Early recognition of muscle injury, up to development of exertional rhabdomyolysis (ER), is essential for many clinical and practical reasons, such as planning the suitable period of recovery and deciding an appropriate time for return to exercise. Albeit magnetic resonance imaging (MRI) remains the reference technique for assessing muscle injuries, and ultrasonography (US) may be a complementary approach for easy, inexpensive and fast screening, the potential drawbacks of both techniques may be overcome by some laboratory tests, which may help guiding both diagnostic reasoning and clinical decision making. Current evidence attest that creatine kinase remains the most validated test across the clinical spectrum of muscles injuries, as its measurement may be helpful for screening subjects with suggestive signs and symptoms, its concentration substantially reflects the amount of injured muscle and its kinetics appears suitable, combined with clinics and results of imaging testing, for making decisions on return to exercise. Relatively low cost and widespread availability are additional advantages of this test. In athletes with ER, myoglobin assessment may provide adjunctive useful information, due to high predictive value for development of acute kidney injury. Regarding other historical biomarkers, namely aldolase and lactate dehydrogenase, the kinetics, correlation with injury severity, laboratory standardization and availability make their measurement unsuitable and redundant. Some innovative biomarkers have also been tested in recent years, including fatty acid-binding proteins and carbonic anhydrase III, myosin light chain 3 and muscle micro RNAs. However, their clinical effectiveness, standardization, availability in clinical laboratories and costs are still regarded as major drawbacks.

Diagnostic biomarkers of muscle injury and exertional rhabdomyolysis.

Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic traits may render a pregnant woman susceptible to development of severe hypertriglyceridemia and pancreatitis, especially in the third trimester. To elucidate the underlying mechanism of gestational hypertriglyceridemic pancreatitis, we undertook DNA mutation analysis of the lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), lipase maturation factor 1 (LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) genes in five unrelated pregnant Chinese women with severe hypertriglyceridemia and pancreatitis. DNA sequencing showed that three out of five patients had the same homozygous variation, p.G185C, in APOA5 gene. One patient had a compound heterozygous mutation, p.A98T and p.L279V, in LPL gene. Another patient had a compound heterozygous mutation, p.A98T & p.C14F in LPL and GPIHBP1 gene, respectively. No mutations were seen in APOC2 or LMF1 genes. All patients were diagnosed with partial LPL deficiency in non-pregnant state. As revealed in our study, genetic variants appear to play an important role in the development of severe gestational hypertriglyceridemia, and, p.G185C mutation in APOA5 gene appears to be the most common variant implicated in the Chinese population. Antenatal screening for mutations in susceptible women, combined with subsequent interventions may be invaluable in the prevention of potentially life threatening gestational hypertriglyceridemia-induced pancreatitis.

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Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis.

The search for common genetic determinants of plasma lipoproteins began in the early 1980s. Despite some exceptions, these efforts have not yet yielded a set of biological markers that can be used in clinical practice. By contrast, successes in defining the molecular basis of rare single-gene disorders, such as familial hypoalphalipoproteinemia, have shown the value of experimental designs that focus on genomic analysis of individuals within the tails of Gaussian distributions of quantitative lipoprotein traits. For example, this strategy showed that a small but relevant proportion of individuals within the <5% tail of plasma HDL-cholesterol distribution have mutations in genes that cause familial hypoalphalipoproteinemia. The value of clinical testing for genomic variants as an adjunct to a biochemical measurement of plasma lipoproteins, however, is at best questionable. A more direct impact of genetic studies is that definitions of 'common' and 'large genetic effects' have become more tempered, reflecting perhaps the biological reality that plasma lipoproteins are probably determined by the aggregate of numerous modest and occasional large genetic effects in addition to environmental factors. Here, we review recent progress on genomic variants and cholesterol metabolism, and discuss the impact these genetic studies will have on clinical cardiology.

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Genetic determinants of plasma lipoproteins.

Apolipoprotein A5 (APOA5) −1131C allele is associated with higher triglyceride, an independent cardiovascular risk factor and a commonly recognized lipid abnormality in diabetes mellitus (DM). We investigated the association of APOA5 −1131T>C or S19W with DM. Study subjects were all women and categorized into metabolically healthy controls (n = 2033) and DM subjects (n = 304). Association of APOA5 −1131T>C with DM was calculated by odds ratio (OR). Anthropometric parameters, fasting glucose, and lipid profiles were measured. C carriers, particularly those with CC homozygote, had higher triglyceride and lower high-density lipoprotein cholesterol in both healthy controls (P

Contribution of APOA5−1131C allele to the increased susceptibility of diabetes mellitus in association with higher triglyceride in Korean women

Atherosclerosis, a major cause of ischemic stroke, may be associated with variability of triglyceride (TG) levels. Apolipoprotein A5 (APOA5) genetic polymorphisms are associated with altered TG levels. The objective of this study was to investigate the coding region polymorphisms S19W (rs3135506) and G185C (rs2075291) and the promoter region polymorphism -1131T>C (rs662799) of the APOA5 gene as risk factors for ischemic stroke in Turkish population. Study group consisted of 272 ischemic stroke patients and 123 controls. Genotypes were determined by real-time polymerase chain reaction (PCR) for S19W and PCR-restriction fragment length polymorphism analysis (PCR-RFLP) for -1131T>C and G185C. 19W allele frequency was 0.090 in stroke patients and 0.062 in controls (P = 0.191). Minor allele frequencies of -1131T>C and G185C in patients were 0.106 and 0.004, respectively, and were nearly the same in controls. Total cholesterol and LDL-cholesterol levels were significantly higher for stroke patients having at least one 19W allele compared to non-carriers. A significant difference was also found for LDL-cholesterol levels of stroke patients; higher in -1131C allele carriers compared to wild type patients. There was a trend for higher frequency of ischemic stroke among -1131C allele carrier hypertensive, diabetic or obese subjects compared to non-carriers. However, APOA5 genotypes were not associated with the risk of ischemic stroke by logistic regression analysis. The present study demonstrated that carrying rare alleles of APOA5 S19W, -1131T>C and G185C alone do not constitute a risk for ischemic stroke in the studied Turkish subjects.

Apolipoprotein A5 polymorphisms in Turkish population: association with serum lipid profile and risk of ischemic stroke

Background: Several independent population studies have reported that c.553G>T polymorphism of the apolipoprotein A5 gene (APOA5) is associated with hypertriglyceridaemia. The aim of this study is to investigate the association between this genetic variation and the risk of type 2 diabetes mellitus. Methods: In this study, APOA5 c.553G>T polymorphisms in 152 healthy individuals and 71 type 2 diabetes mellitus patients were detected by PCR-restriction fragment length polymorphism and agarose electrophoresis methods, and serum levels of lipids were also estimated by biochemical methods. Results: The frequency of T alleles in the diabetes and control groups was 0.085 and 0.049, respectively. Compared with controls, there was no significant difference in the distribution of genotype and allele frequencies of c.553G>T polymorphic sites in diabetic patients (p=0.27 and p=0.15, respectively). However, the frequency of GT and TT genotypes and the T allele in the subgroup with hypertriglyceridaemia was significantly higher than that in the subgroup with normal triglyceridaemia in both the control group (p=0.034 and p=0.014, respectively) and the diabetes group (p=0.037 and p=0.007, respectively). In the diabetes and control groups, triglyceride levels in (GT+TT) genotype individuals were significantly higher than in GG genotype individuals (p=0.001 and p=0.003, respectively), and levels of low-density lipoprotein cholesterol were also significantly higher (p=0.044 and p=0.022, respectively). Conclusions: APOA5 c.553G>T polymorphism is not significantly associated with susceptibility to type 2 diabetes mellitus, but is associated with plasma triglyceride and low-density lipoprotein cholesterol levels.

Association of APOA5 c.553G>T polymorphism with type 2 diabetes mellitus in a Chinese population.

Early diagnosis and prognosis evaluation are of great significance to hepatitis E virus (HEV)‐related acute liver failure (HEV‐ALF) patients. We collected serum samples from 200 health controls (HCs), 200 patients with acute hepatitis E (AHE), and 200 HEV‐ALF patients to evaluate serum exosome‐derived carbamoyl phosphate synthase 1 (CPS1) levels and determine its diagnostic and prognostic value. The exosome‐derived CPS1 levels in the HEV‐ALF group were significantly higher than those in the AHE and HCs groups. The AUC of exosome‐derived CPS1 to predict the occurrence of HEV‐ALF was 0.850 (0.811−0.883). Both logistical regression and orthogonal partial least squares discriminant analysis (OPLS‐DA) showed that exosome‐derived CPS1 is an independent risk factor for HEV‐ALF. The exosome‐derived CPS1 levels were positively correlated with organ failure and the outcomes in HEV‐ALF patients. The exosome‐derived CPS1 levels in the worsening group were significantly higher than those in the fluctuating and the improving groups. The AUC of serum exosome‐derived CPS1 to predict 30‐day mortality was 0.829 (0.770−0.879), which was significantly greater than that of the Child‐Pugh, KCH, and MELD models. The level of serum exosome‐derived CPS1 might serve as a promising diagnostic and prognostic biomarker for HEV‐ALF patients, which may provide better guidance for the diagnosis, prognosis, and treatment of HEV‐ALF patients.

The diagnostic and prognostic value of serum exosome‐derived carbamoyl phosphate synthase 1 in HEV‐related acute liver failure patients

Immunotherapy with immune checkpoint inhibitor (ICI) drugs is gradually becoming a hot topic in cancer treatment. To comprehensively evaluate the safety and efficacy of ICI drugs, we employed the Bayesian model and conducted a network meta-analysis in terms of progression-free survival (PFS), overall survival (OS) and severe adverse events (AEs). Our study found that treatment with ipilimumab was significantly worse than standard therapies in terms of PFS, whereas treatment with cemiplimab significantly improved PFS. The results also indicated that cemiplimab was the best choice for PFS. Treatment with nivolumab, pembrolizumab and nivolumab plus ipilimumab significantly improved OS compared to standard therapies. In terms of OS, cemiplimab was found to be the best choice, whereas avelumab was the worst. In terms of severe AEs, atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab all significantly reduced the risk of grade 3 or higher AEs compared to standard therapy. The least likely to be associated with severe AEs were as follows: cemiplimab, avelumab, nivolumab, atezolizumab, and camrelizumab, with nivolumab plus ipilimumab to be the worst. Therefore, different ICI drug therapies may pose different risks in terms of PFS, OS and severe AEs. Our study may provide new insights and strategies for the clinical practice of ICI drugs.

Comprehensive Evaluation of Anti-PD-1, Anti-PD-L1, Anti-CTLA-4 and Their Combined Immunotherapy in Clinical Trials: A Systematic Review and Meta-analysis

Mesenchymal stem cells (MSCs) were reported to have strong immunomodulatory ability, and inhibit the proliferation of T cells and their immune response through cell-to-cell interactions and the generation of cytokines. With high differentiation potential and self-renewal ability, MSCs are considered to function in alleviating inflammatory responses, promoting tissue regeneration and inhibiting tissue fibrosis formation. As the most common malignancies, gastrointestinal (GI) cancers have high incidence and mortality. The accurate diagnosis, exact prognosis and treatment of GI cancers have always been a hot topic. Therefore, the potential applications of MSCs in terms of GI cancers are receiving more and more attention. Recently, there is increasing evidence that MSCs may serve as a key point in the growth, metastasis, inhibition, treatment and prognosis of GI cancers. In this review, we summarized the roles of MSCs in GI cancers, mainly focusing on esophageal cancer (EC), gastric cancer (GC), liver cancer (LC), colorectal cancer (CRC) and pancreatic cancer. Besides, we proposed MSCs as potential targets and treatment strategies for the effective treatment of GI cancers, which may provide better guidance for the clinical treatment of GI cancers.

The Roles of Mesenchymal Stem Cells in Gastrointestinal Cancers

The purpose of this study was to explore the frequency of apolipoprotein A5 (APOA5) -1131T/C polymorphism in Zhenjiang and its effects on lipid metabolism and insulin resistance in type II diabetes mellitus(DM) patients. The genotypes of APOA5 -1131T/C polymorphism were determined in 152 healthy individuals and 71 type II DM patients by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum levels of lipids, glucose and insulin in these subjects were also estimated by biochemical methods. The frequency of the APOA5-1131C allele in DM patients was significantly higher than that of the control group (0.430 vs 0.296, P = 0.006). When compared with the TT genotype, CC homozygotes had a significantly increased DM risk (OR=3.75, 95% CI: 1.57-8.92). In the DM group, the serum levels of triglyceride (TG) of C carriers (TC+CC) were significantly higher than those of non-C carriers (TT) (P 0.01), and serum levels of total cholesterol (TC) and low density lipoprotein cholesterol(LDL-c) in subjects with the CC genotype were also significantly higher than those with the TT genotype (P 0.05). However, there was no significance in profiles of insulin resistance in various genotypes in both groups. The APOA5 single nucleotide polymorphism was associ-ated with serum TG level in the population. The -1131C allele contributed to the increase of serum levels of TG, TC and LDL-c and but had no effect on profiles of insulin resistance in DM patients. The APOA5 -1131C allele may be associated with increased susceptibility to type II diabetes mellitus.

Guang-Hua Zhai

Papers

Association of APOA5 c.553G>T polymorphism with type 2 diabetes mellitus in a Chinese population.

The diagnostic and prognostic value of serum exosome‐derived carbamoyl phosphate synthase 1 in HEV‐related acute liver failure patients

Comprehensive Evaluation of Anti-PD-1, Anti-PD-L1, Anti-CTLA-4 and Their Combined Immunotherapy in Clinical Trials: A Systematic Review and Meta-analysis

The Roles of Mesenchymal Stem Cells in Gastrointestinal Cancers

[Association of apolipoprotein A5 gene -1131T/C polymorphism with lipid metabolism and insulin resistance in patients with type II diabetes mellitus].