Resveratrol attenuates high-fat diet-induced non-alcoholic steatohepatitis by maintaining gut barrier integrity and inhibiting gut inflammation through regulation of the endocannabinoid system

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IKZF1 Deletion Subtyping and Outcome Analysis in BCR–ABL1-Negative Pediatric B-Cell Acute Lymphoblastic Leukemia: A Single-Institution Experience from North India

BackgroundIKZF1 deletions are associated with adverse outcomes in B-cell acute lymphoblastic leukemia (B-ALL). We assessed the prevalence and clinical impact of functional subtypes of IKZF1 deletions in pediatric BCR–ABL1-negative B-ALL. Patients andMethodsThis retrospective study of IKZF1 deletions was done in cases of pediatric BCR–ABL1-negative B-ALL. The genomic DNA of cases, over a 53-month period, was analyzed using multiplex ligation-dependent probe amplification and multiplex fluorescent polymerase chain reaction. The deletions were divided into functional subgroups: (1) loss-of-function/haploinsufficiency, (2) dominant-negative, and (3) a combination of both types of deletion. The post-induction remission status, event-free survival (EFS), and overall survival (OS) were noted.ResultsOut of 320 cases, 47 (14.7%) had IKZF1 deletions. Thirty-six of the 47 (77%) had loss-of-function deletions, 10 (21%) had dominant-negative deletions, and one (2%) had a combination of both types. The post-induction remission rates in cases with loss-of-function deletions (22/30, 73%; P = .060) and dominant-negative deletions (4/5, 80%; P = .517) were lower compared with those without deletions (215/248, 86.7%). These cases also had worse median EFS: 21.1 months (P = .006) for loss-of-function and 15.4 months (P = .156) for dominant-negative deletions, compared with 46.4 months in cases without IKZF1 deletions. They also had worse median OS: 23.4 months (P = .012) for loss-of-function deletions and 15.7 months (P = .233) for dominant-negative deletions, compared with median not reached in cases without IKZF1 deletions.ConclusionThe IKZF1 deletions were seen in 14.7% of BCR–ABL1-negative pediatric B-ALL. Most of these deletions (77%) were loss-of-function type. The cases with loss-of-function deletions had lower remission rates and poor EFS and OS compared with cases without IKZF1 deletions. A similar trend of poor outcome was seen in the few cases with dominant-negative IKZF1 deletions.     

A 16-year review of seroprevalence studies on measles and rubella

The determination of the seroprevalence of vaccine-preventable diseases is critical in monitoring the efficacy of vaccination programmes and to assess the gaps in population immunity but requires extensive organisation and is time and resource intensive. The results of the studies are frequently reported in peer-reviewed scientific, government and non-government publications. A review of scientific literature was undertaken to advise the development of WHO guidelines for the assessment of measles and rubella seroprevalence. A search of the National Library of Medicine’s PubMed online publications using key words of ‘measles’, ‘rubella’, combined with ‘serosurvey’, ‘seroprevalence’, ‘immunity’ and ‘population immunity’ was conducted. A total of 97 articles published between January 1998 and June 2014 were retrieved, 68 describing serosurveys for measles and 58 serosurveys for rubella, conducted in 37 and 36 different countries respectively. Only 13 (19%) and 8 (14%) respectively were UN classified “least developed countries”. The study sample varied markedly and included combinations of male and female infants, children, adolescents and adults. The study sizes also varied with 28% and 33% of measles and rubella studies respectively, having greater than 2000 participants. Microtitre plate enzyme immunoassays were used in 52 (76%) measles studies and 40 (69%) rubella studies. A total of 39 (57%) measles and 44 (76%) rubella studies reported quantitative test results. Seroprevalence ranged from 60.8% to 95.9% for measles and 53.0% to 99.3% for rubella studies. The review highlighted that infants lost maternally-acquired immunity within 9 months of birth and were unprotected until vaccination. Two groups at higher risk of infection were identified: young adults between the ages of 15 and 30 years and immigrants.     

Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters

Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CL_h) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CL_h involving OATP1B-mediated hepatic uptake. CL_h can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CL_h and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction.     

Knee replacement surgery significantly elevates the urinary inflammatory biomarkers neopterin and 7,8-dihydroneopterin

ContextKnee arthroplasty surgery is significant trauma, leading to an activated immune system causing inflammation and oxidative stress. Many current biomarkers are invasive, costly, and often slow to analyse, limiting their use for rapid inflammatory measurements.ObjectivesWe have examined the use of urinary neopterin and total neopterin in knee arthroplasty patients to non-invasively measure oxidative stress and inflammation from immune system activation. We aim to validate the use of these biomarkers for quick, cost effective and predictive measurements of post-surgical inflammation assessment.Methodology19 Knee arthroplasty patients were analysed pre-operatively and for a defined post-operative period to determine the urinary levels of neopterin and total neopterin (neopterin +7,8-dihydroneopterin) using high performance liquid chromatography with fluorescence detection. These results were then compared to a control group of 20 participants with normal knee function.Results7,8-Dihydroneopterin was stable in urine over 12 h when refrigerated. Knee arthritis was associated with an increase in pre-operative neopterin (oxidative stress) and total neopterin (inflammation). The subsequent arthroplasty surgery generated a significant increase neopterin and total neopterin. Both biomarkers were reduced immediately post-operatively, before becoming elevated on the following days. There was no clear evidence of an association between initial neopterin and total neopterin levels and a patient's level of inflammation during in-hospital recovery.ConclusionsThe stability of 7,8-dihydroneopterin in urine allows for its use as an inflammatory marker. Urinary neopterin and total neopterin provided a fast, non-invasive, and simple measure of oxidative stress and inflammation after knee arthroplasty.     

Osteoporosis and sarcopenia in older age

Osteoporosis and sarcopenia are common in older age and associated with significant morbidity and mortality. Consequently, they are both attended by a considerable socioeconomic burden. Osteoporosis was defined by the World Health Organisation (WHO) in 1994 as a bone mineral density of less than 2.5 standard deviations below the sex-specific young adult mean and this characterisation has been adopted globally. Subsequently, a further step forward was taken when bone mineral density was incorporated into fracture risk prediction algorithms, such as the Fracture Risk Assessment Tool (FRAX®) also developed by the WHO. In contrast, for sarcopenia there have been several diagnostic criteria suggested, initially relating to low muscle mass alone and more recently low muscle mass and muscle function. However, none of these have been universally accepted. This has led to difficulties in accurately delineating the burden of disease, exploring geographic differences, and recruiting appropriate subjects to clinical trials. There is also uncertainty about how improvement in sarcopenia should be measured in pharmaceutical trials. Reasons for these difficulties include the number of facets of muscle health available, e.g. mass, strength, function, and performance, and the various clinical outcomes to which sarcopenia can be related such as falls, fracture, disability and premature mortality. It is imperative that a universal definition of sarcopenia is reached soon to facilitate greater progress in research into this debilitating condition.This article is part of a Special Issue entitled “Muscle Bone Interactions”.     

A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors

Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20–120 nm) depending on the PPT-to-PEG molar ratio (2–20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ∼5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (∼2.5%/day and ∼1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity.