Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31+ vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVMs and angiogenic tufts in the retina of mice with oxygen-induced retinopathy, suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis. Inhibition of RUNX1 activity with the Ro5–3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.
In the US, community circulation of the SARS-CoV-2 virus likely began in February 2020 after mostly travel-related cases. Children's Hospital of Philadelphia began testing on 3/9/2020 for pediatric and adult patients, and for all admitted patients on 4/1/2020, allowing an early glimpse into the local molecular epidemiology of the virus. We obtained 169 SARS-CoV-2 samples (83 from patients <21 years old) from March through May and produced whole genome sequences. We used genotyping tools to track variants over time and to test for possible genotype associated clinical presentations and outcomes in children. Our analysis uncovered 13 major lineages that changed in relative abundance as cases peaked in mid-April in Philadelphia. We detected at least 6 introductions of distinct viral variants into the population. As a group, children had more diverse virus genotypes than the adults tested. No strong differences in clinical variables were associated with genotypes. Whole genome analysis revealed unexpected diversity, and distinct circulating viral variants within the initial peak of cases in Philadelphia. Most introductions appeared to be local from nearby states. Although limited by sample size, we found no evidence that different genotypes had different clinical impacts in children in this study.
Abstract Purpose: Germline alterations in the RB1 tumor suppressor gene predispose patients to developing retinoblastoma (RB) in both eyes. However, tumors in bilateral RB may not respond identically to treatment. The additional genomic events that occur independently in each eye during tumorigenesis are not well characterized. The aqueous humor (AH) provides a novel source of cell-free tumor-derived DNA (ctDNA) for liquid biopsy, enabling the in vivo study of RB tumors. In this case report, we use our AH liquid biopsy to compare genomic profiles between the right and left eyes of a single patient with heritable RB while also showing that ctDNA longitudinal dynamics correspond to therapeutic response. Methods: One patient with bilateral RB was included. Multiple samples of AH were obtained from each eye during routine intravitreal melphalan therapy and following enucleation of the left eye. Routine clinical blood testing was performed to determine germline RB1 status. CtDNA was isolated from the AH and sequenced on an Illumina platform to assess genome-wide somatic copy number alterations (SCNAs). The same sequencing libraries were used to identify somatic RB1 pathogenic variants using a custom hybridization and next generation sequencing panel targeting RB1. Tumor fraction (TFx) was estimated using ichorCNA software. Results: Five AH samples from both eyes (3 from the right eye and 2 from the left eye) were included. Peripheral blood RB1 testing detected germline 13q and 16p deletions. Targeted RB1 mutational analysis of AH ctDNA identified a different somatic RB1 mutation in each eye. At initial AH sampling, three SCNAs were present in the right eye and these same SCNAs persisted in further samples. Two SCNAs were initially detected in the left eye and were consistently identified in later sampling. Despite the same germline RB1 mutation, the second somatic mutation was different in each eye and there were distinct, non-overlapping patterns of SCNAs in each eye. In addition, the right eye demonstrated a progressive decrease in TFx corresponding with therapeutic responsiveness and ocular salvage. The left eye had persistently larger TFx values and required enucleation due to tumor recurrence. Conclusions: Our AH liquid biopsy detected distinct genomic events between eyes in a patient with bilateral RB and TFx changes corresponding with disease activity. Identifying inter-eye genomic heterogeneity without the need for enucleated tumor tissue may help direct active management of RB, with particular usefulness in bilateral cases. Citation Format: Elyssa Y. Wong, Liya Xu, Lishuang Shen, Mary E. Kim, Ashley Polski, Rishvanth K. Prabakar, Rachana Shah, Rima Jubran, Jonathan W. Kim, Jaclyn A. Biegel, Xiaowu Gai, Peter Kuhn, James Hicks, Jesse L. Berry. Genomic heterogeneity in the aqueous humor cell-free DNA in a patient with bilateral retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2247.
Background: Diabetes mellitus (DM) has become a major public health problem in China. Although a number of researchers have investigated DM risk factors, little is known about the associations between values of fasting blood glucose (FBG) and influencing factors. This study aims to explore these associations by the quantile regression (QR) model. Methods: A cross-sectional survey based on a sample of 23,050 adults aged 18 to 79 years was conducted in Jilin in 2012, and some subjects were excluded due to missing values with respect to necessary variables or having glycemic control, in accordance with the purposes of this study. Finally, in total 14,698 people were included in this study. QR was performed to identify the factors influencing the level of FBG in different quantiles of FBG. Results: The distribution of FBG status was different between males and females (χ² = 175.30, p < 0.001). The QR model provided more detailed views on the associations of FBG with different factors and revealed apparent quantile-related patterns separately for different factors. Body mass index (BMI) was positively associated with the low and middle quantiles of FBG. Waist circumference (WC) had a positive association with the high quantiles of FBG. Conclusions: FBG had a positive association with BMI in normal FBG, and a positive association with WC in high FBG. Diet and alcohol intake were associated with FBG in normal FBG. FBG was more likely to be elevated in the elderly, female workers, and people with family history of DM.
Resistant starch (RS) is fermentable dietary fiber. Inclusion of RS in the diet causes decreased body fat accumulation and altered gut hormone profile. This study investigates the effect of feeding RS on the neuropeptide messenger RNA (mRNA) expressions in the arcuate nucleus (ARC) of the hypothalamus and whether vagal afferent nerves are involved. The rats were injected intraperitoneally with capsaicin to destroy unmyelinated small vagal afferent nerve fibers. The cholecystokinin (CCK) food suppression test was performed to validate the effectiveness of the capsaicin treatment. Then, capsaicin-treated rats and vehicle-treated rats were subdivided into a control diet or a RS diet group, and fed the corresponding diet for 65 days. At the end of study, body fat, food intake, plasma peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), and hypothalamic pro-opiomelanocortin (POMC), neuropeptide Y (NPY), agouti-related peptide (AgRP) gene expressions were measured. RS-fed rats had decreased body fat, increased POMC expression in the hypothalamic ARC, and elevated plasma PYY and GLP-1 in both the capsaicin and vehicle-treated rats. Hypothalamic NPY and AgRP gene expressions were not changed by RS or capsaicin. Therefore, destruction of the capsaicin-sensitive afferent nerves did not alter the response to RS in rats. These findings suggest that dietary RS might reduce body fat through increasing the hypothalamic POMC expression and vagal afferent nerves are not involved in this process. This is the first study to show that dietary RS can alter hypothalamic POMC expression.
Objective To investigate the relationship between asthmatic symptoms in preschool children and decorative materials and durations. Methods From April 2011 to April 2012, the questionnaires were sent in 72 kindergartens in three urban districts and two suburban districts of Shanghai, and 13 335 questionnaires of children aged 4-6 years were recovered, which were used to analyze the associations by chi-squared test and logistic regression analysis. Results In Shanghai, 66.7% and 51.2% residents used solid wood and latex paint as floor materials and wall face materials in child's room respectively. The amounts of residential renovation during mother's pregnancy or children aged 0-1 year were obviously less than those during one year before mother's pregnancy or after children aged one year. For causing childhood dry cough and asthma, using solid wood and laminate wood as floor had higher risk in getting asthma or wheeze than using cement(OR=1.11-2.13,P0.05, P0.01); Using latex paint and oil paint as wall-face materials had higher risk in getting dry cough and asthma than using lime(OR=1.10-1.27,P0.05,P0.01). After adjustment of the potential confounders, using solid wood and laminate wood as floor had higher risk than using cement in inducing dry cough and asthma(AOR =1.13-1.23,P 0.05,P 0.01). Moreover, using laminate wood had higher risk than using solid wood. Some positive associations between buying new furniture in different durations and children wheeze and dry cough were statistically significant as before. The positive association between decoration for families with children aged 0-1 year and children dry cough was still the strongest(AOR =1.57,P 0.01). Conclusion Shanghai residents have strong awareness in selecting the duration of residential renovation with considering pregnant woman's health and infant health. Compared with the ordinary materials(cement and lime), the new-type decorative materials seems to increase the preschool children's risk in suffering from asthmatic symptoms. Early buying new furniture and residential renovation are risk factors for later asthmatic symptoms among preschool children.
To understand the genetic control of allelopathy in rice ( Oryza sativa L.), quantitative trait loci (QTL) mapping was performed using a population of 142 recombinant inbred lines derived from a cross between cultivar IAC 165 ( japonica upland variety) and cultivar CO 39 ( indica irrigated variety). The map contained 140 DNA markers. The relay seeding technique, which is a laboratory bioassay measuring the inhibition in weed root growth due to the presence of rice seedlings, was used to evaluate the allelopathic effect of the rice lines. Cultivar IAC 165 showed strong and consistent allelopathic activity against barnyardgrass [ Echinochloa crus‐galli (L.) Beauv.], whereas CO 39 was weakly allelopathic. Transgressive segregation for allelopathic activity in both directions was observed in the population. No significant correlation was found between root morphology of the lines and their allelopathic potential, suggesting that allelopathy in rice was under genetic control independent from root morphology. Four main‐effect QTLs located on three chromosomes were identified, which collectively explained 35% of the total phenotypic variation of the allelopathic activity in the population. One pair of digenic epistatic loci, not involving any of the main‐effect loci, was also detected. Once confirmed, these QTLs may be useful for genetic improvement of allelopathy in rice using marker‐assisted selection.
Abstract Effective response to the Coronavirus Disease 2019 (COVID-19) pandemic requires genomic resources and bioinformatics tools for genomic epidemiology and surveillance studies that involve characterizing full-length viral genomes, identifying origins of infections, determining the relatedness of viral infections, performing phylogenetic analyses, and monitoring the continuous evolution of the SARS-CoV-2 viral genomes. The Children’s Hospital, Los Angeles (CHLA) COVID-19 Analysis Research Database (CARD) ( https://covid19.cpmbiodev.net/ ) is a comprehensive genomic resource that provides access to full-length SARS-CoV-2 viral genomes and associated meta-data for over 30,000 (as of May 20, 2020) isolates collected from global sequencing repositories and the sequencing performed at the Center for Personalized Medicine (CPM) at CHLA. Reference phylogenetic trees of global and USA viral isolates were constructed and are periodically updated using selected high quality SARS-CoV-2 genome sequences. These provide the baseline and analytical context for identifying the origin of a viral infection, as well as the relatedness of SARS-CoV-2 genomes of interest. A web-based and interactive Phylogenetic Tree Browser supports flexible tree manipulation and advanced analysis based on keyword search while highlighting time series animation, as well as subtree export for graphical representation or offline exploration. A Virus Genome Tracker accepts complete or partial SARS-CoV-2 genome sequence, compares it against all available sequences in the database (>30,000 at time of writing), detects and annotates the variants, and places the new viral isolate within the global or USA phylogenetic contexts based upon variant profiles and haplotype comparisons, in a few seconds. The generated analysis can potentially aid in genomic surveillance to trace the transmission of any new infection. Using CHLA CARD, we demonstrate the identification of a candidate outbreak point where 13 of 31 CHLA internal isolates may have originated. We also discovered multiple indels of unknown clinical significance in the orf3a gene, and revealed a number of USA-specific variants and haplotypes.
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