Positron emission tomography measures the activity of radioactively labeled compounds which distribute and accumulate in central nervous system regions in proportion to their metabolic rate or blood flow. Specific cir...Positron emission tomography measures the activity of radioactively labeled compounds which distribute and accumulate in central nervous system regions in proportion to their metabolic rate or blood flow. Specific circuits such as the dopaminergic nigrostriatal projection can be studied with ligands that bind to the pre-synaptic dopamine transporter or post-synaptic dopamine receptors(D1 and D2). Single photon emission computerized tomography(SPECT) measures the activity of similar tracers labeled with heavy radioactive species such as technetium and iodine. In essential tremor, there is cerebellar hypermetabolism and abnormal GABAergic function in premotor cortices, dentate nuclei and ventral thalami, without significant abnormalities in dopaminergic transmission. In Huntington's disease, there is hypometabolism in the striatum, frontal and temporal cortices. Disease progression is accompanied by reduction in striatal D1 and D2 binding that correlates with trinucleotide repeat length, disease duration and severity. In dystonia, there is hypermetabolism in the basal ganglia, supplementary motor areas and cerebellum at rest. Thalamic and cerebellar hypermetabolism is seen during dystonic movements, which can be modulated by globus pallidus deep brain stimulation(DBS). Additionally, GABA-A receptor activity is reduced in motor, premotor and somatosensory cortices. In Tourette's syndrome, there is hypermetabolism in premotor and sensorimotor cortices, as well as hypometabolism in the striatum, thalamus and limbic regions at rest. During tics, multiple areas related to cognitive, sensory and motor functions become hypermetabolic. Also, there is abnormal serotoninergic transmission in prefrontal cortices and bilateral thalami, as well as hyperactivity in the striatal dopaminergic system which can be modulated with thalamic DBS. In Parkinson's disease(PD), there is asymmetric progressive decline in striatal dopaminergic tracer accumulation, which follows a caudal-to-rostral direction. Uptake declines prior to symptom presentation and progresses from contralateral to the most symptomatic side to bilateral, correlating with symptom severity. In progressive supranuclear palsy(PSP) and multiple system atrophy(MSA), striatal activity is symmetrically and diffusely decreased. The caudal-to-rostral pattern is lost in PSP, but could be present in MSA. In corticobasal degeneration(CBD), there is asymmetric, diffuse reduction of striatal activity, contralateral to the most symptomatic side. Additionally, there is hypometabolism in contralateral parietooccipital and frontal cortices in PD; bilateral putamen and cerebellum in MSA; caudate, thalamus, midbrain, mesial frontal and prefrontal cortices in PSP; and contralateral cortices in CBD. Finally, cardiac sympathetic SPECT signal is decreased in PD. The capacity of molecular imaging to provide in vivo time courses of gene expression, protein synthesis, receptor and transporter binding, could facilitate the development and evaluation of novel medical, surgical and genetic therapies in movement disorders.展开更多
Recent cancer research has demonstrated the existence of circulating tumor cells(CTCs)in cancer patient’s blood.Once identified,CTC biomarkers will be invaluable tools for clinical diagnosis,prognosis and treatment.I...Recent cancer research has demonstrated the existence of circulating tumor cells(CTCs)in cancer patient’s blood.Once identified,CTC biomarkers will be invaluable tools for clinical diagnosis,prognosis and treatment.In this review,we propose ex vivo culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample,to derive enough CTCs for accurate and reproducible characterization of the biophysical,biochemical,gene expressional and behavioral properties of the harvested cells.Because of tumor cell heterogeneity,it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer metastasis.By analyzing critical steps and technical issues in ex vivo CTC culture,we developed a cost-effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells,relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells.展开更多
Various single or multi-modality therapeutic options are available to treat pain of bone metastasis in patients with prostate cancer.Different radionuclides that emitβ-rays such as 153Samarium and 89Strontium and ach...Various single or multi-modality therapeutic options are available to treat pain of bone metastasis in patients with prostate cancer.Different radionuclides that emitβ-rays such as 153Samarium and 89Strontium and achieve palliation are commercially available.In contrast toβ-emitters,223Radium as a a-emitter has a short path-length.The advantage of the a-emitter is thus a highly localized biological effect that is caused by radiation induced DNA double-strand breaks and subsequent cell killing and/or limited effectiveness of cellular repair mechanisms.Due to the limited range of the a-particles the bone surface to red bone marrow dose ratio is also lower for 223Radium which is expressed in a lower myelotoxicity.The a emitter 223Radium dichloride is the first radiopharmaceutical that significantly prolongslife in castrate resistant prostate cancer patients with wide-spread bone metastatic disease.In a phaseⅢ,randomized,double-blind,placebo-controlled study 921patients with castration-resistant prostate cancer and bone metastases were randomly assigned.The analysis confirmed the 223Radium survival benefit compared to the placebo(median,14.9 mo vs 11.3 mo;P<0.001).In addition,the treatment results in pain palliation and thus,improved quality of life and a delay of skeletal related events.At the same time the toxicity profile of223Radium was favourable.Since May 2013,223Radium dichloride(Xofigo?)is approved by the US Food and Drug Administration.展开更多
Age and gender are the important factors for brain metabolic declines in both normal aging and neurodegeneration,and the confounding effects may influence early and differential diagnosis of neurodegenerative diseases...Age and gender are the important factors for brain metabolic declines in both normal aging and neurodegeneration,and the confounding effects may influence early and differential diagnosis of neurodegenerative diseases based on the[^(18)F]fluorodeoxyglucose positron emission tomography([^(18)F]FDG PET).We aimed to explore the potential of the adjustment of age-and gender-related confounding factors on[^(18)F]FDG PET images in differentiation of Parkinson’s disease(PD),multiple system atrophy(MSA)and progressive supra-nuclear palsy(PSP).Eight hundred and seventy-seven clinically definitely diagnosed Parkinsonian patients from a benchmark Huashan Parkinsonian PET imaging database were included.An age-and gender-adjusted Z(AGAZ)score was established based on the gender-specific longitudinal metabolic changes on healthy subjects.AGAZ scores and standardized uptake value ratio(SUVR)values were quantified at regional-level and support vector machine-based error-correcting output codes method was applied for classification.Additional references of the classifications based on metabolic pattern scores were included.The feature-based AGAZ score showed the best performance in classification(accuracy for PD,MSA,PSP:93.1%,96.3%,94.8%).In both genders,the AGAZ score con-sistently achieved the best efficiency,and the improvements compared to the conventional SUVR value for PD,MSA,and PSP mainly laid in specificity(Male:5.7%;Female:11.1%),sensitivity(Male:7.2%;Female:7.3%),and sensitivity(Male:7.3%;Female:17.2%).Female patients benefited more from the adjustment on[^(18)F]FDG PET in MSA and PSP groups(absolute net reclassification index,p<0.001).Collectively,the adjustment of age-and gender-related confounding factors may improve the differential diagnosis of Parkinsonism.Particularly,the diagnosis of female Parkinsonian population has the best improvement from this correction.展开更多
Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and mortality of prostate cancer increase dramatically in several oriental countries including China. Rapidly evolving tech...Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and mortality of prostate cancer increase dramatically in several oriental countries including China. Rapidly evolving technology in molecular biology such as high-throughput sequencing and integrative analysis of genomic and transcriptomic landscapes have enabled the identification of key oncogenic events for prostate cancer initiation, progression and resistance to hormonal therapy. These surging data of prostate cancer genome also provide insights on ethnic variation and the differences in histological subtype of this disease. In this review, differences in the incidence of prostate cancer and the prevalence of main genetic alterations between Asian and Western populations are discussed. We also review the recent findings on the mechanisms underlying neuroendocrine differentiation of prostate cancer and the development of small cell neuroendocrine carcinoma after androgen deprivation therapy.展开更多
To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide(NBP),we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids(S1-S8).These hybrids inhibited adenosin...To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide(NBP),we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids(S1-S8).These hybrids inhibited adenosine diphosphate(ADP)-or arachidonic acid(AA)-induced platelet aggregation,among them,S2 was 30-fold more water-soluble,and over 10-fold more potent in inhibition of platelet aggregation,as well as reduced ROS generation and protected primary neuronal cells from OGD/Rinduced damage,in comparison with NB P.Additionally,S2 was more active than its three moieties alone or in combination,suggesting that the activity of S2 may be attributed to the synergistic effects of these moieties.Importantly,in vivo studies indicated that S2 not only possessed good pharmacokinetic profile,but also improved NBP distribution in rodent brain,suggesting that the glucose moiety in S2 may be recognized by glucose transporter 1(GLUT1)on blood-brain barrier(BBB),promoting it to penetrate through BBB.Our findings suggest that S2 may be a promising candidate for the intervention of ischemic stroke,warranting further study.展开更多
The incidence of prostate cancer(PCa)within Asian population used to be much lower than in the Western population;however,in recent years the incidence and mortality rate of PCa in some Asian countries have grown rapi...The incidence of prostate cancer(PCa)within Asian population used to be much lower than in the Western population;however,in recent years the incidence and mortality rate of PCa in some Asian countries have grown rapidly.This collaborative report summarized the latest epidemiology information,risk factors,and racial differences in PCa diagnosis,current status and new trends in surgery management and novel agents for castration-resistant prostate cancer.We believe such information would be helpful in clinical decision making for urologists and oncologists,health-care ministries and medical researchers.展开更多
Background:Increased hypoxia-inducible factor 2α(HIF2α)activation is a common event in clear cell renal cell carcinoma(ccRCC)progression.However,the function and underlying mechanism of HIF2α in ccRCC remains uninv...Background:Increased hypoxia-inducible factor 2α(HIF2α)activation is a common event in clear cell renal cell carcinoma(ccRCC)progression.However,the function and underlying mechanism of HIF2α in ccRCC remains uninvestigated.We conducted this study to access the potential link between junction plakoglobin(JUP)and HIF2αin ccRCC.Methods:Affinity purification and mass spectrometry(AP-MS)screening,glutathione-s-transferase(GST)pull-down and co-immunoprecipitation(Co-IP)assays were performed to detect the interacting proteins of HIF2α.Quantitative PCR(qPCR)and Western blotting were used to detect the expression of JUP in human ccRCC samples.Luciferase reporter assays,chromatin immunoprecipitation(ChIP),cycloheximide chase assays,and ubiquitination assays were conducted to explore the regulation of JUP on the activity of HIF2α.Cell Counting Kit-8(CCK-8)assays,colony formation assays,transwell assays,and xenograft tumor assays were performed to investigate the effect of JUP knockdown or overexpression on the tumorigenicity of renal cancer cells.Results:We identified JUP as a novel HIF2α-binding partner and revealed an important role of JUP in recruiting von Hippel-Lindau(VHL)and histone deacetylases 1/2(HDAC1/2)to HIF2α to regulate its stability and transactivation.JUP knockdown promoted and overexpression suppressed the tumorigenicity of renal cell carcinoma in vitro and in vivo.Importantly,the low expression of JUP was found in clinical ccRCC samples and correlated with enhanced hypoxia scores and poor treatment outcomes.Conclusion:Taken together,these data support a role of JUP in modulating HIF2α signaling during ccRCC progression and identify JUP as a potential therapeutic target.展开更多
OBJECTIVES:We sought to evaluate effects of obesity, insulin resistance, and inflammation on coronary circulatory function and its relationship to leptin plasma levels. BACKGROUND: It is not known whether obesity, com...OBJECTIVES:We sought to evaluate effects of obesity, insulin resistance, and inflammation on coronary circulatory function and its relationship to leptin plasma levels. BACKGROUND: It is not known whether obesity, commonly paralleled by insulin resistance, inflammation, and leptin, is independently associated with coronary circulatory dysfunction. METHODS: Myocardial blood flow(MBF) responses to cold pressor test(CPT) and pharmacologic vasodilation was measured with positron emission tomography and 13N-ammonia. Study participants were divided into three groups based on their body mass index(BMI, kg/m2): control, 20 ≤ BMI<25(n=19); overweight, 25 ≤ BMI<30(n=21); and obese, BMI >30(n=32). RESULTS: Body mass index was significantly correlated to the Homeostasis Model Assessment Index of insulin resistance and C-reactive protein levels(r=0.60 and r=0.47, p< 0.0001). Compared with control subjects, endothelium related change in MBF(Δ MBF) to CPT progressively declined in overweight and obese groups(0.32± 0.09 vs. 0.21± 0.19 and 0.07± 0.16 ml/g/min; p< 0.03 and p< 0.0001). The dipyridamole-in- duced total vasodilator capacity was significantly lower in obese than in control subjects(1.77± 0.51 vs. 2.04± 0.37 ml/g/min, p< 0.02). On multivariate analysis, BMI(p< 0.012) and age(p< 0.035) were significant independent predictors of Δ MBF. Finally, only in the obese group leptin plasma levels significantly correlated with Δ MBF(r=0.37, p< 0.036). CONCLUSIONS: Increased body weight is independently associated with abnormal coronary circulatory function that progresses from an impairment in endothelium related coronary vasomotion in overweight individuals to an impairment of the total vasodilator capacity in obese individuals. The findings that elevated leptin plasma levels in patients that are obese might exert beneficial effects on the coronary endothelium to counterbalance the adverse effects of increases in body weight on coronary circulatory function should be tested.展开更多
Local cerebral metabolic rate of glucose(LCMRGlc) is an important index for the description of neural function.Dynamic 18 F-fluoro-2-deoxy-D-glucose(FDG) positron emission tomography(PET) has been used for quantitativ...Local cerebral metabolic rate of glucose(LCMRGlc) is an important index for the description of neural function.Dynamic 18 F-fluoro-2-deoxy-D-glucose(FDG) positron emission tomography(PET) has been used for quantitative imaging of LCMRGlc in humans,but is seldom used routinely because of the difficulty in obtaining the input function noninvasively.A reference tissue-based Patlak plot model(rPatlak) was proposed to generate parametric images of LCMRGlc in a quantitative dynamic FDG-PET study without requiring blood sampling.Dynamic emission scans(4×0.5,4×2 and 10×5 min) were acquired simultaneously with an IV bolus injection of 155 MBq of FDG.Arterial blood samples were collected during the scans via a catheter placed in the radial artery.Simulation data were also generated using the same scan sequence.The last ten scan data sets were used in a graphical analysis using the Patlak plot.The ratio of LCMRGlc estimated from the original Patlak(oPatlak,using plasma input) was used as the gold standard,and the standardized uptake value ratio(SUVR) was also calculated for comparison.Eight different tissues including white matter,gray matter,and whole brain were chosen as reference tissues for evaluation.Regardless of the reference region used,the slopes in the linear regression between oPatlak and rPatlak were closer to unity than the regression slopes between oPatlak and SUVR.The intercepts for the former were also closer to 0 than those for the latter case.The squared correlation coefficients were close to 1.0 for both cases.This showed that the results of rPatlak were in good agreement with those of oPatlak,however,SUVR exhibited more deviation.The simulation study also showed that the relative variance and bias for rPatlak were less than those for SUVR.The images obtained with rPatlak were very similar to those obtained with oPatlak,while there were differences in the relative spatial distribution between the images of SUVR and oPatlak.This study validates that the rPatlak method is better than the SUVR method and is a good approximation to the oPatlak method.The new method is suitable for generating LCMRGlc parametric images noninvasively.展开更多
Abnormal coronary endothelial reactivity has been demonstrated in diabetes and is associated with an increased rate of cardiovascular events. Our objectives were to investigate the presence of functional coronary circ...Abnormal coronary endothelial reactivity has been demonstrated in diabetes and is associated with an increased rate of cardiovascular events. Our objectives were to investigate the presence of functional coronary circulatory abnormalities over the full spectrum of insulin resistance and to determine whether these would differ in severity with more advanced states of insulin resistance. Methods and Results-Myocardial blood flow(MBF) was measured with positron emission tomography and 13N-ammonia to characterize coronary circulatory function in states of insulin resistance without carbohydrate intolerance(IR), impaired glucose tolerance(IGT), and normotensive and hypertensive type 2 diabetes mellitus(DM) compared with insulin-sensitive(IS) individuals. Indices of coronary function were total vasodilator capacity(mostly vascular smooth muscle-mediated) during pharmacological vasodilation and the nitric oxide-mediated, endothelium-dependent vasomotion in response to cold pressor testing. Total vasodilator capacity was similar in normoglycemic individuals(IS, IR, and IGT), whereas it was significantly decreased in normotensive(- 17% ) and hypertensive(- 34% )DM patients. Compared with IS, endothelium- dependent coronary vasomotion was significantly diminished in IR(- 56% ), as well as in IGT and normotensive and hypertensive diabetic patients(- 85% ,- 91% , and- 120% , respectively). Conclusions-Progressively worsening functional coronary circulatory abnormalities of nitric oxide-mediated, endothelium-dependent vasomotion occur with increasing severity of insulin-resistance and carbohydrate intolerance. Attenuated total vasodilator capacity accompanies the more clinically evident metabolic abnormalities in diabetes.展开更多
Plastics such as polyvinyl chlorides(PVC) are widely used in many indoor constructed environments; however, their unbound chemicals, such as di-(2-ethylhexyl) phthalates(DEHP), can leach into the surrounding environme...Plastics such as polyvinyl chlorides(PVC) are widely used in many indoor constructed environments; however, their unbound chemicals, such as di-(2-ethylhexyl) phthalates(DEHP), can leach into the surrounding environment. This study focused on DEHP's effect on the central nervous system by determining the precise DEHP content in mice brain tissue after exposure to the chemical, to evaluate the specific exposure range. Primary neuronal-astrocyte co-culture systems were used as in vitro models for chemical hazard identification of DEHP. Oxidative stress was hypothesized as a probable mechanism involved, and therefore the total reactive oxygen species(ROS) concentration was determined as a biomarker of oxidative stress. In addition, NeuriteTracer, a neurite tracing plugin with ImageJ, was used to develop an assay for neurotoxicity to provide quantitative measurements of neurological parameters, such as neuronal number, neuron count and neurite length, all of which could indicate neurotoxic effects. The results showed that with 1 nmol/L DEHP exposure, there was a significant increase in ROS concentrations, indicating that the neuronal-astrocyte cultures were injured due to exposure to DEHP. In response, astrocyte proliferation(gliosis) was initiated, serving as a mechanism to maintain a homeostatic environment for neurons and protect neurons from toxic chemicals. There is a need to assess the cumulative effects of DEHP in animals to evaluate the possible uptake and effects on the human neuronal system from exposure to DEHP in the indoor environment.展开更多
Cholesterol is a critical lipid for all mammalian cells,ensuring proper membrane integrity,fluidity,and biochemical function.Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their chol...Cholesterol is a critical lipid for all mammalian cells,ensuring proper membrane integrity,fluidity,and biochemical function.Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their cholesterol metabolism in response to activation signals to support host defense processes.However,our understanding of the molecular details underlying how and why cholesterol homeostasis is specifically reshaped during immune responses remains less well understood.This review discusses our current knowledge of cellular cholesterol homeostatic machinery and introduces emerging concepts regarding how plasma membrane cholesterol is partitioned into distinct pools.We then discuss how proinflammatory signals can markedly reshape the cholesterol metabolism of macrophages,with a focus on the differences between MyD88-dependent pattern recognition receptors and the interferon signaling pathway.We also discuss recent work investigating the capacity of these proinflammatory signals to selectively reshape plasma membrane cholesterol homeostasis.We examine how these changes in plasma membrane cholesterol metabolism influence sensitivity to a set of microbial pore-forming toxins known as cholesterol-dependent cytolysins that specifically target cholesterol for their effector functions.We also discuss whether lipid metabolic reprogramming can be leveraged for therapy to mitigate tissue damage mediated by cholesterol-dependent cytolysins in necrotizing fasciitis and other related infections.We expect that advancing our understanding of the crosstalk between metabolism and innate immunity will help explain how inflammation underlies metabolic diseases and highlight pathways that could be targeted to normalize metabolic homeostasis in disease states.展开更多
Cancer of the urological system commonly occurs in the kidney,bladder,and prostate gland.The clear cell subtype of renal cell carcinoma(ccRCC)constitutes the great majority of kidney cancer.Metastatic ccRCC portends a...Cancer of the urological system commonly occurs in the kidney,bladder,and prostate gland.The clear cell subtype of renal cell carcinoma(ccRCC)constitutes the great majority of kidney cancer.Metastatic ccRCC portends a very poor outcome with no effective treatment available.Prostate cancer is the most common cancer in males in the US.Despite recent advances in selective kinase inhibitors and immunotherapies,the rate of developing new treatment from bench to bedside is slow.A time-consuming step is at the animal drug testing stage,in which the mouse model is the gold standard.In the pursuit to streamline the in vivo cancer biology research and drug development,we explored the feasibility of the chicken chorioallantoic membrane(CAM)model to establish xenografts.The CAM model greatly shortens the time of tumor growth and lowers the cost comparing to immunocompromised mice.We generated CAM xenografts from ccRCC,bladder and prostate cancer,with established cancer cell lines and freshly isolated patient-derived tissues,either as primary tumor cells or small pieces of tumors.The successful CAM engraftment rate from the different tumor sources is 70%or above.Using our previously established metastatic ccRCC mouse model,we showed that the CAM xenograft maintains the same tumor growth pattern and metastatic behavior as observed in mice.Taken together,CAM can serve as a valuable platform to establish new patient-derived xenografts(PDXs)to study tumor biology,thus accelerating the development of individualized treatment to halt the deadly metastatic stage of cancer.展开更多
Hepatocellular carcinoma(HCC)is among the leading causes of cancer incidence and mortality worldwide.Surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essenti...Hepatocellular carcinoma(HCC)is among the leading causes of cancer incidence and mortality worldwide.Surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essential for early detection and improved overall survival.Biannual ultrasonography with or without alpha-fetoprotein is widely recommended as the standard method for HCC surveillance,but it has limited sensitivity in early disease and may be inadequate in certain individuals.This review article will provide a comprehensive overview of the current landscape of HCC surveillance,including the rationale and indications for HCC surveillance,standard methods for HCC surveillance,and their strengths/limitations.Alternative surveillance methods such as the role of cross-sectional imaging,emerging circulating biomarkers,as well as the problem of under-utilization of HCC surveillance and surveillance-related harms will also be discussed in this review.展开更多
Objective::In contrast to the most commonly reported forms of maturity-onset diabetes of the young(MODY),including MODY2,MODY3 and MODY5,MODY6 is a relatively rare subtype.To investigate whether NEUROD1 is responsible...Objective::In contrast to the most commonly reported forms of maturity-onset diabetes of the young(MODY),including MODY2,MODY3 and MODY5,MODY6 is a relatively rare subtype.To investigate whether NEUROD1 is responsible for MODY in Chinese individuals,we screened its mutations in MODY pedigrees and explored the potential pathogenic mechanisms.Methods::Polymerase chain reaction direct sequencing was performed to screen NEUROD1 mutations in 32 Chinese MODY probands who were negative for the GCK/MODY2,HNF1A/MODY3 and HNF1B/MODY5 genes in this observational study.In addition,we enrolled 201 unrelated,non-diabetic control subjects of Han Chinese descent.The functional significance of newly identified mutations was analyzed using clinical phenotype,pathophysiology and three-dimensional structure studies.This study was approved by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,China(approval No.YS-2017-83)on March 3,2017.Results::E59Q(c.175 G>C,p.Glu59Gln),a heterozygous missense mutation in the NEUROD1 gene,was identified in one family with MODY.The Glu59 residue in NeuroD1 is highly conserved across mammalian species.Four diabetic patients carrying the mutation(a proband and her son,brother and sister)were lean,with a body mass index of 20.9(20.3-21.2)kg/m 2.Compared with their unaffected relatives(n=4),E59Q carriers(n=4)had significantly decreased ratios of fasting and 2-hour insulin to plasma glucose(both fasting plasma insulin/fasting plasma glucose and 2-hour postprandial plasma insulin/2-hour postprandial plasma glucose,P<0.005).The proband’s father had an E59Q mutation and normal glucose tolerance,which suggested non-penetrance.The E59Q mutation was not detected in other probands or in the 201 control subjects with normal glucose tolerance.Two salt-bridge bonds of Glu59 were disrupted at the Q59 mutation site.Conclusion::The NEUROD1-E59Q mutation changed the molecular conformation of the N-terminal in NeuroD1,which may decrease binding of the E59Q mutant to the insulin promoter and insulin gene transcription activity,therefore causing the MODY6 subtype with defective insulin secretion.展开更多
文摘Positron emission tomography measures the activity of radioactively labeled compounds which distribute and accumulate in central nervous system regions in proportion to their metabolic rate or blood flow. Specific circuits such as the dopaminergic nigrostriatal projection can be studied with ligands that bind to the pre-synaptic dopamine transporter or post-synaptic dopamine receptors(D1 and D2). Single photon emission computerized tomography(SPECT) measures the activity of similar tracers labeled with heavy radioactive species such as technetium and iodine. In essential tremor, there is cerebellar hypermetabolism and abnormal GABAergic function in premotor cortices, dentate nuclei and ventral thalami, without significant abnormalities in dopaminergic transmission. In Huntington's disease, there is hypometabolism in the striatum, frontal and temporal cortices. Disease progression is accompanied by reduction in striatal D1 and D2 binding that correlates with trinucleotide repeat length, disease duration and severity. In dystonia, there is hypermetabolism in the basal ganglia, supplementary motor areas and cerebellum at rest. Thalamic and cerebellar hypermetabolism is seen during dystonic movements, which can be modulated by globus pallidus deep brain stimulation(DBS). Additionally, GABA-A receptor activity is reduced in motor, premotor and somatosensory cortices. In Tourette's syndrome, there is hypermetabolism in premotor and sensorimotor cortices, as well as hypometabolism in the striatum, thalamus and limbic regions at rest. During tics, multiple areas related to cognitive, sensory and motor functions become hypermetabolic. Also, there is abnormal serotoninergic transmission in prefrontal cortices and bilateral thalami, as well as hyperactivity in the striatal dopaminergic system which can be modulated with thalamic DBS. In Parkinson's disease(PD), there is asymmetric progressive decline in striatal dopaminergic tracer accumulation, which follows a caudal-to-rostral direction. Uptake declines prior to symptom presentation and progresses from contralateral to the most symptomatic side to bilateral, correlating with symptom severity. In progressive supranuclear palsy(PSP) and multiple system atrophy(MSA), striatal activity is symmetrically and diffusely decreased. The caudal-to-rostral pattern is lost in PSP, but could be present in MSA. In corticobasal degeneration(CBD), there is asymmetric, diffuse reduction of striatal activity, contralateral to the most symptomatic side. Additionally, there is hypometabolism in contralateral parietooccipital and frontal cortices in PD; bilateral putamen and cerebellum in MSA; caudate, thalamus, midbrain, mesial frontal and prefrontal cortices in PSP; and contralateral cortices in CBD. Finally, cardiac sympathetic SPECT signal is decreased in PD. The capacity of molecular imaging to provide in vivo time courses of gene expression, protein synthesis, receptor and transporter binding, could facilitate the development and evaluation of novel medical, surgical and genetic therapies in movement disorders.
基金This work is supported by US NIH/NCI research grant(2PO1CA098912)edars-Sinai Medical Center Board of Governors Cancer Research Chair(LWKC),and US NIH/NCI(UO1CA198900)(HRT/EMP).
文摘Recent cancer research has demonstrated the existence of circulating tumor cells(CTCs)in cancer patient’s blood.Once identified,CTC biomarkers will be invaluable tools for clinical diagnosis,prognosis and treatment.In this review,we propose ex vivo culture as a rational strategy for large scale amplification of the limited numbers of CTCs from a patient sample,to derive enough CTCs for accurate and reproducible characterization of the biophysical,biochemical,gene expressional and behavioral properties of the harvested cells.Because of tumor cell heterogeneity,it is important to amplify all the CTCs in a blood sample for a comprehensive understanding of their role in cancer metastasis.By analyzing critical steps and technical issues in ex vivo CTC culture,we developed a cost-effective and reproducible protocol directly culturing whole peripheral blood mononuclear cells,relying on an assumed survival advantage in CTCs and CTC-like cells over the normal cells to amplify this specified cluster of cancer cells.
文摘Various single or multi-modality therapeutic options are available to treat pain of bone metastasis in patients with prostate cancer.Different radionuclides that emitβ-rays such as 153Samarium and 89Strontium and achieve palliation are commercially available.In contrast toβ-emitters,223Radium as a a-emitter has a short path-length.The advantage of the a-emitter is thus a highly localized biological effect that is caused by radiation induced DNA double-strand breaks and subsequent cell killing and/or limited effectiveness of cellular repair mechanisms.Due to the limited range of the a-particles the bone surface to red bone marrow dose ratio is also lower for 223Radium which is expressed in a lower myelotoxicity.The a emitter 223Radium dichloride is the first radiopharmaceutical that significantly prolongslife in castrate resistant prostate cancer patients with wide-spread bone metastatic disease.In a phaseⅢ,randomized,double-blind,placebo-controlled study 921patients with castration-resistant prostate cancer and bone metastases were randomly assigned.The analysis confirmed the 223Radium survival benefit compared to the placebo(median,14.9 mo vs 11.3 mo;P<0.001).In addition,the treatment results in pain palliation and thus,improved quality of life and a delay of skeletal related events.At the same time the toxicity profile of223Radium was favourable.Since May 2013,223Radium dichloride(Xofigo?)is approved by the US Food and Drug Administration.
基金supported by National Natural Science Foundation of China(81671239,81361120393,82171252,81701250,81401135,81971641,91949118,81771372,82021002)the Ministry of Science and Technology of China(2016YFC1306504)+5 种基金Shanghai Municipal Science and Technology Major Project(2017SHZDZX01,2018SHZDZX03)ZJ Lab,Shanghai Aging and Maternal and Child Health Research Special Project(2020YJZX0111)Clinical Research Plan of Shanghai Hospital Development Center(SHDC-2020CR1038B),Science and Technology Innovation 2030 Major Projects(2022ZD0211600)Youth Medical Talents-Medical Imaging Practitioner Program by Shanghai Municipal Health Commission and Shanghai Medical and Health Development Foundation(SHWRS(2020)_087)the Swiss National Science Foundation(188350)Jacques&Gloria Gossweiler Foundation and Siemens Healthineers.
文摘Age and gender are the important factors for brain metabolic declines in both normal aging and neurodegeneration,and the confounding effects may influence early and differential diagnosis of neurodegenerative diseases based on the[^(18)F]fluorodeoxyglucose positron emission tomography([^(18)F]FDG PET).We aimed to explore the potential of the adjustment of age-and gender-related confounding factors on[^(18)F]FDG PET images in differentiation of Parkinson’s disease(PD),multiple system atrophy(MSA)and progressive supra-nuclear palsy(PSP).Eight hundred and seventy-seven clinically definitely diagnosed Parkinsonian patients from a benchmark Huashan Parkinsonian PET imaging database were included.An age-and gender-adjusted Z(AGAZ)score was established based on the gender-specific longitudinal metabolic changes on healthy subjects.AGAZ scores and standardized uptake value ratio(SUVR)values were quantified at regional-level and support vector machine-based error-correcting output codes method was applied for classification.Additional references of the classifications based on metabolic pattern scores were included.The feature-based AGAZ score showed the best performance in classification(accuracy for PD,MSA,PSP:93.1%,96.3%,94.8%).In both genders,the AGAZ score con-sistently achieved the best efficiency,and the improvements compared to the conventional SUVR value for PD,MSA,and PSP mainly laid in specificity(Male:5.7%;Female:11.1%),sensitivity(Male:7.2%;Female:7.3%),and sensitivity(Male:7.3%;Female:17.2%).Female patients benefited more from the adjustment on[^(18)F]FDG PET in MSA and PSP groups(absolute net reclassification index,p<0.001).Collectively,the adjustment of age-and gender-related confounding factors may improve the differential diagnosis of Parkinsonism.Particularly,the diagnosis of female Parkinsonian population has the best improvement from this correction.
基金supported by the Prostate Cancer Foundationthe Broad Stem Cell Research Center at University of California, Los Angeles+5 种基金supported by the Department of Defense Prostate Cancer Research Program W81XWH-11-1-0227 (PI: Jiaoti Huang)W81XWH-12-1-0206 (PI: Lily Wu)UCLA SPORE in prostate cancer (PI: Robert Reiter)NCI 1R01CA158627 (PI: Leonard Marks)Stand-up-to-Cancer Dream Team Award (PI: Small and Witte)Prostate Cancer Foundation Honorable A. David Mazzone Special Challenge Award (PI: Robert Reiter)
文摘Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and mortality of prostate cancer increase dramatically in several oriental countries including China. Rapidly evolving technology in molecular biology such as high-throughput sequencing and integrative analysis of genomic and transcriptomic landscapes have enabled the identification of key oncogenic events for prostate cancer initiation, progression and resistance to hormonal therapy. These surging data of prostate cancer genome also provide insights on ethnic variation and the differences in histological subtype of this disease. In this review, differences in the incidence of prostate cancer and the prevalence of main genetic alterations between Asian and Western populations are discussed. We also review the recent findings on the mechanisms underlying neuroendocrine differentiation of prostate cancer and the development of small cell neuroendocrine carcinoma after androgen deprivation therapy.
基金the National Natural Science Foundation of China(Nos.81773573,81822041,21977116 and 81673305)National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(No.2018ZX09711002006-013)+2 种基金the open project of State Key Laboratory of Natural Medicines(No.SKLNMZZCX201824)State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund(No.SKL-HIDCA-2018-1)Part of the work was supported by Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX18_0795)。
文摘To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide(NBP),we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids(S1-S8).These hybrids inhibited adenosine diphosphate(ADP)-or arachidonic acid(AA)-induced platelet aggregation,among them,S2 was 30-fold more water-soluble,and over 10-fold more potent in inhibition of platelet aggregation,as well as reduced ROS generation and protected primary neuronal cells from OGD/Rinduced damage,in comparison with NB P.Additionally,S2 was more active than its three moieties alone or in combination,suggesting that the activity of S2 may be attributed to the synergistic effects of these moieties.Importantly,in vivo studies indicated that S2 not only possessed good pharmacokinetic profile,but also improved NBP distribution in rodent brain,suggesting that the glucose moiety in S2 may be recognized by glucose transporter 1(GLUT1)on blood-brain barrier(BBB),promoting it to penetrate through BBB.Our findings suggest that S2 may be a promising candidate for the intervention of ischemic stroke,warranting further study.
基金supported by the Program for Changjiang Scholars and Innovative Research Team in University scheme of the Ministry of Education of China(NO.IRT1111)the National Basic Research Program of China(2012CB518300)+2 种基金the National Natural Science Foundation of China(81101946)the Shanghai Pujiang Program(12PJD008)Prostate Cancer Foundation Young Investigator Award,Shanghai Municipal Health and Family Planning Commission Outstanding Young Investigator(XYQ2013077).
文摘The incidence of prostate cancer(PCa)within Asian population used to be much lower than in the Western population;however,in recent years the incidence and mortality rate of PCa in some Asian countries have grown rapidly.This collaborative report summarized the latest epidemiology information,risk factors,and racial differences in PCa diagnosis,current status and new trends in surgery management and novel agents for castration-resistant prostate cancer.We believe such information would be helpful in clinical decision making for urologists and oncologists,health-care ministries and medical researchers.
基金supported by National Natural Science Foundation of China(grant number 81772721,81874089,81602236,81702522)Natural Science Foundation of Jiangxi Province of China(20202BABL216060)National Major Scientific and Technological Special Project for“Significant New Drugs Development”(2017ZX09304022).
文摘Background:Increased hypoxia-inducible factor 2α(HIF2α)activation is a common event in clear cell renal cell carcinoma(ccRCC)progression.However,the function and underlying mechanism of HIF2α in ccRCC remains uninvestigated.We conducted this study to access the potential link between junction plakoglobin(JUP)and HIF2αin ccRCC.Methods:Affinity purification and mass spectrometry(AP-MS)screening,glutathione-s-transferase(GST)pull-down and co-immunoprecipitation(Co-IP)assays were performed to detect the interacting proteins of HIF2α.Quantitative PCR(qPCR)and Western blotting were used to detect the expression of JUP in human ccRCC samples.Luciferase reporter assays,chromatin immunoprecipitation(ChIP),cycloheximide chase assays,and ubiquitination assays were conducted to explore the regulation of JUP on the activity of HIF2α.Cell Counting Kit-8(CCK-8)assays,colony formation assays,transwell assays,and xenograft tumor assays were performed to investigate the effect of JUP knockdown or overexpression on the tumorigenicity of renal cancer cells.Results:We identified JUP as a novel HIF2α-binding partner and revealed an important role of JUP in recruiting von Hippel-Lindau(VHL)and histone deacetylases 1/2(HDAC1/2)to HIF2α to regulate its stability and transactivation.JUP knockdown promoted and overexpression suppressed the tumorigenicity of renal cell carcinoma in vitro and in vivo.Importantly,the low expression of JUP was found in clinical ccRCC samples and correlated with enhanced hypoxia scores and poor treatment outcomes.Conclusion:Taken together,these data support a role of JUP in modulating HIF2α signaling during ccRCC progression and identify JUP as a potential therapeutic target.
文摘OBJECTIVES:We sought to evaluate effects of obesity, insulin resistance, and inflammation on coronary circulatory function and its relationship to leptin plasma levels. BACKGROUND: It is not known whether obesity, commonly paralleled by insulin resistance, inflammation, and leptin, is independently associated with coronary circulatory dysfunction. METHODS: Myocardial blood flow(MBF) responses to cold pressor test(CPT) and pharmacologic vasodilation was measured with positron emission tomography and 13N-ammonia. Study participants were divided into three groups based on their body mass index(BMI, kg/m2): control, 20 ≤ BMI<25(n=19); overweight, 25 ≤ BMI<30(n=21); and obese, BMI >30(n=32). RESULTS: Body mass index was significantly correlated to the Homeostasis Model Assessment Index of insulin resistance and C-reactive protein levels(r=0.60 and r=0.47, p< 0.0001). Compared with control subjects, endothelium related change in MBF(Δ MBF) to CPT progressively declined in overweight and obese groups(0.32± 0.09 vs. 0.21± 0.19 and 0.07± 0.16 ml/g/min; p< 0.03 and p< 0.0001). The dipyridamole-in- duced total vasodilator capacity was significantly lower in obese than in control subjects(1.77± 0.51 vs. 2.04± 0.37 ml/g/min, p< 0.02). On multivariate analysis, BMI(p< 0.012) and age(p< 0.035) were significant independent predictors of Δ MBF. Finally, only in the obese group leptin plasma levels significantly correlated with Δ MBF(r=0.37, p< 0.036). CONCLUSIONS: Increased body weight is independently associated with abnormal coronary circulatory function that progresses from an impairment in endothelium related coronary vasomotion in overweight individuals to an impairment of the total vasodilator capacity in obese individuals. The findings that elevated leptin plasma levels in patients that are obese might exert beneficial effects on the coronary endothelium to counterbalance the adverse effects of increases in body weight on coronary circulatory function should be tested.
基金supported by the National Natural Science Foundation of China (30840033,30770615 and 30970818)the National Basic Research Program of China (2011CB707701)the Joint Research Foundation of Beijing Education Committee (JD100010607)
文摘Local cerebral metabolic rate of glucose(LCMRGlc) is an important index for the description of neural function.Dynamic 18 F-fluoro-2-deoxy-D-glucose(FDG) positron emission tomography(PET) has been used for quantitative imaging of LCMRGlc in humans,but is seldom used routinely because of the difficulty in obtaining the input function noninvasively.A reference tissue-based Patlak plot model(rPatlak) was proposed to generate parametric images of LCMRGlc in a quantitative dynamic FDG-PET study without requiring blood sampling.Dynamic emission scans(4×0.5,4×2 and 10×5 min) were acquired simultaneously with an IV bolus injection of 155 MBq of FDG.Arterial blood samples were collected during the scans via a catheter placed in the radial artery.Simulation data were also generated using the same scan sequence.The last ten scan data sets were used in a graphical analysis using the Patlak plot.The ratio of LCMRGlc estimated from the original Patlak(oPatlak,using plasma input) was used as the gold standard,and the standardized uptake value ratio(SUVR) was also calculated for comparison.Eight different tissues including white matter,gray matter,and whole brain were chosen as reference tissues for evaluation.Regardless of the reference region used,the slopes in the linear regression between oPatlak and rPatlak were closer to unity than the regression slopes between oPatlak and SUVR.The intercepts for the former were also closer to 0 than those for the latter case.The squared correlation coefficients were close to 1.0 for both cases.This showed that the results of rPatlak were in good agreement with those of oPatlak,however,SUVR exhibited more deviation.The simulation study also showed that the relative variance and bias for rPatlak were less than those for SUVR.The images obtained with rPatlak were very similar to those obtained with oPatlak,while there were differences in the relative spatial distribution between the images of SUVR and oPatlak.This study validates that the rPatlak method is better than the SUVR method and is a good approximation to the oPatlak method.The new method is suitable for generating LCMRGlc parametric images noninvasively.
文摘Abnormal coronary endothelial reactivity has been demonstrated in diabetes and is associated with an increased rate of cardiovascular events. Our objectives were to investigate the presence of functional coronary circulatory abnormalities over the full spectrum of insulin resistance and to determine whether these would differ in severity with more advanced states of insulin resistance. Methods and Results-Myocardial blood flow(MBF) was measured with positron emission tomography and 13N-ammonia to characterize coronary circulatory function in states of insulin resistance without carbohydrate intolerance(IR), impaired glucose tolerance(IGT), and normotensive and hypertensive type 2 diabetes mellitus(DM) compared with insulin-sensitive(IS) individuals. Indices of coronary function were total vasodilator capacity(mostly vascular smooth muscle-mediated) during pharmacological vasodilation and the nitric oxide-mediated, endothelium-dependent vasomotion in response to cold pressor testing. Total vasodilator capacity was similar in normoglycemic individuals(IS, IR, and IGT), whereas it was significantly decreased in normotensive(- 17% ) and hypertensive(- 34% )DM patients. Compared with IS, endothelium- dependent coronary vasomotion was significantly diminished in IR(- 56% ), as well as in IGT and normotensive and hypertensive diabetic patients(- 85% ,- 91% , and- 120% , respectively). Conclusions-Progressively worsening functional coronary circulatory abnormalities of nitric oxide-mediated, endothelium-dependent vasomotion occur with increasing severity of insulin-resistance and carbohydrate intolerance. Attenuated total vasodilator capacity accompanies the more clinically evident metabolic abnormalities in diabetes.
基金supported by the Key Project of National Natural Science Foundation of China(No.51136002)China Key Technologies R&D Program(No.2012BAJ02B03)
文摘Plastics such as polyvinyl chlorides(PVC) are widely used in many indoor constructed environments; however, their unbound chemicals, such as di-(2-ethylhexyl) phthalates(DEHP), can leach into the surrounding environment. This study focused on DEHP's effect on the central nervous system by determining the precise DEHP content in mice brain tissue after exposure to the chemical, to evaluate the specific exposure range. Primary neuronal-astrocyte co-culture systems were used as in vitro models for chemical hazard identification of DEHP. Oxidative stress was hypothesized as a probable mechanism involved, and therefore the total reactive oxygen species(ROS) concentration was determined as a biomarker of oxidative stress. In addition, NeuriteTracer, a neurite tracing plugin with ImageJ, was used to develop an assay for neurotoxicity to provide quantitative measurements of neurological parameters, such as neuronal number, neuron count and neurite length, all of which could indicate neurotoxic effects. The results showed that with 1 nmol/L DEHP exposure, there was a significant increase in ROS concentrations, indicating that the neuronal-astrocyte cultures were injured due to exposure to DEHP. In response, astrocyte proliferation(gliosis) was initiated, serving as a mechanism to maintain a homeostatic environment for neurons and protect neurons from toxic chemicals. There is a need to assess the cumulative effects of DEHP in animals to evaluate the possible uptake and effects on the human neuronal system from exposure to DEHP in the indoor environment.
基金MSL was supported by NIH Ruth L.Kirschstein National Research Service Award AI 007323.SJB was supported by NIH HL 146358 and HL 157710.Figures were created with Biorender software at Biorender.com.
文摘Cholesterol is a critical lipid for all mammalian cells,ensuring proper membrane integrity,fluidity,and biochemical function.Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their cholesterol metabolism in response to activation signals to support host defense processes.However,our understanding of the molecular details underlying how and why cholesterol homeostasis is specifically reshaped during immune responses remains less well understood.This review discusses our current knowledge of cellular cholesterol homeostatic machinery and introduces emerging concepts regarding how plasma membrane cholesterol is partitioned into distinct pools.We then discuss how proinflammatory signals can markedly reshape the cholesterol metabolism of macrophages,with a focus on the differences between MyD88-dependent pattern recognition receptors and the interferon signaling pathway.We also discuss recent work investigating the capacity of these proinflammatory signals to selectively reshape plasma membrane cholesterol homeostasis.We examine how these changes in plasma membrane cholesterol metabolism influence sensitivity to a set of microbial pore-forming toxins known as cholesterol-dependent cytolysins that specifically target cholesterol for their effector functions.We also discuss whether lipid metabolic reprogramming can be leveraged for therapy to mitigate tissue damage mediated by cholesterol-dependent cytolysins in necrotizing fasciitis and other related infections.We expect that advancing our understanding of the crosstalk between metabolism and innate immunity will help explain how inflammation underlies metabolic diseases and highlight pathways that could be targeted to normalize metabolic homeostasis in disease states.
基金This study was supported by National Cancer Institute/-National Institutes of Health(Grant No.1R21CA216770)UC Tobacco-related Disease Research Program(Grant No.27IR-0016),Department of Defense(Grant No.W81XWH-15-1-0256)Cancer Research Coordinating Committee(Grant No.CRC15-380768)to L.W.UCLA institutional support grant support included:UCLA JCCC grant no.P30CA016042,and UCLA CTSI grant no.UL1TR001881(to L.W.).We thank UCLA Translational Pathology Core Laboratory for the preparation of tumor samples.
文摘Cancer of the urological system commonly occurs in the kidney,bladder,and prostate gland.The clear cell subtype of renal cell carcinoma(ccRCC)constitutes the great majority of kidney cancer.Metastatic ccRCC portends a very poor outcome with no effective treatment available.Prostate cancer is the most common cancer in males in the US.Despite recent advances in selective kinase inhibitors and immunotherapies,the rate of developing new treatment from bench to bedside is slow.A time-consuming step is at the animal drug testing stage,in which the mouse model is the gold standard.In the pursuit to streamline the in vivo cancer biology research and drug development,we explored the feasibility of the chicken chorioallantoic membrane(CAM)model to establish xenografts.The CAM model greatly shortens the time of tumor growth and lowers the cost comparing to immunocompromised mice.We generated CAM xenografts from ccRCC,bladder and prostate cancer,with established cancer cell lines and freshly isolated patient-derived tissues,either as primary tumor cells or small pieces of tumors.The successful CAM engraftment rate from the different tumor sources is 70%or above.Using our previously established metastatic ccRCC mouse model,we showed that the CAM xenograft maintains the same tumor growth pattern and metastatic behavior as observed in mice.Taken together,CAM can serve as a valuable platform to establish new patient-derived xenografts(PDXs)to study tumor biology,thus accelerating the development of individualized treatment to halt the deadly metastatic stage of cancer.
基金funded by the American College of Gastroenterology,grant name“Junior Faculty Development Award”United States Department of Defense,grant number CA191051National Institutes of Health,grant number R01CA246304,R01CA253651,R01CA255727,R21CA235340,and R21CA240887.
文摘Hepatocellular carcinoma(HCC)is among the leading causes of cancer incidence and mortality worldwide.Surveillance of individuals with cirrhosis or other conditions that confer a high risk of HCC development is essential for early detection and improved overall survival.Biannual ultrasonography with or without alpha-fetoprotein is widely recommended as the standard method for HCC surveillance,but it has limited sensitivity in early disease and may be inadequate in certain individuals.This review article will provide a comprehensive overview of the current landscape of HCC surveillance,including the rationale and indications for HCC surveillance,standard methods for HCC surveillance,and their strengths/limitations.Alternative surveillance methods such as the role of cross-sectional imaging,emerging circulating biomarkers,as well as the problem of under-utilization of HCC surveillance and surveillance-related harms will also be discussed in this review.
基金supported by the National Natural Science Foundation of China(Nos.81970686,81770791,81471012,81270876,to LL)the Interdisciplinary Program of Shanghai Jiao Tong University,China(No.YG2019ZDA08,to LL)+1 种基金the Shanghai Leading Talent,China(No.SLJ15055,to LL)the National Institute of Diabetes and Digestive and Kidney Diseases(No.SC1DK104821,to YL)
文摘Objective::In contrast to the most commonly reported forms of maturity-onset diabetes of the young(MODY),including MODY2,MODY3 and MODY5,MODY6 is a relatively rare subtype.To investigate whether NEUROD1 is responsible for MODY in Chinese individuals,we screened its mutations in MODY pedigrees and explored the potential pathogenic mechanisms.Methods::Polymerase chain reaction direct sequencing was performed to screen NEUROD1 mutations in 32 Chinese MODY probands who were negative for the GCK/MODY2,HNF1A/MODY3 and HNF1B/MODY5 genes in this observational study.In addition,we enrolled 201 unrelated,non-diabetic control subjects of Han Chinese descent.The functional significance of newly identified mutations was analyzed using clinical phenotype,pathophysiology and three-dimensional structure studies.This study was approved by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,China(approval No.YS-2017-83)on March 3,2017.Results::E59Q(c.175 G>C,p.Glu59Gln),a heterozygous missense mutation in the NEUROD1 gene,was identified in one family with MODY.The Glu59 residue in NeuroD1 is highly conserved across mammalian species.Four diabetic patients carrying the mutation(a proband and her son,brother and sister)were lean,with a body mass index of 20.9(20.3-21.2)kg/m 2.Compared with their unaffected relatives(n=4),E59Q carriers(n=4)had significantly decreased ratios of fasting and 2-hour insulin to plasma glucose(both fasting plasma insulin/fasting plasma glucose and 2-hour postprandial plasma insulin/2-hour postprandial plasma glucose,P<0.005).The proband’s father had an E59Q mutation and normal glucose tolerance,which suggested non-penetrance.The E59Q mutation was not detected in other probands or in the 201 control subjects with normal glucose tolerance.Two salt-bridge bonds of Glu59 were disrupted at the Q59 mutation site.Conclusion::The NEUROD1-E59Q mutation changed the molecular conformation of the N-terminal in NeuroD1,which may decrease binding of the E59Q mutant to the insulin promoter and insulin gene transcription activity,therefore causing the MODY6 subtype with defective insulin secretion.
