Publications by authors named "Cindy Zhang"

59 Publications

TGFβ2 and TGFβ3 mediate appropriate context-dependent phenotype of rat valvular interstitial cells.

iScience 2021 Mar 3;24(3):102133. Epub 2021 Feb 3.

Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA.

This study focused on characterizing the potential mechanism of valvular toxicity caused by TGFβ receptor inhibitors (TGFβRis) using rat valvular interstitial cells (VICs) to evaluate early biological responses to TGFβR inhibition. Three TGFβRis that achieved similar exposures in the rat were assessed. Two dual TGFβRI/-RII inhibitors caused valvulopathy, whereas a selective TGFβRI inhibitor did not, leading to a hypothesis that TGFβ receptor selectivity may influence the potency of valvular toxicity. The dual valvular toxic inhibitors had the most profound effect on altering VIC phenotype including altered morphology, migration, and extracellular matrix production. Reduction of TGFβ expression demonstrated that combined TGFβ2/β3 inhibition by small interfering RNA or neutralizing antibodies caused similar alterations as TGFβRis. Inhibition of transcription was only associated with the dual TGFβRis, suggesting that TGFβRII inhibition impacts transcriptional regulation, and that the potency of valvular toxicity may relate to alteration of TGFβ2/β3-mediated processes involved in maintaining proper balance of VIC phenotypes in the heart valve.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900227PMC
March 2021

Assessing Linkage Eligibility Bias in the National Health Interview Survey.

Vital Health Stat 2 2021 Mar(186):1-28

Background Linking health survey data to administrative records expands the analytic utility of survey participant responses, but also creates the potential for new sources of bias when not all participants are eligible for linkage. Residual differences-bias-can occur between estimates made using the full survey sample and the subset eligible for linkage. Objective To assess linkage eligibility bias and provide examples of how bias may be reduced by changes in questionnaire design and adjustment of survey weights for linkage eligibility. Methods Linkage eligibility bias was estimated for various sociodemographic groups and health-related variables for the 2000-2013 National Health Interview Surveys. Conclusions Analysts using the linked data should consider the potential for linkage eligibility bias when planning their analyses and use approaches to reduce bias, such as survey weight adjustments, when appropriate.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2021

The extent of the neurocognitive impairment in elderly survivors of war suffering from PTSD: meta-analysis and literature review.

AIMS Neurosci 2021 25;8(1):47-73. Epub 2020 Nov 25.

School of Rehabilitation Science, McMaster University, Hamilton ON, Canada.

Objectives: We performed a meta-analysis and systematic review on elderly survivors of war suffering from PTSD to estimate the variability in their cognitive impairment based on individual neuropsychological tests.

Methods: We included case control studies that explored the association of cognitive deficits in elderly PTSD civilian survivor of wars (age >60 years), using MEDLINE, Embase and PsycINFO from the inception to January 2018. We compared the cognitive performances in three comparisons i) PTSD+ vs. PTSD- civilian survivors of war; ii) PTSD+ vs. Control and iii) PTSD- vs. Control. The risk of bias was assessed using the Newcastle-Ottawa Scale for case-control studies.

Results: Out of 2939 titles and abstracts, 13 studies were eligible for data extraction. As compared to PTSD- civilian survivors of war, PTSD+ civilian survivors of war demonstrated significant deficits on TMT-A, TMT-B, Digit span backward, explicit memory low pair associate, CVLT recognition, WAIS-verbal and non-verbal tests. As compared to health controls, PTSD+ survivors demonstrated significantly lower performance on explicit memory low pair and high associate, RAVLT immediate and delayed recall, CVLT delayed and short cued recall. Performance on the neuropsychological test between PTSD- survivors of war and controls was not significant for all tests.

Conclusion: The pattern suggests that PTSD+ survivors of war had poorer performance in tasks requiring processing speed, executive function, attention, working memory and learning. The magnitude of the cognitive deficits in our pooled analysis was small to moderate depending on the neuropsychological test. Most of our pooled analysis suffered from a high risk of bias, which lowered the confidence in our results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3934/Neuroscience.2021003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815483PMC
November 2020

Using Precision Medicine with a Neurodevelopmental Perspective to Study Inflammation and Depression.

Curr Psychiatry Rep 2020 12 8;22(12):87. Epub 2020 Dec 8.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Purpose Of Review: To consider various precision medicine approaches to further elucidate the relationship between inflammation and depression and to illustrate how a neurodevelopmental perspective can help in this regard.

Recent Findings: Inflammation associates most strongly with phenotypes of depression that reflect illness behavior and/or metabolic dysfunction and obesity. A separate body of research has shown that maternal inflammation during pregnancy can alter brain circuitry important for mood regulation and/or reward in the developing fetus. Our research group is finding that maternal CRP levels differentially predict positive and negative affect in children assessed at age 4 years, depending on the timing of plasma sampling during pregnancy and the sex of the child. Recent authors have stressed the need to use a variety of precision medicine approaches to refine our understanding of inflammation-depression links. Adding a neurodevelopmental perspective may help to address some of the methodological challenges in this active area of study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11920-020-01206-8DOI Listing
December 2020

Comparative Analysis of the National Health Interview Survey Public-use and Restricted-use Linked Mortality Files.

Natl Health Stat Report 2020 06(143):1-32

Linking national survey data with administrative data sources enables researchers to conduct analyses that would not be possible with each data source alone. Recently, the Data Linkage Program at the National Center for Health Statistics (NCHS) released updated linked mortality files, including the National Health Interview Survey data linked to the National Death Index mortality files. Two versions of the files were released: restricted-use files available through NCHS and Federal Statistical Research Data Centers and public-use files. To reduce the reidentification risk, statistical disclosure limitation methods were applied to the public-use files before they were released. This included limiting the amount of mortality information available and perturbing cause of death and follow-up time for select records. To assess the comparability of the restricted-use and public-use files, relative hazard ratios for all-cause and cause-specific mortality using Cox proportional hazards models were estimated and compared. The comparative analysis found that the two data files yielded very similar descriptive and model results.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2020

Different receptor mechanisms underlying phytocannabinoid- versus synthetic cannabinoid-induced tetrad effects: Opposite roles of CB /CB versus GPR55 receptors.

Br J Pharmacol 2020 04 11;177(8):1865-1880. Epub 2020 Feb 11.

Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland.

Background And Purpose: Cannabis or cannabinoids produce characteristic tetrad effects-analgesia, hypothermia, catalepsy and suppressed locomotion, which are believed to be mediated by the activation of cannabinoid CB receptors. Given recent findings of CB and GPR55 receptors in the brain, we examined whether these receptors are also involved in cannabinoid action.

Experimental Approach: We compared Δ -tetrahydrocannabinol (Δ -THC)-, WIN55212-2-, or XLR11-induced tetrad effects between wild-type (WT) and each genotype of CB -, CB - or GPR55-knockout (KO) mice and then observed the effects of antagonists of these receptors on these tetrad effects in WT mice.

Key Results: Systemic administration of Δ -THC, WIN55212-2 or XLR11 produced dose-dependent tetrad effects in WT mice. Genetic deletion or pharmacological blockade of CB receptors abolished the tetrad effects produced by all three cannabinoids. Unexpectedly, genetic deletion of CB receptor abolished analgesia and catalepsy produced by Δ -THC or WIN55212-2, but not by XLR11. Microinjections of Δ -THC into the lateral ventricles also produced tetrad effects in WT, but not in CB -KO mice. CB -KO mice displayed a reduction in intraventricular Δ -THC-induced analgesia and catalepsy. In contrast to CB and CB receptors, genetic deletion of GPR55 receptors caused enhanced responses to Δ -THC or WIN55212-2. Antagonisim of CB , CB or GPR55 receptors produced alterations similar to those observed in each genotype mouse line.

Conclusions And Implications: These findings suggest that in addition to CB , both CB and GPR55 receptors are also involved in some pharmacological effects produced by cannabinoids. CB /CB , in contrast to GPR55, receptors appears to play opposite roles in cannabinoid action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.14958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070166PMC
April 2020

Clinical pharmacology of vc-MMAE antibody-drug conjugates in cancer patients: learning from eight first-in-human Phase 1 studies.

MAbs 2020 Jan-Dec;12(1):1699768

Genentech Research & Early Development, Genentech, Inc, South San Francisco, CA, USA.

vc-MMAE antibody-drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile valine-citrulline (vc) linker. The objective of this study was to characterize the pharmacokinetics (PK) and explore exposure-response relationships of eight vc-MMAE ADCs, against different targets and for diverse tumor indications, using data from eight first-in-human Phase 1 studies. PK parameters of the three analytes, namely antibody-conjugated MMAE (acMMAE), total antibody, and unconjugated MMAE, were estimated using non-compartmental approaches and compared across the eight vc-MMAE ADCs. Relationships between analytes were assessed by linear regression. Exposure-response relationships were explored with key efficacy (objective response rate) and safety (Grade 2+ peripheral neuropathy) endpoints. PK profiles of acMMAE, total antibody and unconjugated MMAE following the first dose of 2.4 mg/kg were comparable across the eight ADCs; the exposure differences between molecules were small relative to the inter-subject variability. acMMAE exposure was strongly correlated with total antibody exposure for all the eight ADCs, but such correlation was less evident between acMMAE and unconjugated MMAE exposure. For multiple ADCs evaluated, efficacy and safety endpoints appeared to correlate well with acMMAE exposure, but not with unconjugated MMAE over the doses tested. PK of vc-MMAE ADCs was well characterized and demonstrated remarkable similarity at 2.4 mg/kg across the eight ADCs. Results from analyte correlation and exposure-response relationship analyses suggest that measurement of acMMAE analyte alone might be adequate for vc-MMAE ADCs to support the clinical pharmacology strategy used during late-stage clinical development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19420862.2019.1699768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927763PMC
January 2021

Exercise-Induced Fatigue in One Leg Does Not Impair the Neuromuscular Performance in the Contralateral Leg but Improves the Excitability of the Ipsilateral Corticospinal Pathway.

Brain Sci 2019 Sep 25;9(10). Epub 2019 Sep 25.

Faculty of Kinesiology, University of Calgary, Calgary, AB T2N 1N4, Canada.

To investigate the influence of pre-induced fatigue in one leg on neuromuscular performance and corticospinal responses of the contralateral homologous muscles, three experiments were conducted with different exercise protocols; A = 12): a 60 s rest vs. time-matched sustained left leg knee extension maximum voluntary contraction (MVC), B ( = 12): a 60 s rest vs. time-matched left leg MVC immediately followed by 60 s right leg MVC, and C ( = 9): a similar protocol to experiment B, but with blood flow occluded in the left leg while the right leg was performing the 60 s MVC. The neuromuscular assessment included 5 s knee extensions at 100%, 75%, and 50% of MVC. At each force level, transcranial magnetic and peripheral nerve stimuli were elicited to investigate the influence of different protocols on the right (tested) knee extensors' maximal force output, voluntary activation, corticospinal excitability, and inhibition. The pre-induced fatigue in the left leg did not alter the performance nor the neuromuscular responses recorded from the right leg in the three experiments (all > 0.3). However, enhanced corticospinal pathway excitability was evident in the tested knee extensors ( = 0.002). These results suggest that the pre-induced fatigue and muscle ischemia in one leg did not compromise the central and peripheral components of the neuromuscular function in the tested contralateral leg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci9100250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827080PMC
September 2019

Drug-induced severe cutaneous adverse reactions: Determine the cause and prevention.

Ann Allergy Asthma Immunol 2019 11 7;123(5):483-487. Epub 2019 Aug 7.

Department of Medicine and Pediatrics, Allergy and Immunology, Program, Penn State University, Hershey, Pennsylvania. Electronic address:

Background: Approximately 45% of all adverse drug reactions are manifested in the skin. Although most are mild, severe cutaneous adverse reactions (SCARs) are potentially lethal.

Objective: To review the etiology and clinical manifestations of severe cutaneous adverse reactions (SCARs) and the demographic characteristics of patients with SCARs.

Methods: This study is a retrospective review of electronic medical records for patients who developed drug-induced cutaneous reactions and were treated for initial or ongoing care at a university medical center from June 4, 2008, to August 10, 2018. Search terms included Stevens-Johnson syndrome(SJS) , drug rash with eosinophilia and systemic symptoms(DRESS), acute generalized exanthematous pustulosis(AGEP), toxic epidermal necrolysis (TEN), and TEN/SJS overlap.

Results: Of 596 cases of drug-induced rash, 35 cases (5.9%) of SCARs were encountered (male-to-female ratio, 1.06:1.0; mean age, 48.5 years). Of those 35 cases, 32 were in white patients (91.4%). The most common manifestations were DRESS (19 [54.3%]), SJS (8 [22.8%]), AGEP (6 [17.1%]), TEN (1 [2.9%]), and overlap (1 [2.9%]). Multiple causative drugs were implicated in 14 cases, whereas a single drug was responsible in 21 cases. The most common drugs implicated were antibiotics (88.1%). The most common causative antibiotics were cephalosporins (23.7%). Most of the patients with SCARs were given triamcinolone cream and prednisone alone (18 [51.4%]), methylprednisolone alone (1 [2.9%]), methylprednisolone and prednisone combined (4 [11.4%]), methylprednisolone and prednisolone (1 [2.9%]) or prednisone and prednisolone (1 [2.9%]).

Conclusion: The most common SCARs were, in order, DRESS, SJS, AGEP, TEN, and overlap. The most common causative drugs were, in order, cephalosporins, penicillins, trimethoprim-sulfamethoxazole, and fluoroquinolones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anai.2019.08.004DOI Listing
November 2019

Stem Cell-Derived Hepatocyte-Like Cells as Model for Viral Hepatitis Research.

Stem Cells Int 2019 12;2019:9605252. Epub 2019 Jun 12.

State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Viral hepatitis, the leading cause of liver diseases worldwide, is induced upon infection with hepatotropic viruses, including hepatitis A, B, C, D, and E virus. Due to their obligate intracellular lifestyles, culture systems for efficient viral replication are vital. Although basic and translational research on viral hepatitis has been performed for many years, conventional hepatocellular culture systems are not optimal. These studies have greatly benefited from recent efforts on improving cell culture models for virus replication and infection studies. Here we summarize the use of human stem cell-derived hepatocyte-like cells for hepatotropic virus infection studies, including the dissection of virus-host interactions and virus-induced pathogenesis as well as the identification and validation of novel antiviral agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/9605252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594266PMC
June 2019

Prediction of Human Pharmacokinetics of Antibody-Drug Conjugates From Nonclinical Data.

Clin Transl Sci 2019 09 11;12(5):534-544. Epub 2019 Jun 11.

Genentech Inc., South San Francisco, California, USA.

Prediction of human pharmacokinetics (PK) based on preclinical information for antibody-drug conjugates (ADCs) provide important insight into first-in-human (FIH) study design. This retrospective analysis was conducted to identify an appropriate scaling method to predict human PK for ADCs from animal PK data in the linear range. Different methods for projecting human clearance (CL) from animal PK data for 11 ADCs exhibiting linear PK over the tested dose ranges were examined: multiple species allometric scaling (CL vs. body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent, and scaling from only cynomolgus monkey PK data. Two analytes of interest for ADCs, namely total antibody and conjugate (measured as conjugated drug or conjugated antibody), were assessed. Percentage prediction errors (PEs) and residual sum of squares (RSS) were compared across methods. Human CL was best estimated using cynomolgus monkey PK data alone and an allometric scaling exponent of 1.0 for CL. This was consistently observed for both conjugate and total antibody analytes. Other scaling methods either underestimated or overestimated human CL, or produced larger average absolute PEs and RSS. Human concentration-time profiles were also reasonably predicted from the cynomolgus monkey data using species-invariant time method with a fixed exponent of 1.0 for CL and 1.0 for volume of distribution. In conclusion, results from this retrospective analysis of 11 ADCs indicate that allometric scaling of CL with an exponent of 1.0 using cynomolgus monkey PK data alone can successfully project human PK profiles of an ADC within linear range.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cts.12649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742937PMC
September 2019

Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue.

J Clin Oncol 2019 02 4;37(6):461-470. Epub 2019 Jan 4.

23 Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Purpose: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD.

Patients And Methods: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome.

Results: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days.

Conclusion: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.00474DOI Listing
February 2019

Folic acid supplement use and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a case-control study.

Breast Cancer Res Treat 2019 Apr 2;174(3):741-748. Epub 2019 Jan 2.

Women's College Hospital, Women's College Research Institute, 76 Grenville St., 6th Floor, Toronto, ON, M5S 1B2, Canada.

Purpose: Supplemental folic acid (the more bioavailable and synthetic form of folate) and breast cancer risk in BRCA mutation carriers have not been studied. We evaluated folic acid, vitamin B6 and vitamin B12 supplement use, and breast cancer risk among BRCA mutation carriers.

Methods: In this case-control study, dietary supplement use was collected from BRCA mutation carriers living in Canada. Supplement use was categorized as never or ever use. Total average daily supplement use was categorized as never, moderate, and high use based on tertiles. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI) for supplement use and breast cancer risk.

Results: We included 129 breast cancer cases and 271 controls. Women who used any folic acid-containing supplement had a significantly decreased risk of breast cancer compared to women who never used a folic acid-containing supplement (OR 0.45; 95%CI 0.25, 0.79; P = 0.006). This was significant for BRCA1 mutation carriers only. The OR for moderate folic acid supplement intake was 0.39; P = 0.01, and high intake was 0.54; P = 0.09, compared to never users. Moderate vitamin B12 supplement intake was associated with decreased risk of breast cancer compared to never use (OR 0.48; 95%CI 0.24, 0.96; P = 0.04).

Conclusions: In this first investigation of folic acid supplement use and breast cancer risk in BRCA mutation carriers, these findings suggest that moderate folic acid- and vitamin B12-containing supplement use may be protective for BRCA-associated breast cancer, particularly among BRCA1 mutation carriers. Future studies with larger samples and prospective follow-up are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-018-05118-3DOI Listing
April 2019

Outcomes and Return to Sport After Pectoralis Major Tendon Repair: A Systematic Review.

Sports Health 2019 Mar/Apr;11(2):134-141. Epub 2018 Dec 13.

Department of Surgery, McMaster University, Hamilton, Ontario, Canada.

Context:: Pectoralis major tendon ruptures are becoming increasingly common due to the growing prevalence of active lifestyles. Studies investigating the efficacy of pectoralis major tendon repair have limited sample sizes and offer mixed results, while existing reviews do not explore postoperative activity outcomes for patients.

Objective:: To summarize and synthesize the clinical outcomes and rate of return to activity after isolated pectoralis major tendon repair.

Data Sources:: Four databases (MEDLINE, EMBASE, PubMed, and CINAHL) were searched from database inception through March 7, 2018.

Study Selection:: Studies reporting outcomes of isolated pectoralis major tendon repair for pectoralis major tendon rupture were included.

Study Design:: Systematic review.

Level Of Evidence:: Level 4.

Data Extraction:: Data including patient demographics, intervention details, and clinical outcomes were extracted. The methodological quality of included studies was evaluated.

Results:: Of 2332 retrieved articles, 18 studies were included, with a total of 536 patients. A majority (90%; 134/149) of patients undergoing pectoralis major tendon repair successfully returned to sport at a mean 6.1 ± 1.7 months postsurgery, of which 74% (95/128) successfully returned to their preinjury level of sport. The majority (95%; 269/284) of patients returned to work at a mean 6.9 ± 1 months. Postsurgically, 81% (83/102) of patients experienced complete pain relief after the surgery, and 19% (21/109) had cosmetic complaints after pectoralis major repair. Of the 10 studies that reported complications, 18% (75/423) of patients had postoperative complications, including reruptures and wound infections; 7% (30/423) of patients required reoperation for their complications.

Conclusion:: Pectoralis major tendon repair is an effective treatment that results in a high rate of return to sport and work, pain relief, and improved cosmetic appearance, albeit with a significant rate of complication. The evidence supporting all outcomes was limited by the rarity of the injury, the variable surgical techniques, and outcome assessment criteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1941738118818060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391551PMC
May 2019

DNA hypermethylation within TERT promoter upregulates TERT expression in cancer.

J Clin Invest 2019 01 3;129(1):223-229. Epub 2018 Dec 3.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Replicative immortality is a hallmark of cancer cells governed by telomere maintenance. Approximately 90% of human cancers maintain their telomeres by activating telomerase, driven by the transcriptional upregulation of telomerase reverse transcriptase (TERT). Although TERT promoter mutations (TPMs) are a major cancer-associated genetic mechanism of TERT upregulation, many cancers exhibit TERT upregulation without TPMs. In this study, we describe the TERT hypermethylated oncological region (THOR), a 433-bp genomic region encompassing 52 CpG sites located immediately upstream of the TERT core promoter, as a cancer-associated epigenetic mechanism of TERT upregulation. Unmethylated THOR repressed TERT promoter activity regardless of TPM status, and hypermethylation of THOR counteracted this repressive function. THOR methylation analysis in 1,352 human tumors revealed frequent (>45%) cancer-associated DNA hypermethylation in 9 of 11 (82%) tumor types screened. Additionally, THOR hypermethylation, either independently or along with TPMs, accounted for how approximately 90% of human cancers can aberrantly activate telomerase. Thus, we propose that THOR hypermethylation is a prevalent telomerase-activating mechanism in cancer that can act independently of or in conjunction with TPMs, further supporting the utility of THOR hypermethylation as a prognostic biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI121303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307937PMC
January 2019

Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer.

Int J Cancer 2019 04 30;144(7):1676-1684. Epub 2018 Dec 30.

Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.

In urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self-renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations (TERTp ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTp and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTp were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher-risk disease in nonmuscle invasive bladder cancers (NMIBC). TERTp alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THOR /TERTp increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERTp and TERTp NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTp is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.31935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519346PMC
April 2019

HLA-F on HLA-Null 721.221 Cells Activates Primary NK Cells Expressing the Activating Killer Ig-like Receptor KIR3DS1.

J Immunol 2018 07 9;201(1):113-123. Epub 2018 May 9.

Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada;

NK cells elicit important responses against transformed and virally infected cells. Carriage of the gene encoding the activating killer Ig-like receptor KIR3DS1 is associated with slower time to AIDS and protection from HIV infection. Recently, open conformers of the nonclassical MHC class Ib Ag HLA-F were identified as KIR3DS1 ligands. In this study, we investigated whether the interaction of KIR3DS1 on primary NK cells with HLA-F on the HLA-null cell line 721.221 (221) stimulated KIR3DS1 NK cells. We used a panel of Abs to detect KIR3DS1CD56 NK cells that coexpressed the inhibitory NK cell receptors KIR2DL1/L2/L3, 3DL2, NKG2A, and ILT2; the activating NK cell receptors KIR2DS1/S2/S3/S5; and CCL4, IFN-γ, and CD107a functions. We showed that both untreated and acid-pulsed 221 cells induced a similar frequency of KIR3DS1 cells to secrete CCL4/IFN-γ and express CD107a with a similar intensity. A higher percentage of KIR3DS1 than KIR3DS1 NK cells responded to 221 cells when either inclusive or exclusive (i.e., coexpressing none of the other inhibitory NK cell receptors and activating NK cell receptors detected by the Ab panel) gating strategies were employed to identify these NK cell populations. Blocking the interaction of HLA-F on 221 cells with KIR3DS1-Fc chimeric protein or anti-HLA-F Abs on exclusively gated KIR3DS1 cells reduced the frequency of functional cells compared with that of unblocked conditions for stimulated KIR3DS1 NK cells. Thus, ligation of KIR3DS1 activates primary NK cells for several antiviral functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1701370DOI Listing
July 2018

HIV exposed seronegative (HESN) compared to HIV infected individuals have higher frequencies of telomeric Killer Immunoglobulin-like Receptor (KIR) B motifs; Contribution of KIR B motif encoded genes to NK cell responsiveness.

PLoS One 2017 22;12(9):e0185160. Epub 2017 Sep 22.

Research Institute of the McGill University Health Center (RI-MUHC), Montreal, Quebec, Canada.

Previously, we showed that Killer Immunoglobulin-like Receptor (KIR)3DS1 homozygotes (hmz) are more frequent in HIV exposed seronegative (HESN) than in recently HIV infected (HIV+) individuals. KIR3DS1 encodes an activating Natural Killer (NK) cell receptor (NKR). The link between KIR genotype and HIV outcomes likely arises from the function that NK cells acquire through expression of particular NKRs. An initial screen of 97 HESN and 123 HIV+ subjects for the frequency of KIR region gene carriage observed between-group differences for several telomeric KIR region loci. In a larger set of up to 106 HESN and 439 HIV+ individuals, more HESN than HIV+ subjects were KIR3DS1 homozygotes, lacked a full length KIR2DS4 gene and carried the telomeric group B KIR haplotype motif, TB01. TB01 is characterized by the presence of KIR3DS1, KIR2DL5A, KIR2DS3/5 and KIR2DS1, in linkage disequilibrium with each other. We assessed which of the TB01 encoded KIR gene products contributed to NK cell responsiveness by stimulating NK cells from 8 HIV seronegative KIR3DS1 and TB01 motif homozygotes with 721.221 HLA null cells and evaluating the frequency of KIR3DS1+/-KIR2DL5+/-, KIR3DS1+/-KIR2DS1+/-, KIR3DS1+/-KIR2DS5+/- NK cells secreting IFN-γ and/or expressing CD107a. A higher frequency of NK cells expressing, versus not, KIR3DS1 responded to 721.221 stimulation. KIR2DL5A+, KIR2DS1+ and KIR2DS5+ NK cells did not contribute to 721.221 responses or modulate those by KIR3DS1+ NK cells. Thus, of the TB01 KIR gene products, only KIR3DS1 conferred responsiveness to HLA-null stimulation, demonstrating its ligation can activate ex vivo NK cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185160PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609756PMC
October 2017

Oxidized Low-Density Lipoprotein Loading of Macrophages Downregulates TLR-Induced Proinflammatory Responses in a Gene-Specific and Temporal Manner through Transcriptional Control.

J Immunol 2017 09 7;199(6):2149-2157. Epub 2017 Aug 7.

Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada.

Hypercholesterolemia is a key risk factor for atherosclerosis and leads to the uptake of native and oxidized low-density lipoprotein (oxLDL) by macrophages (Mϕs) and foam cell formation. Inflammatory processes accompany Mϕ foam cell formation in the artery wall, yet the relationship between Mϕ lipid loading and their response to inflammatory stimuli remains elusive. We investigated proinflammatory gene expression in thioglycollate-elicited peritoneal Mϕs, bone marrow-derived Mϕs and dendritic cells, and RAW264.7 cells. Loading with oxLDL did not induce peritoneal Mϕ apoptosis or modulate basal-level expression of proinflammatory genes. Upon stimulation of TLR4, the rapid induction of IFN-β was inhibited in cells loaded with oxLDL, whereas the induction of other proinflammatory genes by TLR4 (LPS), TLR3 (polyriboinosinic-polyribocytidylic acid), TLR2 (PamCSK), and TLR9 (CpG) remained comparable within the first 2 h. Subsequently, the expression of a subset of proinflammatory genes (e.g., IL-1β, IL-6, CCL5) was reduced in oxLDL-loaded cells at the level of transcription. This phenomenon was partially dependent on NF erythroid 2-related factor 2 (NRF2) but not on nuclear liver X receptors α and β (LXRα,β), peroxisome proliferator-activated receptor-γ (PPARγ), and activating transcription factor 3 (ATF3). LPS-induced NF-κB reporter activity and intracellular signaling by NF-κB and MAPK pathways were comparable in oxLDL-loaded Mϕs, yet the binding of p65/RelA (the prototypic NF-κB family member) was reduced at IL-6 and CCL5 promoters. This study revealed that oxLDL loading of Mϕs negatively regulates transcription at late stages of TLR-induced proinflammatory gene expression and implicates epigenetic mechanisms such as histone deacetylase activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1601363DOI Listing
September 2017

A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study.

Oncotarget 2016 09;7(36):57726-57736

Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

The identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa).We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data.Most cancers (n = 3056) including PCa (n = 300) exhibited hypermethylation of THOR. THOR was the only region within the TERT gene that is differentially methylated between normal and malignant prostate tissue (p < 0.0001). Also, THOR was significantly hypermethylated in PCa when compared to paired benign tissues (n = 164, p < 0.0001). THOR hypermethylation correlated with Gleason scores and was associated with tumor invasiveness (p = 0.0147). Five years biochemical progression free survival (BPFS) for PCa patients in the discovery cohort was 87% (95% CI 73-100) and 65% (95% CI 52-78) for THOR non-hypermethylated and hypermethylated cancers respectively (p = 0.01). Similar differences in BPFS were noted in the validation cohort (p = 0.03). Importantly, THOR was able to predict outcome in the challenging (Gleason 6 and 7 (3 + 4)) PCa (p = 0.007). For this group, THOR was an independent risk factor for BPFS with a hazard-ratio of 3.685 (p = 0.0247). Finally, THOR hypermethylation more than doubled the risk of recurrence across all PSA levels (OR 2.5, p = 0.02).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.10639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295385PMC
September 2016

Telomere dysfunction and chromothripsis.

Int J Cancer 2016 Jun 29;138(12):2905-14. Epub 2016 Feb 29.

Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Chromothripsis is a recently discovered form of genomic instability, characterized by tens to hundreds of clustered DNA rearrangements resulting from a single dramatic event. Telomere dysfunction has been suggested to play a role in the initiation of this phenomenon, which occurs in a large number of tumor entities. Here, we show that telomere attrition can indeed lead to catastrophic genomic events, and that telomere patterns differ between cells analyzed before and after such genomic catastrophes. Telomere length and telomere stabilization mechanisms diverge between samples with and without chromothripsis in a given tumor subtype. Longitudinal analyses of the evolution of chromothriptic patterns identify either stable patterns between matched primary and relapsed tumors, or loss of the chromothriptic clone in the relapsed specimen. The absence of additional chromothriptic events occurring between the initial tumor and the relapsed tumor sample points to telomere stabilization after the initial chromothriptic event which prevents further shattering of the genome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.30033DOI Listing
June 2016

High Peak Estradiol Predicts Higher Miscarriage and Lower Live Birth Rates in High Responders Triggered with a GnRH Agonist in IVF/ICSI Cycles.

J Reprod Med 2015 Nov-Dec;60(11-12):463-70

Objective: To investigate parameters predictive of pregnancy outcomes in high responders undergoing fresh, autologous, GnRH antagonist IVF/ICSI cycles using a GnRH agonist trigger.

Study Design: Retrospective cohort study of all patients deemed high-risk for ovarian hyperstimulation syndrome who underwent fresh, autologous IVF/ICSI using a GnRH agonist trigger at an academic fertility center from 2010-2012.

Results: A total of 71 first cycles were analyzed. Rates of clinical pregnancy, live birth (LB), and total (clinical plus biochemical) miscarriage (MC) were 52%, 38%, and 25%, respectively. Mean peak estradiol (E2) and the number of oocytes retrieved were 3,701 pg/mL and 15.2, respectively. Peak E2 was significantly higher in those cycles resulting in clinical MC (p = 0.003). After adjusting for age, basal follicle stimulating hormone, and the number of oocytes retrieved, elevated peak E2 remained associated with increased clinical MC (p = 0.029) and trended towards a relationship with higher total MC (p = 0.062). When peak E2 was treated as a binary variable based on the threshold value of > 5,000 pg/mL, peak E2 above this value was associated with a higher rate of clinical MC (OR = 16.14 with 95% CI 1.25-209.35, p = 0.033) and total MC (OR = 6.81 with 95% CI 1.12-41.54, p = 0.037), as well as a lower LB rate (OR = 0.095 with 95% CI 0.01-0.90, p = 0.041).

Conclusion: Clinicians should recognize most IVF/ICSI patients triggered with a GnRH agonist as inherently in danger of excessively high serum E2 and avoid peak levels > 5,000 pg/mL in order to avoid higher MC and lower LB rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2016

In Vitro Developmental Toxicology Screens: A Report on the Progress of the Methodology and Future Applications.

Chem Res Toxicol 2016 Apr 1;29(4):534-44. Epub 2016 Feb 1.

Discovery Toxicology, Bristol Myers Squibb , Pennington, New Jersey 08534, United States.

There has been increasing focus on generation and assessment of in vitro developmental toxicology models for assessing teratogenic liability of chemicals. The driver for this focus has been to find reliable in vitro assays that will reduce or replace the use of in vivo tests for assessing teratogenicity. Such efforts may be eventually applied in testing pharmaceutical agents where a developmental toxicology assay or battery of assays may be incorporated into regulatory testing to replace one of the two species currently used in teratogenic assessment. Such assays may be eventually applied in testing a broader spectrum of chemicals, supporting efforts aligned with Tox21 strategies and responding to REACH legislation. This review describes the developmental toxicology assays that are of focus in these assessments: rodent whole embryo culture, zebrafish embryo assays, and embryonic stem cell assays. Progress on assay development as well as future directions of how these assays are envisioned to be applied for broader safety testing of chemicals are discussed. Altogether, the developmental model systems described in this review provide rich biological systems that can be utilized in better understanding teratogenic mechanisms of action of chemotypes and are promising in providing proactive safety assessment related to developmental toxicity. Continual advancements in refining/optimizing these in vitro assays are anticipated to provide a robust data set to provide thoughtful assessment of how whole animal teratogenicity evaluations can be reduced/refined in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.chemrestox.5b00458DOI Listing
April 2016

A Developmental Toxicology Assay Platform for Screening Teratogenic Liability of Pharmaceutical Compounds.

Birth Defects Res B Dev Reprod Toxicol 2016 Feb 5;107(1):4-20. Epub 2016 Jan 5.

Discovery Toxicology Group, Bristol Myers-Squibb, Hopewell, New Jersey.

Increasing need for proactive safety optimization of pharmaceutical compounds has led to generation and/or refinement of in vitro developmental toxicology assays. Our laboratory has developed three in vitro developmental toxicology assays to assess teratogenic liability of pharmaceutical compounds. These assays included a mouse molecular embryonic stem cell assay (MESCA), a dechorionated zebrafish embryo culture (ZEC) assay, and a streamlined rat whole embryo culture (rWEC) assay. Individually, the assays presented good (73-82%) predictivity. However, it remains to be determined whether combining or tiering the assays could enhance performance. Seventy-three compounds representing a broad spectrum of pharmaceutical targets and chemistry were evaluated across the assays to generate testing strategies that optimized performance. The MESCA and ZEC assays were found to have two limitations: compound solubility and frequent misclassification of compounds with H1 receptor or GABAnergic activity. The streamlined rWEC assay was found to be a cost-effective stand-alone assay for supporting poorly soluble compounds and/or ones with H1 or GABAnergic activity. For all other compounds, a tiering strategy using the MESCA and ZEC assays additionally optimized throughput, cost, and minimized animal use. The tiered strategy resulted in improved performance achieving 88% overall predictivity and was comparable with 89% overall predictivity achieved with frequency analysis (final teratogenic classification made from most frequent teratogenic classification from each individual assay). Furthermore there were 21 compounds in the test set characterized as definitive or suspect human teratogens and the multiassay approach achieved 95 and 91% correct classification using the tiered or frequency screening approach, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdrb.21168DOI Listing
February 2016

Optimization and Performance Assessment of the Chorion-Off [Dechorinated] Zebrafish Developmental Toxicity Assay.

Toxicol Sci 2015 Jul 14;146(1):127-34. Epub 2015 Apr 14.

Discovery Toxicology, Bristol-Myers Squibb Company, Princeton, New Jersey 08534.

The Dechorinated Zebrafish Embryo Developmental toxicity assay was originally developed from a training set of 31 compounds and reported to be 87% concordant with in vivo teratogenicity data (Brannen, K. C., Panzica-Kelly, J. M., Danberry, T. L., and Augustine-Rauch, K. A. (2010). Development of a zebrafish embryo teratogenicity assay and quantitative prediction model. Birth Defects Res. 89, 66-77.). The assay includes scoring larva treated in a concentration range for malformations of specific morphological structures/organ systems. The model includes identifying a no-adverse-effect-level (NOAEL) and the concentration resulting in 25% lethality (LC25) at 5 days postfertilization. An LC25/NOAEL ratio ≥10 classifies a compound positive for teratogenic potential. A consortium effort evaluated a modified version of this assay which involved enzymatic chorion treatment instead of manual dissection and used experimental replicates for final classification. The modified assay achieved an 85% overall predictivity (Gustafson, A. L., Stedman, D. B., Ball, J., Hillegass, J. M., Flood, A., Zhang, C. X., Panzica-Kelly, J., Cao, J., Coburn, A., Enright, B. P., et al. (2012). Inter-laboratory assessment of a harmonized zebrafish developmental toxicology assay - progress report on phase I. Reprod. Toxicol. 33, 155-164.). The objective of this study was to perform a thorough performance evaluation of the dechorinated assay by repeating the original training set and testing additional compounds in experimental replicates. When the initial training set was repeated with inclusion of experimental replicates, the overall predictivity was 83%. Model performance was tested with an additional 34 compounds and achieved overall predictivity of 74%. When the training and test sets were combined (63 compounds) the assay's final sensitivity was 83% and the specificity was 71%. Total predictivity was 78% with relatively balanced predictivity for nonteratogens (77%) and teratogens (78%). The chorion-off assay achieved superior sensitivity (83%) compared with sensitivity (63-74%) reported by consortium efforts testing a similar assay with chorion-intact embryos (Ball, J. S., Stedman, D. B., Hillegass, J. M., Zhang, C. X., Panzica-Kelly, J., Coburn, A., Enright, B. P., Tornesi, B., Amouzadeh, H. R., Hetheridge, M., et al. (2014). Fishing for teratogens: a consortium effort for a harmonized zebrafish developmental toxicology assay. Toxicol. Sci. 139, 210-219.). Additional protocol modifications were made to increase assay throughput.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfv076DOI Listing
July 2015

BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma.

J Clin Oncol 2015 Mar 9;33(9):1015-22. Epub 2015 Feb 9.

Matthew Mistry, Nataliya Zhukova, Daniele Merico, Rahul Krishnatry, Mary Shago, James Stavropoulos, Noa Alon, Peter N. Ray, Vilma Navickiene, Joshua Mangerel, Marc Remke, Vijay Ramaswamy, Ana Guerreiro Stucklin, Martin Li, Edwin J. Young, Cindy Zhang, Pedro Castelo-Branco, Doua Bakry, Suzanne Laughlin, James T. Rutka, Peter B. Dirks, Michael D. Taylor, Mark Greenberg, David Malkin, Annie Huang, Eric Bouffet, Cynthia E. Hawkins, and Uri Tabori; The Hospital for Sick Children; Matthew Mistry, Patricia Rakopoulos, Rahul Krishnatry, Joshua Mangerel, Pawel Buczkowicz, Ana Guerreiro Stucklin, Doua Bakry, Adam Shlien, Mark Greenberg, David Malkin, Annie Huang, Eric Bouffet, Cynthia E. Hawkins, and Uri Tabori, University of Toronto; Jason D. Pole, Pediatric Oncology Group of Ontario, Toronto, Ontario; Jennifer Chan, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Pedro Castelo-Branco, Universidade do Algarve, Faro, Portugal; Keith L. Ligon, Dana-Farber/Boston Children's Cancer Center, Boston, MA.

Purpose: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG).

Patients And Methods: We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained.

Results: sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024).

Conclusion: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2014.58.3922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356711PMC
March 2015

WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma.

Acta Neuropathol Commun 2014 Dec 24;2:174. Epub 2014 Dec 24.

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-014-0174-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297452PMC
December 2014

Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors.

Acta Neuropathol 2014 Dec 15;128(6):853-62. Epub 2014 Oct 15.

The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.

Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-014-1348-1DOI Listing
December 2014

Fishing for teratogens: a consortium effort for a harmonized zebrafish developmental toxicology assay.

Toxicol Sci 2014 May 4;139(1):210-9. Epub 2014 Feb 4.

AstraZeneca, Brixham, Devon TQ5 8BA, UK.

A consortium of biopharmaceutical companies previously developed an optimized Zebrafish developmental toxicity assay (ZEDTA) where chorionated embryos were exposed to non-proprietary test compounds from 5 to 6 h post fertilization and assessed for morphological integrity at 5 days post fertilization. With the original 20 test compounds, this achieved an overall predictive value for teratogenicity of 88% of mammalian in vivo outcome [Gustafson, A. L., Stedman, D. B., Ball, J., Hillegass, J. M., Flood, A., Zhang, C. X., Panzica-Kelly, J., Cao, J., Coburn, A., Enright, B. P., et al. (2012). Interlaboratory assessment of a harmonized Zebrafish developmental toxicology assay-Progress report on phase I. Reprod. Toxicol. 33, 155-164]. In the second phase of this project, 38 proprietary pharmaceutical compounds from four consortium members were evaluated in two laboratories using the optimized method using either pond-derived or cultivated-strain wild-type Zebrafish embryos at concentrations up to 100μM. Embryo uptake of all compounds was assessed using liquid chromatography-tandem mass spectrometry. Twenty eight of 38 compounds had a confirmed embryo uptake of >5%, and with these compounds the ZEDTA achieved an overall predictive value of 82% and 65% at the two respective laboratories. When low-uptake compounds (≤ 5%) were retested with logarithmic concentrations up to 1000μM, the overall predictivity across all 38 compounds was 79% and 62% respectively, with the first laboratory achieving 74% sensitivity (teratogen detection) and 82% specificity (non-teratogen detection) and the second laboratory achieving 63% sensitivity (teratogen detection) and 62% specificity (non-teratogen detection). Subsequent data analyses showed that technical differences rather than strain differences were the primary contributor to interlaboratory differences in predictivity. Based on these results, the ZEDTA harmonized methodology is currently being used for compound assessment at lead optimization stage of development by 4/5 of the consortium companies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfu017DOI Listing
May 2014
-->