Application of metabolomics in clinical and laboratory gastrointestinal oncology

Metabolites are versatile bioactive molecules.They are not only the substrates and/or the products of enzymatic reactions but also act as the regulators in the systemic metabolism.Metabolomics is a high-throughput analytical strategy to qualify or quantify as many metabolites as possible in the metabolomes.It is an indispensable part of systems biology.The leading techniques in this field are mainly based on mass spectrometry and nuclear magnetic resonance spectroscopy.The metabolomic analysis has gained wide use in bioscience fields.In the tumor research arena,metabolomics can be employed to identify biomarkers for prediction,diagnosis,and prognosis.Chemotherapeutic effect evaluation and personalized medicine decision-making can also benefit from metabolomic analysis of patient biofluid or biopsy samples.Many cell-level studies can help in disease exploration.In this review,the basic features and principles of varied metabolomic analysis are introduced.The value of metabolomics in clinical and laboratory gastrointestinal cancer studies is discussed,especially for mass spectrometry applications.Besides,combined use of metabolomics and other tools to solve problems in cancer practice is briefly illustrated.In summary,metabolomics paves a new way to explore cancerous diseases in the light of small molecules.

Effect of Half-dose and Standard-dose Conjugated Equine Estrogens Combined with Natural Progesterone or Dydrogesterone on Components of Metabolic Syndrome in Healthy Postmenopausal Women： A Randomized Controlled Trial

Background： Menopausal hormone therapy （MHT） has been proven to have beneficial effects on several components of metabolic syndrome. However, the effects vary according to different regimens, dosages, and duration of MHT. The aim of the study was to evaluate the effect of standard-dose 0.625 mg conjugated equine estrogen （CEE） and half-dose 0.3 mg CEE daily with different progestogens in a continuous sequential regimen on postmenopausal metabolic parameters in generally healthy postmenopausal women. Methods： A prospective, open-label, randomized controlled clinical trial was conducted between February 2014 and December 2015. Totally 123 Chinese postmenopausal women with climacteric symptoms were included in this study and were randomly assigned to three groups： Group A received CEE 0.3 mg/micronized progesterone （MP） 100 mg daily; Group B received CEE 0.625 mg/MP 100 mg daily; and Group C received CEE 0.625 mg/dydrogesterone 10 mg daily. Drugs were given in a continuous sequential pattern. The duration of treatment was 12 months. Clinical, anthropometrical, and metabolic variables were measured. Data were analyzed according to intention-to-treat analysis, using Student＇s t-test and analysis of variance. Results： A total of 107 participants completed the 12-month follow-up and were included in the data analysis. At 12 months of treatment, high-density lipoprotein cholesterol and apolipoprotein A significantly increased, and low-density lipoprotein cholesterol, fasting glucose, and glycosylated hemoglobin significantly decreased in Groups B and C, compared with baseline （all P 〈 0.05）. Among the three groups, only Group C showed significantly increased triglycerides compared with baseline （ 1.61 ± 0.80 mmol/L vs. 1.21 ± 0.52 mmol/L, P 0.026）. Each group showed a neutral effect on total cholesterol, lipoprotein A, apolipoprotein B, and fasting insulin levels. No cardiovascular and venous thromboembolic events occurred in the three groups. Conclusions： Among Chinese postmenopausal women, half-dose CEE was not sufficient to induce a favorable lipid and carbohydrate profile compared with standard-dose CEE. Adding natural MP may counterbalance the TG-increasing effect of CEE.

Nine-month Angiographic and Two-year Clinical Follow-up of Novel Biodegradable-polymer Arsenic Trioxide-eluting Stent Versus Durable-polymer Sirolimus-eluting Stent For Coronary Artery Disease

Background:Despite great reduction of in-stent restenosis,first-generation drug-eluting stents (DESs) have increased the risk of late stent thrombosis due to delayed endothelialization.Arsenic trioxide,a natural substance that could inhibit cell proliferation and induce cell apoptosis,seems to be a promising surrogate of sirolimus to improve DES performance.This randomized controlled trial was to evaluate the efficacy and safety of a novel arsenic trioxide-eluting stent (AES),compared with traditional sirolimus-eluting stent (SES).Methods:Patients with symptoms of angina pectoris were enrolled and randomized to AES or SES group.The primary endpoint was target vessel failure (TVF),and the second endpoint includes rates of all-cause death,cardiac death or myocardial infarction,target lesion revascularization (TLR) by telephone visit and late luminal loss (LLL) at 9-month by angiographic follow-up.Results:From July 2007 to 2009,212 patients were enrolled and randomized 1 ∶1 to receive either AES or SES.At 2 years of follow-up,TVF rate was similar between AES and SES group (6.67％ vs.5.83％,P =0.980).Frequency of all-cause death was significantly lower in AES group (0 vs.4.85％,P =0.028).There was no significant difference between AES and SES in frequency of TLR and in-stent restenosis,but greater in-stent LLL was observed for AES group (0.29 ± 0.52 mm vs.0.1 0 ± 0.25 mm,P =0.008).Conclusions:After 2 years of follow-up,AES demonstrated comparable efficacy and safety to SES for the treatment of de novo coronary artery lesions.

Short-term combined treatment with exenatide and metformin for overweight/obese women with polycystic ovary syndrome

Background:Obesity and insulin resistance(IR)are common features of polycystic ovary syndrome(PCOS).Metformin(MET)increases insulin sensitivity,but it is associated with unsatisfactory weight loss.The glucagon-like peptide-1 receptor agonist exenatide has been shown to reduce weight and IR in patients with diabetes.This study aimed to explore the therapeutic effects of exenatide once-weekly(QW)combined with MET on body weight,as well as metabolic and endocrinological parameters in overweight/obese women with PCOS.Methods:Fifty overweight/obese women with PCOS diagnosed via the Rotterdam criteria were randomized to one of two treatment groups:MET(500 mg three times a day[TID])or combination treatment(COM)(MET 500 mg TID,exenatide 2 mg QW)for 12 weeks.The primary outcomes were anthropometric changes associated with obesity,and the secondary outcomes included changes in reproductive hormone levels,glucose and lipid metabolism,and C-reactive protein.Results:Forty(80%)patients completed the study.COM therapy was superior to MET monotherapy in reducing weight(P=0.045),body mass index(BMI)(P=0.041),and waist circumference(P=0.023).Patients in the COM group on an average lost 3.8±2.4 kg compared with 2.1±3.0 kg in the MET group.In the COM group,BMI and waist circumference decreased by 1.4±0.87 kg/m2 and 4.63±4.42 cm compared with 0.77±1.17 kg/m2 and 1.72±3.07 cm in the MET group,respectively.Moreover,levels of fasting glucose,oral glucose tolerance test(OGTT)2-h glucose,and OGTT 2-h insulin were significantly lower with COM therapy than with MET(P<0.050).Mild and moderate gastrointestinal reactions were the most common adverse events in both groups.Conclusions:COM therapy was more effective than MET alone in reducing body weight,BMI,and waist circumference,and improving insulin sensitivity in overweight/obese women with PCOS,with acceptable short-term side effects.

Cloning and Expression Analysis of Rice Sucrose Transporter Genes OsSUT2M and OsSUT5Z

Two sucrose transporter （SUT） cDNAs, OsSUT2M and OsSUT5Z, were isolated from rice （Oryza sativa L.） by reverse transcription polymerase chain reaction （RT-PCR）. Sequencing results indicate they are 1 531 bp and 1 635 bp in length including complete open reading frame 1 506bp and 1 608 bp, which encode 502 amino acids and 536 amino acids, respectively. The TopPred program suggested that both sucrose transporter proteins, OsSUT2M and OsSUT5Z, consist of potentially 12 transmembrane domains. Semi-quantitative RT-PCR was carried out to investigate the gene expression patterns of OsSUT2M and OsSUT5Z. In vegetative organs, transcripts of OsSUT2M were higher in source leaf blades than in other organs at the same development stage, whereas transcripts of OsSUT5Z were less traceable in all organs investigated. In reproductive organs, both transcripts of these two genes were high in panicles from the booting stage to 7 days after flowering （DAF） and then sharply declined. The potential physiology functions of these two sucrose transporters are discussed.

Cell-wall Invertases from Rice are Differentially Expressed in Caryopsis during the Grain Filling Stage

Cell-wall invertase plays an important role in sucrose partitioning between source and sink organs in higher plants. To investigate the role of cell-wall invertases for seed development in rice （Oryza sativa L.）, cDNAs of three putative cell- wall invertase genes OsCIN1, OsCIN2 and OsCIN3 were isolated. Semi-quantitative reverse transcription-polymerase chain reaction analysis revealed different expression patterns of the three genes in various rice tissues/organs. In developing caryopses, they exhibited similar temporal expression patterns, expressed highly at the early and middle grain filling stages and gradually declined to low levels afterward. However, the spatial expression patterns of them were very different, with OsCIN1 primarily expressed in the caryopsis coat, OsCIN2 in embryo and endosperm, and OsCIN3 in embryo. Further RNA in situ hybridization analysis revealed that a strong signal of OsCIN2 mRNA was detected in the vascular parenchyma surrounding the xylem of the chalazal vein and the aleurone layer, whereas OsCIN3 transcript was strongly detected in the vascular parenchyma surrounding the phloem of the chalazal vein, cross-cells, the aleurone layer and the nuceUar tissue. These data indicate that the three cell-wall invertase genes play complementary/synergetic roles in assimilate unloading during the grain filling stage. In addition, the cell type-specific expression patterns of OsCIN3 in source leaf blades and anthers were also investigated, and its corresponding physiological roles were discussed.

Ultrasonographic Observation of the Breast in Early Postmenopausal Women during Therapy with Cimicifuga Foetida Extract and Sequential Therapy with Estrogen and Progestin

Background： It is now recognized that Cimicifuga foetida （C. foetida） extract is effective in alleviating menopausal symptoms. But the durations reported were usually short, The aim of this study was to investigate the effects of C. fl）etida extract therapy and different estrogen and progesterone sequential therapies, on the breasts of early postmenopausal women. Methods： This was a prospective randomized trial. Ninety-six early menopausal women were recruited and randomly assigned into three groups treated with different therapies for 2 years. Patients were given C. foetida extract in Group A, estradiol valerate and medroxyprogesterone acetate in Group B, and estradiol valerate and progesterone in Group C. Ultrasonography was used to monitor changes in breast during treatment. Results： In comparing breast glandular section thickness before and after 1 and 2 years of treatment, no significant difference was observed in Group A （11.97 ± 2.84 mm vs. 12.09 ± 2.58 mm and 12.61 ± 3.73 mm, P 〉 0.05）; in Group B glandular section thickness had increased significantly （10.98 ± 2.34 mm vs. 11.84± 2.72 mm and 11.90 ± 3.33 mm, P 〈 0.05） after treatment, the same as Group C （ 11.56 ± 3.03 mm vs. 12.5 ± 3.57 mm and 12.22 ± 4.39 mm P 〈 0.05）. In comparing breast duct width betbre and after 1 and 2 years of treatment, no significant difference was seen in Group A （1.07 ± 0.19 mm vs. 1.02 ±0.18 mm and 0.98 ± 0.21 mm, P 〉 0.05）; in Group B the duct width had a downward trend after treatment （0.99 ± 0.14 mm vs. 0.96 ± 0.22 mm and 0.90 ± 0.18 mm, P 〈 0.05）, the same as Group C （ 1.07 ± 0.20 mm vs. 1.02 ± 0.17 mm and 0.91 ± 0.19 mm, P 〈 0.05）. The nodules detected before treatment had disappeared after 1 -year of treatment or exhibited no distinct changes in the three groups. However, new breast nodules had appeared after 2 years of treatment： There was one case in Group A, two cases in Group B and four cases in Group C, with breast hyperplasia after the molybdenum target check. Conclusions： In early postmenopausal patients, C. foetida extract therapy and estrogen and progesterone therapy at low doses did not increase the incidence of malignant breast tumors.

Nationwide survey on the usage of ovulation-induction agents among obstetricians and gynecologists in China

Ovulation-induction refers to the type of ovarian stimulation for anovulatory women aimed at restoring normal fertility by generating normal ovulatory cycles and inducing single dominant follicle selection and ovulation. In China, a great number of women with ovulatory disorders are treated by obstetricians and gynecologists (ob-gyns) who are not specialized in infertility. The aim of this study was to investigate the self-reported ob-gyns proficiency of ovulation induction and the most commonly used drug for this procedure.

Deficiency of mitochondrial aldehyde dehydrogenase increases type 2 diabetes risk in males via autophagy dysregulation

Metrics To the editor:The diabetes epidemic has increasingly become a major public health concern worldwide.In 2014,there were 102.9 million diabetic adults in China,representing 24.4%of the world's diabetic population,even though China only comprised 18.7%of the global population at the time.[1]Furthermore,the estimated overall prevalence of diabetes and prediabetes was 10.9%and 35.7%,respectively,indicating China as one of the countries with the highest prevalence of diabetes in the world.[2]Although factors,including sedentary lifestyles and energy-dense diets,drive the diabetes epidemic,genetic architecture may also contribute to the susceptibility of an individual's response to environmental challenges.Aldehyde dehydrogenase(ALDH)2 is a key enzyme that eliminates toxic aldehydes by catalyzing their oxidation to non-reactive acids.Emerging evidence has suggested that individuals with ALDH2 deficiency have an increased risk of cardiovascular and metabolic diseases,in addition to alcohol intolerance,nitroglycerin tolerance,and carcinoma.[3]Notably,a unique ALDH2 loss-of-function allele,ALDH2∗2,is found in approximately 50%of the East Asian and 8%of the global populations.It has been reported that this ALDH2 mutation is associated with a higher prevalence of diabetes in coronary artery disease(CAD)patients,accompanied with increased C-reactive protein(CRP)levels.[4]ALDH2 mutation is also related to various diabetes risk factors,but the direct correlation remains elusive.Herein,we have explored the potential pathogenicity and mechanisms of ALDH2 deficiency in the development of type 2 diabetes in both laboratory and clinical settings.