Publications by authors named "Zhihai Ma"

27 Publications

  • Page 1 of 1

Comparison of Pregnancy Outcomes of Patients Treated With Ondansetron vs Alternative Antiemetic Medications in a Multinational, Population-Based Cohort.

JAMA Netw Open 2021 04 1;4(4):e215329. Epub 2021 Apr 1.

ICES, Toronto, Ontario, Canada.

Importance: Ondansetron is frequently used to treat nausea and vomiting during pregnancy. Although some studies reported important safety signals, few studies have been sufficiently large to assess rare pregnancy outcomes.

Objective: To study the association between ondansetron exposure during pregnancy and the risks of spontaneous abortion, stillbirth, and major congenital malformations.

Design, Setting, And Participants: This is a cohort study conducted in 3 countries, with a meta-analysis. Participants included women and girls aged 12 to 55 years who experienced spontaneous abortion, induced abortion, stillbirth, or live birth between April 2002 and March 2016, as recorded in administrative data from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, and Ontario), the US IBM MarketScan Research Databases, and the UK Clinical Practice Research Datalink. The statistical analysis was completed in October 2020.

Exposures: Exposure to ondansetron during pregnancy was compared with exposure to other commonly used antiemetics to minimize confounding by indication.

Main Outcomes And Measures: The primary outcome was fetal death, defined as either spontaneous abortion or stillbirth. Secondary outcomes were the 2 components of the primary outcome and major congenital malformations identified during the year after a live birth. Adjusted hazard ratios were estimated using Cox proportional hazards models with time-dependent drug exposures and were adjusted using high-dimensional propensity scores. For major congenital malformations, adjusted odds ratios were estimated from logistic models. Site-level results were pooled using random-effects meta-analysis. Sensitivity analyses considered second-line antiemetic exposure and exposure specifically during 4 to 10 weeks of gestation.

Results: Data from 456 963 pregnancies were included in this study of fetal death (249 787 [54.7%] in Canada, 197 913 [43.3%] in the US, and 9263 [2.0%] in the UK; maternal age, ≤24 years, 93 201 patients [20.4%]; 25-29 years, 149 117 patients [32.6%]; 30-34 years, 142 442 patients [31.2%]; and ≥35 years, 72 203 patients [15.8%]). Fetal death occurred in 12 907 (7.9%) of 163 810 pregnancies exposed to ondansetron, and 17 476 (5.7%) of 306 766 pregnancies exposed to other antiemetics. The adjusted hazard ratios were 0.91 (95% CI, 0.67-1.23) for fetal death with time-dependent ondansetron exposure during pregnancy, 0.82 (95% CI, 0.64-1.04) for spontaneous abortion, and 0.97 (95% CI, 0.79-1.20) for stillbirth. For major congenital malformations, the estimated odds ratio was 1.06 (95% CI, 0.91-1.22). Results of sensitivity analyses were generally consistent with those of the primary analyses.

Conclusions And Relevance: In this large, multicenter cohort study, there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.5329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065380PMC
April 2021

CTLA-4 expression by B-1a B cells is essential for immune tolerance.

Nat Commun 2021 01 22;12(1):525. Epub 2021 Jan 22.

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism.
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http://dx.doi.org/10.1038/s41467-020-20874-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822855PMC
January 2021

Estimated GFR and Incidence of Major Surgery: A Population-Based Cohort Study.

Am J Kidney Dis 2021 03 9;77(3):365-375.e1. Epub 2020 Oct 9.

Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Rationale & Objective: Kidney disease is associated with an increased risk for postoperative morbidity and mortality. However, the incidence of major surgery on a population level is unknown. We aimed to determine the incidence of major surgery by level of kidney function.

Study Design: Retrospective cohort study with entry from January 1, 2008, through December 31, 2009, and outcome surveillance from January 1, 2010, through December 31, 2016.

Setting & Participants: Population-based study using administrative health data from Alberta, Canada; adults with an outpatient serum creatinine measurement or receiving maintenance dialysis formed the study cohort.

Exposure: Participants were categorized into 6 estimated glomerular filtration rate (eGFR) categories: ≥60 (G1-G2), 45 to 59 (G3a), 30 to 44 (G3b), 15 to 29 (G4), and<15mL/min/1.73m with (G5D) and without (G5) dialysis. eGFR was examined as a time-varying exposure based on means of measurements within 3-month ascertainment periods throughout the study period.

Outcome: Major surgery defined as surgery requiring admission to the hospital for at least 24 hours.

Analytical Approach: Incidence rates (IRs) for overall major surgery were estimated using quasi-Poisson regression and adjusted for age, sex, income, location of residence, albuminuria, and Charlson comorbid conditions. Age- and sex-stratified IRs of 13 surgery subtypes were also estimated.

Results: 1,455,512 cohort participants were followed up for a median of 7.0 (IQR, 5.3) years, during which time 241,989 (16.6%) underwent a major surgery. Age and sex modified the relationship between eGFR and incidence of surgery. Men younger than 65 years receiving maintenance dialysis experienced the highest rates of major surgery, with an adjusted IR of 243.8 (95% CI, 179.8-330.6) per 1,000 person-years. There was a consistent trend of increasing surgery rates at lower eGFRs for most subtypes of surgery.

Limitations: Outpatient preoperative serum creatinine measurement was necessary for inclusion and outpatient surgical procedures were not included.

Conclusions: People with reduced eGFR have a significantly higher incidence of major surgery compared with those with normal eGFR, and age and sex modify this increased risk. This study informs our understanding of how surgical burden changes with differing levels of kidney function.
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http://dx.doi.org/10.1053/j.ajkd.2020.08.009DOI Listing
March 2021

Association between change in physician remuneration and use of peritoneal dialysis: a population-based cohort analysis.

CMAJ Open 2020 Jan-Mar;8(1):E96-E104. Epub 2020 Feb 18.

Department of Internal Medicine (Trachtenberg), University of Manitoba, Winnipeg, Man.; Departments of Community Health Sciences (Quinn, Ma, Hemmelgarn, Tonelli, Faris, Weaver, Au, Zhang, Manns) and Medicine (Hemmelgarn, Tonelli, Manns), and Libin Cardiovascular Institute of Alberta and O'Brien Institute for Public Health (Hemmelgarn, Tonelli, Manns), Cumming School of Medicine, University of Calgary, Calgary, Alta.; Department of Medicine (Klarenbach), University of Alberta, Edmonton, Alta.; Alberta Health Services (Faris), Calgary, Alta.

Background: Health care payers are interested in policy-level interventions to increase peritoneal dialysis use in end-stage renal disease. We examined whether increases in physician remuneration for peritoneal dialysis were associated with greater peritoneal dialysis use.

Methods: We studied a cohort of patients in Alberta who started long-term dialysis with at least 90 days of preceding nephrologist care between Jan. 1, 2001, and Dec. 31, 2014. We compared peritoneal dialysis use 90 days after dialysis initiation in patients cared for by fee-for-service nephrologists and those cared for by salaried nephrologists before and after weekly peritoneal dialysis remuneration increased from $0 to $32 (fee change 1, Apr. 1, 2002), $49 to $71 (fee change 2, Apr. 1, 2007), and $71 to $135 (fee change 3, Apr. 1, 2009). Remuneration for peritoneal dialysis remained less than hemodialysis until fee change 3. We performed a patient-level differences-in-differences logistic regression, adjusted for demographic characteristics and comorbidities, as well as an unadjusted interrupted time-series analysis of monthly outcome data.

Results: Our cohort included 4262 patients. There was no statistical evidence of a difference in the adjusted differences-indifferences estimator following fee change 1 (0.89, 95% confidence interval [CI] 0.44-1.81), 2 (1.15, 95% CI 0.73-1.83), or 3 (1.52, 95% CI 0.96-2.40). There was no significant difference in the immediate change or the trend over time in peritoneal dialysis use between fee-for-service and salaried groups following any of the fee changes in the interrupted time-series analysis.

Interpretation: We identified no statistical evidence of an increase in peritoneal dialysis use following increased fee-for-service remuneration for peritoneal dialysis. It remains unclear what role, if any, physician payment plays in selection of dialysis modality.
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http://dx.doi.org/10.9778/cmajo.20190132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028166PMC
February 2021

Association of Specialist Physician Payment Model With Visit Frequency, Quality, and Costs of Care for People With Chronic Disease.

JAMA Netw Open 2019 11 1;2(11):e1914861. Epub 2019 Nov 1.

Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Importance: Specialist physicians are key members of chronic care management teams; to date, however, little is known about the association between specialist payment models and outcomes for patients with chronic diseases.

Objective: To examine the association of payment model with visit frequency, quality of care, and costs for patients with chronic diseases seen by specialists.

Design, Setting, And Participants: A retrospective cohort study using propensity-score matching in patients seen by a specialist physician was conducted between April 1, 2011, and September 31, 2014. The study was completed on March 31, 2015, and data analysis was conducted from June 2017 to February 2018 and finalized in August 2019. In a population-based design, 109 839 adults with diabetes or chronic kidney disease newly referred to specialists were included. Because patients seen by independent salary-based and fee-for-service (FFS) specialists were significantly different in observed baseline characteristics, patients were matched 1:1 on demographic, illness, and physician characteristics.

Exposures: Specialist physician payment model (salary-based or FFS).

Main Outcomes And Measures: Follow-up outpatient visits, guideline-recommended care delivery, adverse events, and costs.

Results: A total of 90 605 patients received care from FFS physicians and 19 234 received care from salary-based physicians. Before matching, the patients seen by salary-based physicians had more advanced chronic kidney disease (2630 of 14 414 [18.2%] vs 6627 of 54 489 [12.2%]), and a higher proportion had 5 or more comorbidities (5989 of 19 234 [31.3%] vs 23 326 of 90 605 [25.7%]). Propensity-score matching resulted in a cohort of 31 898 patients (15 949 FFS, 15 949 salary-based) seeing 489 specialists. In the matched cohort, patients were similar (mean [SD] age, 61.3 [18.2] years; 17 632 women [55.3%]; 29 251 residing in urban settings [91.7%]). Patients seen by salary-based specialists had a higher follow-up visit rate compared with those seen by FFS specialists (1.74 visits; 95% CI, 1.58-1.92 visits vs 1.54 visits; 95% CI, 1.41-1.68 visits), but the difference was not significant (rate ratio, 1.13; 95% CI, 0.99-1.28; P = .06). There was no statistical difference in guideline-recommended care delivery, hospital or emergency department visits for ambulatory care-sensitive conditions, or costs between patients seeing FFS and salary-based specialists. The median association of physician clustering with health care use and quality outcomes was consistently greater than the association with the physician payment, suggesting variation between physicians (eg, median rate ratio for follow-up outpatient visit rate was 1.74, which is greater than the rate ratio of 1.13).

Conclusions And Relevance: Specialist physician payment does not appear to be associated with variation in visits, quality, and costs for outpatients with chronic diseases; however, there is variation in outcomes between physicians. This finding suggests the need to consider other strategies to reduce physician variation to improve the value of care and outcomes for people with chronic diseases.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.14861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902778PMC
November 2019

Genome-wide effects of social status on DNA methylation in the brain of a cichlid fish, Astatotilapia burtoni.

BMC Genomics 2019 Sep 11;20(1):699. Epub 2019 Sep 11.

Department of Biology, Stanford, CA, 94305, USA.

Background: Successful social behavior requires real-time integration of information about the environment, internal physiology, and past experience. The molecular substrates of this integration are poorly understood, but likely modulate neural plasticity and gene regulation. In the cichlid fish species Astatotilapia burtoni, male social status can shift rapidly depending on the environment, causing fast behavioral modifications and a cascade of changes in gene transcription, the brain, and the reproductive system. These changes can be permanent but are also reversible, implying the involvement of a robust but flexible mechanism that regulates plasticity based on internal and external conditions. One candidate mechanism is DNA methylation, which has been linked to social behavior in many species, including A. burtoni. But, the extent of its effects after A. burtoni social change were previously unknown.

Results: We performed the first genome-wide search for DNA methylation patterns associated with social status in the brains of male A. burtoni, identifying hundreds of Differentially Methylated genomic Regions (DMRs) in dominant versus non-dominant fish. Most DMRs were inside genes supporting neural development, synapse function, and other processes relevant to neural plasticity, and DMRs could affect gene expression in multiple ways. DMR genes were more likely to be transcription factors, have a duplicate elsewhere in the genome, have an anti-sense lncRNA, and have more splice variants than other genes. Dozens of genes had multiple DMRs that were often seemingly positioned to regulate specific splice variants.

Conclusions: Our results revealed genome-wide effects of A. burtoni social status on DNA methylation in the brain and strongly suggest a role for methylation in modulating plasticity across multiple biological levels. They also suggest many novel hypotheses to address in mechanistic follow-up studies, and will be a rich resource for identifying the relationships between behavioral, neural, and transcriptional plasticity in the context of social status.
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http://dx.doi.org/10.1186/s12864-019-6047-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737626PMC
September 2019

Association of Mental Health Disorders With Health Care Utilization and Costs Among Adults With Chronic Disease.

JAMA Netw Open 2019 08 2;2(8):e199910. Epub 2019 Aug 2.

Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Importance: A population-based study using validated algorithms to estimate the costs of treating people with chronic disease with and without mental health disorders is needed.

Objective: To determine the association of mental health disorders with health care costs among people with chronic diseases.

Design, Setting, And Participants: This population-based cohort study in the Canadian province of Alberta collected data from April 1, 2012, to March 31, 2015, among 991 445 adults 18 years and older with a chronic disease (ie, asthma, congestive heart failure, myocardial infarction, diabetes, epilepsy, hypertension, chronic pulmonary disease, or chronic kidney disease). Data analysis was conducted from October 2017 to August 2018.

Exposures: Mental health disorder (ie, depression, schizophrenia, alcohol use disorder, or drug use disorder).

Main Outcomes And Measures: Resource use, mean total unadjusted and adjusted 3-year health care costs, and mean total unadjusted 3-year costs for hospitalization and emergency department visits for ambulatory care-sensitive conditions.

Results: Among 991 445 participants, 156 296 (15.8%) had a mental health disorder. Those with no mental health disorder were older (mean [SD] age, 58.1 [17.6] years vs 55.4 [17.0] years; P < .001) and less likely to be women (50.4% [95% CI, 50.3%-50.5%] vs 57.7% [95% CI, 57.4%-58.0%]; P < .001) than those with mental health disorders. For those with a mental health disorder, mean total 3-year adjusted costs were $38 250 (95% CI, $36 476-$39 935), and for those without a mental health disorder, mean total 3-year adjusted costs were $22 280 (95% CI, $21 780-$22 760). Having a mental health disorder was associated with significantly higher resource use, including hospitalization and emergency department visit rates, length of stay, and hospitalization for ambulatory care-sensitive conditions. Higher resource use by patients with mental health disorders was not associated with health care presentations owing to chronic diseases compared with patients without a mental health disorder (chronic disease hospitalization rate per 1000 patient days, 0.11 [95% CI, 0.11-0.12] vs 0.06 [95% CI, 0.06-0.06]; P < .001; overall hospitalization rate per 1000 patient days, 0.88 [95% CI, 0.87-0.88] vs 0.43 [95% CI, 0.43-0.43]; P < .001).

Conclusions And Relevance: This study suggests that mental health disorders are associated with substantially higher resource utilization and health care costs among patients with chronic diseases. These findings have clinical and health policy implications.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.9910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714022PMC
August 2019

The association between payment model and specialist physicians' selection of patients with diabetes: a descriptive study.

CMAJ Open 2019 Jan-Mar;7(1):E109-E116. Epub 2019 Feb 18.

Departments of Community Health Sciences (Quinn, McBrien, Hemmelgarn, Manns), Medicine (Edwards, Hemmelgarn, Tonelli, Au, Ma, Weaver, Manns) and Family Medicine (McBrien), University of Calgary, Calgary, Alta.; Department of Medicine (Senior), University of Alberta, Edmonton, Alta.

Background: As the number of people with chronic diseases increases, understanding the impact of payment model on the types of patients seen by specialists has implications for improving the quality and value of care. We sought to determine if there is an association between specialist physician payment model and the types of patients seen.

Methods: In this descriptive study, we used administrative data to compare demographic characteristics, illness severity and visit indication of patients with diabetes seen by fee-for-service and salary-based internal medicine and diabetes specialists in Calgary and Edmonton between April 2011 and September 2014. The study cohort included all newly referred adults with diabetes (no appointment with a specialist in prior 4 yr). Diabetes was identified using a validated algorithm that excludes gestational diabetes.

Results: Patients managed by salary-based physicians ( = 2736) were sicker than those managed by fee-for-service physicians ( = 21 218). Patients managed by salary-based specialists were more likely to have 5 or more comorbidities (23.0% [ = 628] v. 18.1% [ = 3843]) and to have been admitted to hospital or seen in an emergency department for an ambulatory care sensitive condition in the year before their index visit, probably reflecting poorer disease control or barriers to optimal outpatient care. A higher proportion of visits to salary-based physicians were for appropriate indications (65.2% [ = 744] v. 55.6% [ = 5553]; risk ratio 1.17, 95% confidence interval 1.09-1.27).

Interpretation: Salary-based specialists were more likely to see patients with a clear indication for a specialist visit, while fee-for-service specialists were more likely to see healthier patients. Future research is needed to determine if the differences in types of patients are attributable to payment model or other provider- or system-level factors.
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http://dx.doi.org/10.9778/cmajo.20180171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380900PMC
February 2019

Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression.

Nat Commun 2017 05 10;8:14995. Epub 2017 May 10.

Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.

The senescence of mammalian cells is characterized by a proliferative arrest in response to stress and the expression of an inflammatory phenotype. Here we show that histone H2A.J, a poorly studied H2A variant found only in mammals, accumulates in human fibroblasts in senescence with persistent DNA damage. H2A.J also accumulates in mice with aging in a tissue-specific manner and in human skin. Knock-down of H2A.J inhibits the expression of inflammatory genes that contribute to the senescent-associated secretory phenotype (SASP), and over expression of H2A.J increases the expression of some of these genes in proliferating cells. H2A.J accumulation may thus promote the signalling of senescent cells to the immune system, and it may contribute to chronic inflammation and the development of aging-associated diseases.
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http://dx.doi.org/10.1038/ncomms14995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436145PMC
May 2017

Warfarin Initiation, Atrial Fibrillation, and Kidney Function: Comparative Effectiveness and Safety of Warfarin in Older Adults With Newly Diagnosed Atrial Fibrillation.

Am J Kidney Dis 2017 Jun 18;69(6):734-743. Epub 2016 Dec 18.

Cumming School of Medicine, Division of Nephrology, University of Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada. Electronic address:

Background: The effectiveness and safety of warfarin use among patients with atrial fibrillation (AF) and reduced kidney function are uncertain.

Study Design: Community-based retrospective cohort study (May 1, 2003, to March 31, 2012) using province-wide laboratory and administrative data in Alberta, Canada.

Setting & Participants: 14,892 adults 66 years or older with new AF and a measurement of kidney function. Long-term dialysis patients or kidney transplant recipients were excluded.

Predictor: Propensity scores were used to construct a matched-pairs cohort of patients with AF who did and did not have a warfarin prescription within a 60-day period surrounding their AF diagnosis.

Outcomes: Within 1 year of initiating warfarin therapy (or the matched date for nonusers): (1) the composite of all-cause death, ischemic stroke, or transient ischemic attack (also assessed as separate end points) and (2) first hospitalization or emergency department visit for a major bleeding episode defined as an intracranial, upper or lower gastrointestinal, or other bleeding.

Measurements: Baseline glomerular filtration rate (GFR) was estimated using the CKD-EPI creatinine equation. Patients were matched within estimated GFR (eGFR) categories: ≥90, 60 to 89, 45 to 59, 30 to 44, and <30mL/min/1.73m. Information for baseline characteristics (sociodemographics, comorbid conditions, and prescription drug use) was obtained.

Results: Across eGFR categories, warfarin therapy initiation was associated with lower risk for the composite outcome compared to nonuse (adjusted HRs [95% CI] for eGFR categories ≥ 90, 60-89, 45-59, 30-44, and <30mL/min/1.73m: 0.59 [0.35-1.01], 0.61 [0.54-0.70], 0.55 [0.47-0.65], 0.54 [0.44-0.67], and 0.64 [0.47-0.87] mL/min/1.73m, respectively). Compared to nonuse, warfarin therapy was not associated with higher risk for major bleeding except for those with eGFRs of 60 to 89mL/min/1.73m (HR, 1.36; 95% CI, 1.13-1.64).

Limitations: Selection bias.

Conclusions: Among older adults with AF, warfarin therapy initiation was associated with a significantly lower 1-year risk for the composite outcome across all strata of kidney function. The risk for major bleeding associated with warfarin use was increased only among those with eGFRs of 60 to 89mL/min/1.73m.
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http://dx.doi.org/10.1053/j.ajkd.2016.10.018DOI Listing
June 2017

Lifetime risk of diabetes among First Nations and non-First Nations people.

CMAJ 2016 Nov 19;188(16):1147-1153. Epub 2016 Sep 19.

Department of Family Medicine (Turin), Department of Community Health Sciences (Turin, Manns, Hemmelgarn), Institute of Public Health (Turin, Manns, Hemmelgarn) and Department of Medicine (Saad, Jun, Tonelli, Ma, Barnabe, Manns, Hemmelgarn), University of Calgary, Calgary, Alta.

Background: Lifetime risk is a relatively straightforward measure used to communicate disease burden, representing the cumulative risk of an outcome during the remainder of an individual's life starting from a disease-free index age. We estimated the lifetime risk of diabetes among men and women in both First Nations and non-First Nations populations using a cohort of adults in a single Canadian province.

Methods: We used a population-based cohort consisting of Alberta residents from 1997 to 2008 who were free of diabetes at cohort entry to estimate the lifetime risk of diabetes among First Nations and non-First Nations people. We calculated age-specific incidence rates with the person-year method in 5-year bands. We estimated the sex- and index-age-specific lifetime risk of incident diabetes, after adjusting for the competing risk of death.

Results: The cohort included 70 631 First Nations and 2 732 214 non-First Nations people aged 18 years or older. The lifetime risk of diabetes at 20 years of age was 75.6% among men and 87.3% among women in the First Nations group, as compared with 55.6% among men and 46.5% among women in the non-First Nations group. The risk was higher among First Nations people than among non-First Nations people for all index ages and for both sexes. Among non-First Nations people, men had a higher lifetime risk of diabetes than women across all index ages. In contrast, among First Nations people, women had a higher lifetime risk than men across all index ages.

Interpretation: About 8 in 10 First Nations people and about 5 in 10 non-First Nations people of young age will develop diabetes in their remaining lifetime. These population-based estimates may help health care planners and decision-makers set priorities and increase public awareness and interest in the prevention of diabetes.
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http://dx.doi.org/10.1503/cmaj.150787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088075PMC
November 2016

Identification of Human Neuronal Protein Complexes Reveals Biochemical Activities and Convergent Mechanisms of Action in Autism Spectrum Disorders.

Cell Syst 2015 Nov;1(5):361-374

Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford, California, 94305 USA.

The prevalence of autism spectrum disorders (ASDs) is rapidly growing, yet its molecular basis is poorly understood. We used a systems approach in which ASD candidate genes were mapped onto the ubiquitous human protein complexes and the resulting complexes were characterized. The studies revealed the role of histone deacetylases (HDAC1/2) in regulating the expression of ASD orthologs in the embryonic mouse brain. Proteome-wide screens for the co-complexed subunits with HDAC1 and six other key ASD proteins in neuronal cells revealed a protein interaction network, which displayed preferential expression in fetal brain development, exhibited increased deleterious mutations in ASD cases, and were strongly regulated by FMRP and MECP2 causal for Fragile X and Rett syndromes, respectively. Overall, our study reveals molecular components in ASD, suggests a shared mechanism between the syndromic and idiopathic forms of ASDs, and provides a systems framework for analyzing complex human diseases.
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http://dx.doi.org/10.1016/j.cels.2015.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776331PMC
November 2015

The association between kidney function and major bleeding in older adults with atrial fibrillation starting warfarin treatment: population based observational study.

BMJ 2015 Feb 3;350:h246. Epub 2015 Feb 3.

Department of Medicine, Division of Nephrology, University of Calgary, AB, Canada, T2N 2T9 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada

Objective: To determine rates of major bleeding by level of kidney function for older adults with atrial fibrillation starting warfarin.

Design: Retrospective cohort study.

Setting: Community based, using province wide laboratory and administrative data in Alberta, Canada.

Participants: 12,403 adults aged 66 years or more, with atrial fibrillation who started warfarin treatment between 1 May 2003 and 31 March 2010 and had a measure of kidney function at baseline. Kidney function was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation and participants were categorised based on estimated glomerular filtration rate (eGFR): ≥ 90, 60-89, 45-59, 30-44, 15-29, <15 mL/min/1.73 m(2). We excluded participants with end stage renal disease (dialysis or renal transplant) at baseline.

Main Outcome Measures: Admission to hospital or visit to an emergency department for major bleeding (intracranial, upper and lower gastrointestinal, or other).

Results: Of 12,403 participants, 45% had an eGFR <60 mL/min/1.73 m(2). Overall, 1443 (11.6%) experienced a major bleeding episode over a median follow-up of 2.1 (interquartile range: 1.0-3.8) years. During the first 30 days of warfarin treatment, unadjusted and adjusted rates of major bleeding were higher at lower eGFR (P for trend <0.001 and 0.001, respectively). Adjusted bleeding rates per 100 person years were 63.4 (95% confidence interval 24.9 to 161.6) in participants with eGFR <15 mL/min/1.73 m(2) compared with 6.1 (1.9 to 19.4) among those with eGFR >90 mL/min/1.73 m(2) (adjusted incidence rate ratio 10.3, 95% confidence interval 2.3 to 45.5). Similar associations were observed at more than 30 days after starting warfarin, although the magnitude of the increase in rates across eGFR categories was attenuated. Across all eGFR categories, adjusted rates of major bleeding were consistently higher during the first 30 days of warfarin treatment compared with the remainder of follow-up. Increases in major bleeding rates were largely due to gastrointestinal bleeding (3.5-fold greater in eGFR <15 mL/min/1.73 m(2) compared with ≥ 90 mL/min/1.73 m(2)). Intracranial bleeding was not increased with worsening kidney function.

Conclusions: Reduced kidney function was associated with an increased risk of major bleeding among older adults with atrial fibrillation starting warfarin; excess risks from reduced eGFR were most pronounced during the first 30 days of treatment. Our results support the need for careful consideration of the bleeding risk relative to kidney function when assessing the risk-benefit ratio of warfarin treatment in people with chronic kidney disease and atrial fibrillation, particularly in the first 30 days of treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169066PMC
http://dx.doi.org/10.1136/bmj.h246DOI Listing
February 2015

Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

Mol Syst Biol 2014 Dec 30;10:774. Epub 2014 Dec 30.

Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA

Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300495PMC
http://dx.doi.org/10.15252/msb.20145487DOI Listing
December 2014

Principles of regulatory information conservation between mouse and human.

Nature 2014 Nov;515(7527):371-375

Department of Genetics, Stanford University, Stanford, CA 94305, USA.

To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human-mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences.
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http://dx.doi.org/10.1038/nature13985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343047PMC
November 2014

A comparative encyclopedia of DNA elements in the mouse genome.

Nature 2014 Nov;515(7527):355-64

Bioinformatics and Genomics, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, 08003 Barcelona, Catalonia, Spain.

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.
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http://dx.doi.org/10.1038/nature13992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266106PMC
November 2014

Insect-induced tree mortality of boreal forests in eastern Canada under a changing climate.

Ecol Evol 2014 Jun 16;4(12):2384-94. Epub 2014 May 16.

Department of Biological Sciences, Center for Forest Research, University of Quebec at Montreal C.P. 8888, Succ. Centre-Ville, Montreal, H3C 3P8, Canada.

Forest insects are major disturbances that induce tree mortality in eastern coniferous (or fir-spruce) forests in eastern North America. The spruce budworm (SBW) (Choristoneura fumiferana [Clemens]) is the most devastating insect causing tree mortality. However, the relative importance of insect-caused mortality versus tree mortality caused by other agents and how this relationship will change with climate change is not known. Based on permanent sample plots across eastern Canada, we combined a logistic model with a negative model to estimate tree mortality. The results showed that tree mortality increased mainly due to forest insects. The mean difference in annual tree mortality between plots disturbed by insects and those without insect disturbance was 0.0680 per year (P < 0.0001, T-test), and the carbon sink loss was about 2.87t C ha(-1) year(-1) larger than in natural forests. We also found that annual tree mortality increased significantly with the annual climate moisture index (CMI) and decreased significantly with annual minimum temperature (T min), annual mean temperature (T mean) and the number of degree days below 0°C (DD0), which was inconsistent with previous studies (Adams et al. 2009; van Mantgem et al. 2009; Allen et al. 2010). Furthermore, the results for the trends in the magnitude of forest insect outbreaks were consistent with those of climate factors for annual tree mortality. Our results demonstrate that forest insects are the dominant cause of the tree mortality in eastern Canada but that tree mortality induced by insect outbreaks will decrease in eastern Canada under warming climate.
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http://dx.doi.org/10.1002/ece3.988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203287PMC
June 2014

Widespread contribution of transposable elements to the innovation of gene regulatory networks.

Genome Res 2014 Dec 15;24(12):1963-76. Epub 2014 Oct 15.

Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA;

Transposable elements (TEs) have been shown to contain functional binding sites for certain transcription factors (TFs). However, the extent to which TEs contribute to the evolution of TF binding sites is not well known. We comprehensively mapped binding sites for 26 pairs of orthologous TFs in two pairs of human and mouse cell lines (representing two cell lineages), along with epigenomic profiles, including DNA methylation and six histone modifications. Overall, we found that 20% of binding sites were embedded within TEs. This number varied across different TFs, ranging from 2% to 40%. We further identified 710 TF-TE relationships in which genomic copies of a TE subfamily contributed a significant number of binding peaks for a TF, and we found that LTR elements dominated these relationships in human. Importantly, TE-derived binding peaks were strongly associated with open and active chromatin signatures, including reduced DNA methylation and increased enhancer-associated histone marks. On average, 66% of TE-derived binding events were cell type-specific with a cell type-specific epigenetic landscape. Most of the binding sites contributed by TEs were species-specific, but we also identified binding sites conserved between human and mouse, the functional relevance of which was supported by a signature of purifying selection on DNA sequences of these TEs. Interestingly, several TFs had significantly expanded binding site landscapes only in one species, which were linked to species-specific gene functions, suggesting that TEs are an important driving force for regulatory innovation. Taken together, our data suggest that TEs have significantly and continuously shaped gene regulatory networks during mammalian evolution.
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http://dx.doi.org/10.1101/gr.168872.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248313PMC
December 2014

Whole-genome haplotyping using long reads and statistical methods.

Nat Biotechnol 2014 Mar 23;32(3):261-266. Epub 2014 Feb 23.

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.

The rapid growth of sequencing technologies has greatly contributed to our understanding of human genetics. Yet, despite this growth, mainstream technologies have not been fully able to resolve the diploid nature of the human genome. Here we describe statistically aided, long-read haplotyping (SLRH), a rapid, accurate method that uses a statistical algorithm to take advantage of the partially phased information contained in long genomic fragments analyzed by short-read sequencing. For a human sample, as little as 30 Gbp of additional sequencing data are needed to phase genotypes identified by 50× coverage whole-genome sequencing. Using SLRH, we phase 99% of single-nucleotide variants in three human genomes into long haplotype blocks 0.2-1 Mbp in length. We apply our method to determine allele-specific methylation patterns in a human genome and identify hundreds of differentially methylated regions that were previously unknown. SLRH should facilitate population-scale haplotyping of human genomes.
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http://dx.doi.org/10.1038/nbt.2833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073643PMC
March 2014

In-depth characterization of microRNA transcriptome in melanoma.

PLoS One 2013 4;8(9):e72699. Epub 2013 Sep 4.

Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut, United States of America ; Department of Computer Science and Engineering, University of Connecticut, Storrs, Connecticut, United States of America.

The full repertoire of human microRNAs (miRNAs) that could distinguish common (benign) nevi from cutaneous (malignant) melanomas remains to be established. In an effort to gain further insight into the role of miRNAs in melanoma, we applied Illumina next-generation sequencing (NGS) platform to carry out an in-depth analysis of miRNA transcriptome in biopsies of nevi, thick primary (>4.0 mm) and metastatic melanomas with matched normal skin in parallel to melanocytes and melanoma cell lines (both primary and metastatic) (n=28). From this data representing 698 known miRNAs, we defined a set of top-40 list, which properly classified normal from cancer; also confirming 23 (58%) previously discovered miRNAs while introducing an additional 17 (42%) known and top-15 putative novel candidate miRNAs deregulated during melanoma progression. Surprisingly, the miRNA signature distinguishing specimens of melanoma from nevus was significantly different than that of melanoma cell lines from melanocytes. Among the top list, miR-203, miR-204-5p, miR-205-5p, miR-211-5p, miR-23b-3p, miR-26a-5p and miR-26b-5p were decreased in melanomas vs. nevi. In a validation cohort (n=101), we verified the NGS results by qRT-PCR and showed that receiver-operating characteristic curves for miR-211-5p expression accurately discriminated invasive melanoma (AUC=0.933), melanoma in situ (AUC=0.933) and dysplastic (atypical) nevi (AUC=0.951) from common nevi. Target prediction analysis of co-transcribed miRNAs showed a cooperative regulation of key elements in the MAPK signaling pathway. Furthermore, we found extensive sequence variations (isomiRs) and other non-coding small RNAs revealing a complex melanoma transcriptome. Deep-sequencing small RNAs directly from clinically defined specimens provides a robust strategy to improve melanoma diagnostics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072699PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762816PMC
April 2014

An encyclopedia of mouse DNA elements (Mouse ENCODE).

Genome Biol 2012 Aug 13;13(8):418. Epub 2012 Aug 13.

To complement the human Encyclopedia of DNA Elements (ENCODE) project and to enable a broad range of mouse genomics efforts, the Mouse ENCODE Consortium is applying the same experimental pipelines developed for human ENCODE to annotate the mouse genome.
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http://dx.doi.org/10.1186/gb-2012-13-8-418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491367PMC
August 2012

Regional drought-induced reduction in the biomass carbon sink of Canada's boreal forests.

Proc Natl Acad Sci U S A 2012 Feb 30;109(7):2423-7. Epub 2012 Jan 30.

Department of Biology Sciences, Institute of Environment Sciences, University of Quebec, Montreal, QC, Canada H3C 3P8.

The boreal forests, identified as a critical "tipping element" of the Earth's climate system, play a critical role in the global carbon budget. Recent findings have suggested that terrestrial carbon sinks in northern high-latitude regions are weakening, but there has been little observational evidence to support the idea of a reduction of carbon sinks in northern terrestrial ecosystems. Here, we estimated changes in the biomass carbon sink of natural stands throughout Canada's boreal forests using data from long-term forest permanent sampling plots. We found that in recent decades, the rate of biomass change decreased significantly in western Canada (Alberta, Saskatchewan, and Manitoba), but there was no significant trend for eastern Canada (Ontario and Quebec). Our results revealed that recent climate change, and especially drought-induced water stress, is the dominant cause of the observed reduction in the biomass carbon sink, suggesting that western Canada's boreal forests may become net carbon sources if the climate change-induced droughts continue to intensify.
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http://dx.doi.org/10.1073/pnas.1111576109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289349PMC
February 2012

Detecting one-hundred-year environmental changes in Western China using seven-year repeat photography.

PLoS One 2011 22;6(9):e25008. Epub 2011 Sep 22.

Laboratory for Ecological Forecasting and Global Change, College of Forestry, Northwest Agriculture and Forest University, Yanglin, China.

Due to its diverse, wondrous plants and unique topography, Western China has drawn great attention from explorers and naturalists from the Western World. Among them, Ernest Henry Wilson (1876 -1930), known as 'Chinese' Wilson, travelled to Western China five times from 1899 to 1918. He took more than 1,000 photos during his travels. These valuable photos illustrated the natural and social environment of Western China a century ago. Since 1997, we had collected E.H. Wilson's old pictures, and then since 2004, along the expedition route of E.H. Wilson, we took 7 years to repeat photographing 250 of these old pictures. Comparing Wilson's photos with ours, we found an obvious warming trend over the 100 years, not only in specific areas but throughout the entire Western China. Such warming trend manifested in phenology changes, community shifts and melting snow in alpine mountains. In this study, we also noted remarkable vegetation changes. Out of 62 picture pairs were related to vegetation change, 39 indicated vegetation has changed to the better condition, 17 for degraded vegetation and six for no obvious change. Also in these photos at a century interval, we found not only rapid urbanization in Western China, but also the disappearance of traditional cultures. Through such comparisons, we should not only be amazed about the significant environmental changes through time in Western China, but also consider its implications for protecting environment while meeting the economic development beyond such changes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025008PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178569PMC
June 2012

Up-regulated Dicer expression in patients with cutaneous melanoma.

PLoS One 2011 17;6(6):e20494. Epub 2011 Jun 17.

Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.

Background: MicroRNAs (miRNAs) are small non-coding RNAs (18-24 nucleotides) that have recently been shown to regulate gene expression during cancer progression. Dicer, a central enzyme in the multi-component miRNA biogenesis pathway, is involved in cutting precursor miRNAs to functionally mature forms. Emerging evidence shows that Dicer expression is deregulated in some human malignancies and it correlates with tumor progression, yet this role has not yet been investigated in skin cancers.

Methods And Findings: Using an anti-human monoclonal antibody against Dicer and immunohistochemistry, we compared the expression of Dicer protein among 404 clinically annotated controls and skin tumors consisting of melanocytic nevi (n = 71), a variety of melanomas (n = 223), carcinomas (n = 73) and sarcomas (n = 12). Results showed a cell-specific up-regulated Dicer in 81% of cutaneous, 80% of acrolentiginous and 96% of metastatic melanoma specimens compared to carcinoma or sarcoma specimens (P<0.0001). The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001). In patients with cutaneous melanomas, Dicer up-regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow's depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009). Using western blot analysis, we confirmed the cell-specific up-regulation of Dicer protein in vitro. A pooled-analysis on mRNA profiling in cutaneous tumors showed up-regulation of Dicer at the RNA level in cutaneous melanoma, also showing deregulation of other enzymes that participate in the biogenesis and maturation of canonical miRNAs.

Conclusions: Increased Dicer expression may be a clinically useful biomarker for patients with cutaneous melanoma. Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020494PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117784PMC
November 2011

Profiling and discovery of novel miRNAs from formalin-fixed, paraffin-embedded melanoma and nodal specimens.

J Mol Diagn 2009 Sep;11(5):420-9

Departments of Pathology, Stanford University School of Medicine,Stanford, California, USA.

Archived formalin-fixed, paraffin-embedded human tumors are widely available and represent a unique source of morphologically defined material. Formalin-fixed, paraffin-embedded tissue is known to contain a wealth of molecular information in the form of microRNAs (miRNAs), which could be correlated with clinical outcome for improved prognostication and/or treatment response. miRNAs are endogenous, noncoding RNAs ( approximately 22 nucleotides) and may function as tumor suppressors or oncogenes. A reliable, robust methodology is needed to take full advantage of archived human cancers, especially for those where fresh-frozen tumor banks are unavailable, for example, malignant melanoma. To this end, we applied a simple-to-use protocol for extracting total RNA from various formalin-fixed, paraffin-embedded specimens (colon, liver, prostate, thyroid, uterus, and skin), optimized for small RNA recovery. Using a "poison primer" strategy (ie, primer silencing), we blocked the amplification of ribosomal RNA, enabling the successful sequencing of 17 novel and 53 known miRNAs (including small RNAs) from 10-year-old archived normal skin, cutaneous scalp melanoma, and sentinel lymph nodes (both negative and positive for metastasis) excised from a 52-year-old man. The cloning incidence provided an estimation of the level of specific miRNA expression, which was confirmed by Northern analysis and quantitative real-time polymerase chain reaction. This methodology can therefore be used to facilitate miRNA discovery from archived human cancers.
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http://dx.doi.org/10.2353/jmoldx.2009.090041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729839PMC
September 2009

Lymphatic invasion in cutaneous melanoma is associated with sentinel lymph node metastasis.

J Cutan Pathol 2009 Jul 5;36(7):772-80. Epub 2008 Nov 5.

Department of Pathology, Stanford University Medical Center, Stanford, CA 94305-5324, USA.

Background: Sentinel lymph node (SLN) metastasis is a major determinant for staging, prognostication and clinical management of patients with cutaneous melanoma. However, the role of lymphatic vs. vascular invasion (VI) for SLN spread remains unclear.

Methods: We compared the frequency of lymphatic invasion (LI) vs. VI in melanoma sections from 94 patients with a mean three-year clinical follow up using immunostains for the lymphatic endothelial markers D2-40 (podoplanin) and LYVE-1 and the panvascular marker CD31.

Results: LI occurred more frequently than VI (16 vs. 3%, respectively, p = 0.001) and correlated with higher American Joint Committee on Cancer stage at diagnosis (p = 0.0004). In a univariate analysis, LI was strongly associated with SLN metastasis (p = 0.008), independent of tumor thickness. In a multivariate analysis, LI was not a significant risk factor for SLN metastasis. The presence of intratumoral lymphatics (ITLs) was associated with distant metastasis, whereas VI was rare and did not correlate with SLN or distant metastasis. A combination of LI and ITL had higher positive and negative predictive values for the risk of developing SLN metastasis compared with routine histology and VI.

Conclusion: Detection of LI in the primary tumor may aid in identifying melanoma patients with the propensity to develop SLN metastasis.
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http://dx.doi.org/10.1111/j.1600-0560.2008.01166.xDOI Listing
July 2009

Involvement of the C-terminal proline-rich motif of G protein-coupled receptor kinases in recognition of activated rhodopsin.

J Biol Chem 2004 Nov 16;279(48):49741-6. Epub 2004 Sep 16.

Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

G protein-coupled receptor kinases (GRKs) are a family of serine/threonine kinases that phosphorylate many activated G protein-coupled receptors (GPCRs) and play an important role in GPCR desensitization. Our previous work has demonstrated that the C-terminal conserved region (CC) of GRK-2 participates in interaction with rhodopsin and that this interaction is necessary for GRK-2-mediated receptor phosphorylation (Gan, X. Q., Wang, J. Y., Yang, Q. H., Li, Z., Liu, F., Pei, G., and Li, L. (2000) J. Biol. Chem. 275, 8469-8474). In this report, we further investigated whether the CC of other GRKs had the same functions and defined the specific sequences in CC that are required for the functions. The CC regions of GRK-1, GRK-2, and GRK-5, representatives of the three subfamilies of GRKs, could bind rhodopsin in vitro and inhibit GRK-2-mediated phosphorylation of rhodopsin, but not a peptide GRK substrate. Through a series of mutagenesis analyses, a proline-rich motif in the CC was identified as the key element involved in the interaction between the CC region and rhodopsin. Point mutations of this motif not only disrupted the interaction of GRK-2 with rhodopsin but also abolished the ability of GRK-2 to phosphorylate rhodopsin. The findings that the CC region of GRKs interact only with the light-activated but not the non-activated rhodopsin and that the N-terminal domain of GRK-2 interacts with rhodopsin in a light-independent manner suggest that the CC region is responsible for the recognition of activated GPCRs in the canonical model.
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http://dx.doi.org/10.1074/jbc.M407570200DOI Listing
November 2004
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