Differential Expression between Human Dermal Papilla Cells from Balding and Non-Balding Scalps Reveals New Candidate Genes for Androgenetic Alopecia

Agency for Science, Technology and Research (A*STAR). EC is supported by the A*STAR Graduate Scholarship program

FOXM1 Induces a Global Methylation Signature That Mimics the Cancer Epigenome in Head and Neck Squamous Cell Carcinoma

The oncogene FOXM1 has been implicated in all major types of human cancer. We recently showed that aberrant FOXM1 expression causes stem cell compartment expansion resulting in the initiation of hyperplasia. We have previously shown that FOXM1 regulates HELLS, a SNF2/helicase involved in DNA methylation, implicating FOXM1 in epigenetic regulation. Here, we have demonstrated using primary normal human oral keratinocytes (NOK) that upregulation of FOXM1 suppressed the tumour suppressor gene p16INK4A (CDKN2A) through promoter hypermethylation. Knockdown of HELLS using siRNA re-activated the mRNA expression of p16INK4A and concomitant downregulation of two DNA methyltransferases DNMT1 and DNMT3B. The dose-dependent upregulation of endogenous FOXM1 (isoform B) expression during tumour progression across a panel of normal primary NOK strains (n = 8), dysplasias (n = 5) and head and neck squamous cell carcinoma (HNSCC) cell lines (n = 11) correlated positively with endogenous expressions of HELLS, BMI1, DNMT1 and DNMT3B and negatively with p16INK4A and involucrin. Bisulfite modification and methylation-specific promoter analysis using absolute quantitative PCR (MS-qPCR) showed that upregulation of FOXM1 significantly induced p16INK4A promoter hypermethylation (10-fold, P<0.05) in primary NOK cells. Using a non-bias genome-wide promoter methylation microarray profiling method, we revealed that aberrant FOXM1 expression in primary NOK induced a global hypomethylation pattern similar to that found in an HNSCC (SCC15) cell line. Following validation experiments using absolute qPCR, we have identified a set of differentially methylated genes, found to be inversely correlated with in vivo mRNA expression levels of clinical HNSCC tumour biopsy samples. This study provided the first evidence, using primary normal human cells and tumour tissues, that aberrant upregulation of FOXM1 orchestrated a DNA methylation signature that mimics the cancer methylome landscape, from which we have identified a unique FOXM1-induced epigenetic signature which may have clinical translational potentials as biomarkers for early cancer screening, diagnostic and/or therapeutic interventions

The global distribution of fatal pesticide self-poisoning: Systematic review

<p>Abstract</p> <p>Background</p> <p>Evidence is accumulating that pesticide self-poisoning is one of the most commonly used methods of suicide worldwide, but the magnitude of the problem and the global distribution of these deaths is unknown.</p> <p>Methods</p> <p>We have systematically reviewed the worldwide literature to estimate the number of pesticide suicides in each of the World Health Organisation's six regions and the global burden of fatal self-poisoning with pesticides. We used the following data sources: Medline, EMBASE and psycINFO (1990–2007), papers cited in publications retrieved, the worldwide web (using Google) and our personal collections of papers and books. Our aim was to identify papers enabling us to estimate the proportion of a country's suicides due to pesticide self-poisoning.</p> <p>Results</p> <p>We conservatively estimate that there are 258,234 (plausible range 233,997 to 325,907) deaths from pesticide self-poisoning worldwide each year, accounting for 30% (range 27% to 37%) of suicides globally. Official data from India probably underestimate the incidence of suicides; applying evidence-based corrections to India's official data, our estimate for world suicides using pesticides increases to 371,594 (range 347,357 to 439,267). The proportion of all suicides using pesticides varies from 4% in the European Region to over 50% in the Western Pacific Region but this proportion is not concordant with the volume of pesticides sold in each region; it is the pattern of pesticide use and the toxicity of the products, not the quantity used, that influences the likelihood they will be used in acts of fatal self-harm.</p> <p>Conclusion</p> <p>Pesticide self-poisoning accounts for about one-third of the world's suicides. Epidemiological and toxicological data suggest that many of these deaths might be prevented if (a) the use of pesticides most toxic to humans was restricted, (b) pesticides could be safely stored in rural communities, and (c) the accessibility and quality of care for poisoning could be improved.</p

Recommended adult immunization schedule, United States, 2020

In October 2019, the Advisory Committee on Immunization Practices (ACIP) voted to approve the Recommended Adult Immunization Schedule for Ages 19 Years or Older, United States, 2020. The 2020 adult immunization schedule, available at www.cdc.gov/vaccines /schedules/hcp/imz/adult.html, summarizes ACIP recommendations in 2 tables and accompanying notes (Figure). The full ACIP recommendations for each vaccine are available at www.cdc.gov/vaccines/hcp/acip-recs/index.html. The 2020 schedule has also been approved by the director of the Centers for Disease Control and Prevention (CDC) and by the American College of Physicians (www .acponline.org), American Academy of Family Physicians (www.aafp.org), American College of Obstetricians and Gynecologists (www.acog.org), and American College of Nurse-Midwives (www.midwife.org)

Regulation of cell cycle drivers by Cullin-RING ubiquitin ligases

Cell biology: Cell cycle mediators offer therapeutic targets A large group of protein complexes involved in regulating cell division offers an array of promising new drug targets for treating cancer and neurodegeneration. Mirit Aladjem, Sang-Min Jang and colleagues from the US National Cancer Institute in Bethesda, USA, review the structure and function of cullin-RING ubiquitin ligases (CRLs), a “super-family” of multi-subunit enzymes that serve as critical checkpoints on the cell cycle and DNA replication. CRLs promote progression through the cell cycle by targeting other key proteins for degradation or modification. They also work with other protein complexes to ensure genome integrity in the face of DNA damage. Because CRL components are often mutated or otherwise dysregulated in tumors and other diseased cells, small-molecule inhibitors and modulators of CRL activity could have therapeutic benefit for patients

Performance of goats and sheep under communal grazing in Botswana using various growth measures

We conducted a survey to evaluate the growth of goats and sheep under communal grazing, and to determine the relationship between weight, heart girth, shoulder height, and body condition score in Kweneng, Central and Kgalagadi districts, Botswana. The same animals were measured on two separate occasions, approximately one month apart, to allow growth rates to be recorded. Significant differences in growth rates between the three case study districts were found for both goats and sheep. Amongst the goats measured, gains in height and weight were significantly greater in the Kweneng district, while gains in heart girth measurement were greatest in the Central district. In the case of sheep, weight gain was significantly higher in the Central and Kgalagadi districts, increases in girth measurement were significantly higher in the Central district, and shoulder height gain was significantly greater in the Kweneng district. Statistical tests were used to determine the relationships between animal weight and the other measures taken for goats and sheep. Heart girth in both goats and sheep was shown to be a significant predictor of weight across all three districts. Likewise, shoulder height proved to be a statistically significant predictor of animal weight for both goats and sheep, across each district. The data therefore suggest that heart girth and shoulder height have potential to act as proxy measurements of weight in both goats and sheep, potentially providing smallholder farmers with a cost-effective way of estimating small-stock productivity

Using path analysis to predict bodyweight from body measurements of goats and sheep of communal rangelands in Botswana

The objective of this study was to determine the practicality of using linear body measurement traits to predict live weight of goats and sheep under communal grazing in three districts of Botswana, namely Central, Kweneng, and Kgalagadi. Pairwise (Pearson) correlations were estimated using bodyweight (BW) and morphological trait measurements, namely heart girth (HG), shoulder height (SH), and body condition score (BCS) for a sample of 1447 goats and 588 sheep. These ranged from 0.19 to 0.94 for goats and 0.44 to 0.94 for sheep, and were statistically significant. In both animals, regardless of sex, the highest positive correlations were found between BW and HG, followed by BW and SH, then BW and BCS. The direct and indirect relationship between BW and morphological traits using a path analysis approach were also estimated. This analysis suggested that the direct effect of HG on BW was higher at 0.761 for male and 0.662 for female goats, respectively. Similarly, the direct effect of HG on BW was higher among sheep at 0.764 for males and 0.882 for females. The direct effects of SH in all the animals were also positively influenced by BW. It was concluded that among these three morphological traits, the most valuable for estimating the BW for goats and sheep in Botswana is HG, followed by SH. BCS was found non-significant. Path analysis therefore has an advantage over previous empirical studies by providing more detailed information on the relationships (direct and indirect) between these variables. A further implication of this study is that a conversion table could be constructed to help smallholder farmers to estimate the live weight of their sheep and goats from linear measurements. This would aid in the management and marketing of their livestock

Upregulation of <i>FOXM1</i> (isoform B) induces a global shift in methylation pattern that mimics the cancer epigenome.

<p>(<b>A</b>) Genome-wide promoter microarray analysis of primary normal oral human keratinocytes expressing either <i>EGFP</i> (NOKG, black dots) or <i>FOXM1</i> (NOKF, yellow dots) and an established squamous cell carcinoma cell line (SCC15, red dots). Each dot represents a single gene. (<b>B</b>) A non-linear 2^nd order polynomial regression analyses were performed on the relative methylation patterns between NOKG vs NOKF (inverse correlation), NOKG vs SCC15 (inverse correlation) and NOKF vs SCC15 (positive correlation). (<b>C</b>) Gene selection criteria for differentially methylated genes between control (NOKG) and tests groups (NOKF and SCC15). 100-most hypermethylated and 100-most hypomethylated genes were inversely matched with differentially methylated genes from NOKF and SCC15. The adjacent gene lists show the shortlisted FOXM1-induced (also found in SCC15) differentially hypermethylated (red) and hypomethylated (green) genes compared to control NOKG cells. The CDKN2A (encodes <i>p16^INK4A</i>) gene, its promoter known to be hypermethylated in HNSCC, was included as a positive control for promoter hypermethylation. (<b>D</b>) Clinical tumour tissue sample correlation between the relative levels of methylation and gene expression of each shortlisted gene in a cohort of 10 patients with paired normal margin and HNSCC tumour tissue samples. Each dot represents mean ± SEM of each gene. Vertical error bars were derived from relative gene expression of 10 margin-tumour tissue pairs and horizontal error bars were derived from relative promoter methylation of 3 independent primary NOK (NOKG/NOKF) experiments. Correlation coefficient (R²) of a non-linear 2^nd order polynomial regression analyses were performed on all 30 candidate genes (left panel), 16 hypermethylated genes (middle panel) or 14 hypomethylated genes (right panel), respectively.</p