Understanding metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics in the clinic. Here, using transcriptomic ...data for 10,704 tumor and normal samples from The Cancer Genome Atlas, across 26 disease sites, we present a novel bioinformatics pipeline that distinguishes tumor from normal tissues, based on differential gene expression for 114 metabolic pathways. We confirm pathway dysregulation in separate patient populations, demonstrating the robustness of our approach. Bootstrapping simulations were then applied to assess the biological significance of these alterations. We provide distinct examples of the types of analysis that can be accomplished with this tool to understand cancer specific metabolic dysregulation, highlighting novel pathways of interest, and patterns of metabolic flux, in both common and rare disease sites. Further, we show that Master Metabolic Transcriptional Regulators explain why metabolic differences exist, can segregate patient populations, and predict responders to different metabolism-targeted therapeutics.
In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment ...of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.
Blood-brain barrier (BBB) pathology leads to neurovascular disorders and is an important target for therapies. However, the study of BBB pathology is difficult in the absence of models that are ...simple and relevant. In vivo animal models are highly relevant, however they are hampered by complex, multi-cellular interactions that are difficult to decouple. In vitro models of BBB are simpler, however they have limited functionality and relevance to disease processes. To address these limitations, we developed a 3-dimensional (3D) model of BBB on a microfluidic platform. We verified the tightness of the BBB by showing its ability to reduce the leakage of dyes and to block the transmigration of immune cells towards chemoattractants. Moreover, we verified the localization at endothelial cell boundaries of ZO-1 and VE-Cadherin, two components of tight and adherens junctions. To validate the functionality of the BBB model, we probed its disruption by neuro-inflammation mediators and ischemic conditions and measured the protective function of antioxidant and ROCK-inhibitor treatments. Overall, our 3D BBB model provides a robust platform, adequate for detailed functional studies of BBB and for the screening of BBB-targeting drugs in neurological diseases.
Long-term exposure to particulate matter (PM) air pollution may increase blood pressure and the risk of hypertension. However, epidemiological evidence is scarce and inconsistent.
We investigated the ...associations between long-term exposure to PM with an aerodynamic diameter <2.5μm (PM
), blood pressure, and incident hypertension in a large Taiwanese cohort.
We studied 361,560 adults ≥18y old from a large cohort who participated in a standard medical examination program during 2001 to 2014. Among this group, 125,913 nonhypertensive participants were followed up. A satellite-based spatiotemporal model was used to estimate the 2-y average PM
concentrations at each participant's address. Multivariable linear regression was used in the cross-sectional data analysis with the 361,560 participants to investigate the associations between PM
and systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP), and Cox proportional hazard regression was used in the cohort data analysis with the 125,913 participants to investigate the associations between PM
and incident hypertension.
Each 10-μg/m
increment in the 2-y average PM
concentration was associated with increases of 0.45 mmHg 95% confidence interval (CI): 0.40, 0.50, 0.07 mmHg (95% CI: 0.04, 0.11), and 0.38 mmHg (95% CI: 0.33, 0.42) in SBP, DBP, and PP, respectively, after adjusting for a wide range of covariates and possible confounders. Each 10-μg/m
increment in the 2-y average PM
concentration was associated with an increase of 3% in the risk of developing hypertension hazard ratio=1.03 (95% CI: 1.01, 1.05). Stratified and sensitivity analyses yielded similar results.
Long-term exposure to PM
air pollution is associated with higher blood pressure and an increased risk of hypertension. These findings reinforce the importance of air pollution mitigation strategies to reduce the risk of cardiovascular disease. https://doi.org/10.1289/EHP2466.
Information on the effects of long-term exposure to fine particulate matter with an aerodynamic diameter of 2·5 μm or less (PM2·5) on lung health is scarce. We aimed to investigate the associations ...between long-term exposure to PM2·5, lung function, and chronic obstructive pulmonary disease (COPD) in a large-scale longitudinal cohort.
We included 285 046 participants aged 20 years or older from the Taiwan MJ Health Management Institution cohort, who were recruited between 2001 and 2014 and had spirometric tests during the medical examination visit. We used a satellite-based spatiotemporal model to estimate the 2-year average ground concentration of PM2·5 (for the calendar year of each participant's medical examination and for the previous year) at each participant's address. We used the generalised linear mixed model to examine the associations between PM2·5 concentrations and lung function and the Cox proportional hazard regression model with time-dependent covariates to investigate the PM2·5 effects on COPD development.
Every 5 μg/m3 increment in PM2·5 was associated with a decrease of 1·18% for forced vital capacity (FVC), 1·46% for forced expiratory volume in 1 s (FEV1), 1·65% for maximum mid-expiratory flow (MMEF), and 0·21% for FEV1:FVC ratio. The decrease accelerated over time. Additional annual declines were observed for FVC (0·14%), FEV1 (0·24%), MMEF (0·44%), and FEV1:FVC ratio (0·09%). Compared with the participants exposed to the first quartile of PM2·5, participants exposed to the fourth, third, and second quartiles of PM2·5 had a hazard ratio of 1·23 (95% CI 1·09–1·39), 1·30 (1·16–1·46), and 1·39 (1·24–1·56) for COPD development, respectively.
Long-term exposure to ambient PM2·5 is associated with reduced, and faster declines in, lung function. Long-term exposure to ambient PM2·5 is also associated with an increased risk of the incidence of COPD. This study reinforces the urgency of global strategies to mitigate air pollution for improvement of pulmonary health and prevention of COPD.
Environmental Health Research Fund of the Chinese University of Hong Kong and PhD Studentship of the Chinese University of Hong Kong.
Inflammation and healing of marginal ulceration at the GJ anastomosis results in scar tissue formation, and this can lead to the late development of a chronic anastomotic stricture. These late ...strictures tend to be recalcitrant and are less likely to be resolved with serial dilatation 3. We present a case of a late recalcitrant GJ stricture due to marginal ulceration, and share our experience in dealing with the adverse events and challenges that can arise during the management of this complication.
This study sought to develop a novel technique called bioprosthetic or native aortic scallop intentional laceration to prevent coronary artery obstruction (BASILICA).
Coronary artery obstruction is a ...rare but fatal complication of transcatheter aortic valve replacement (TAVR).
We lacerated pericardial leaflets in vitro using catheter electrosurgery, and tested leaflet splaying after benchtop TAVR. The procedure was tested in swine. BASILICA was then offered to patients at high risk of coronary obstruction from TAVR and ineligible for surgical aortic valve replacement. BASILICA used marketed devices. Catheters directed an electrified guidewire to traverse and lacerate the aortic leaflet down the center line. TAVR was performed as usual.
TAVR splayed lacerated bovine pericardial leaflets. BASILICA was successful in pigs, both to left and right cusps. Necropsy revealed full length lacerations with no collateral thermal injury. Seven patients underwent BASILICA on a compassionate basis. Six had failed bioprosthetic valves, both stented and stent-less. Two had severe aortic stenosis, including 1 patient with native disease, 3 had severe aortic regurgitation, and 2 had mixed aortic valve disease. One patient required laceration of both left and right coronary cusps. There was no hemodynamic compromise in any patient following BASILICA. All patients had successful TAVR, with no coronary obstruction, stroke, or any major complications. All patients survived to 30 days.
BASILICA may durably prevent coronary obstruction from TAVR. The procedure was successful across a range of presentations, and requires further evaluation in a prospective trial. Its role in treatment of degenerated TAVR devices remains untested.
Abstract Background Laparoscopic resection of gastric gastrointestinal stromal tumors (GISTs) has been shown by several retrospective studies to be technically feasible and associated with favorable ...outcomes when compared to the open approach. This study aims to mitigate potential selection bias by performing a case control study of laparoscopic (LWR) versus open wedge resection (OWR) matched by resection type, location and tumor size. Methods We retrospectively identified 50 consecutive patients who underwent LWR for a suspected gastric GIST from a prospective database and matched this cohort with 50 patients who underwent OWR. Results There was no statistical difference between the key baseline clinicopathological features of patients' who underwent LWR versus OWR. Patients who underwent LWR had longer operating times 150 (range, 65–270) minutes vs 92.5 (25–200) minutes, P < .001 but decreased median blood loss 0 (0–300) ml vs 0 (0–1200) ml, P = .015, decreased frequency of intraoperative or postoperative blood transfusion 1 (2%) vs 8 (16%), P = .031, decreased median time to liquid diet 2 (0–5) vs 3 (1–7) days, P < .001, decreased median time to solid diet 3 (1–6) vs 5 (2–11) days, P < .001 and decreased postoperative stay 4 (2–10) vs 4.5 (3–17), P < .001 compared to OWR. There was no difference in oncological outcomes such as frequency of close margins (≤1 mm) and recurrence-free survival. Conclusion This matched case–control study provides supporting evidence that LWR results in superior perioperative outcomes compared to OWR without compromising on oncological outcomes.
Abstract
Metformin has been shown to modulate meta-inflammation, an important pathogenesis in knee osteoarthritis (OA). The study aimed to test the association between regular metformin use with ...total knee replacement (TKR) in patients with diabetes. This is a retrospective study with electronic records retrieved in Hong Kong public primary care. Patients with diabetes aged ≥ 45 who visited during 2007 to 2010, were followed up for a four-year period from 2011 to 2014 to determine the incidence of TKR. Propensity score matching based on age, sex, co-medications and chronic conditions was conducted to adjust for confounding. Cox regression was implemented to examine the association between metformin use and TKR. In total, 196,930 patients were eligible and 93,330 regular metformin users (defined as ≥ 4 prescriptions over the previous year) and non-users were matched. Among 46,665 regular users, 184 TKRs were conducted, 17.1% fewer than that among non-users. Cox regression showed that regular metformin users had a 19%-lower hazard of TKR hazard ratio (HR) = 0.81, 95% confidence interval: 0.67 to 0.98, P = 0.033, with a dose–response relationship. Findings suggest a potential protective effect of metformin on knee OA progression and later TKR incidence among diabetic patients.
Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation ...in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs.
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