Expression of aldehyde dehydrogenase 1 as a marker of mammary stem cells in benign and malignant breast lesions of Ghanaian women

BACKGROUND: Breast cancers that are negative for the estrogen receptor (ER), the progesterone receptor (PR), and the HER2 (human epidermal growth factor receptor 2) marker are more prevalent among African women, and the biologically aggressive nature of these triple‐negative breast cancers (TNBCs) may be attributed to their mammary stem cell features. Little is known about expression of the mammary stem cell marker aldehyde dehydrogenase 1 (ALDH1) in African women. Novel data are reported regarding ALDH1 expression in benign and cancerous breast tissue of Ghanaian women. METHODS: Formalin‐fixed, paraffin‐embedded specimens were transported from the Komfo Anoyke Teaching Hospital in Kumasi, Ghana to the University of Michigan for centralized histopathology study. Expression of ER, PR, HER2, and ALDH1 was assessed by immunohistochemistry. ALDH1 staining was further characterized by its presence in stromal versus epithelial and/or tumor components of tissue. RESULTS: A total of 173 women contributed to this study: 69 with benign breast conditions, mean age 24 years, and 104 with breast cancer, mean age 49 years. The proportion of benign breast conditions expressing stromal ALDH1 (n = 40, 58%) was significantly higher than those with cancer (n = 44, 42.3%) ( P = .043). Among the cancers, TNBC had the highest prevalence of ALDH1 expression, either in stroma or in epithelial cells. More than 2‐fold higher likelihood of ALDH1 expression was observed in TNBC cases compared with other breast cancer subtypes (odds ratio = 2.38, 95% confidence interval 1.03‐5.52, P = .042). CONCLUSIONS: ALDH1 expression was higher in stromal components of benign compared with cancerous lesions. Of the ER‐, PR‐, and HER2‐defined subtypes of breast cancer, expression of ALDH1 was highest in TNBC. Cancer 2013. © 2012 American Cancer Society. Mammary stem cells, as identified by cells expressing the marker aldehyde dehydrogenase 1 (ALDH1), appear to be correlated with malignant transformation and progression of breast tissue into biologically aggressive phenotypes. This study reveals increased expression of ALDH1 in benign and malignant tissue of women from the western sub‐Saharan African nation of Ghana, a population known to have higher frequency of triple‐negative breast cancer, and ALDH1 expression in the malignant specimens was found to be associated with risk of triple‐negative breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96403/1/27737_ftp.pd

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Common variants in P2RY11 are associated with narcolepsy.

l e t t e r s Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genomewide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10 −10 , odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The diseaseassociated allele is correlated with reduced expression of P2RY11 in CD8 + T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases

Common variants in P2RY11 are associated with narcolepsy.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov'tresearch support, u.s. gov't, p.h.s.2011 Jan2010 12 19importedErratum in : Nat Genet. 2011 Oct;43(10):1040

Sleep-wake characteristics, daytime sleepiness, and glycemia in young adults with type 1 diabetes

STUDY OBJECTIVES: The purpose of this study was to describe objective sleep-wake characteristics and glycemia over 7-14 days in young adults with type 1 diabetes. In addition, person-level associations among objective sleep-wake characteristics (total sleep time, sleep variability, and sleep fragmentation index), daytime sleepiness, and glycemia (glycemic control and glucose variability) were examined. METHODS: In this cross-sectional study, objective sleep-wake characteristics were measured via actigraphy and glucose variability via continuous glucose monitoring over 6-14 days. At baseline, participants completed the Psychomotor Vigilance Test, the Trail Making Test, and questionnaires on daytime sleepiness, sleep quality, and sleep disturbance including sleep diaries. RESULTS: Forty-six participants (mean age, 22.3 +/- 3.2 years) wore a wrist actigraph and underwent continuous glucose monitoring concurrently for 6-14 days. Greater sleep variability was directly associated with greater glucose variability (mean of daily differences; r = .33, P = .036). Higher daytime sleepiness was directly associated with greater glucose variability (mean of daily differences; r = .50, P = .001). The association between sleep variability and glucose variability (mean of daily differences) was no longer significant when accounting for daytime sleepiness and controlling for type 1 diabetes duration (P \u3e .05). A higher sleep fragmentation index was associated with greater glucose variability (B = 1.27, P = .010, pr2 = 0.40) after controlling for type 1 diabetes duration and accounting for higher daytime sleepiness. CONCLUSIONS: Sleep-wake variability, sleep fragmentation, daytime sleepiness, and the associations with glycemia are new dimensions to consider in young adults with type 1 diabetes. Sleep habits in this population may explain higher glucose variability, and optimizing sleep may improve overall diabetes management

Variations in Sleep Characteristics and Glucose Regulation in Young Adults With Type 1 Diabetes

CONTEXT: Short sleep duration and sleep disruptions are associated with impaired glucoregulation in type 1 diabetes (T1D). However, the mechanistic pathways between sleep and glucose variability remain unclear. OBJECTIVE: To determine within- and between-person associations between objective sleep-wake characteristics and glucose variability indices. METHODS: Multilevel models were used to analyze concurrent sleep and glucose patterns over 7 days in 42 young adults with T1D in their natural home environment. Young adults with T1D (mean age 22.2 +/- 3.0 years, HbA1c 7.2%, 32.6% male) for at least 6 months with no other medical or major psychiatric comorbidity were included. Sleep-wake characteristics were measured via wrist actigraphy and glucose variability indices via a continuous glucose monitor (CGM). RESULTS: Lower sleep efficiency predicted higher glucose variability (less time in range beta = 0.011 and more time in hyperglycemia beta = -0.011) within-person. A longer wake after sleep onset and more sleep disruptions were associated with higher glucose variability between persons (beta = 0.28 and 0.31). Higher glucose variability predicted poorer sleep within-person (delayed bedtime, waketime, mid-sleep time, and lower sleep efficiency), while higher glucose variability was associated with poorer sleep and more sleep disruptions between persons (lower sleep efficiency, longer wake after sleep onset, and a higher sleep fragmentation index). CONCLUSION: Clinicians can address the reciprocal nature of the sleep-glucose relationship by optimizing sleep and targeting efforts toward a euglycemic range overnight. Sleep habits are a modifiable personal target in diabetes care

Increased HbA1c Variability May Shorten Time to Microalbuminuria Development in Type 1 Diabetes (T1D)

We aim to understand the impact of HbA1c variability, as measured by SD-HbA1c, on risk of microalbuminuria in T1D population. An analysis was performed utilizing data of 8,680 participants in the T1D Exchange Clinic Registry (50% female, 86% non-Hispanic white, mean age 34 years, mean diabetes duration 14 years at enrollment) who met the following criteria: ≥2 clinic visit records, T1D duration ≥1 year at enrollment, age of diagnosis ≥10 years old and no known renal disease (including no microalbuminuria) at the time of registry enrollment. Median number of albuminuria and HbA1c measures were 4 and 21 per participant, respectively. Microalbuminuria was present during follow-up in 562 (6.5%) participants. Median intrapersonal mean HbA1c and SD-HbA1c were 7.8% and 0.6% respectively. Participants with high HbA1c variability had shorter time to first microalbuminuria (p<0.001, Figure 1a.) Those with high (≥50th percentile) mean HbA1c and high SD-HbA1c also had shorter diabetes duration prior to first reported microalbuminuria compared to high mean-HbA1c but low SD-HbA1c (p<0.001, Figure 1b). HbA1c variability relates to risk of microalbuminuria in T1D; its relationship to other outcomes should be studied. Disclosure M.A. Clements: Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Glooko, Inc.. M. Wu: None. N.C. Foster: None. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC.. V.N. Shah: None. F. Vendrame: Consultant; Self; Novo Nordisk Inc.. R.S. Kingman: None. G.T. Alonso: None. A. Carlson: Advisory Panel; Self; Sanofi, Insulet Corporation. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Medtronic, Novo Nordisk A/S. D.J. DeSalvo: Consultant; Self; Dexcom, Inc.. Speaker's Bureau; Self; Insulet Corporation. B.A. Buckingham: Advisory Panel; Self; Novo Nordisk Inc., ConvaTec Inc.. Research Support; Self; Medtronic, Insulet Corporation, Dexcom, Inc., Tandem Diabetes Care, Inc.. Consultant; Self; Tandem Diabetes Care, Inc., Becton, Dickinson and Company. J. Sherr: Consultant; Self; Medtronic MiniMed, Inc.. Advisory Panel; Self; Insulet Corporation, Eli Lilly and Company, Bigfoot Biomedical. R. Benjamin: Speaker's Bureau; Self; Pfizer Inc.. E. Eyth: None. S. DuBose: None

Common variants in P2RY11 are associated with narcolepsy.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases