Publications by authors named "Xiaomei Ma"

182 Publications

Cytokine levels at birth in children who developed acute lymphoblastic leukemia.

Cancer Epidemiol Biomarkers Prev 2021 Jun 2. Epub 2021 Jun 2.

Epidemiology, University of California, Berkeley, School of Public Health.

Background: Prenatal immune development may play an important role in the etiology of childhood acute lymphoblastic leukemia (ALL).

Methods: Seven cytokines - interleukin 1β (IL1β), IL4, IL6, IL8, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFα), and vascular endothelial growth factor (VEGF) - were analyzed in blood spots collected at birth from 1,020 ALL cases and 1,003 controls participating in the California Childhood Leukemia Study. Odds ratios (ORs) and 95% confidence intervals (95% CI) associated with an interquartile range increment in cytokine levels were calculated using logistic regression adjusting for sociodemographic and birth characteristics.

Results: We found that ALL patients were born with higher levels of a group of correlated cytokines than controls [IL1β: OR of 1.18 (95% CI: 1.03, 1.35); IL8: 1.19 (1.03, 1.38); TNFα: 1.15 (1.01, 1.30); VEGF: 1.16 (1.01, 1.33)], especially among children of Latina mothers (ORs from 1.31 to 1.40) and for ALL with high hyperdiploidy (ORs as high as 1.27). We found that neonatal cytokine levels were correlated with neonatal levels of endogenous metabolites which had been previously associated with ALL risk; however, there was no evidence that the cytokines were mediating the relationship between these metabolites and ALL risk.

Conclusions: We posit that children born with altered cytokine levels are set on a trajectory towards an increased risk for subsequent aberrant immune reactions that can initiate ALL.

Impact: This is the first study to evaluate the interplay between levels of immunomodulatory cytokines at birth, prenatal exposures, and the risk of childhood ALL.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1704DOI Listing
June 2021

An Optimal Choice of Cognitive Diagnostic Model for Second Language Listening Comprehension Test.

Front Psychol 2021 16;12:608320. Epub 2021 Apr 16.

School of Psychology, Guizhou Normal University, Guiyang, China.

Cognitive diagnostic models (CDMs) show great promise in language assessment for providing rich diagnostic information. The lack of a full understanding of second language (L2) listening subskills made model selection difficult. In search of optimal CDM(s) that could provide a better understanding of L2 listening subskills and facilitate accurate classification, this study carried a two-layer model selection. At the test level, A-CDM, LLM, and R-RUM had an acceptable and comparable model fit, suggesting mixed inter-attribute relationships of L2 listening subskills. At the item level, Mixed-CDMs were selected and confirmed the existence of mixed relationships. Mixed-CDMs had better model and person fit than G-DNIA. In addition to statistical approaches, the content analysis provided theoretical evidence to confirm and amend the item-level CDMs. It was found that semantic completeness pertaining to the attributes and item features may influence the attribute relationships. Inexplicable attribute conflicts could be a signal of suboptimal model choice. Sample size and the number of multi-attribute items should be taken into account in L2 listening cognitive diagnostic modeling studies. This study provides useful insights into the model selection and the underlying cognitive process for L2 listening tests.
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http://dx.doi.org/10.3389/fpsyg.2021.608320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085248PMC
April 2021

Clinical effectiveness of DNA methyltransferase inhibitors and lenalidomide in older patients with refractory anemia with ring sideroblasts: a population-based study in the United States.

Leuk Lymphoma 2021 Apr 24:1-10. Epub 2021 Apr 24.

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.

Existing studies regarding the role of DNA methyltransferase inhibitors (DNMTi) and lenalidomide in refractory anemia with ring sideroblasts (RARS) are limited. Using the surveillance, epidemiology, and end results-medicare database, we assembled a population-based cohort of older adults diagnosed with non-del(5q) lower-risk myelodysplastic syndromes during 2007-2015. Of 2167 patients, 30% had RARS. About 16% of RARS and non- ring sideroblasts (RS) patients received DNMTi. RARS patients were more likely to receive lenalidomide (11.1% vs. 7.1%,  < 0.01). Among patients who were transfusion-dependent at treatment initiation, 55.6% of those treated with DNMTi only and 42.5% treated with lenalidomide only achieved red blood cell transfusion independence (RBC-TI) for a median duration of 21 and 12 weeks, respectively. RS status did not impact rate of RBC-TI. RARS patients had a significantly better survival, and the median survival of RARS patients varied by treatment group. In this population-based study of older RARS patients, DNMTi and lenalidomide were clinically active.
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http://dx.doi.org/10.1080/10428194.2021.1913142DOI Listing
April 2021

CS2164 and Venetoclax Show Synergistic Antitumoral Activities in High Grade B-Cell Lymphomas With and Rearrangements.

Front Oncol 2021 10;11:618908. Epub 2021 Mar 10.

Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China.

High-grade B-cell lymphoma with concurrent and rearrangements (HGBL-DHL) is a rare, aggressive mature B-cell malignancy with a high likelihood of treatment failure following front-line immunochemotherapies. Patients with HGBL-DHL who develop a relapsed or refractory disease have little effective therapeutic strategies and show very poor clinical outcomes, thus calling for development of novel therapies for this specific patient population. In this study, we investigated the preclinical anti-lymphoma efficacies and potential mechanism of action of a novel treatment approach, combining the BCL2 inhibitor venetoclax with CS2164, a new orally active multitarget inhibitor, in HGBL-DHL models. This combination therapy exhibited a robust synergistic cytotoxicity against HGBL-DHL cells, evidenced by cooperatively inducing loss of cell viability and promoting cell apoptosis. Moreover, coadministration of CS2164 and venetoclax resulted in significant superior suppression of HGBL-DHL cell growth and remarkably abrogated tumor burden in a HGBL-DHL-xenografted mouse model. The synergistic lethality of CS2164 and venetoclax in HGBL-DHL cells was associated with induction of DNA damage and impairment of DNA repair ability. Of importance, the combined treatment almost abolished the expression of both BCL2 and MYC, two hallmark proteins of HGBL-DHL, and substantially blunted the activity of PI3K/AKT/mTOR signaling cascade. In addition, MCL1 and BCL-XL, two well-characterized contributors for venetoclax resistance, were significantly lessened in the presence of CS2164 and venetoclax, thus leading to the accumulation of proapoptotic proteins BAX and PUMA and then initiating the intrinsic apoptosis pathway. Taken together, these findings suggest that the regimen of CS2164 and venetoclax is highly effective to eliminate HGBL-DHL cells in the preclinical setting, warranting further clinical investigations of this regimen for the treatment of unfavorable HGBL-DHL patients.
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http://dx.doi.org/10.3389/fonc.2021.618908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988232PMC
March 2021

Patterns of Care for Older Patients With Myelofibrosis: A Population-based Study.

Clin Lymphoma Myeloma Leuk 2021 Jun 5;21(6):e551-e558. Epub 2021 Feb 5.

Department of Internal Medicine (Hematology), Yale School of Medicine, New Haven, CT; Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, New Haven, CT. Electronic address:

Background: Current treatments for myelofibrosis (MF) are largely palliative, with the JAK inhibitor ruxolitinib being the breakthrough approved for higher-risk patients by the United States Food and Drug Administration in November 2011. There are limited data on the "real-world" clinical experiences among patients with MF who are treated in the JAK inhibitor era.

Patients And Methods: We evaluated patterns of care for older patients with MF before and after ruxolitinib approval, using the Surveillance, Epidemiology, and End Results-Medicare database. Treatment patterns were assessed using Medicare part B and D claims.

Results: This study included 528 patients diagnosed during 2007 to 2015, with a median age at diagnosis of 76 years. Among 298 patients diagnosed in the ruxolitinib era (2012-2015), 113 (37.9%) were ruxolitinib users. Similar numbers of users started ruxolitinib at 5, 10, 15, or 20 milligrams twice a day (BID). Among 31 patients starting at 5 milligrams BID or less, 48.4% were unable to escalate the dose, and < 11 users could increase the dose to the maximum 25 mg BID. Approximately one-half of ruxolitinib users took hydroxyurea and/or prednisone simultaneously with ruxolitinib. The median time on ruxolitinib was 11.9 months (interquartile range, 4.2-21.7 months).

Conclusion: It would be important to optimize the use of ruxolitinib and develop new drugs that may be administered together with or after ruxolitinib to accomplish better outcomes in older patients with MF.
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http://dx.doi.org/10.1016/j.clml.2021.01.025DOI Listing
June 2021

A Stakeholder-Driven Qualitative Study to Define High Quality End-of-Life Care for Children With Cancer.

J Pain Symptom Manage 2021 Feb 5. Epub 2021 Feb 5.

Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Massachusetts, USA; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Context: Among adults with cancer, measures for high quality end-of-life care (EOLC) include avoidance of hospitalizations near end of life. For children with cancer, no measures exist to evaluate or improve EOLC, and adult quality measures may not apply.

Objective: We engaged key stakeholders to explore EOLC priorities for children with cancer and their families, and to examine relevance of existing adult EOLC quality measures for children with cancer.

Methods: In a multicenter qualitative study, we conducted interviews and focus groups with: adolescents and young adults (AYAs) with advanced cancer, parents of children with advanced cancer, bereaved parents, and interdisciplinary healthcare professionals. We transcribed, coded, and employed thematic analysis to summarize findings.

Results: We enrolled 54 stakeholders (25 parents [including 12 bereaved parents], 10 AYAs, and 19 healthcare professionals). Participants uniformly prioritized direct communication with children about preferences and prognosis, interdisciplinary care, symptom management, and honoring family preference for location of death. Many participants valued access to the emergency department or hospital for symptom management or supportive care, which diverges from measures for high quality EOLC in adults. Most wished to avoid mechanical ventilation and cardiopulmonary resuscitation. Notably, participants generally valued hospice; however, few understood hospice care or had utilized its services.

Conclusion: Childhood cancer stakeholders define high quality EOLC primarily through person-centered measures, characterizing half of existing adult-focused measures as limited in relevance to children. Future research should focus on developing techniques for person-centered quality measurement to capture attributes of greatest importance to children with cancer and their families.
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http://dx.doi.org/10.1016/j.jpainsymman.2021.01.134DOI Listing
February 2021

The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.

Nat Commun 2021 02 5;12(1):821. Epub 2021 Feb 5.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.
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http://dx.doi.org/10.1038/s41467-021-21064-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865055PMC
February 2021

CPEB4-Promoted Paclitaxel Resistance in Ovarian Cancer Relies on Translational Regulation of CSAG2.

Front Pharmacol 2020 13;11:600994. Epub 2021 Jan 13.

Medical College of Northwest Minzu University, Lanzhou, China.

Drug resistance is a major obstacle in chemotherapy for ovarian cancer, wherein the up regulation of drug-resistant genes plays an important role. The cytoplasmic polyadenylation element binding protein 4 (CPEB4) is an RNA binding protein that controls mRNA cytoplasmic polyadenylation and translation. The expression of CPEB4 in paclitaxel-resistant ovarian cancer cell lines and recurrent ovarian tumors relative to counterparts was determined by qRT-PCR, Western blotting and immunohistochemistry. The response to paclitaxel treatment was evaluated by cellular viability test and colony formation assay. RNA immunoprecipitation and poly(A) tail test were applied to examine the levels of RNA binding and cytoplasmic polyadenylation. CPEB4 is elevated in paclitaxel-resistant ovarian cancer cells and recurrent ovarian tumors treated with paclitaxel-based chemotherapy. In addition, CPEB4 overexpression promotes paclitaxel resistance in ovarian cancer cells , and vice versa, CPEB4 knockdown restores paclitaxel sensitivity, indicating that CPEB4 confers paclitaxel resistance in ovarian cancer cells. Mechanistically, CPEB4 binds with the taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2) mRNAs and induces its expression at a translational level. Moreover, CSAG2 expression is upregulated in paclitaxel-resistant ovarian carcinoma and cancer cell lines, and more importantly, siRNA-mediated CSAG2 knockdown overtly attenuates CPEB4-mediated paclitaxel resistance. This study suggests that the drug-resistant protein CSAG2 is translationally induced by CPEB4, which underlies CPEB4-promoted paclitaxel resistance in ovarian cancer . Thus, interfering CPEB4/CSAG2 axis might be of benefit to overcome paclitaxel-resistant ovarian cancer.
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http://dx.doi.org/10.3389/fphar.2020.600994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838559PMC
January 2021

Regional Adoption of Commercial Gene Expression Testing for Prostate Cancer.

JAMA Oncol 2021 Jan;7(1):52-58

Yale Cancer Outcomes, Public Policy, and Effectiveness Research Center, New Haven, Connecticut.

Importance: Although tissue-based genomic tests can aid in treatment decision-making for patients with prostate cancer, little is known about their clinical adoption.

Objective: To evaluate regional adoption of genomic testing for prostate cancer and understand common trajectories of uptake shared by regions.

Design, Setting, And Participants: This dynamic cohort study of patients diagnosed with prostate cancer used administrative claims from Blue Cross Blue Shield Axis, the largest source of commercial health insurance in the US, to characterize temporal trends in the use of commercial, tissue-based genomic testing and calculate the proportion of tested patients at the hospital referral region (HRR) level. Eligible patients from July 1, 2012, through June 30, 2018, were those aged 40 to 89 years with prostate cancer diagnosed from July 1, 2012, through June 30, 2018.

Main Outcomes And Measures: Group-based trajectory modeling was used to classify regions according to discrete trajectories of adoption of commercial, tissue-based genomic testing for prostate cancer. Across regions with distinct trajectories, HRR-level sociodemographic and health care contextual characteristics were compared, using data previously calculated among Medicare beneficiaries.

Results: A total of 92 418 men with prostate cancer who met inclusion criteria were identified; the median (interquartile range) age at diagnosis was 60 (56-63) years. Overall, the proportion of patients who received genomic testing increased from 0.8% in July 2012 to June 2013 to 11.3% in July 2017 to June 2018. Trajectory modeling identified 5 distinct regional trajectories of genomic testing adoption. Although less than 1% of patients in each group were tested at baseline, group 1 (lowest adoption) increased to 4.0%. Groups 2 (7.8%), 3 (14.6%), and 4 (17.3%) experienced more modest growth, while in group 5 (highest adoption), use increased to 33.8% of patients tested from June 2017 to July 2018. Compared with regions that more slowly adopted testing, HRRs with the highest rate of adoption (group 5) had higher HRR-level education measures (percentage [SD] with college education: group 1, 25.6% [4.8%]; vs group 2, 27.5% [7.3%]; vs group 3, 30.3% [9.1%]; vs group 4, 29.8% [8.2%]; vs group 5, 30.4% [11.4%]; P for trend = .03), median (SD) household income (group 1, $50 412.8 [$6907.4]; vs group 2, $54 419.6 [$11 324.5]; vs group 3, $61 424.0 [$17 723.8]; vs group 4, $58 508.3 [$15 174.6]; vs group 5, $58 367.0 [$13 180.5]; P for trend = .005), and prostate cancer resources, including clinician density (No. [SD] of clinicians per 100 000: group 1, 2.5 [0.3]; vs group 2, 2.5 [0.5]; vs group 3, 2.6 [0.5]; vs group 4, 2.7 [0.7]; vs group 5, 2.6 [0.5]; P for trend = .04) and prostate cancer screening (percentage [SD] of prostate-specific antigen testing among patients aged 68-74 y: group 1, 29.4% [11.8%]; vs group 2, 32.4% [11.2%]; vs group 3, 33.1% [12.7%]; vs group 4, 36.1% [9.7%]; vs group 5, 28.8% [11.8%]; P for trend = .05).

Conclusions And Relevance: In this cohort study of patients with prostate cancer, the adoption of commercial tissue-based genomic testing for prostate cancer was highly variable in the US at the regional level and may be associated with contextual measures related to socioeconomic status and patterns of prostate cancer care. These findings highlight factors underlying differential adoption of prognostic technologies for patients with cancer.
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http://dx.doi.org/10.1001/jamaoncol.2020.6086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689565PMC
January 2021

Socioeconomic status and childhood central nervous system tumors in California.

Cancer Causes Control 2021 Jan 28;32(1):27-39. Epub 2020 Oct 28.

Department of Epidemiology and Biostatistics, University of California, Berkeley, USA.

Purpose: Childhood central nervous system (CNS) tumors are the leading cause of cancer mortality in children. Previous studies have suggested that some childhood cancers, including primary CNS tumors, may be associated with higher socioeconomic status (SES).

Methods: We linked data from the California Cancer Registry to California birth records for children (age 0-19 years) diagnosed with primary CNS tumors during 1988-2011 and analyzed multiple measures of parental SES around the birth of their children and subsequent risk for childhood CNS tumors. Our SES measures included birth record-derived parental education and insurance utilization. For a subset of subjects born between 1997 and 2007, we geocoded addresses and examined census-derived median household income and educational level.

Results: We analyzed data for 3,022 children with primary CNS tumors and 10,791 matched controls. We found consistent evidence across multiple measures that lower estimates of SES are associated with a reduced risk of CNS tumors. In tumor subgroup analyses, this relationship was most consistent in astrocytomas and ependymomas, with varying findings for embryonal tumors.

Conclusion: Higher parental SES appears to be a risk factor for childhood CNS tumors in California. Further research is needed to determine specific exposures that may explain this increased risk.
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http://dx.doi.org/10.1007/s10552-020-01348-3DOI Listing
January 2021

Primary congenital choledochal cyst with squamous cell carcinoma: a case report.

J Int Med Res 2020 Sep;48(9):300060520946871

Gansu University of Traditional Chinese Medicine, Lanzhou, China.

Cases of extrahepatic bile duct carcinoma are mostly adenocarcinomas and extrahepatic bile duct squamous cell carcinomas are rare. We report here a case of choledochal squamous cell carcinoma in a young woman who underwent surgery and chemotherapy. The woman presented with abdominal discomfort. A physical examination showed tenderness in the upper abdomen. Laboratory tests showed elevated direct bilirubin, total bilirubin, and C-reactive protein levels. Abdominal computed tomography and magnetic resonance imaging showed a cystic-solid mixed soft tissue mass in the common bile duct. Pain symptoms in the patient were not relieved and surgical treatment was performed. Postoperative pathological results showed a choledochal cyst complicated by squamous cell carcinoma. The patient was treated by biliary intestinal anastomosis followed by chemotherapy. However, the patient developed liver metastasis and recurrence at a 6-month follow-up. Primary congenital bile duct cysts with squamous cell carcinoma are extremely rare. Surgical resection is the main treatment option for choledochal squamous cell carcinoma. Postoperative chemoradiotherapy can be used, but the efficacy is poor and chemotherapy does not significantly prolong the patient's survival.
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http://dx.doi.org/10.1177/0300060520946871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518012PMC
September 2020

Birth Characteristics and Risk of Pediatric Thyroid Cancer: A Population-Based Record-Linkage Study in California.

Thyroid 2021 04 7;31(4):596-606. Epub 2020 Oct 7.

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.

Incidence rates of thyroid cancer in children and young adults (age 0-19 years) have nearly doubled over a recent 15-year period in the United States. Children with thyroid cancer may require long-term therapy and surveillance and are at greater risk for second primary malignancies. High-dose exposure to ionizing radiation is the only known nongenetic risk factor; the vast majority of cases have an unknown etiology. We conducted a population-based nested case-control study to evaluate the relationship between a range of birth characteristics and the risk of pediatric thyroid cancer. Using linked birth records and cancer registry data from California, we included 1012 cases who were diagnosed with first primary thyroid cancer at the age of 0-19 years from 1988 to 2015 and 50,600 birth-year matched controls (1:50 case to control ratio). We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) by using multivariable logistic regression models applied to the full population and stratified by thyroid cancer subtypes (papillary and follicular), race/ethnicity (white and Hispanic), and age at diagnosis (0-14 and 15-19 years). Hispanic ethnicity (OR: 1.20 [CI 1.01-1.42]), higher birth weight (OR: 1.11 [CI 1.04-1.18] per 500g), and higher maternal education (13-15 years OR: 1.35 [CI 1.09-1.68], 16+ years OR: 1.35 [CI 1.07-1.71]) were associated with an increased risk of pediatric thyroid cancer, while male sex (OR: 0.21 [CI 0.18-0.25]) and higher birth order (third or higher OR: 0.81 [CI 0.68-0.98]) were associated with a decreased risk. Some heterogeneity was observed across subtype, most notably an elevated OR with higher birth order for follicular thyroid cancer, in contrast to the reduced risk for this category among papillary thyroid cancer cases (-value for interaction = 0.01). Hispanic ethnicity was a risk factor for papillary, but not follicular thyroid cancer (-value for interaction = 0.07). In this population-based study of birth characteristics and pediatric thyroid cancer, we identified several important risk factors for pediatric thyroid cancer, including female sex, Hispanic ethnicity, higher birth weight, higher maternal educational attainment, and lower birth order. Our data provide new areas for replication and investigation of biological mechanisms for this poorly understood malignancy.
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http://dx.doi.org/10.1089/thy.2020.0217DOI Listing
April 2021

Induction of the Unfolded Protein Response during Bovine Alphaherpesvirus 1 Infection.

Viruses 2020 09 2;12(9). Epub 2020 Sep 2.

Ruminant Diseases Research Center, College of Life Sciences, Shandong Normal University, Jinan 250014, China.

Bovine herpesvirus 1 (BoHV-1) is an alphaherpesvirus that causes great economic losses in the cattle industry. Herpesvirus infection generally induces endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) in infected cells. However, it is not clear whether ER stress and UPR can be induced by BoHV-1 infection. Here, we found that ER stress induced by BoHV-1 infection could activate all three UPR sensors (the activating transcription factor 6 (ATF6), the inositol-requiring enzyme 1 (IRE1), and the protein kinase RNA-like ER kinase (PERK)) in MDBK cells. During BoHV-1 infection, the ATF6 pathway of UPR did not affect viral replication. However, both knockdown and specific chemical inhibition of PERK attenuated the BoHV-1 proliferation, and chemical inhibition of PERK significantly reduced the viral replication at the post-entry step of the BoHV-1 life cycle. Furthermore, knockdown of IRE1 inhibits BoHV-1 replication, indicating that the IRE1 pathway may promote viral replication. Further study revealed that BoHV-1 replication was enhanced by IRE1 RNase activity inhibition at the stage of virus post-entry in MDBK cells. Furthermore, IRE1 kinase activity inhibition and RNase activity enhancement decrease BoHV1 replication via affecting the virus post-entry step. Our study revealed that BoHV-1 infection activated all three UPR signaling pathways in MDBK cells, and BoHV-1-induced PERK and IRE1 pathways may promote viral replication. This study provides a new perspective for the interactions of BoHV-1 and UPR, which is helpful to further elucidate the mechanism of BoHV-1 pathogenesis.
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http://dx.doi.org/10.3390/v12090974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552016PMC
September 2020

Diet and Risk of Myeloproliferative Neoplasms in Older Individuals from the NIH-AARP Cohort.

Cancer Epidemiol Biomarkers Prev 2020 11 31;29(11):2343-2350. Epub 2020 Aug 31.

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.

Background: The etiology of myeloproliferative neoplasms (MPN) is obscure, and no previous studies have evaluated the role of diet.

Methods: In the NIH-AARP Diet and Health Study, a prospective cohort of 463,049 participants ages 50 to 71 years at baseline (1995-1996), we identified 490 MPN cases after a median follow-up of 15.5 years, including 190 with polycythemia vera (PV) and 146 with essential thrombocythemia (ET). We examined possible associations between various dietary factors and the risk of MPN as a group, as well as PV and ET, using multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) and adjust for potential confounding variables.

Results: An increased risk was observed between fruit consumption and the risk of MPN overall (third tertile vs. first tertile, HR = 1.32; 95% CI, 1.04-1.67; = 0.02) and PV (third tertile vs. first tertile, HR = 2.00; 95% CI, 1.35-2.95; < 0.01). Increased risk of PV was also observed among those with high intake of sugar (HR = 1.77; 95% CI, 1.12-2.79), sugar from natural sources (HR = 1.77; 95% CI, 1.16-2.71), sugar from natural beverage sources (HR = 1.57; 95% CI, 1.08-2.29), and fructose (HR = 1.84; 95% CI, 1.21-2.79).

Conclusions: The intake of fat and protein did not appear to influence PV risk-neither did meat or vegetable consumption. None of the dietary factors studied was associated with the risk of ET. The role of sugar intake in the etiology of PV in older individuals warrants further investigation.

Impact: Our results indicate that high sugar intake is associated with an increased risk of polycythemia vera.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0592DOI Listing
November 2020

Preparation and Properties of an Alginate-Based Fiber Separator for Lithium-Ion Batteries.

ACS Appl Mater Interfaces 2020 Aug 17;12(34):38175-38182. Epub 2020 Aug 17.

School of Materials Science and Engineering, Qingdao University, Qingdao 266071, China.

The membrane is one of the key inner parts of lithium-ion batteries, which determines the interfacial structure and internal resistance, ultimately affecting the capacity, cycling, and safety performance of the cell. In this article, an alginate-based fiber composite membrane was successfully fabricated from cellulose and calcium alginate with flame-retardant properties via a traditional papermaking process. In the membrane, the calcium alginate plays a bridging role and the cellulose acts as a filler. After 100 cycles, lithium-ion batteries by the alginate-based fiber separator exhibited better capacity retention ratios (approximately 90%) compared with those of commercial PP separators. Furthermore, the alginate-based fiber separator demonstrated fine thermal stability and electrochemical properties, showing a stable charge-discharge capability and no hot melt shrinkage at higher temperatures, which is a breakthrough in improving the safety of the cell. This research affords a new way for the large-scale fabrication of safe lithium-ion battery separators.
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http://dx.doi.org/10.1021/acsami.0c10630DOI Listing
August 2020

National trends in the management of patients with positive surgical margins at radical prostatectomy.

World J Urol 2021 Apr 19;39(4):1141-1151. Epub 2020 Jun 19.

Department of Urology, Yale School of Medicine, 789 Howard Avenue, FMP 300, New Haven, CT, 06520, USA.

Purpose: To evaluate practice patterns of planned post-operative radiation therapy (RT) among men with positive surgical margins (PSM) at radical prostatectomy.

Methods: We identified 43,806 men within the National Cancer Database with pathologic node-negative prostate cancer diagnosed in 2010 through 2014 with PSM. The primary endpoint was receipt of planned (RT) within a patient's initial course of treatment. We examined post-RP androgen deprivation therapy (ADT) with RT as a secondary endpoint. We evaluated patterns of post-operative management and characteristics associated with planned post-prostatectomy RT.

Results: Within 12 months of RP, 87.0% received no planned RT, 8.5% RT alone, 1.3% ADT alone, and 3.1% RT with ADT. In a multivariable logistic regression model, planned RT use was associated with clinical and pathologic characteristics as estimated by surgical Cancer of the Prostate Risk Assessment (CAPRA-S) category (intermediate versus low, OR = 2.87, 95% CI 2.19-3.75, P < 0.001; high versus low, OR = 10.23, 95% CI 7.79-13.43, P < 0.001), treatment at community versus academic centers (OR = 1.24, 95% CI 1.15-1.34, P < 0.001), shorter distance to a treatment facility (OR = 0.97 for each 10-mile, 95% CI 0.96-0.98, P < 0.001), and uninsured status (OR = 1.39, 95% CI 1.10-1.77, P = 0.005). The odds of receiving planned RT were lower in 2014 versus 2010 (OR = 0.76, 95% CI 0.68-0.85, P < 0.001). There was no significant change in the use of ADT with RT. High versus low CAPRA-S category was associated with the use of ADT in addition to RT (OR = 5.13, 95% CI 1.57-16.80, P = 0.007).

Conclusion: The use of planned post-prostatectomy RT remained stable among patients with PSM and appears driven primarily by the presence of other adverse pathologic features.
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http://dx.doi.org/10.1007/s00345-020-03298-6DOI Listing
April 2021

T follicular helper cell-mediated IL-21 production suppresses FOXP3 expression of T follicular regulatory-like cells in diffuse large B cell lymphoma patients.

Hum Immunol 2020 Aug 10;81(8):452-459. Epub 2020 Jun 10.

Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen University, Xiamen, Fujian, China. Electronic address:

Based on CD25 expression, T follicular helper cells (Tfh) could be divided into T follicular regulatory (Tfr)-like subset (CD25CD4CXCR5) and CD25 Tfh subset (CD25CD4CXCR5). Patients with diffuse large B cell lymphoma (DLBCL) display high level of Tfr-like cells in blood and tumor. This Tfr-like subset could suppress CD8 T cell response while promote tumor cell proliferation. In this study, we investigated the transcription factors and regulatory elements associated with Tfr-like cells in DLBCL patients. Both circulating and tumor-infiltrating Tfr-like cells presented slightly higher Blimp-1 expression and significantly higher Foxp3 expression than the CD25 Tfh subset. As the IL-2 receptor, CD25 could be moderately upregulated in stimulated CD25 Tfh cells. However, stimulated CD25 Tfh cells could not upregulate Foxp3, indicating that the distinction between Foxp3-low CD25CXCR5CD4 T cells and Foxp3-high CD25CXCR5CD4 T cells was not due to differences in stimulation status. Regarding cytokine production, while both Tfr-like and CD25 Tfh cells upregulated IL-21 and IL-10 during stimulation, the CD25 Tfh cells presented significantly higher IL-21 and lower IL-10 expression than the Tfr-like cells, and the TGF-β expression was only increased in Tfr-like cells. Interestingly, IL-21 secreted from CD25 Tfh cells negatively regulated the expression of Foxp3 and IL-10 of autologous Tfr-like cells. Together, these results demonstrated that the Tfr-like and CD25 Tfh subsets of circulating Tfh cells presented different functions and should be investigated separately.
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http://dx.doi.org/10.1016/j.humimm.2020.05.008DOI Listing
August 2020

Epidemiology of the classical myeloproliferative neoplasms: The four corners of an expansive and complex map.

Blood Rev 2020 07 22;42:100706. Epub 2020 May 22.

Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, USA; Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, USA. Electronic address:

The classical myeloproliferative neoplasms (MPNs), specifically chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), represent clonal myeloid disorders whose pathogenesis is driven by well-defined molecular abnormalities. In this comprehensive review, we summarize the epidemiological literature and present our own analysis of the most recent the Surveillance, Epidemiology, and End Results (SEER) program data through 2016. Older age and male gender are known risk factors for MPNs, but the potential etiological role of other variables is less established. The incidences of CML, PV, and ET are relatively similar at 1.0-2.0 per 100,000 person-years in the United States, while PMF is rarer with an incidence of 0.3 per 100,000 person-years. The availability of tyrosine kinase inhibitor therapy has dramatically improved CML patient outcomes and yield a life expectancy similar to the general population. Patients with PV or ET have better survival than PMF patients.
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http://dx.doi.org/10.1016/j.blre.2020.100706DOI Listing
July 2020

Chromosome 1 abnormalities and survival of patients with multiple myeloma in the era of novel agents.

Blood Adv 2020 05;4(10):2245-2253

Cancer Outcomes, Public Policy, and Effectiveness Research Center and.

Chromosome 1 abnormalities (C1As) are common genetic aberrations among patients with multiple myeloma (MM). We aimed to evaluate the significance of C1As among a contemporary cohort of patients with MM in the United States. We used electronic health records from the Flatiron Health database to select patients newly diagnosed with MM from January 2011 to March 2018 who were tested using fluorescence in situ hybridization within 90 days of diagnosis. We characterized patients as having documented C1As or other high-risk chromosomal abnormalities (HRCAs) as defined by the Revised-International Staging System (R-ISS) such as del(17p), t(14;16), and t(4;14). We used Kaplan-Meier methods to compare overall survival (OS) of patients with or without C1As and stratified log-rank tests (with the presence of HRCAs as a stratifying variable). We used Cox proportional hazards regression models to compare OS, adjusting for age, sex, stage, HRCAs, and type of first-line therapy. Of 3578 eligible patients, 844 (24%) had documented C1As. Compared with patients without C1As, patients with C1As were more likely to have higher stage (R-ISS stage III; 18% vs 12%), to have HRCAs (27% vs 14%), and to receive combinations of proteasome inhibitors and immunomodulatory agents (41% vs 34%). Median OS was lower for patients with C1As (46.6 vs 70.1 months; log-rank P < .001). C1As were independently associated with worse OS (adjusted hazard ratio, 1.42; 95% confidence interval, 1.19-2.69; P < .001), as were older age, higher R-ISS stage, HRCAs, and immunoglobulin A isotype. C1As were associated with inferior OS, independent of other HRCAs, despite greater use of novel therapies. Clinical trials testing newer therapies for high-risk MM should incorporate patients with C1As.
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http://dx.doi.org/10.1182/bloodadvances.2019001425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252537PMC
May 2020

Clinical outcomes of older patients with AML receiving hypomethylating agents: a large population-based study in the United States.

Blood Adv 2020 05;4(10):2192-2201

Cancer Outcomes, Public Policy, and Effectiveness Research Center.

The hypomethylating agents (HMAs) azacitidine and decitabine have been the de facto standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive therapy. Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 2263 older adults (age ≥66 years) diagnosed with AML during 2005-2015 who received a first-line HMA; 1154 (51%) received azacitidine, and 1109 (49%) received decitabine. Median survival from diagnosis was 7.1 and 8.2 months (P < .01) for azacitidine- and decitabine-treated patients, respectively. Mortality risk was higher with azacitidine vs decitabine (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.01-1.21; P = .02). The findings were similar when evaluating only patients completing ≥4 cycles (42% of patients treated with either azacitidine or decitabine). These findings lost significance when evaluating those completing a standard 7-day schedule of azacitidine (34%) vs 5-day schedule for decitabine (66%) (HR, 0.95; 95% CI, 0.83-1.08; P = .43). Red blood cell (RBC) transfusion independence (TI) was achieved in one-third of patients with no difference between the 2 HMAs. In conclusion, the majority of older AML patients did not receive the minimum of 4 cycles of HMA often needed to elicit clinical benefit. We observed no clinically meaningful differences between azacitidine- and decitabine-treated patients in their achievement of RBC TI or survival.
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http://dx.doi.org/10.1182/bloodadvances.2020001779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252544PMC
May 2020

Patterns of care and clinical outcomes with cytarabine-anthracycline induction chemotherapy for AML patients in the United States.

Blood Adv 2020 04;4(8):1615-1623

Yale Cancer Outcomes, Public Policy, and Effectiveness Research Center, New Haven, CT; and.

Cytarabine-anthracycline based intensive induction chemotherapy (IC) remains the standard of care for remission induction among fit patients with newly diagnosed acute myeloid leukemia (AML) in the United States (US). However, the mortality rate outside of clinical IC trials, predictors of death, and resource utilization during admission for IC have not been thoroughly examined. We used the Premier Healthcare database to identify adult patients (aged 18-89 years) treated with cytarabine-anthracycline-based IC during their first recorded inpatient stay for AML during the contemporary period of 2010 to 2017. We identified factors associated with inpatient death or discharge to hospice, using multivariable logistic regression models. We also assessed the patterns of inpatient healthcare resource utilization. A total of 6442 patients with AML from 313 hospitals who were treated with IC were identified. Median age was 61 years (interquartile range [IQR], 50-68 years), and 56% were men. Median length of stay was 29 (IQR, 25-38) days, with rates of in-hospital death and discharge to hospice of 12.3% and 3.7% (17.9% and 6.3% among patients aged ≥65 years), respectively. Predictors of in-hospital death or discharge to hospice included older age, geographic region, and lower hospital volume. During admission, 28.0%, 12.6%, and 4.0% of patients required treatment in intensive care units, mechanical ventilation, and dialysis, respectively. Despite improvements in supportive care in the contemporary era, inpatient mortality during first hospitalization for adult patients with AML treated with IC in the US remains high particularly among older patients.
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http://dx.doi.org/10.1182/bloodadvances.2020001728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189301PMC
April 2020

Birth Characteristics and Risk of Early-Onset Synovial Sarcoma.

Cancer Epidemiol Biomarkers Prev 2020 06 3;29(6):1162-1167. Epub 2020 Apr 3.

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.

Background: Synovial sarcoma is a rare cancer with peak incidence in the young adult period. Despite poor outcomes of this aggressive cancer, there is little epidemiologic research addressing its etiology.

Methods: We collected birth characteristic data on synovial sarcoma cases born during 1978-2015 and diagnosed during 1988-2015 in California ( = 244), and 12,200 controls frequency-matched on year of birth. We also constructed a dataset of cancer cases in siblings of sarcoma subjects to assess familial risk.

Results: In multivariable logistic regression analyses, synovial sarcoma was more frequent in Hispanics compared with non-Hispanic whites [OR, 1.48; 95% confidence interval (CI), 1.06-2.08]. Higher birth weight was a risk factor in Hispanics; each 500 g increase in birth weight was associated with a 22% increase in disease risk (OR, 1.22; 95% CI, 1.00-1.48). Also, a strong role for birth order was suggested, with highest risk for the first born (second child compared with first: OR, 0.61; 95% CI, 0.44-0.84; third or later compared with first: OR, 0.53; 95% CI, 0.36-0.77). Siblings of patients with synovial sarcoma did not display elevated cancer incidence, suggesting the low likelihood that strong familial predisposition alleles play a significant role in this disease.

Conclusions: The associations with birth weight and birth order suggest that nutritional, developmental, and environmental factors may play a role in the etiology of synovial sarcoma.

Impact: Further epidemiologic research on synovial sarcoma should evaluate epigenetic and developmental mechanisms and the formation of the archetypical t(X;18) translocation that defines this disease.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605594PMC
June 2020

Metal ions modulation of the self-assembly of short peptide conjugated nonsteroidal anti-inflammatory drugs (NSAIDs).

Nanoscale 2020 Apr 31;12(14):7960-7968. Epub 2020 Mar 31.

College of Chemistry and Chemical Engineering, State Key Laboratory of Bio-Fibers and Eco-Textiles, Qingdao University, Qingdao 266071, China.

Metal ions are essential components that help maintain the processes of normal life, and they can be used to fabricate self-assembled building blocks for peptide derivatives, proteins and nucleic acids. Here, we have developed a novel strategy to construct supramolecular hydrogels modulated using metal cations. Upon introducing a variety of metal ions into aqueous solutions of a gelator (naproxen-FF), including a nonsteroidal anti-inflammatory drug (NSAID) and dipeptide, we obtain stable hydrogels under neutral or alkaline conditions. It is found that these hydrogels with three-dimensional nanofiber networks exhibit excellent mechanical properties and thixotropy, as well as superb responsivity to multiple metal ions. Due to the significance of potassium ions in biological processes, the K-triggered hydrogel has been chosen as a model, and its self-assembly mechanism has been explored via various spectral analysis processes. In addition, the self-assembly performances of peptides are significantly affected by the chemical structures of the gelator molecules. This work provides deep insight into the aggregation mechanism of dipeptide-conjugating drug molecules through introducing a variety of metal ions, laying the foundation for further biological applications.
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http://dx.doi.org/10.1039/d0nr00572jDOI Listing
April 2020

Reply to comments on: Lifestyles and myeloproliferative neoplasms with special reference to coffee consumption.

Int J Cancer 2020 06 30;146(12):3523. Epub 2020 Mar 30.

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.

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http://dx.doi.org/10.1002/ijc.32974DOI Listing
June 2020

Age-, sex- and disease subtype-related foetal growth differentials in childhood acute myeloid leukaemia risk: A Childhood Leukemia International Consortium analysis.

Eur J Cancer 2020 05 9;130:1-11. Epub 2020 Mar 9.

Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden. Electronic address:

Aim: Evidence for an association of foetal growth with acute myeloid leukaemia (AML) is inconclusive. AML is a rare childhood cancer, relatively more frequent in girls, with distinct features in infancy. In the context of the Childhood Leukemia International Consortium (CLIC), we examined the hypothesis that the association may vary by age, sex and disease subtype using data from 22 studies and a total of 3564 AML cases.

Methods: Pooled estimates by age, sex and overall for harmonised foetal growth markers in association with AML were calculated using the International Fetal and Newborn Growth Consortium for the 21st Century Project for 17 studies contributing individual-level data; meta-analyses were, thereafter, conducted with estimates provided ad hoc by five more studies because of administrative constraints. Subanalyses by AML subtype were also performed.

Results: A nearly 50% increased risk was observed among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03-2.14), reduced to 34% in boys aged <2 years (OR: 1.34, 95% CI: 1.05-1.71) and 25% in boys aged 0-14 years (OR: 1.25, 95% CI: 1.06-1.46). The association of large for gestational age became stronger in boys with M0/M1subtype (OR: 1.80, 95% CI: 1.15-2.83). Large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00-1.92) in boys. By contrast, there were null associations in girls, as well as with respect to associations of decelerated foetal growth markers.

Conclusions: Accelerated foetal growth was associated with AML, especially in infant boys and those with minimally differentiated leukaemia. Further cytogenetic research would shed light into the underlying mechanisms.
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http://dx.doi.org/10.1016/j.ejca.2020.01.018DOI Listing
May 2020

Risk factors for hepatocellular carcinoma (HCC) in the northeast of the United States: results of a case-control study.

Cancer Causes Control 2020 Apr 14;31(4):321-332. Epub 2020 Feb 14.

Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.

Purpose: HCC incidence has been continuously rising in the US for the past 30 years. To understand the increase in HCC risk, we conducted a case-control study in Connecticut, New Jersey and part of New York City.

Methods: Through rapid case ascertainment and random digit dialing, we recruited 673 incident HCC patients and 1,166 controls. Information on demographic and anthropometric characteristics, lifestyle factors, medical and family cancer histories, were ascertained through telephone interviews using a structured questionnaire. Saliva specimens were collected for testing hepatitis C virus (HCV) antibodies. Unconditional logistic regression models were utilized to calculate odds ratio (OR) and 95% confidence interval (CI) to determine HCC associations with risk factors.

Results: The study confirmed that HCV infection and obesity were important risk factors for HCC, ORs 110 (95% CI 59.2-204) and 2.13 (95% CI 1.52-3.00), respectively. High BMI and HCV infection had synergy in association with elevated HCC risk. Patients both obese and infected with HCV had HCC detected on average nearly 10 years earlier than those with neither factor. Diabetes, cigarette smoking and heavy alcohol intake were all associated with increased risk of HCC, whereas aspirin and other NSAID use were associated with reduced risk. HCC cases tended to attain less education, with lower household incomes, unmarried, and to have had more sexual partners than the controls.

Conclusions: Individuals at risk of HCC in the US comprise a unique population with low socioeconomic status and unhealthy lifestyle choices. Given the multifactorial nature, a comprehensive approach is needed in HCC prevention.
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http://dx.doi.org/10.1007/s10552-020-01277-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136513PMC
April 2020

Germline cancer predisposition variants and pediatric glioma: a population-based study in California.

Neuro Oncol 2020 06;22(6):864-874

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.

Background: Pediatric astrocytoma constitutes a majority of malignant pediatric brain tumors. Previous studies that investigated pediatric cancer predisposition have primarily been conducted in tertiary referral centers and focused on cancer predisposition genes. In this study, we investigated the contribution of rare germline variants to risk of malignant pediatric astrocytoma on a population level.

Methods: DNA samples were extracted from neonatal dried bloodspots from 280 pediatric astrocytoma patients (predominantly high grade) born and diagnosed in California and were subjected to whole-exome sequencing. Sequencing data were analyzed using agnostic exome-wide gene-burden testing and variant identification for putatively pathogenic variants in 175 a priori candidate cancer-predisposition genes.

Results: We identified 33 putatively pathogenic germline variants among 31 patients (11.1%) which were located in 24 genes largely involved in DNA repair and cell cycle control. Patients with pediatric glioblastoma were most likely to harbor putatively pathogenic germline variants (14.3%, N = 9/63). Five variants were located in tumor protein 53 (TP53), of which 4 were identified among patients with glioblastoma (6.3%, N = 4/63). The next most frequently mutated gene was neurofibromatosis 1 (NF1), in which putatively pathogenic variants were identified in 4 patients with astrocytoma not otherwise specified. Gene-burden testing also revealed that putatively pathogenic variants in TP53 were significantly associated with pediatric glioblastoma on an exome-wide level (odds ratio, 32.8, P = 8.04 × 10-7).

Conclusion: A considerable fraction of pediatric glioma patients, especially those of higher grade, harbor a putatively pathogenic variant in a cancer predisposition gene. Some of these variants may be clinically actionable or may warrant genetic counseling.
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http://dx.doi.org/10.1093/neuonc/noaa014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283023PMC
June 2020

Lifestyle factors and risk of myeloproliferative neoplasms in the NIH-AARP diet and health study.

Int J Cancer 2020 08 29;147(4):948-957. Epub 2020 Jan 29.

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT.

The etiology of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) is largely unknown. We assessed potential associations between lifestyle factors and MPN risk in the NIH-AARP Diet and Health Study. In this prospective cohort with 463,049 participants aged 50-71 years at baseline (1995-1996) and a median follow-up of 15.5 years, we identified 490 MPN cases, including 190 with polycythemia vera (PV) and 146 with essential thrombocythemia (ET). Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Smoking was not associated with MPN risk in the overall cohort, but analyses stratified by sex suggested that smoking increased the risk of MPN in women (former smoker vs. nonsmokers, HR = 1.43, 95% CI: 1.03-2.00, p = 0.03; current smokers vs. nonsmokers, HR = 1.71, 95% CI: 1.08-2.71, p = 0.02). Coffee consumption was inversely associated with the risk of PV (high vs. low intake, HR = 0.53, 95% CI: 0.33-0.84, p-trend < 0.01), but not the risk of ET or MPN overall. Further analysis revealed an inverse association between the amount of caffeine intake and PV risk (high vs. low intake, HR = 0.55, 95% CI: 0.39-0.79, p-trend < 0.01). While the consumption of caffeinated coffee appeared to confer a protective effect against PV, the consumption of decaffeinated coffee did not. This large prospective study identified smoking as a risk factor for MPN in women and suggests that caffeine intake is associated with a lower risk of PV.
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http://dx.doi.org/10.1002/ijc.32853DOI Listing
August 2020

Hypomethylating agent (HMA) therapy use and survival in older adults with Refractory Anemia with Excess Blasts (RAEB) in the United States (USA): a large propensity score-matched population-based study.

Leuk Lymphoma 2020 05 26;61(5):1178-1187. Epub 2019 Dec 26.

Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT, USA.

Hypomethylating agents (HMA) showed overall survival (OS) benefits in patients with higher-risk myelodysplastic syndromes (HR-MDS) in clinical trials. We conducted a retrospective cohort study of Surveillance, Epidemiology, and End Results (SEER)-Medicare data of patients ≥66 years diagnosed with refractory anemia with excess blasts (RAEB), a proxy for HR-MDS, in 01/2001-04/2004 (pre-period) or 01/2006-12/2011 (post-period). Association between post-period diagnosis and OS was examined using propensity scores (PS)-matched samples. Among 1876 RAEB patients, median OS was 9 months and 30.8% received HMAs (3.6% in pre-period; 43.0% in post-period) with no association between post-period diagnosis and OS. In the top PS quartile, post-period diagnosis was associated with a 74% lower risk of death (Hazard ratio [HR] = 0.26, 95%-CI: 0.10-0.69,  = 0.007), while outcomes were worse in the lowest PS quartile (HR = 2.80, 95%-CI: 1.06-7.36,  = 0.037). HMA lead to a 3-month OS benefit for patients most likely to receive HMA but not for unselected RAEB cohort.
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http://dx.doi.org/10.1080/10428194.2019.1703970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735409PMC
May 2020

Spatial-Temporal Cluster Analysis of Childhood Cancer in California.

Epidemiology 2020 03;31(2):214-223

Division of Epidemiology, University of California, Berkeley, CA.

Background: The observance of nonrandom space-time groupings of childhood cancer has been a concern of health professionals and the general public for decades. Many childhood cancers are suspected to have initiated in utero; therefore, we examined the spatial-temporal randomness of the birthplace of children who later developed cancer.

Methods: We performed a space-time cluster analysis using birth addresses of 5,896 cases and 23,369 population-based, age-, sex-, and race/ethnicity-matched controls in California from 1997 to 2007, evaluating 20 types of childhood cancer and three a priori designated subgroups of childhood acute lymphoblastic leukemia (ALL). We analyzed data using a newly designed semiparametric analysis program, ClustR, and a common algorithm, SaTScan.

Results: We observed evidence for nonrandom space-time clustering for ALL diagnosed at 2-6 years of age in the South San Francisco Bay Area (ClustR P = 0.04, SaTScan P = 0.07), and malignant gonadal germ cell tumors in a region of Los Angeles (ClustR P = 0.03, SaTScan P = 0.06). ClustR did not identify evidence of clustering for other childhood cancers, although SaTScan suggested some clustering for Hodgkin lymphoma (P = 0.09), astrocytoma (P = 0.06), and retinoblastoma (P = 0.06).

Conclusions: Our study provides evidence that childhood ALL diagnosed at 2-6 years and malignant gonadal germ cell tumors sporadically occurs in nonrandom space-time clusters. Further research is warranted to identify epidemiologic features that may inform the underlying etiology.
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http://dx.doi.org/10.1097/EDE.0000000000001121DOI Listing
March 2020