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- Gaudet, Mia M, et al.
(författare)
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Pooled Analysis of Nine Cohorts Reveals Breast Cancer Risk Factors by Tumor Molecular Subtype.
- 2018
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 78:20, s. 6011-6021
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Tidskriftsartikel (refereegranskat)abstract
- Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 exhibit etiologic differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiologic heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A–like (ER+ or PR+/HER2−), 1,368 luminal B–like (ER+ or PR+/HER2+), 521 HER2-enriched (ER−/PR−/HER2+), and 1,152 triple-negative (ER−/PR−/HER2−) disease. Ever parous compared with never was associated with lower risk of luminal A–like (HR, 0.78; 95% CI, 0.73–0.83) and luminal B–like (HR, 0.74; 95% CI, 0.64–0.87) as well as a higher risk of triple-negative disease (HR, 1.23; 95% CI, 1.02–1.50; P value for overall tumor heterogeneity < 0.001). Direct associations with luminal-like, but not HER2-enriched or triple-negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause (P value for overall tumor heterogeneity < 0.001). Age-specific associations with baseline body mass index differed for risk of luminal A–like and triple-negative breast cancer (P value for tumor heterogeneity = 0.02). These results provide the strongest evidence for etiologic heterogeneity of breast cancer to date from prospective studies.Significance: These findings comprise the largest study of prospective data to date and contribute to the accumulating evidence that etiological heterogeneity exists in breast carcinogenesis. Cancer Res; 78(20); 6011–21. ©2018 AACR..
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- Lee, Ji Soo, et al.
(författare)
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Genetic Association and Expression Analyses of the Phosphatidylinositol-4-Phosphate 5-Kinase (PIP5K1C) Gene in Alcohol Use DisorderRelevance for Pain Signaling and Alcohol Use
- 2018
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Ingår i: Alcoholism. - : WILEY. - 0145-6008 .- 1530-0277. ; 42:6, s. 1034-1043
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe gene encoding phosphatidylinositol-4-phosphate 5-kinase (PIP5K1C) has been recently implicated in pain regulation. Interestingly, a recent cross-tissue and cross-phenotypic epigenetic analysis identified the same gene in alcohol use disorder (AUD). Given the high comorbidity between AUD and chronic pain, we hypothesized that genetic variation in PIP5K1C might contribute to susceptibility to AUD. MethodsWe conducted a case-control association study of genetic variants in PIP5K1C. Association analyses of 16 common PIP5K1C single nucleotide polymorphisms (SNPs) were conducted in cases and controls of African (427 cases and 137 controls) and European ancestry (488 cases and 324 controls) using standard methods. In addition, given the prominent role of the opioid system in pain signaling, we investigated the effects of acute alcohol exposure on PIP5K1C expression in humanized transgenic mice for the -opioid receptor that included the OPRM1 A118G polymorphism, a widely used mouse model to study analgesic response to opioids in pain. PIP5K1C expression was measured in the thalamus and basolateral amygdala (BLA) in mice after short-term administration (single 2g/kg dose) of alcohol or saline using immunohistochemistry and analyzed by 2-way analysis of variance. ResultsIn the case-control association study using an NIAAA discovery sample, 8 SNPs in PIP5K1C were significantly associated with AUD in the African ancestry (AA) group (pamp;lt;0.05 after correction; rs4807493, rs10405681, rs2074957, rs10432303, rs8109485, rs1476592, rs10419980, and rs4432372). However, a replication analysis using an independent sample (N=3,801) found no significant associations after correction for multiple testing. In the humanized transgenic mouse model with the OPRM1 polymorphism, PIP5K1C expression was significantly different between alcohol and saline-treated mice, regardless of genotype, in both the thalamus (pamp;lt;0.05) and BLA (pamp;lt;0.01). ConclusionsOur discovery sample shows that genetic variants in PIP5K1C are associated with AUD in the AA group, and acute alcohol exposure leads to up-regulation of PIP5K1C, potentially explaining a mechanism underlying the increased risk for chronic pain conditions in individuals with AUD.
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- Johannsson, Gudmundur, 1960, et al.
(författare)
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Growth Hormone Research Society perspective on biomarkers of GH action in children and adults
- 2018
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Ingår i: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. Participants: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. Evidence: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. Consensus process: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. Conclusions: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.
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| 5. |
- Lai, L, et al.
(författare)
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The Prognostic Factors of Alcoholic Cardiomyopathy: A single-center cohort study.
- 2018
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Ingår i: Medicine. - 1536-5964. ; 97:31
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Tidskriftsartikel (refereegranskat)abstract
- Alcoholic cardiomyopathy (ACM) is considered one of the main causes of left ventricular dysfunction and is the leading cause of nonischemic dilated cardiomyopathy (DCM) in developed countries. However, very few studies have investigated the relationship between clinical characteristics and prognosis in ACM.This study aimed to identify risk factors related to a poor outcome in ACM patients.Retrospective cohort study.This study included 321 patients with ACM admitted to our hospital between 2003 and 2013. This study aimed to investigate the clinical characteristics and outcomes of the patients with ACM, and the primary endpoint of the study was all-cause mortality, which was assessed through patient medical records (review of patient hospital records and periodic examination of patients in the outpatient clinic) and medical follow-up calls with trained personnel. All-cause mortality was assessed using Kaplan-Meier survival curves, and the risk factors were assessed using Cox regression. A receiver operating characteristic (ROC) curve analysis was performed to optimize the cutoff point for discriminating between the 2 risk groups.After a median follow-up period of 3.78 years (interquartile range: 2.08-6.52 years), 83 (27.7%) patients were dead. The independent predictors of all-cause mortality due to ACM were the QRS duration (HR: 1.014; 95% CI: 1.004-1.019; P=.003), systolic blood pressure (HR: 0.980; 95% CI: 0.963- 0.997; P=.020), and New York Heart Association classification (HR: 1.595; 95% CI: 1.110-2.290; P=.011) at admission.Our study indicated that the QRS duration, systolic blood pressure, and New York Heart Association classification at admission provided independent prognostic information in patients with ACM.
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| 6. |
- Liu, Ning-Ning, et al.
(författare)
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Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence
- 2018
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 14:7
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Tidskriftsartikel (refereegranskat)abstract
- Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial element in the phosphate homeostatic system of this model yeast. We found that loss of Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species (ROS): pho84-/- cells were no more susceptible than wild type C. albicans to neutrophils from a patient with chronic granulomatous disease, or to those whose oxidative burst was pharmacologically inhibited or neutralized. pho84-/- mutants hyperactivated oxidative stress signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in high as well as low ambient phosphate conditions. ROS accumulation correlated with diminished levels of the unique superoxide dismutase Sod3 in pho84-/- cells, while SOD3 overexpression from a conditional promoter substantially restored these cells' oxidative stress resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor driving oxidative stress effects on pho84-/- cells, though, because overexpressing SOD3 did not ameliorate these cells' hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has further roles in oxidative stress resistance and virulence. Measurement of cellular metal concentrations demonstrated that diminished Sod3 expression was not due to decreased import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we found its role in TORC1 activation to impact oxidative stress management: overexpression of the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/- null mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence support host defenses by sensitizing C. albicans to oxidative stress.
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