Human enzyme-mediated, systemic depletion of methionine for glioblastoma treatment

Glioblastoma multiforme (GBM) is the most lethal and common type of malignant brain tumor in adults. To date, no curative treatment exists for GBM despite continuous research efforts. Like many other cancers, GBM requires higher levels of methionine for survival compared with normal cells. We aim to exploit GBM methionine dependency as a therapeutic target for this lethal cancer. Our results showed that methionine depletion with an engineered human methionine-γ-lyase (hMGL) reduced GBM cell survival in vitro. Metabolic profiling and MSEA revealed that aminoacyl tRNA biosynthesis, glutathione metabolism, and nucleotide metabolism were significantly changed by hMGL treatment. Mechanistic study showed hMGL treatment resulted in notable increases in oxidative stress in GBM cell lines, leading to DNA damage, and caused cell cycle arrest at the S/G2 phase. In line with this, thioredoxin reductase inhibitor, auranofin, and ATR inhibitor, ceralasertib, showed synergistic effects with hMGL in inhibiting GBM cells. Furthermore, hMGL treatment caused a decrease of global DNA methylation and altered histone methylation patterns. This upregulated the expression of tumor-suppressive microRNAs miR-124 and miR-137, which are frequently silenced in gliomagenesis due to aberrant DNA methylation. Accordingly, hMGL inhibited the phosphorylation and activation of their downstream target, STAT3, a central mediator of GBM growth. Finally, hMGL inhibited the growth of orthotopic human GBM xenografts in vivo and prolonged survival time of tumor-bearing animals. Our data provides strong rationale to investigate the efficacy of hMGL in the treatment for GBM.Cellular and Molecular Biolog

Survival of Staphylococcus aureus ST398 in the human nose after artificial inoculation.

There is evidence that MRSA ST398 of animal origin is only capable of temporarily occupying the human nose, and it is therefore, often considered a poor human colonizer.We inoculated 16 healthy human volunteers with a mixture of the human MSSA strain 1036 (ST931, CC8) and the bovine MSSA strain 5062 (ST398, CC398), 7 weeks after a treatment with mupirocin and chlorhexidine-containing soap. Bacterial survival was studied by follow-up cultures over 21 days. The human strain 1036 was eliminated faster (median 14 days; range 2-21 days) than the bovine strain 5062 (median 21 days; range 7-21 days) but this difference was not significant (p = 0.065). The bacterial loads were significantly higher for the bovine strain on day 7 and day 21. 4/14 volunteers (28.6%) showed elimination of both strains within 21 days. Of the 10 remaining volunteers, 5 showed no differences in bacterial counts between both strains, and in the other 5 the ST398 strain far outnumbered the human S. aureus strain. Within the 21 days of follow-up, neither human strain 1036 nor bovine strain 5062 appeared to acquire or lose any mobile genetic elements. In conclusion, S. aureus ST398 strain 5062 is capable of adequately competing for a niche with a human strain and survives in the human nose for at least 21 days

Improving surveillance and prediction of emerging and re-emerging infectious diseases

Infectious diseases are emerging at an unprecedent rate in recent years, such as the flu pandemic initialized from Mexico in 2009, the 2014 Ebola epidemic in West Africa, and the 2016-2017 expansion of Zika across Americas. They rarely happened previously and thus lack resources and data to detect and predict their spread. This highlights the challenges in emerging an re-emerging infectious disease surveillance. In the dissertation, I mainly put efforts in developing methods for early detection of such diseases, and assessing predictive power of various models in early phase of an epidemic. In Chapter 2, I developed a two-layer early detection framework which provides early warning of emerging epidemics based on the idea of anomaly detection. The framework could evaluate and identify data sources to achieve the best performance automatically from available data, such as data from the Internet and public health surveillance systems. I demonstrated the framework using historical influenza data in the US, and found that the optimal combination of predictors includes data sources from Google search query and Wikipedia page view. The optimized system is able to detect the onset of seasonal influenza outbreaks an average of 16.4 weeks in advance, and the second wave of the 2009 flu pandemic 5 weeks ahead. In Chapter 3, I extended the framework in Chapter 2 to identify large dengue outbreaks from small ones. The results show that the framework could personalize optimal combinations of predictors for different locations, and an optimal combination for one location might not perform well for other locations. In Chapter 4, I investigated the contribution of different population structures to total epidemic incidence, peak intensity and timing, and also explored the ability of various models with different population structures in predicting epidemic dynamics. The results suggest that heterogeneous contact pattern and direct contacts dominate the evolution of epidemics, and a homogeneous model is not able to provide reliable prediction for an epidemic. In summary, my dissertation not only provides method frameworks for building early detection systems for emerging and re-emerging infectious diseases, but also gives insight to the effects of various models in predicting epidemics.Cellular and Molecular Biolog

The Core Protein of Glypican Daily-Like Determines Its Biphasic Activity in Wingless Morphogen Signaling

Dally-like (Dlp) is a glypican-type heparan sulfate proteoglycan (HSPG), containing a protein core and attached glycosaminoglycan (GAG) chains. In Drosophila wing discs, Dlp represses short-range Wingless (Wg) signaling, but activates long-range Wg signaling. Here, we show that Dlp core protein has similar biphasic activity as wild-type Dlp. Dlp core protein can interact with Wg; the GAG chains enhance this interaction. Importantly, we find that Dlp exhibits a biphasic response, regardless of whether its glycosylphosphatidylinositol linkage to the membrane can be cleaved. Rather, the transition from signaling activator to repressor is determined by the relative expression levels of Dlp and the Wg receptor, Frizzled (Fz) 2. Based on these data, we propose that the principal function of Dlp is to retain Wg on the cell surface. As such, it can either compete with the receptor or provide ligands to the receptor, depending on the ratios of Wg, Fz2, and Dlp.National Institutes of Health American Cancer Society March of Dimes American Heart Associatio

Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer: Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses.

BACKGROUND: Observational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers. METHODS AND FINDINGS: A systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Using meta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified from a recent GWAS of adult height and from a cancer genetics consortium study of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from the meta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate. CONCLUSIONS: Our study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers.US NIH (Grant ID: R37CA070867), Ingram Professorship, Anne Potter Wilson , National Institutes of Health (Grant IDs: R25CA160056-03, U19CA148065, U19CA148107, U19CA148127, U19CA148537, Cancer Research UK, Prostate Cancer UK, The Institute of Cancer Research, Royal Marsden Biomedical Research Centre, National Institute of Health Research (Grant ID: C5047/A17528)This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.100211

Investigating the genetic relationship between Alzheimer's disease and cancer using GWAS summary statistics.

Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer's disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from 9931 to 54,162; SNPs were imputed to the 1000 Genomes European panel. Our results based on cross-trait LD Score regression showed a significant positive genetic correlation between AD and five cancers combined (colon, breast, prostate, ovarian, lung; r g = 0.17, P = 0.04), and specifically with breast cancer (ER-negative and overall; r g = 0.21 and 0.18, P = 0.035 and 0.034) and lung cancer (adenocarcinoma, squamous cell carcinoma and overall; r g = 0.31, 0.38 and 0.30, P = 0.029, 0.016, and 0.006). Estimating the genetic correlation in specific functional categories revealed mixed positive and negative signals, notably stronger at annotations associated with increased enhancer activity. This suggests a role of gene expression regulators in the shared genetic etiology between AD and cancer, and that some shared variants modulate disease risk concordantly while others have effects in opposite directions. Due to power issues, we did not detect cross-phenotype associations at individual SNPs. This genetic overlap is not likely driven by a handful of major loci. Our study is the first to examine the co-heritability of AD and cancer leveraging large-scale GWAS results. The functional categories highlighted in this study need further investigation to illustrate the details of the genetic sharing and to bridge between different levels of associations

Post-exercise recovery for the endurance athlete with type 1 diabetes: a consensus statement.

There has been substantial progress in the knowledge of exercise and type 1 diabetes, with the development of guidelines for optimal glucose management. In addition, an increasing number of people living with type 1 diabetes are pushing their physical limits to compete at the highest level of sport. However, the post-exercise recovery routine, particularly with a focus on sporting performance, has received little attention within the scientific literature, with most of the focus being placed on insulin or nutritional adaptations to manage glycaemia before and during the exercise bout. The post-exercise recovery period presents an opportunity for maximising training adaption and recovery, and the clinical management of glycaemia through the rest of the day and overnight. The absence of clear guidance for the post-exercise period means that people with type 1 diabetes should either develop their own recovery strategies on the basis of individual trial and error, or adhere to guidelines that have been developed for people without diabetes. This Review provides an up-to-date consensus on post-exercise recovery and glucose management for individuals living with type 1 diabetes. We aim to: (1) outline the principles and time course of post-exercise recovery, highlighting the implications and challenges for endurance athletes living with type 1 diabetes; (2) provide an overview of potential strategies for post-exercise recovery that could be used by athletes with type 1 diabetes to optimise recovery and adaptation, alongside improved glycaemic monitoring and management; and (3) highlight the potential for technology to ease the burden of managing glycaemia in the post-exercise recovery period

Student politics, teaching politics, black politics: an interview with Ansel Wong

Ansel Wong is the quiet man of British black politics, rarely in the limelight and never seeking political office. And yet his ‘career’ here – from Black Power firebrand to managing a multimillion budget as head of the Greater London Council’s Ethnic Minority Unit in the 1980s – spells out some of the most important developments in black educational and cultural projects. In this interview, he discusses his identification with Pan-Africanism, his involvement in student politics, his role in the establishment of youth projects and supplementary schools in the late 1960s and 1970s, and his involvement in black radical politics in London in the same period, all of which took place against the background of revolutionary ferment in the Third World and the world of ideas, and were not without their own internal class and ethnic conflicts

Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer

BACKGROUND:Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS:Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS:The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy

Genetic structure of fragmented southern populations of African Cape buffalo (Syncerus caffer caffer)

peer reviewedBackground African wildlife experienced a reduction in population size and geographical distribution over the last millennium, particularly since the 19th century as a result of human demographic expansion, wildlife overexploitation, habitat degradation and cattle-borne diseases. In many areas, ungulate populations are now largely confined within a network of loosely connected protected areas. These metapopulations face gene flow restriction and run the risk of genetic diversity erosion. In this context, we assessed the “genetic health” of free ranging southern African Cape buffalo populations (S.c. caffer) and investigated the origins of their current genetic structure. The analyses were based on 264 samples from 6 southern African countries that were genotyped for 14 autosomal and 3 Y-chromosomal microsatellites. Results The analyses differentiated three significant genetic clusters, hereafter referred to as Northern (N), Central (C) and Southern (S) clusters. The results suggest that splitting of the N and C clusters occurred around 6000 to 8400 years ago. Both N and C clusters displayed high genetic diversity (mean allelic richness (Ar) of 7.217, average genetic diversity over loci of 0.594, mean private alleles (Pa) of 11), low differentiation, and an absence of an inbreeding depression signal (mean FIS = 0.037). The third (S) cluster, a tiny population enclosed within a small isolated protected area, likely originated from a more recent isolation and experienced genetic drift (FIS = 0.062, mean Ar = 6.160, Pa = 2). This study also highlighted the impact of translocations between clusters on the genetic structure of several African buffalo populations. Lower differentiation estimates were observed between C and N sampling localities that experienced translocation over the last century. Conclusions We showed that the current genetic structure of southern African Cape buffalo populations results from both ancient and recent processes. The splitting time of N and C clusters suggests that the current pattern results from human-induced factors and/or from the aridification process that occurred during the Holocene period. The more recent S cluster genetic drift probably results of processes that occurred over the last centuries (habitat fragmentation, diseases). Management practices of African buffalo populations should consider the micro-evolutionary changes highlighted in the present study