Bloom's syndrome is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin resistance, and a greatly ...increased risk of early onset of cancer and for the development of multiple cancers. Loss-of-function mutations of
, which codes for a RecQ helicase, cause Bloom's syndrome. The absence of a functional BLM protein causes chromosome instability, excessive homologous recombination, and a greatly increased number of sister chromatid exchanges that are pathognomonic of the syndrome. A common founder mutation designated
is present in about 1 in 100 persons of Eastern European Jewish ancestry, and there are additional recurrent founder mutations among other populations. Missense, nonsense, and frameshift mutations as well as multiexonic deletions have all been observed. Bloom's syndrome is a prototypical chromosomal instability syndrome, and the somatic mutations that occur as a result of that instability are responsible for the increased cancer risk. Although there is currently no treatment aimed at the underlying genetic abnormality, persons with Bloom's syndrome benefit from sun protection, aggressive treatment of infections, surveillance for insulin resistance, and early identification of cancer.
Objective Health care generated data have become an important source for clinical and genomic research. Often, investigators create and iteratively refine phenotype algorithms to achieve high ...positive predictive values (PPVs) or sensitivity, thereby identifying valid cases and controls. These algorithms achieve the greatest utility when validated and shared by multiple health care systems.
Materials and Methods We report the current status and impact of the Phenotype KnowledgeBase (PheKB, http://phekb.org), an online environment supporting the workflow of building, sharing, and validating electronic phenotype algorithms. We analyze the most frequent components used in algorithms and their performance at authoring institutions and secondary implementation sites.
Results As of June 2015, PheKB contained 30 finalized phenotype algorithms and 62 algorithms in development spanning a range of traits and diseases. Phenotypes have had over 3500 unique views in a 6-month period and have been reused by other institutions. International Classification of Disease codes were the most frequently used component, followed by medications and natural language processing. Among algorithms with published performance data, the median PPV was nearly identical when evaluated at the authoring institutions (n = 44; case 96.0%, control 100%) compared to implementation sites (n = 40; case 97.5%, control 100%).
Discussion These results demonstrate that a broad range of algorithms to mine electronic health record data from different health systems can be developed with high PPV, and algorithms developed at one site are generally transportable to others.
Conclusion By providing a central repository, PheKB enables improved development, transportability, and validity of algorithms for research-grade phenotypes using health care generated data.
The early life environment markedly influences brain and behavioral development, with adverse experiences associated with increased risk of anxiety and depressive phenotypes, particularly in females. ...Indeed, early life adversity (ELA) in humans (i.e., caregiver deprivation, maltreatment) and rodents (i.e., maternal separation, resource scarcity) is associated with sex-specific emergence of anxious and depressive behaviors. Although these disorders show clear sex differences in humans, little attention has been paid toward evaluating sex as a biological variable in models of affective dysfunction; however, recent rodent work suggests sex-specific effects. Two widely used rodent models of ELA approximate caregiver deprivation (i.e., maternal separation) and resource scarcity (i.e., limited bedding). While these approaches model aspects of ELA experienced in humans, they span different portions of the pre-weaning developmental period and may therefore differentially contribute to underlying mechanistic risk. This is borne out in the literature, where evidence suggests differences in trajectories of behavior depending on the type of ELA and/or sex; however, the neural underpinning of these differences is not well understood. Because anxiety and depression are thought to involve dysregulation in the balance of excitatory and inhibitory signaling in ELA-vulnerable brain regions (e.g., prefrontal cortex, amygdala, hippocampus), outcomes are likely driven by alterations in local and/or circuit-specific inhibitory activity. The most abundant GABAergic subtypes in the brain, accounting for approximately 40% of inhibitory neurons, contain the calcium-binding protein Parvalbumin (PV). As PV-expressing neurons have perisomatic and proximal dendritic targets on pyramidal neurons, they are well-positioned to regulate excitatory/inhibitory balance. Recent evidence suggests that PV outcomes following ELA are sex, age, and region-specific and may be influenced by the type and timing of ELA. Here, we suggest the possibility of a combined role of PV and sex hormones driving differences in behavioral outcomes associated with affective dysfunction following ELA. This review evaluates the literature across models of ELA to characterize neural (PV) and behavioral (anxiety- and depressive-like) outcomes as a function of sex and age. Additionally, we detail a putative mechanistic role of PV on ELA-related outcomes and discuss evidence suggesting hormone influences on PV expression/function which may help to explain sex differences in ELA outcomes.
To evaluate the global impact of adopting highest-level MPOWER tobacco control policies in different countries and territories from 2007 to 2010.
Policy effect sizes based on previously-validated ...SimSmoke models were applied to determine the reduction in the number of smokers as a result of policy adoption during this period. Based on previous research suggesting that half of all smokers die from smoking, we also derived the estimated smoking-attributable deaths (SADs) averted due to MPOWER policy implementation. The results from use of this simple yet powerful method are consistent with those predicted by using previously validated SimSmoke models.
In total, 41 countries adopted at least one highest-level MPOWER policy between 2007 and 2010. As a result of all policies adopted during this period, the number of smokers is estimated to have dropped by 14.8 million, with a total of 7.4 million SADs averted. The largest number of SADs was averted as a result of increased cigarette taxes (3.5 million), smoke-free air laws (2.5 million), health warnings (700,000), cessation treatments (380,000), and bans on tobacco marketing (306,000).
From 2007 to 2010, 41 countries and territories took action that will collectively prevent nearly 7.5 million smoking-related deaths globally. These findings demonstrate the magnitude of the actions already taken by countries and underscore the potential for millions of additional lives to be saved with continued adoption of MPOWER policies.
Mucosal-associated invariant T (MAIT) cells can recognize and respond to some bacterially infected cells. Several in vitro and in vivo models of Mycobacterium tuberculosis (Mtb) infection suggest ...that MAIT cells can contribute to control of Mtb, but these studies are often cross-sectional and use peripheral blood cells. Whether MAIT cells are recruited to Mtb-affected granulomas and lymph nodes (LNs) during early Mtb infection and what purpose they might serve there is less well understood. Furthermore, whether HIV/SIV infection impairs MAIT cell frequency or function at the sites of Mtb replication has not been determined. Using Mauritian cynomolgus macaques (MCM), we phenotyped MAIT cells in the peripheral blood and bronchoalveolar lavage (BAL) before and during infection with SIVmac239. To test the hypothesis that SIV co-infection impairs MAIT cell frequency and function within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb Erdman, and necropsied at 6 weeks post Mtb-challenge. MAIT cell frequency and function were examined within the peripheral blood, BAL, and Mtb-affected lymph nodes (LN) and granulomas. MAIT cells did not express markers indicative of T cell activation in response to Mtb in vivo within granulomas in animals infected with Mtb alone. SIV and Mtb co-infection led to increased expression of the activation/exhaustion markers PD-1 and TIGIT, and decreased ability to secrete TNFα when compared to SIV-naïve MCM. Our study provides evidence that SIV infection does not prohibit the recruitment of MAIT cells to sites of Mtb infection, but does functionally impair those MAIT cells. Their impaired function could have impacts, either direct or indirect, on the long-term containment of TB disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines ...the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.
Reactive oxygen species (ROS) arise as a result from, and are essential in, numerous cellular processes. ROS, however, are highly reactive and if left unneutralised by endogenous antioxidant systems, ...can result in extensive cellular damage and/or pathogenesis. In addition, exposure to a wide range of environmental stressors can also result in surplus ROS production leading to oxidative stress (OS) and downstream tissue toxicity.
Our aim was to produce a stable transgenic zebrafish line, unrestricted by tissue-specific gene regulation, which was capable of providing a whole organismal, real-time read-out of tissue-specific OS following exposure to a wide range of OS-inducing environmental contaminants and conditions. This model could, therefore, serve as a sensitive and specific mechanistic in vivo biomarker for all environmental conditions that result in OS.
To achieve this aim, we exploited the pivotal role of the electrophile response element (EpRE) as a globally-acting master regulator of the cellular response to OS. To test tissue specificity and quantitative capacity, we selected a range of chemical contaminants known to induce OS in specific organs or tissues, and assessed dose-responsiveness in each using microscopic measures of mCherry fluorescence intensity.
We produced the first stable transgenic zebrafish line Tg (3EpRE:hsp70:mCherry) with high sensitivity for the detection of cellular RedOx imbalances, in vivo in near-real time. We applied this new model to quantify OS after exposure to a range of environmental conditions with high resolution and provided quantification both of compound- and tissue-specific ROS-induced toxicity.
Our model has an extremely diverse range of potential applications not only for biomonitoring of toxicants in aqueous environments, but also in biomedicine for identifying ROS-mediated mechanisms involved in the progression of a number of important human diseases, including cancer.
•New sensitive biosensor zebrafish model for rapid detection of oxidative stress•Identification of compound-specific oxidative toxicity across a whole organism•Biosensor model applications span environmental biomonitoring to biomedicine.
The diaphragm is an essential mammalian skeletal muscle, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDHs), a common and often lethal birth defect. The ...diaphragm is derived from multiple embryonic sources, but how these give rise to the diaphragm is unknown, and, despite the identification of many CDH-associated genes, the etiology of CDH is incompletely understood. Using mouse genetics, we show that the pleuroperitoneal folds (PPFs), which are transient embryonic structures, are the source of the diaphragm's muscle connective tissue and regulate muscle development, and we show that the striking migration of PPF cells controls diaphragm morphogenesis. Furthermore, Gata4 mosaic mutations in PPF-derived muscle connective tissue fibroblasts result in the development of localized amuscular regions that are biomechanically weaker and more compliant, leading to CDH. Thus, the PPFs and muscle connective tissue are critical for diaphragm development, and mutations in PPF-derived fibroblasts are a source of CDH.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
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