Improved outcome with standardized plan for clinical management of acute decompensated chronic heart failure

Background Our overall goal is to improve clinical care for inpatients with chronic heart failure(CHF).A retrospective assessment of CHF patients admitted to our hospital over the past decade(2005 vs.2014)indicated a need for better strategies to evaluate clinical treatment,implement best practices and achieve optimal patient outcome.To that purpose,we developed a standardized plan to improve in-hospital treatment of acute decompensated CHF patients.Methods&Results Retrospective chart reviews were conducted to compare three cohorts of CHF patients admitted to the University Hospital of Lund at different time points over a 12-year period:2005(365 patients),2014(172 patients)and 2017-2018(57 patients).Little improvement was seen between 2005 and 2014 with respect to one-year mortality(35%vs.34%)and adequate treatment with recommended medications,e.g.,use of renin-angiotensin system blockers(45%vs.51%).A standardized treatment plan was devised to improve outcomes.A third cohort,treated under the plan(2017-2018),was compared with the 2014 cohort.One-year mortality(18%vs.34%)and 30-day readmission(5%vs.30%)were dramatically decreased,and adherence to medication guidelines was achieved.Key elements of the plan included well-defined treatment procedures,enhanced communication and teamwork,education,adequate time for treatment(5 days)and post-discharge follow-up as necessary.Natriuretic peptide(NT-proBNP)levels were useful for assessing patient status,prognosis and response to treatment.Conclusion Developmeof a standard plan for clinical management of acute decompensated CHF patients resulted in significant improvements in patient outcome,as reflected in decreased rates of 30-day readmission and one-year mortality.

Usefulness of fecal lactoferrin in predicting and monitoring the clinical severity of infectious diarrhea

AIM:To explore the value of fecal lactoferrin in predicting and monitoring the clinical severity of infectious diarrhea.METHODS:Patients with acute infectious diarrhea ranging from 3 mo to 10 years in age were enrolled,and one to three stool samples from each subject were collected.Certain parameters,including white blood cells /differential count,C-reactive protein,fecal mucus,fecal pus cells,duration of fever,vomiting,diarrhea and severity(indicated by Clark and Vesikari scores),were recorded and analyzed.Fecal lactoferrin was determined by enzyme-linked immunosorbent assay and compared in different pathogen and disease activity.Generalized estimating equations(GEE) were also used for analysis.RESULTS:Data included 226 evaluations for 117 individuals across three different time points.Fecal lactoferrin was higher in patients with Salmonella(11.17 μg/g ± 2.73 μg/g) or Campylobacter(10.32 μg/g ± 2.94 μg/g) infections and lower in patients with rotavirus(2.82 μg/g ± 1.27 μg/g) or norovirus(3.16 μg/g ± 1.18 μg/g) infections.Concentrations of fecal lactoferrin were significantly elevated in patients with severe(11.32 μg/g ± 3.29 μg/g) or moderate(3.77 μg/g ± 2.08 μg/g) disease activity compared with subjects with mild(1.51 μg/g ± 1.36 μg/g) disease activity(P < 0.05).GEE analysis suggests that this marker could be used to monitor the severity and course of gastrointestinal infections and may provide information for disease management.CONCLUSION:Fecal lactoferrin increased during bacterial infection and with greater disease severity and may be a good marker for predicting and monitoring intestinal inflammation in children with infectious diarrhea.

Interspinous Process Implants Causes Wear of the Spinous Processes in Patients Treated for Spinal Stenosis—An Experimental Biomechanical Study with Comparison to Clinical Cases

There are few biomechanical studies on Interspinous Process Implants (IPD);however none investigate the amount of wear on spinous processes. Therefore the objective of the present study was to investigate the effect of repetitive loading of the IPD Aperius on the spinous processes in a biomechanical porcine model. For comparison, three patients treated surgically with the same device have been followed for one to two years clinically and with image analyses (X-rays, MRI, CT-scans). Four lumbar spines from 6 months old porcine were divided into seven segments, which received IPD. The segments were exposed to 20,000 cyclical loads. Afterwards the deformation (wear) of the segments was registered. The wear of the spinous processes was measured in mm on a following CT-scan. Additionally, the wear of the ex-vivo was compared to that of the spinous processes investigated by CT-scans or X-ray in three patients treated surgically with the same interspinous implant. The mean maximal deformation of porcine specimens was 1.79 mm (SD 0.25) with the largest deformation occurring in the first quarter of the loading (<5000 cycles). The mean wear of the spinous processes after loading was 6.57 mm. A similar level of wear (mean 12.7 mm) of the spinous processes was detected in the patients. The Aperius IPD creates significant wear on the spinous processes in an experimental biomechanical study. Similar wear of the spinous processes is also present in patients treated with the same device post-operatively. How these findings influence the short and long term result of this implant device remains to be investigated in further biomechanical as well as clinical studies. For future development of this type of devices a proper selection of materials and design is essential to minimize wear effects on the spinous processes and thereby increases the possibilities for the devices to function as suggested.

Proteomics-based identification of proteins in tumor-derived exosomes as candidate biomarkers for colorectal cancer

BACKGROUND Colorectal cancer(CRC)is the second leading cause of cancer-related death,with high morbidity worldwide.There is an urgent need to find reliable diagnostic biomarkers of CRC and explore the underlying molecular mechanisms.Exosomes are involved in intercellular communication and participate in multiple pathological processes,serving as an important part of the tumor microenvironment.AIM To investigate the proteomic characteristics of CRC tumor-derived exosomes and to identify candidate exosomal protein markers for CRC.METHODS In this study,10 patients over 50 years old who were diagnosed with moderately differentiated adenocarcinoma were recruited.We paired CRC tissues and adjacent normal intestinal tissues(>5 cm)to form the experimental and control groups.Purified exosomes were extracted separately from each tissue sample.Data-independent acquisition mass spectrometry was implemented in 8 matched samples of exosomes to explore the proteomic expression profiles,and differentially expressed proteins(DEPs)were screened by bioinformatics analysis.Promising exosomal proteins were verified using parallel reaction monitoring(PRM)analysis in 10 matched exosome samples.RESULTS A total of 1393 proteins were identified in the CRC tissue group,1304 proteins were identified in the adjacent tissue group,and 283 proteins were significantly differentially expressed between them.Enrichment analysis revealed that DEPs were involved in multiple biological processes related to cytoskeleton construction,cell movement and migration,immune response,tumor growth and telomere metabolism,as well as ECM-receptor interaction,focal adhesion and mTOR signaling pathways.Six differentially expressed exosomal proteins(NHP2,OLFM4,TOP1,SAMP,TAGL and TRIM28)were validated by PRM analysis and evaluated by receiver operating characteristic curve(ROC)analysis.The area under the ROC curve was 0.93,0.96,0.97,0.78,0.75,and 0.88(P<0.05)for NHP2,OLFM4,TOP1,SAMP,TAGL,and TRIM28,respectively,indicating their good ability to distinguish CRC tissues from adjacent intestinal tissues.CONCLUSION In our study,comprehensive proteomic profiles were obtained for CRC tissue exosomes.Six exosomal proteins,NHP2,OLFM4,TOP1,SAMP,TAGL and TRIM28,may be promising diagnostic markers and effective therapeutic targets for CRC,but further experimental investigation is needed.

Modified constraint-induced movement therapy alters synaptic plasticity of rat contralateral hippocampus following middle cerebral artery occlusion

Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb.However,the molecular mechanism underlying its efficacy remains unclear.In this study,a middle cerebral artery occlusion(MCAO)rat model was produced by the suture method.Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days,starting from the 7^th day after middle cerebral artery occlusion.Day 1 of treatment lasted for 10 minutes at 2r/min,day 2 for 20 minutes at 2 r/min,and from day 3 onward for 20 minutes at 4 r/min.CatWalk gait analysis,adhesive removal test,and Y-maze test were used to investigate motor function,sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21^st day after MCAO.On the 21^st day after MCAO,the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay.The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography.The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats,but had no effect on cognitive function.The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3(Gria3)in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1 A,Avprla in the middle cerebral artery-occluded rats.In the ipsilateral hippocampus,only Adra2 a was downregulated,and there was no significant change in Gria3.Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3,which is an a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor,within 240 nm of the postsynaptic density in the contralateral cornu ammonis 3 region.The size and distribution of the synaptic vesicles within 100 nm of the presynaptic active zone were unchanged.Western blot analysis showed that modified constraint-induced movement therapy also increased the expression of glutamate receptor 2/3 and brain-derived neurotrophic factor in the hippocampus of rats with middle cerebral artery occlusion,but had no effect on Synapsin I levels.Besides,we also found modified constraint-induced movement therapy effectively reduced glutamate content in the contralateral hippocampus.This study demonstrated that modified constraint-induced movement therapy is an effective rehabilitation therapy in middle cerebral artery-occluded rats,and suggests that these positive effects occur via the upregulation of the postsynaptic membrane a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor expression.This study was approved by the Institutional Animal Care and Use Committee of Fudan University,China(approval No.201802173 S)on March 3,2018.

Current practices and future prospects for the management of gallbladder polyps: A topical review

A gallbladder polyp is an elevation of the gallbladder mucosa that protrudes into the gallbladder lumen. Gallbladder polyps have an estimated prevalence in adults of between 0.3%-12.3%. However, only 5% of polyps are considered to be "true" gallbladder polyps, meaning that they are malignant or have malignant potential. The main radiological modality used for diagnosing and surveilling gallbladder polyps is transabdominal ultrasonography. However, evidence shows that other modalities such as endoscopic ultrasound may improve diagnostic accuracy. These are discussed in turn during the course of this review. Current guidelines recommend cholecystectomy for gallbladder polyps sized 10 mm and greater, although this threshold is lowered when other risk factors are identified. The evidence behind this practice is relatively low quality. This review identifies current gaps in the available evidence and highlights the necessity for further research to enable better decision making regarding which patients should undergo cholecystectomy, and/or radiological follow-up.

Clinicopathological characteristics in the differential diagnosis of hepatoid adenocarcinoma:A literature review

Hepatoid adenocarcinoma (HAC) is a rare but important special type of extrahepatic adenocarcinoma with clinicopathological presentation mimicking hepatocellular carcinoma (HCC), and prompt and correct diagnosis can be a challenge, especially in endemic areas with a high incidence of HCC. To date, HAC has only been reported in case series or single case reports, so we aimed to review the clinicopathological characteristics of HAC to obtain a more complete picture of this rare form of extrahepatic adenocarcinoma. All the articles about HAC published from 2001 to 2011 were reviewed, and clinicopathological findings were extracted for analysis. A late middle-aged male with high serum α-fetoprotein and atypical image finding of HCC should raise the suspicion of HAC, and characteristic pathological immunohistochemical stains can help with the differential diagnosis. Novel immunohistochemical markers may be useful to clearly differentiate HAC from HCC. Once metastatic HAC is diagnosed, the primary tumor origin should be identified for adequate treatment. The majority of HAC originates from the stomach, so panendoscopy should be arranged first.

Variability of cell proliferation in the proximal and distal colon of normal rats and rats with dimethylhydrazine induced carcinogenesis

AIM：To investigate the patterns of cell proliferation in proximal and distal colons in normal rats and rats with1,2-dimethylhydrazine(DMH)induced carcinogenesis using the thymidine analogue bromodeoxyuridine.METHODS:Colonic crypt cell proliferation was immunohistochemically detected using the anti-bromodeoxyuridine Bu20a monoclonal antibody.RESULTS:Marked regional differences were found in both groups.Total labelling index(LI)and proliferative zone size in both normal(8.65±0.34vs7.2±0.45,27.74±1.07vs16.75±1.45)andDMH groups(13.13±0.46vs11.55±0.45,39.60±1.32vs35.52±1.58)were significantly higher in distal than in proximal colon(P<0.05).although the number of cells per proxmal crypt was greater(31.45±0.20vs34.45±0.39,42.68±0.53vs49.09±0.65,P<0.001).Crypt length,total LT and proliferative zone size all increased in both proximal and distal regions of DMH rats compared to normal controls(P<0.0001).In DMH-treated rat colon a shift of labelled cells to higher crypt cell positions was demonstrated distally whist a bi-directional shift was evident proximally(P<0.05).CONCLUSION:Our results show that changes in cell proliferation patterns,as assessed by bromodeoxyuridine uptake,can act as a reliable intermediate marker of colonic cancer formation.Observed differences between proliferation patterns in distal and proximal colon may be associated with the higher incidence of tumors in t he distal colon.

Increased expression of brain-derived neurotrophic factor is correlated with visceral hypersensitivity in patients with diarrheapredominant irritable bowel syndrome

BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS(IBS-D).AIM To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.METHODS Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 ageand sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.RESULTS The patients had a higher anxiety score [median(interquartile range), 6.0(2.0-10.0) vs 3.0(1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0(44.0-61.0)vs 21.0(17.3-30.0), P < 0.001] than controls. The defecating sensation threshold[60.0(44.0-80.0) vs 80.0(61.0-100.0), P = 0.009], maximum tolerable threshold[103.0(90.0-128.0) vs 182.0(142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0(20.0-30.0) vs 30.0(30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46 E-2(3.06 E-2-4.44 E-2) vs3.07 E-2(2.91 E-2-3.48 E-2), P = 0.031] and mRNA [1.57(1.31-2.61) vs 1.09(0.74-1.42), P = 0.001] expression and nerve fiber density [4.12 E-2(3.07 E-2-7.46 E-2) vs1.98 E-2(1.21 E-2-4.25 E-2), P = 0.002] were significantly elevated in the patients.Increased BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters.CONCLUSION Elevated mucosal BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity.

Epidemiology and natural history of hepatitis C virus infection

Hepatitis C virus(HCV)affects 130-210 million people worldwide and is one of the major risk factors for hepatocellular carcinoma.Globally,at least one third of hepatocellular carcinoma cases are attributed to HCV infection,and 350000 people died from HCV related diseases per year.There is a great geographical variation of HCV infection globally,with risk factors for the HCV infection differing in various countries.The progression of chronic hepatitis C to end-stage liver disease also varies in different study populations.A long-term follow-up cohort enrolling participants with asymptomatic HCV infection is essential for elucidating the natural history of HCV-caused hepatocellular carcinoma,and for exploring potential seromarkers that have high predictability for risk of hepatocellular carcinoma.However,prospective cohorts comprising individuals with HCV infection are still uncommon.The risk evaluation of viral load elevation and associated liver disease/cancer in HCV(REVEAL-HCV)study has followed a cohort of 1095 residents seropositive for antibodies against hepatitis C virus living in seven townships in Taiwan for more than fifteen years.Most of them have acquired HCV infection through iatrogenic transmission routes.As the participants in the REVEALHCV study rarely receive antiviral therapies,it provides a unique opportunity to study the natural history of chronic HCV infection.In this review,the prevalence,risk factors and natural history of HCV infection are comprehensively reviewed.The study cohort,data collection,and findings on liver disease progression of the REVEAL-HCV study are described.

Role of body mass index in colon cancer patients in Taiwan

AIM:To determine the effect of body mass index(BMI) on the characteristics and overall outcome of colon cancer in Taiwan.METHODS:From January 1995 to July 2003,2138 patients with colon cancer were enrolled in this study.BMI categories(in kg/m 2) were established according to the classification of the Department of Health of Taiwan.Postoperative morbidities and mortality,and survival analysis including overall survival(OS),diseasefree survival(DFS),and cancer-specific survival(CSS) were compared across the BMI categories.RESULTS:There were 164(7.7%) underweight(BMI < 18.5 kg/m 2),1109(51.9%) normal-weight(BMI = 18.5-23.9 kg/m 2),550(25.7%) overweight(BMI = 24.0-26.9 kg/m 2),and 315(14.7%) obese(BMI ≥27 kg/m 2) patients.Being female,apparently anemic,hypoalbuminemic,and having body weight loss was more likely among underweight patients than among the other patients(P < 0.001).Underweight patients had higher mortality rate(P = 0.007) and lower OS(P < 0.001) and DFS(P = 0.002) than the other patients.OS and DFS did not differ significantly between normal-weight,overweight,and obese patients,while CSS did not differ significantly with the BMI category.CONCLUSION:In Taiwan,BMI does not significantly affect colon-CSS.Underweight patients had a higher rate of surgical mortality and a worse OS and DFS than the other patients.Obesity does not predict a worse survival.

Lower serum folate is associated with development and invasiveness of gastric cancer

AIM: To evaluate the associations of serum folate levelwith development, invasiveness and patient survival of gastric cancer. METHODS: In this nested case-control study, patients with newly diagnosed gastric cancer undergoing gastrectomy were enrolled, and patients receiving chemotherapy prior to surgery, with other concurrent malignancy, or of the aboriginal and alien populations were excluded. In total, 155 gastric cancer patients and 149 healthy controls were enrolled for determination of serum folate levels and their correlation with gastric cancer. Using the median value of serum folate computed among the overall population as the cutoff value, the associations between serum folate and gastric cancer in all cases and different age and gender subgroups were analyzed by multivariate logistic regression analysis. In the patient cohort of gastric cancer, receiver-operating characteristic analyses were performed to calculate the best cutoff values of serum folate, and the associations between serum folate levels and clinicopathological features were further analyzed by multivariate regression analysis. Survival analyses were conducted using the Cox proportional hazards model.RESULTS: The mean serum folate level was significantly lower in gastric cancer patients than that in controls(3.71 ± 0.30 ng/mL vs 8.00 ± 0.54 ng/mL, P < 0.01), and folate levels were consistently lower in gastric cancer patients regardless of age and gender(all P < 0.01). Using the median serum folate value as the cutoff value, low serum folate was significantly associated with gastric cancer risk in the whole population(OR = 19.77, 95%CI: 10.54-37.06, P < 0.001) and all strata(age < 60 years OR = 17.39, 95%CI: 7.28-41.54, age ≥ 60 years(OR = 21.67, 95%CI: 8.27-56.80), males(OR = 17.95, 95%CI: 7.93-40.62), and females(OR = 20.95, 95%CI: 7.66-57.31); all P < 0.001. In the patient cohort of gastric cancer, the respective cutoff values showed that low serum folate levels were significantly associated with serosal invasion(OR = 2.54, 95%CI: 1.23-5.23), lymphatic invasion(OR = 2.23, 95%CI: 1.17-4.26), and liver metastasis(OR =6.67, 95%CI: 1.28-34.91) of gastric cancer(all P < 0.05). Serum folate level below 1.90 ng/mL was associated with poor patient survival(HR = 1.84, 95%CI: 1.04-3.27, P < 0.05) in univariate analysis.CONCLUSION: Lower serum folate levels were significantly associated with gastric cancer development and invasive phenotypes. The role of folate depletion in gastric cancer invasion warrants further study.

Inductive heat property of Fe_3O_4 nanoparticles in AC magnetic field for local hyperthermia

Magnetite (Fe3O4) nanoparticles with different magnetic properties were prepared by coprecipitation of Fe3+ and Fe2+ with aqueous NaOH solution. The inductive heat properties of Fe3O4 nanoparticles in an alternating current (AC) magnetic field were investigated for local hyperthermia. The maximum saturation magnetization Ms of Fe3O4 nanoparticles is 65.53 emu·g-1 under the optimum conditions of Fe3+: Fe2+ molar ratio at 1.8:1. The Ms of Fe3O4 nanoparticles decreased as the Fe3+/Fe2+ molar ratio increased. But the coercivity Hc increases with the increasing of Fe3+/Fe2+ molar ratio. Exposed in the AC magnetic field for 29 min, the temperatures of physiological saline suspension containing Fe3O4 nanoparticles were 42-97.5 ℃. The inductive heat property of Fe3O4 nanoparticles in AC magnetic field decreases as Hc increases, but increases with the increasing of Ms. The Fe3O4 nanoparticles would be useful as good thermoseeds for localized hyperthermia treatment of cancers.

Development of a Derivatization-free GC-FID Method for Evaluation of Free Fatty Acid Levels in Plasma of Diabetic Nephropathy Patients

Metabolism of free fatty acids（FFAs） is related to several important physiological events and therefore their quantitaion in biological samples arouses extensive interest and efforts.Existing gas chromatography with flame ionization detector（GC-FID） methods for the analysis of FFAs normally require derivatization of them in order to lower boiling points.But this extra procedure tends to induce additional error and it is laborious and time-consuming.A derivatization-free method was therefore established in the present investigation to determine FFAs in human plasma by capillary（GC-FID）.After extraction of FFAs from plasma,a highly polar FFAP（free fatty acid in plasma） column was employed to directly quantitate FFAs concentration,free from derivatization reaction.All sample pretreatments were carried out at room temperature,improving recovery of short-chain FFAs.Heptadecanoic acid（C17：0） was employed as internal standard,and the proposed method was validated for recovery,precision,sensitivity,stabi-lity,and linearity.Validation data show that it is suitable for clinical study that has been applied to the evaluation of FFAs levels in plasma of diabetic nephropathy（DN） patients during the course of treatment.Forty-seven patients diagnosed with DN were admitted to the double-blind experiment.Control group（n=17） underwent solely basic treatment and the patients did not show significant change in FFAs concentration during six months of treatment.Experiment group（n=30） was supplied with traditional Chinese medicine besides basic treatment.After six months of medication,their plasma concentration of palmitic acid（C16：0）,stearic acid（C18：0） and oleic acid（C18：1n-9） decreased while linolenic acid（C18：3n-3） increased significantly（P〈0.05）.These four compounds could be served as biomar-kers in the evaluation of drug efficacy,and their quantitation in plasma may provide additional information for disease progression in DN patients.

Prediction of early-stage hepatocellular carcinoma using Onco Scan chromosomal copy number aberration data

AIM To identify chromosomal copy number aberrations(CNAs) in early-stage hepatocellular carcinoma(HCC) and analyze whether they are correlated with patient prognosis.METHODS One hundred and twenty patients with early-stage HCC were enrolled in our study, with the collection of formalin fixed, paraffin-embedded(FFPE) specimens and clinicopathological data. Tumor areas were marked by certified pathologists on a hematoxylin and eosinstained slide, and cancer and adjacent non-cancerous tissues underwent extraction of DNA, which was analyzed with the Affymetrix Onco Scan platform to assess CNAs and loss of heterozygosity(LOH). Ten individuals with nonmalignant disease were used as the control group. Another cohort consisting of 40 patients with stage Ⅰ/Ⅱ HCC were enrolled to analyze gene expression and to correlate findings with the Onco Scan data.RESULTS Copy number amplifications occurred at chromosomes 1 q21.1-q44 and 8 q12.3-24.3 and deletions were found at 4 q13.1-q35.2, 8 p 23.2-21.1, 16 q23.3-24.3, and 17 p13.3-12, while LOH commonly occurred at 1 p32.3, 3 p21.31, 8 p23.2-21.1, 16 q22.1-24.3, and 17 p 13.3-11 in early-stage HCC. Using Cox regression analysis, we also found that a higher percentage of genome change(≥ 60%) was an independent factor for worse prognosis in early-stage HCC(P = 0.031). Among the 875 genes in the Onco Scan Gene Chip, six were independent predictors of worse disease-free survival, of which three were amplified(MYC, ELAC2, and SYK) and three were deleted(GAK, MECOM, and WRN). Further, patients with HCC who exhibited ≥ 3 CNAs involving these six genes have worse outcomes compared to those who had < 3 CNAs(P < 0.001). Similarly, Asian patients with stage I HCC from The Cancer Genome Atlas harboring CNAs with these genes were also predicted to have poorer outcomes.CONCLUSION Patients with early-stage HCC and increased genome change or CNAs involving MYC, ELAC2, SYK, GAK, MECOM, or WRN are at risk for poorer outcome after resection.

Effect of p27mt gene on apoptosis of the colorectal cancer cell line Lovo

AIM:To construct p27mt recombinant adenovirus,transfect the colorectal cell line Lovo and observe the effects of p27mt on Lovo cell apoptosis and cell cycle inhibition.METHODS:We constructed recombinant adenovirus containing p27mt by homologous recombination in bacteria.The colorectal cancer cell line Lovo was infected with recombinant replication-defective adenovirus Ad-p27mt,and expression of p27mt was determined by Western blotting;the inhibitory effect of p27mt on Lovo cells was detected by cytometry.Cell cycle was determined by flow cytometry.DNA fragment analysis identif ied the occurrence of apoptosis.RESULTS:The recombinant adenovirus which already contained p27mt target gene was successfully constructed.When multiplicity of infection was ≥ 50,the infection efficiency was 100%.After transfection of Lovo cells with Ad-p27mt the cells had high p27 expression which was identified by immunoblotting assay.PI staining and ? ow cytometry showed that 77.96% of colorectal cancer cells were inhibited in phase G0/G1,while in the Ad-LacZ group and blank control group,27.57% and 25.29% cells were inhibited in the same phase,respectively.DNA fragment analysis,flow cytometry and TUNEL assay demonstrated that p27mt is able to induce apoptosis in colorectal cancer cells.CONCLUSION:p27mt has an obvious blocking effect on colorectal cancer cell cycle,and most cells were inhibited in phase G0/G1.Therefore,p27mt can induce apoptosis in colorectal cells.

Genetic association of rs7754840 and rs7756992 polymorphisms in the CDKAL1 gene and gestational diabetes mellitus in selected Filipino pregnant women

Objective:To investigate the possible association between rs7754840 and rs7756992 polymorphisms of CDKAL1 gene and susceptibility to gestational diabetes mellitus(GDM)in a Filipino pregnant population.Methods:A total of 101 patients with GDM and 99 women without GDM were included.Two CDKAL1 gene single nucleotide polymorphisms(SNPs),namely rs7754840 and rs7756992,were genotyped by using TaqMan allelic discrimination assays.Mann-Whitney U test,median and interquartile range were used to describe physical and biochemical characteristics.The differences in the genotype and allele distribution of the target genetic variants among the two groups of participants were assessed by using Chi-square test.Conformity to Hardy-Weinberg equilibrium was tested prior to conducting further analysis.Multiple logistic regression model was used to investigate the effects of the genotype models on GDM development.Results:There was no observed correlation between the genotypes of the rs7754840 SNP and oral glucose tolerance test parameters.Consequently,there was no significant association between genetic models of the rs7754840 SNP and GDM risk(additive OR 1.43,95%CI 0.82-2.50,P=0.21;dominant OR 1.21,95%CI 0.57-2.59,P=0.62;recessive OR 1.63,95%CI 0.86-3.09,P=0.13).Conclusions:The results of this study suggest no association between CDKAL1 gene variant rs7754840 and GDM development in Filipino pregnant women.Further studies with a larger population should be performed to validate our findings.

Exogenous BDNF and Chondroitinase ABC Consisted Biomimetic Microenvironment Regulates Survival,Migration and Differentiation of Human Neural Progenitor Cells Transplanted into a Rat Auditory Nerve

Current putative regeneration oriented studies express possible role of stem cell based implantation strategy in the restoration of fundamental perception of hearing. The present work utilizes a rat auditory nerve (AN) directed transplantation of human neural progenitor cells (HNPCs) as a cell replacement therapy for impaired auditory function. Groups of b-bungarotoxin induced auditory function compromised female rats were used to transplant HNPCs in the nerve trunk. In the treatment groups, brain derived neurotrophic factor (BDNF), peptide amphiphile nanofiber bioactive gel (Bgel) and Chondroitinase ABC (ChABC), a digestive enzyme that cleaves the core of chondroitin sulphate proteoglycans, were added along with HNPCs while the control groups were with PA inert gel (Igel) and devoid of ChABC. Six weeks post transplantation survival, migration, and differentiation of HNPCs were studied and compared. The groups treated with BDNF and Bgel showed improved survival and differentiation of transplanted HNPCs while the ChABC treated group showed significant migration of HNPCs along the AN and elongation of neuronal fibers along the nerve towards the cochlear nucleus (CN) which was characterized by immunocytochemical markers for human Nuclei (HuN), human mitochondria (HuM) and neuronal β-tubulin (Tuj1). These findings show that addition of BDNF and ChABC consisted Bgel environment facilitated HNPC survival, migration and differentiation along the transplanted rat AN towards the CN. This transplantation strategy provides unique experimental validation for futuristic role of cell based biomaterial consisted neurotrophic factor application in clinically transferable treatment of sensorineural hearing loss (SNHL) along with cochlear implants (CI).

Possible role of sialylation of retinal protein glycans in the regulation of electroretinogram response in mice

AIM： To evaluate if the nature, degree and extent of Siaa2-3-/Siaa2-6-sialylation of retinal protein glycans plays a possible role in the development and regulation of electroretinogram response （ERG） in mice. METHODS： Proteins extracted, from retinae of postnatal day 2 （PN2）, PN7, and PN14 wild type （wt） and retinal degeneration 1 （rdl） mice were quantified, labeled and used for lectin-microarray profiling with immobilized lectins which recognize a wide range of N-/O-glycans. Net fluorescence intensities of lectin-ligand complexes were measured and images of fluorescent lectin-microarrays were acquired. From the binding curves between each lectin and protein extracts from PN14 wt and PN14 rdl mice retinae, the protein concentration was selected to determine optimum signal intensity for lectin-ligand binding. Mean_＋SEM values of proteins and fluorescence- intensities of lectin-ligand-complexes between 45 lectins and 36 protein extracts from wt and rdl mice retinae were compared for significance of differences. RESULTS： Comparison of the progressive relative changes in the sialylated glycans of retinal proteins from wt and rdl mice showed that Siao2-3Gall-4GIcNAc-glycans （but not Siaa2-6-glycans） were detectable and quantifiable from the retinal-proteins of PN7 and PN14 wt and rdl mice. Siaa2- 3-sialylation of retinal-protein Gal/o-linked-Gal-glycans was significantly increased with age in PN7 and PN14 wt and less so in PN14 rdl mice. Siao2-3-/Siaa2-6-sialylation of retinal-protein Gal/a-linked-Gal-glycans was absent in PN2 wt and rdl mice. Comparison of published ERG responses of wt and rdl mice retinae with degree of Siaa2- 3-sialylation of retinal-protein-glycans showed that PN2 wt and rdl mice lack both the ERG response and Siaa2- 3-/Siao2-6-sialylation of retinal-protein Gal/a-linked-Gal-glycans; rdl mice with relatively lower Siaa2-3-sialylation of retinal-protein Gal/a-linked-Gal-glycans showed aberrant ERG response; and wt mice with significantly higher Siaa2-3-sialylation of retinal-protein Gal/a-linked- Gal-glycans showed normal ERG response. CONCLUSION： Degree of Siaa2-3-sialylation of giycans possibly regulates ERG function in mice.

Increased mortality in elderly heart failure patients receiving infusion of furosemide compared to elderly heart failure patients receiving bolus injection

Heart failure(HF)is a condition of cardiac dysfunction and fluid overload.Neurohormonal activation via the reninangiotensin-aldosterone system and the sympathetic nervous system are the pathophysiological cornerstones.[1]Furthermore,HF is a disorder widely associated with grave adverse outcomes and poor prognosis.[2]A loop diuretic is the fundamental drug used to prevent multiorgan failure and improve symptoms in these patients.[3]