Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring

Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds, are commonly used in the management of inflammatory bowel disease. However, patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. Achieving predefined levels of two major thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is a long-standing clinical practice in ensuring therapeutic efficacy; however, their correlation with treatment response is sometimes unclear. Various genetic markers have also been used to aid the identification of patients who are thiopurine-sensitive or refractory. The recent discovery of novel Asian-specific DNA variants, namely those in the NUDT15 gene, and their link to thiopurine toxicity, have led clinicians and scientists to revisit the utility of Caucasian biomarkers for Asian individuals with inflammatory bowel disease. In this review, we explore the limitations associated with the current methods used for therapeutic monitoring of thiopurine metabolites and how the recent discovery of ethnicity-specific genetic markers can complement thiopurine metabolites measurement in formulating a strategy for more accurate prediction of thiopurine response. We also discuss the challenges in thiopurine therapy, alongside the current strategies used in patients with reduced thiopurine response. The review is concluded with suggestions for future work aiming at using a more comprehensive approach to optimize the efficacy of thiopurine compounds in inflammatory bowel disease

Identifying Hard Noise in Long-Tailed Sample Distribution

Conventional de-noising methods rely on the assumption that all samples are independent and identically distributed, so the resultant classifier, though disturbed by noise, can still easily identify the noises as the outliers of training distribution. However, the assumption is unrealistic in large-scale data that is inevitably long-tailed. Such imbalanced training data makes a classifier less discriminative for the tail classes, whose previously "easy" noises are now turned into "hard" ones -- they are almost as outliers as the clean tail samples. We introduce this new challenge as Noisy Long-Tailed Classification (NLT). Not surprisingly, we find that most de-noising methods fail to identify the hard noises, resulting in significant performance drop on the three proposed NLT benchmarks: ImageNet-NLT, Animal10-NLT, and Food101-NLT. To this end, we design an iterative noisy learning framework called Hard-to-Easy (H2E). Our bootstrapping philosophy is to first learn a classifier as noise identifier invariant to the class and context distributional changes, reducing "hard" noises to "easy" ones, whose removal further improves the invariance. Experimental results show that our H2E outperforms state-of-the-art de-noising methods and their ablations on long-tailed settings while maintaining a stable performance on the conventional balanced settings. Datasets and codes are available at https://github.com/yxymessi/H2E-FrameworkComment: Accepted to ECCV2022(Oral) ; Datasets and codes are available at https://github.com/yxymessi/H2E-Framewor

Seasonal variation of total carotenoids content in the tissues of male and female golden noble scallops Chlamys nobilis

The noble scallop Chlamys nobilis is an economically important edible marine bivalve that has been cultivated in the Southern Sea of China since the 1980s. Noble scallops, particularly the golden scallops, are rich in carotenoids, are of interest for their potential beneficial uses in human healthcare, food processing and pharmaceuticals. However, very little is known about the seasonal variation of total carotenoids content (TCC) in the golden scallops. Therefore, present study was conducted to determine the seasonal variation of TCC in the tissues of male and female of golden scallops. The results of present study revealed that the TCC in adductor, mantle and gonads of golden scallops were ranged from 16.79 to 138.86 μg/ g, 92.86 to 312.98 μg/ g, and 71.5 to 750.0 μg/ g, respectively. Generally, the gonads of golden scallops contain the highest TCC, followed by the mantle and adductor. In comparison of male and female scallops, TCC in the same tissue (except for gonad) was not statistically significant. However, female gonads contain much higher TCC than male gonads. The temporal variation of the TCC in golden scallops showed the highest in March to April and the lowest in October. The findings of current study can be very useful for scallop farmers and industry to determine the best harvest time to obtain the highest quality of golden scallops with high TCC

Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease

Thiopurine therapy of inflammatory bowel disease (IBD) is guided by the relative blood concentrations 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). However, their action is altered by in vivo phosphorylation, and this is not normally measured in clinical studies. Hence, we trialled a novel method for profiling phosphorylated thiopurine metabolites and revisited the association between thiopurine metabolites and IBD treatment outcomes. We first optimised and validated a published high-performance liquid chromatography (HPLC) method for measuring the blood levels of thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), thioguanosine triphosphate (TGTP), and methylthioinosine monophosphate (MeTIMP). Then, we assembled a small cohort of IBD patients (n = 20), who had been treated with azathioprine for at least three months, and obtained blood samples for analysis of the metabolites. The patients received treatments at the Universiti Kebangsaan Malaysia Specialist Centre between March 2018 and April 2019. They were classified as responders (n = 12) or non-responders (n = 6) to azathioprine based on their disease activity scores (CDAI or Mayo score). The HPLC method was precise with intraday and interday variation < 15% for all the tested metabolites, and the relative accuracy ranged from 40.2 to 114.0%. We noted that the responders had higher median 6-TGN but lower median TGTP levels than the non-responders. However, the differences were not statistically significant (Wilcoxon rank-sum tests; 6-TGN, p = 0.925; TGTP, p = 0.189). The higher median 6-TGN level detected in the responders is in keeping with the findings of prior studies, suggesting that HPLC analysis of phosphorylated thiopurine metabolites is both technically feasible and clinically useful

The recent progress and future of oxygen reduction reaction catalysis: A review

© 2016 Elsevier Ltd Proton Exchange Membrane Fuel Cell (PEMFC) technology is an exciting alternative energy prospect, especially in the field of transportation. PEMFCs are three times as efficient as internal combustion (IC) engines and emit only water as a byproduct. The latter point is especially important in a day and age when climate change is upon us. However, platinum required to catalyze the sluggish oxygen reduction reaction (ORR) which takes place on the cathode of the PEMFC has rendered fuel cell automobiles economically unviable until now. Therefore, the pursuit of an inexpensive replacement for platinum has become an active research area. This review covers the promising progress made in this field since 2011. Some of the more promising catalysts reviewed include alloys such as Pt/Pd nanotubes which outperform their platinum counterpart by nine fold and a Pt/Ni alloy which improves upon Pt activity by 16 times. Platinum-free catalysts such as iron carbide and modified graphene which rival Pt activity are also reviewed

Facile, scalable synthesis of edge-halogenated graphene nanoplatelets as efficient metal-free eletrocatalysts for oxygen reduction reaction

A series of edge-selectively halogenated (X = Cl, Br, I) graphene nanoplatelets (XGnPs = ClGnP, BrGnP, IGnP) were prepared simply by ball-milling graphite in the presence of Cl-2, Br-2 and I-2, respectively. High BET surface areas of 471, 579 and 662 m(2)/g were observed for ClGnP, BrGnP and IGnP, respectively, indicating a significant extent of delamination during the ball-milling and subsequent workup processes. The newly-developed XGnPs can be well dispersed in various solvents, and hence are solution processable. Furthermore, XGnPs showed remarkable electrocatalytic activities toward oxygen reduction reaction (ORR) with a high selectivity, good tolerance to methanol crossover/CO poisoning effects, and excellent long-term cycle stability. First-principle density-functional calculations revealed that halogenated graphene edges could provide decent adsorption sites for oxygen molecules, in a good agreement with the experimental observations.open271

Grey scale enhancement by a new self-made contrast agent in early cirrhotic stage of rabbit liver

<p>Abstract</p> <p>Background</p> <p>The development of new ultrasound contrast agents (UCAs) has become one of the most promising fields in ultrasound medicine. This paper evaluates a new self-made contrast agent enhancement effect developed to study the fibrotic stages of the liver in perfusion models <it>in vivo</it>.</p> <p>Methods</p> <p>We constructed experimental models of hepatic fibrosis involving five stages from F0 to F4 via administration of CCL₄(0.01 ml/kg BW) every 3 days for 3 months. The intrahepatic circulatory time of the contrast agent was analyzed via an image and Cine-loop display. Calculations of the perfusion-related parameters including the peak signal intensity (PSI) and peak signal intensity time (PIT) of the portal vein and parenchyma were obtained from an analysis of the time-acoustic intensity curve.</p> <p>Results</p> <p>Hepatic artery to vein transmit time (HA-HVTT) was significantly shorter at F4 stage (mean 5.1 seconds) compared with those in other stages (mean 8.3 s, 7.5 s, 6.9 s, 6.6 s, P < 0.01). The average PSI difference of PV-parenchyma was 13.62 dB in F4 stage, demonstrating significant differences between F4 stage and other early stages (P < 0.001).</p> <p>Conclusion</p> <p>These results indicate that the new self-made contrast agent is capable of indicating intrahepatic hemodynamic changes. HA-HVTT and the PSI difference of the microbubble perfusion in liver parenchyma and PV were considered to differentiate the degree of hepatic fibrosis between F4 and other early stages.</p

Genetic regulation of pituitary gland development in human and mouse

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans

Write-rationing garbage collection for hybrid memories

Emerging Non-Volatile Memory (NVM) technologies offer high capacity and energy efficiency compared to DRAM, but suffer from limited write endurance and longer latencies. Prior work seeks the best of both technologies by combining DRAM and NVM in hybrid memories to attain low latency, high capacity, energy efficiency, and durability. Coarse-grained hardware and OS optimizations then spread writes out (wear-leveling) and place highly mutated pages in DRAM to extend NVM lifetimes. Unfortunately even with these coarse-grained methods, popular Java applications exact impractical NVM lifetimes of 4 years or less. This paper shows how to make hybrid memories practical, without changing the programming model, by enhancing garbage collection in managed language runtimes. We find object write behaviors offer two opportunities: (1) 70% of writes occur to newly allocated objects, and (2) 2% of objects capture 81% of writes to mature objects. We introduce writerationing garbage collectors that exploit these fine-grained behaviors. They extend NVM lifetimes by placing highly mutated objects in DRAM and read-mostly objects in NVM. We implement two such systems. (1) Kingsguard-nursery places new allocation in DRAM and survivors in NVM, reducing NVM writes by 5x versus NVM only with wear-leveling. (2) Kingsguard-writers (KG-W) places nursery objects in DRAM and survivors in a DRAM observer space. It monitors all mature object writes and moves unwritten mature objects from DRAM to NVM. Because most mature objects are unwritten, KG-W exploits NVM capacity while increasing NVM lifetimes by 11x. It reduces the energy-delay product by 32% over DRAM-only and 29% over NVM-only. This work opens up new avenues for making hybrid memories practical