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PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) mutations can help predict the antitumor activity of phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibitors in both preclinical and clinical settings. In light of the recent discovery of tumor-initiating cancer stem cells (CSCs) in various tumor types, we developed an in vitro CSC model from xenograft tumors established in mice from a colorectal cancer patient tumor in which the CD133+/EpCAM+ population represented tumor-initiating cells. CD133+/EpCAM+ CSCs were enriched under stem cell culture conditions and formed 3-dimensional tumor spheroids. Tumor spheroid cells exhibited CSC properties, including the capability for differentiation and self-renewal, higher tumorigenic potential and chemo-resistance. Genetic analysis using an OncoCarta™ panel revealed a PIK3CA (H1047R) mutation in these cells. Using a dual PI3K/mTOR inhibitor, PF-04691502, we then showed that blockage of the PI3K/mTOR pathway inhibited the in vitro proliferation of CSCs and in vivo xenograft tumor growth with manageable toxicity. Tumor growth inhibition in mice was accompanied by a significant reduction of phosphorylated Akt (pAKT) (S473), a well-established surrogate biomarker of PI3K/mTOR signaling pathway inhibition. Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R) mutant CSCs and their derivatives. These results may assist in the clinical development of PF-04691502 for the treatment of a subpopulation of colorectal cancer patients with poor outcomes.

To investigate factors associated with ocular axial elongation and myopia progression during a 4-year follow-up in primary school children in Beijing.This school-based study included 382 grade-1 children at baseline in 2011 (age:6.3±0.4 years) with 305 (79.8%) returning for the follow-up examination in 2015. At baseline and in yearly follow-up examinations, the children underwent a comprehensive eye examination including auto-refractometry, ocular biometry with measurement of axial length, and fundus photography. The parents underwent a standardized interview.During the study period, the mean axial length elongated by 1.15±0.56mm in boys and 1.10±0.63mm in girls. At baseline and at the end of follow-up, axial length was significantly (P

To assess prevalence and associated factors of myopia and high myopia in schoolchildren in Greater Beijing.The school-based, cross-sectional Greater Beijing School Children Myopia study was carried out in the year 2016 in 54 schools randomly selected from 15 districts in Beijing. Non-cycloplegic auto-refractometry of the right eyes was performed.The study included 35,745 (99.4%) out of 35,968 eligible pupils with a mean age of 12.6±3.4 years (range 6-18 years). Prevalence of myopia defined as myopic refractive error of ≥-0.50 diopters (D),≥-1D,≥-6D,≥-8D and ≥-10D was 70.9%(95% confidence intervals (CI):70.5,71.4), 60.9% (95%CI:60.4,61.4), 8.6%(95%CI:8.4,8.9), 2.2%(95%CI:2.0,2.4), and 0.3% (95%CI:0.3,0.4), respectively. The frequency of high myopia (≥-6D, ≥-8D, ≥-10D) increased from 1.5% (95%CI:1.0,2.0), 0.4% (95%CI:0.1,0.6) and 0.1% (95%CI:0.00,0.02), respectively in 10-year-olds to 19.4% (95%CI:17.3,21.6), 5.2% (95%CI:4.0,6.4) and 0.9% (95%CI:0.4,1.5), respectively, in 18-year-olds. Mean refractive error in the 18-year-olds was -3.74±2.56D (median:-3.63D;range:-19.6D to + 6.25D). Higher prevalence of high myopia (≥-6D and ≥-8D) was correlated (all P

PURPOSE:Since high myopia in the younger generation may differ etiologically from high myopia in older generations, we examined whether education-related parameters differ between high myopia in today´s school children and high pathological myopia in today´s elderly generation. METHODS:The investigation included the adult populations of the population-based Beijing Eye Study (BES) (3468 adults;mean age:64.6±9.8years;range:50-93years) and Central India Eye and Medical Study (CIEMS) (4711 adults;age:49.±13.2years;range:30-100years), and the children and teenager populations of the Shandong Children Eye Study (SCES) (6026 children;age:9.7±3.3years;range:4-18years;cycloplegic refractometry), Gobi Desert Children Eye Study (1565;age:11.9±3.5years;range:6-21 years;cycloplegic refractometry), Beijing Pediatric Eye Study (681 children;age:7.7±1.6years;range:5-13 years;non-cycloplegic refractometry,calculation of axial length to corneal curvature radius ratio), Beijing Children Eye Study (15066 children;age:13.2±3.4years;range:7-18years;non-cycloplegic refractometry), Beijing High School Teenager Eye Study (4677 children;age:16.9±0.7years;range:16-18years;non-cycloplegic refractometry). RESULTS:In the BES and CIEMS, educational level did not differ significantly between, or was significantly lower in the highly myopic group (myopic refractive error ≥6 diopters) than in the non-highly myopic group. In all non-adult study populations, higher prevalence of high myopia was significantly associated with higher degree of education related parameters such as attendance of high-level schools, and more time spent for indoors near work versus time spent outdoors. CONCLUSIONS:Comparing associations of old or genetic high myopia in adults with new or acquired high myopia in school children revealed that education-related parameters did not show a clear association with old or genetic high myopia, while in contrast, new high myopia showed strong associations with education. It confirms previous studies that the two forms of high myopia not only differed in age of onset, but also in associations with education as well. The data support the notion of two types of high myopia. Future studies may assess whether the risk of pathologic myopic maculopathy and high myopia associated open-angle glaucoma differs between both types of high myopia.

BACKGROUND:Severely burned patients are highly susceptible to opportunistic infections and sepsis, owing to the loss of the protective skin barrier and immunological dysfunction. Interleukin-15 (IL-15) belongs to the IL-2 family of common gamma chain cytokines and stimulates the proliferation and activation of T (specifically memory CD8), NK and NKT cells. It has been shown to preserve T cell function and improve survival during cecal ligation and puncture (CLP)-induced sepsis in mice. However, the therapeutic efficacy of IL-15 or IL-15 superagonist (SA) during infection after burn injury has not been evaluated. Moreover, very few, if any, studies have examined, in detail, the effect of burn injury and infection on the adaptive immune system. Thus, we examined the effect of burn and sepsis on adaptive immune cell populations and the effect of IL-15 SA treatment on the host response to infection. METHODS:Mice were subjected to a 35% total body surface area burn, followed by wound infection with Pseudomonas aeruginosa. In some experiments, IL-15 SA was administered after burn injury, but before infection. Leukocytes in spleen, liver and peritoneal cavity were characterized using flow cytometry. Bacterial clearance, organ injury and survival were also assessed. RESULTS:Burn wound infection led to a significant decline in total white blood cell and lymphocyte counts and induced organ injury and sepsis. Burn injury caused decline in CD4+ and CD8+ T cells in the spleen, which was worsened by infection. IL-15 treatment inhibited this decline and significantly increased cell numbers and activation, as determined by CD69 expression, of CD4+, CD8+, B, NK and NKT cells in the spleen and liver after burn injury. However, IL-15 SA treatment failed to prevent burn wound sepsis-induced loss of CD4+, CD8+, B, NK and NKT cells and failed to improve bacterial clearance and survival. CONCLUSION:Cutaneous burn injury and infection cause significant adaptive immune dysfunction. IL-15 SA does not augment host resistance to burn wound sepsis in mice despite inducing proliferation and activation of lymphocyte subsets.

PURPOSE: To assess whether a change in myopia related oculometric parameters of primary school children in Beijing was associated with indoors and outdoors activity. METHODS: The longitudinal school-based study included school children who were examined in 2011 and who were re-examined in 2012. The children underwent a comprehensive eye examination including ocular biometry by optical low-coherence reflectometry and non-cycloplegic refractometry. Parents and children had a detailed interview including questions on time spent indoors and outdoors. RESULTS: Out of 681 students examined at baseline, 643 (94.4%) returned for follow-up examination. Within the one-year period, mean time spent daily outdoors increased by 0.4±0.9 hours, mean axial length by 0.26±0.49 mm, the ratio of axial length divided by anterior corneal curvature (AL/CC) by 0.03±0.06, and myopic refractive error by -0.06±0.89 diopters. In multivariate analysis, elongation of axial length was significantly associated with less total time spent outdoors (P = 0.02; standardized coefficient beta -0.12) and more time spent indoors with studying (P = 0.007; beta: 0.14) after adjustment for maternal myopia (P = 0.02; beta: 0.12). An increase in AL/CC was significantly associated with less time spent outdoors (P = 0.01; beta:-0.12) after adjustment for paternal myopia (P = 0.003; beta: 0.15) and if region of habitation was excludedors for leisure (P = 0.006; beta:-0.13), with less total time spent outdoors (P = 0.04; beta:-0.10), or with more time spent i. An increase in myopic refractive error, after adjustment for age, was significantly associated with less time spent outdo ndoors with studying (P = 0.005; beta: 0.13). CONCLUSIONS: A change in oculometric parameters indicating an increase in myopia was significantly associated with less time spent outdoors and more time spent indoors in school children in Greater Beijing within a study period of one year. Our study provides additional information on the potentially helpful role of outdoors activity in the prevention of myopia. Public health care measures such as school agendas may potentially take it into account.

The bony shell of the turtle is an evolutionary novelty not found in any other group of animals, however, research into its formation has suggested that it has evolved through modification of conserved developmental mechanisms. Although these mechanisms have been extensively characterized in model organisms, the tools for characterizing them in non-model organisms such as turtles have been limited by a lack of genomic resources. We have used a next generation sequencing approach to generate and assemble a transcriptome from stage 14 and 17 Trachemys scripta embryos, stages during which important events in shell development are known to take place. The transcriptome consists of 231,876 sequences with an N50 of 1,166 bp. GO terms and EC codes were assigned to the 61,643 unique predicted proteins identified in the transcriptome sequences. All major GO categories and metabolic pathways are represented in the transcriptome. Transcriptome sequences were used to amplify several cDNA fragments designed for use as RNA in situ probes. One of these, BMP5, was hybridized to a T. scripta embryo and exhibits both conserved and novel expression patterns. The transcriptome sequences should be of broad use for understanding the evolution and development of the turtle shell and for annotating any future T. scripta genome sequences.

MicroRNAs (miRs) play major roles in normal hematopoietic differentiation and hematopoietic malignancies. In this work, we report that miR-27a, and its coordinately expressed cluster (miR-23a∼miR-27a∼miR-24-2), was down-regulated in acute leukemia cell lines and primary samples compared to hematopoietic stem-progenitor cells (HSPCs). Decreased miR-23a cluster expression in some acute leukemia cell lines was mediated by c-MYC. Replacement of miR-27a in acute leukemia cell lines inhibited cell growth due, at least in part, to increased cellular apoptosis. We identified a member of the anti-apoptotic 14-3-3 family of proteins, which support cell survival by interacting with and negatively regulating pro-apoptotic proteins such as Bax and Bad, as a target of miR-27a. Specifically, miR-27a regulated 14-3-3θ at both the mRNA and protein levels. These data indicate that miR-27a contributes a tumor suppressor-like activity in acute leukemia cells via regulation of apoptosis, and that miR-27a and 14-3-3θ may be potential therapeutic targets.

PURPOSE: To assess longitudinal changes in parapapillary atrophy in the adult population of Greater Beijing. METHODS: The population-based Beijing Eye Study 2006 included 3251 subjects who had participated in the Beijing Eye Study 2001 and returned for re-examination. The mean age was 60.4 ± 10.1 years. Using optic disc photographs, we measured parapapillary atrophy which was divided into alpha zone and beta zone. RESULTS: Overall progression rate of alpha zone was seen in 0.6 ± 0.1% (95% confidence interval (CI):0.3,0.9) of the subjects and of beta zone in 8.2 ± 0.5% (95%CI:7.2,9.1) of the subjects. In binary regression analysis, rate of progression of alpha zone was significantly associated higher age (P = 0.04) and the co-progression of zone Beta (P

Uncovering population structure is important for properly conducting association studies and for examining the demographic history of a population. Here, we examined the Japanese population substructure using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC), which covers all but the northern region of Japan. Using 222 autosomal loci from 4502 subjects, we investigated population substructure by estimating F(ST) among populations, testing population differentiation, and performing principal component analysis (PCA) and correspondence analysis (CA). All analyses revealed a low but significant differentiation between the Amami Islanders and the mainland Japanese population. Furthermore, we examined the genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders using six loci included in both the Pan-Asian SNP (PASNP) consortium data and the J-MICC data. This analysis revealed that the Amami and Okinawa Islanders were differentiated from the mainland population. In conclusion, we revealed a low but significant level of genetic differentiation between the mainland population and populations in or to the south of the Amami Islands, although genetic variation between both populations might be clinal. Therefore, the possibility of population stratification must be considered when enrolling the islander population of this area, such as in the J-MICC study.

PURPOSE: To evaluate the prevalence and associated factors of steep cornea/keratoconus in the adult Chinese population. METHODS: The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6±9.8 years (range: 50-93 years). A detailed ophthalmic examination was performed including optical low-coherence reflectometry. Steep cornea/keratoconus were defined as an anterior corneal refractive power exceeding 48 diopters. RESULTS: Mean refractive power of the cornea was 43.16±1.45 diopters (range: 36.51 to 48.46 diopters; flattest meridian) and 43.98±1.52 diopters (range: 37.00 to 52.88 diopters; steepest meridian). A steep cornea/keratoconus defined as corneal refractive power of ≥48 diopters and ≥49 diopters was detected in 27 subjects (prevalence rate: 0.9±0.2%) and 6 (0.2± 0.1%) subjects, respectively. Presence of steep cornea/keratoconus was associated with shorter axial length (P