected replication ratio = 0.70, p = 6.2 × 10). An examination of five comparable phenotypes in a second independent cohort of survivors from the Childhood Cancer Survivor Study corroborated the overall limited generalizability of meta-GWAS hits to survivors (n = 4,212; observed-to-expected replication ratio = 0.55, p = 5.6 × 10). Finally, in direct comparisons of survivor samples against independent equivalently powered general population samples from the UK Biobank, we consistently observed lower meta-GWAS hit replication rates and poorer polygenic risk score predictive performance in survivor samples for multiple phenotypes. As a possible explanation, we found that meta-GWAS hits were less likely to be replicated in survivors who had been exposed to cancer therapies that are associated with phenotype risk. Examination of complementary DNA methylation data in a subset of survivors revealed that treatment-related methylation patterns at genomic sites linked to meta-GWAS hits may disrupt established genetic signals in survivors.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536574PMC
October 2020

Effects of partial replacement of NaCl with KCl on bacterial communities and physicochemical characteristics of typical Chinese bacon.

Food Microbiol 2021 Feb 3;93:103605. Epub 2020 Aug 3.

School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, Anhui, China. Electronic address:

This work aimed to determine the effects of partial substitution of NaCl with 0% (control), 30%, 50%, and 70% of KCl on the bacterial communities, proteolysis and lipid oxidation of Chinese bacon during processing. The proportion of genus Lactobacillus increased from 22.45% (fresh meat) to 72.78%, 81.64%, 76.53% and 85.63% at the end of processing for 0%, 30%, 50% and 70% KCl replacement samples, respectively. During the processing, Lactobacillus gradually became the dominant one, and higher the KCl ratio, more rapid was the process. After salting, the TBARS of control was markedly higher (P < 0.05) than that of the others, while a similar lipid oxidation level (P > 0.05) was observed at the end of processing for different groups. After salting, there was no difference in total free amino acids (TFAA) content among four treatments (P > 0.05), whereas KCl replacement samples shared significantly higher (P < 0.05) values than control at the end of processing. Redundancy analysis and Pearson correlation showed positive correlation between Lactobacillus versus TBARS and TFAA. Partial replacement of NaCl with KCl could, directly or subsequently by promoting the growth of Lactobacillus, influence proteolysis and lipid oxidation over the manufacturing process.
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http://dx.doi.org/10.1016/j.fm.2020.103605DOI Listing
February 2021

A Novel Predictive Model for Idiopathic Multicentric Castleman Disease: The International Castleman Disease Consortium Study.

Oncologist 2020 11 18;25(11):963-973. Epub 2020 Sep 18.

Division of Hematopathology and Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.

Background: Patients with multicentric Castleman disease (MCD) who are negative for human immunodeficiency virus and human herpesvirus 8 are considered to have idiopathic MCD (iMCD). The clinical presentation of iMCD varies from mild constitutional symptoms to life-threatening symptoms or death. The treatment strategy varies from "watchful waiting" to high-dose chemotherapy. This diverse clinical presentation calls for a classification stratification system that takes into account the severity of the disease.

Subjects, Materials, And Methods: We analyzed the clinical, laboratory, and pathologic abnormalities and treatment outcomes of 176 patients with iMCD (median follow-up duration 12 years) from the U.S. and China to better understand the characteristics and prognostic factors of this disease. This discovery set of iMCD results was confirmed from the validation set composed of additional 197 patients with iMCD organized from The International Castleman Disease Consortium.

Results: Using these data, we proposed and validated the iMCD international prognostic index (iMCD-IPI), which includes parameters related to patient characteristics (age > 40 years), histopathologic features (plasma cell variant), and inflammatory consequences of iMCD (hepatomegaly and/or splenomegaly, hemoglobin <80 g/L, and pleural effusion). These five factors stratified patients according to their performance status and extent of organ dysfunction into three broad categories: low risk, intermediate risk, and high risk. The iMCD-IPI score accurately predicted outcomes in the discovery study cohort, and the results were confirmed on the validation study cohort.

Conclusion: This study represents the largest series of studies on patients with iMCD in the field and proposed a novel risk-stratification model for iMCD-IPI that could be used to guide risk-stratified treatment strategies in patients with iMCD.

Implications For Practice: Patients with idiopathic multicentric Castleman disease (iMCD) can benefit from care based on clinical symptoms and disease severity. This study in 176 patients with iMCD constructed an iMCD-IPI score based on five clinical factors, including age >40 years, plasmacytic variant subtype, hepatomegaly and/or splenomegaly, hemoglobin <80 g/L, and pleural effusion, and stratified patients into three risk categories: low risk, intermediate risk, and high risk. The predictive value was validated in an independent set of 197 patients with iMCD from The International Castleman Disease Consortium. The proposed novel model is valuable for predicting clinical outcome and selecting optimal therapies using clinical parameters.
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http://dx.doi.org/10.1634/theoncologist.2019-0986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648372PMC
November 2020

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Int J Cancer 2021 01 7;148(2):307-319. Epub 2020 Aug 7.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.
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http://dx.doi.org/10.1002/ijc.33206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757859PMC
January 2021

Effects of different thermal temperatures on the shelf life and microbial diversity of Dezhou-braised chicken.

Food Res Int 2020 10 23;136:109471. Epub 2020 Jun 23.

Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230009, China; School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China; State Key Laboratory of Meat Processing and Quality Control, Yurun Group, Nanjing 211806, China; College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, China. Electronic address:

This work investigated the effects of different thermal temperatures (84 °C for 35 min, 95 °C for 30 min, and 121 °C for 20 min) on the shelf life and microbial diversity of Dezhou-braised chicken. During refrigerated storage at 4 °C, the increase rate of total viable counts, pH and TVB-N value, was lower in 95 °C-treated and 121 °C-sterilized groups, when compared with 84 °C-treated group. Electronic nose revealed that the fresh odor of Dezhou-braised chicken treated by 84 °C and 95 °C could be maintained during storage. Additionally, 95 °C contributed to the maintenance of good texture of chicken. High throughput sequencing showed that Bacillus and Clostridium were only very active in 84 °C-treated samples, but not in 95 °C-treated and 121 °C-sterilized samples. Taken together, 95 °C can be developed as one potential thermal treatment temperature for Dezhou-braised chicken, due to its positive effects on maintaining fresh odor and texture together with extending shelf life while also protecting food safety.
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http://dx.doi.org/10.1016/j.foodres.2020.109471DOI Listing
October 2020

Multi-user high-speed QAM-OFDMA visible light communication system using a 75-µm single layer quantum dot micro-LED.

Opt Express 2020 Jun;28(12):18332-18342

Next-generation visible light communication (VLC) is envisioned to evolve into a high-speed and multi-user system. In this work, a 75-µm single layer quantum dot (QD) micro-LED was fabricated, packaged and used to experimentally demonstrate a 3-meter QAM-OFDMA VLC system affording multiple users with a 1.06-GHz modulation bandwidth. The OFDMA system realized data rates of 1.2 Gbps and 750 Mbps with a BER of 0 and 3.6×10 for two independent users with a 1:1 bandwidth ratio, respectively. Additional sub-carrier allocation strategies and scenarios of 2∼6 users have been further evaluated, and all proposed strategies reach the sum-rate of beyond 1.41 Gbps while satisfying the forward error correction (FEC) criteria.
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http://dx.doi.org/10.1364/OE.395419DOI Listing
June 2020

A Genetic Screen to Identify Gain- and Loss-of-Function Modifications that Enhance T-cell Infiltration into Tumors.

Cancer Immunol Res 2020 09 1;8(9):1206-1214. Epub 2020 Jul 1.

Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.

T-cell-mediated cancer immunotherapies, including anti-PD-1 and T cells expressing chimeric antigen receptors (CAR-T cells), are becoming standard treatments for many cancer types. CAR-T therapy, in particular, has been successful in treating circulating, but not solid, tumors. One challenge limiting immunotherapy success is that tumors lacking T-cell infiltration do not respond to treatment. Therefore, one potential strategy to overcome resistance is to enhance the ability of T cells to traffic into tumors. Here, we describe an unbiased genetic screen approach utilizing the mutagenesis system to identify candidate genes in T cells that might be modified to drive intratumoral T-cell accumulation. This screen identified over 400 candidate genes in three tumor models. These results indicated substantial variation in gene candidate selection, depending on the tumor model and whether or not mice were treated with anti-PD-1, yet some candidate genes were identified in all tumor models and with anti-PD-1 therapy. Inhibition of the most frequently mutated gene, , affected chemokine receptor expression and enhanced T-cell trafficking and Screen candidates should be further validated as therapeutic targets, with particular relevance to enhancing infiltration of adoptively transferred T cells into solid tumors.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483799PMC
September 2020