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1.
Endoscopy ; 56(7): 494-502, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38378019

ABSTRACT

BACKGROUND: Sessile serrated lesions (SSLs) are obscured lesions predominantly in the right-sided colon and associated with interval colorectal cancer; however, their prevalence and risk factors among younger individuals remain unclear. METHODS: This retrospective study enrolled individuals who underwent index colonoscopy. The primary outcome was the SSL prevalence in the younger (<50 years) and older (≥50 years) age groups, while the secondary outcomes included clinically significant serrated polyps (CSSPs). Multivariable logistic regression was employed to identify predictors. RESULTS: Of the 9854 eligible individuals, 4712 (47.8%) were categorized into the younger age group. Individuals in the younger age group exhibited lower prevalences of adenomas (22.6% vs. 46.2%; P<0.001) and right-sided adenomas (11.2% vs. 27.2%; P<0.001) compared with their older counterparts. However, both groups exhibited a similar prevalence of SSLs (7.2% vs. 6.5%; P=0.16) and CSSPs (10.3% vs. 10.3%;P=0.96). Multivariable analysis revealed that age 40-49 years (odds ratio [OR] 1.81, 95%CI 1.01-3.23), longer withdrawal time (OR 1.17, 95%CI 1.14-1.20, per minute increment), and endoscopist performance (OR 3.35, 95%CI 2.44-4.58) were independent predictors of SSL detection in the younger age group. No significant correlation was observed between adenoma and SSL detection rates among endoscopists. CONCLUSION: SSLs are not uncommon among younger individuals. Moreover, diligent effort and expertise are of paramount importance in SSL detection. Future studies should explore the clinical significance of SSLs in individuals of younger age.


Subject(s)
Adenoma , Colonic Polyps , Colonoscopy , Colorectal Neoplasms , Humans , Middle Aged , Female , Male , Retrospective Studies , Prevalence , Colonoscopy/statistics & numerical data , Adult , Colonic Polyps/epidemiology , Colonic Polyps/pathology , Colonic Polyps/diagnosis , Adenoma/epidemiology , Adenoma/pathology , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/pathology , Age Factors , Risk Factors , Aged
2.
World J Urol ; 41(5): 1373-1379, 2023 May.
Article in English | MEDLINE | ID: mdl-36971826

ABSTRACT

PURPOSE: Abnormalities in autonomic function are associated with an overactive bladder (OAB). Heart rate variability is generally used as the sole assessment of autonomic activity; however, we utilized neuECG, a novel method of recording skin electrical signals, to assess autonomic nervous function in healthy controls and patients with OAB before and after treatment. METHODS: The prospective sample included 52 participants: 23 patients newly diagnosed with OAB and 29 controls. Autonomic function was assessed in all participants in the morning using neuECG, which analyzed the average skin sympathetic nerve activity (aSKNA) and electrocardiogram simultaneously. All patients with OAB were administered antimuscarinics; urodynamic parameters were assessed before treatments; autonomic and bladder functions using validated questionnaires for OAB symptoms were evaluated before and after OAB treatment. RESULTS: Patients with OAB had significantly higher baseline aSKNA (p = 0.003), lower standard deviation of the normal-to-normal beat intervals, lower root mean square of the successive differences, lower high-frequency, and higher low-frequency than did controls. Baseline aSKNA had the highest value in predicting OAB (AUROC = 0.783, p < 0.001). The aSKNA was negatively correlated with first desire and normal desire in urodynamic studies (both p = 0.025) and was significantly decreased after treatment at rest, stress, and recovery phases, as compared to those before treatment (p = 0.046, 0.017, and 0.017, respectively). CONCLUSION: Sympathetic activity increased significantly in patients with OAB compared to that in healthy controls, and decreased significantly post-treatment. Higher aSKNA is associated with decreased bladder volume at which voiding is desired. SKNA may be a potential biomarker for diagnosing OAB.


Subject(s)
Urinary Bladder, Overactive , Humans , Prospective Studies , Urination/physiology , Muscarinic Antagonists/therapeutic use , Biomarkers , Urodynamics
3.
Eur Radiol ; 33(6): 4063-4072, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36580096

ABSTRACT

OBJECTIVES: Lower-extremity peripheral arterial disease (PAD) results in limb ischemia and is strongly associated with sarcopenia. This study aimed to retrospectively evaluate the association between the quantity of muscle mass in the lower extremities and the severity of vascular stenosis in PAD patients. METHODS: Between January 2018 and August 2021, 128 patients with PAD and 53 individuals without PAD, diagnosed by computed tomography, were enrolled. The severity of stenosis of lower-extremity arteries was measured using a grading system. The muscle and fat mass areas were calculated in the abdomen at the L3 or L4 level, mid-thigh, and lower leg. Multivariable logistic regression was conducted to clarify the risk associated with low muscle mass. The difference in muscle mass between PAD and non-PAD patients was evaluated by using propensity score matching. RESULTS: A strong positive correlation between the abdomen muscle area and leg muscle area was observed. The muscle area and muscle index of the leg were lower in PAD patients. These changes occurred earlier than in the abdomen muscle area. The group with more severe artery stenosis had more muscle wasting in the lower extremities. Greater age, female, lower BMI, and PAD were associated with low muscle mass. After propensity score matching, the leg muscle area was still lower in PAD patients. CONCLUSIONS: There is a direct association between PAD and regional muscle wasting. This occurs earlier regionally in the lower extremities than in central muscles. Early diagnosis of PAD might prevent progressive muscle loss, improving disease outcome and quality of life. KEY POINTS: • Peripheral arterial disease is strongly associated with sarcopenia. • Muscle wasting in the lower extremities is earlier and more prominent than that in the abdomen. • More severe arterial stenoses are associated with higher muscle wasting in the lower extremities.


Subject(s)
Peripheral Arterial Disease , Sarcopenia , Humans , Female , Sarcopenia/complications , Sarcopenia/diagnostic imaging , Sarcopenia/pathology , Retrospective Studies , Quality of Life , Constriction, Pathologic/pathology , Lower Extremity/diagnostic imaging , Lower Extremity/blood supply , Peripheral Arterial Disease/complications , Peripheral Arterial Disease/diagnostic imaging , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Tomography, X-Ray Computed
4.
BMC Urol ; 21(1): 48, 2021 Mar 27.
Article in English | MEDLINE | ID: mdl-33773582

ABSTRACT

PURPOSE: to describe the methodology of transurethral seminal vesiculoscopy and the anatomy of the area of the verumontanum, and to determine the safety of this procedure, especially in terms of postoperative complications. METHODS: This retrospective observational study enrolled 144 patients with intractable hematospermia from May 2011 and August 2019. A 4.5/6.5-Fr vesiculoscope was inserted into the seminal vesicle to deal with the positive findings. The solution of quinolones was used to rinse each seminal vesicle. RESULTS: In this study, Transurethral seminal vesiculoscopy was successfully performed in 139 patients (96.53%). Hematospermia was alleviated or disappeared in 116 (80.56%) patients by less than half a year after surgery. Common intraoperative manifestations were hemorrhage, stones, utricle polyps and cysts. The surgical approach in our study were categorized into four types, including 24 (16.7%), 73 (50.7%), 42 (29.2%), and 5 (3.5%) cases in Type A (natural opening of the ejaculatory duct), B (trans-duct fenestration), C (trans-utricle fenestration), and D (not founded), respectively. Sexual function change was recorded in 12 patients of 111 patients, all by the method of trans-utricle fenestration, including 8 (7.21%), 3 (2.70%), and 1 (0.90%) patients in shorter intravaginal ejaculatory latency time, worse erection hardness and loss of orgasm, respectively. CONCLUSION: Transurethral seminal vesiculoscopy is an effective and safe procedure for the management of hematospermia. The anatomy of the distal seminal tract should be understood more deeply and Wu'method (uncover-curtain method) needs to be promoted to verify its universality and safety. Besides, the complications of the function dysfunction should be discussed in the future in multi-center clinical trials.


Subject(s)
Endoscopy , Hemospermia/surgery , Adult , Endoscopy/methods , Humans , Male , Middle Aged , Postoperative Complications/epidemiology , Retrospective Studies , Seminal Vesicles , Urologic Surgical Procedures, Male/methods
5.
Medicina (Kaunas) ; 57(12)2021 Dec 07.
Article in English | MEDLINE | ID: mdl-34946284

ABSTRACT

Backgroundand objectives: Patients with BRAF-mutated metastatic colorectal cancer have considerably poorer responses to conventional systemic treatment. The real-world effects of triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in Asia have not been well-reported. Materials and Methods: This single-center case series included patients with BRAF-mutated metastatic colorectal cancer undergoing triplet therapy after failure of prior systemic treatment from 2016 to 2020. The primary outcome was progression-free survival, and secondary outcomes were overall survival, response rate, disease control rate, and adverse events. Results: Nine eligible patients with BRAF-mutated metastatic colorectal cancer receiving triplet therapy were enrolled, with a median follow-up time of 14.5 months (range, 1-26). Most patients (88.8%) had two or more prior systemic treatments, and the triplet regimen was mainly dabrafenib, trametinib, and panitumumab. The overall response rate and disease control rate were 11.1% and 33.3%, respectively. Median progression-free survival and overall survival were 2.9 and 7.4 months, respectively, and a trend toward better overall survival was found with left-sided metastatic colorectal cancer compared with right-sided disease (9.2 vs. 6.9 months, p = 0.093). Adverse events were mostly Grade 1-2, including nausea, hypertension, gastrointestinal symptoms, and skin disorders. Conclusions: In this single-center case series, triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in BRAF-mutated metastatic colorectal cancer had an acceptable safety profile and reasonable efficacy.


Subject(s)
Colorectal Neoplasms , Salvage Therapy , Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , ErbB Receptors/antagonists & inhibitors , Humans , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mutation , Proto-Oncogene Proteins B-raf/antagonists & inhibitors
6.
Br J Cancer ; 123(10): 1570-1581, 2020 11.
Article in English | MEDLINE | ID: mdl-32901134

ABSTRACT

BACKGROUND: It is unclear whether bisphosphonates are associated with risk of cancers. Therefore, this meta-analysis aimed to evaluate the effect of bisphosphonates on overall cancers. METHODS: A search in Pubmed, Embase, Cochrane Library and Web of Science databases was conducted, from the inception date of each resource to September 26, 2019. The summarised effect estimates with 95% CIs were calculated using a random-effect model. Heterogeneity and publication bias were explored. RESULTS: Thirty-four articles were included in this study (4,508,261 participants; 403,196 cases). The results revealed that bisphosphonates significantly decreased the risk of colorectal cancer (RR = 0.89, 95% CI: 0.81-0.98), breast cancer (RR = 0.87, 95% CI: 0.82-0.93) and endometrial cancer (RR = 0.75, 95% CI: 0.61-0.94), but no significant association was observed in all-cause cancer. Furthermore, nitrogen-containing bisphosphonates only had protective effects both on breast cancer (RR = 0.94, 95% CI: 0.90-0.99) and endometrial cancer (RR = 0.70, 95% CI: 0.54-0.92). Non-nitrogen-containing bisphosphonates tended to increase the risk of liver cancer (RR = 2.14, 95% CI: 1.23-3.72) and pancreas cancer (RR = 1.75, 95% CI: 1.32-2.33). CONCLUSION: Bisphosphonates are significantly associated with risk reduction of colorectal, breast and endometrial cancer, especially nitrogen-containing bisphosphonates. It should be noted that non-nitrogen-containing bisphosphonates might increase the risk of liver and pancreas cancer. Large prospective cohort studies are needed to find the causal association between bisphosphonates and risk of cancers.


Subject(s)
Diphosphonates/therapeutic use , Neoplasms/epidemiology , Aged , Breast Neoplasms/epidemiology , Breast Neoplasms/etiology , Colonic Neoplasms/epidemiology , Colonic Neoplasms/etiology , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/etiology , Cytoprotection/drug effects , Diphosphonates/chemistry , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/etiology , Female , Humans , Liver Neoplasms/epidemiology , Liver Neoplasms/etiology , Male , Middle Aged , Neoplasms/etiology , Nitrogen Compounds/chemistry , Nitrogen Compounds/therapeutic use , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/etiology , Prevalence , Risk Factors
7.
Chemistry ; 25(28): 6973-6979, 2019 May 17.
Article in English | MEDLINE | ID: mdl-30901120

ABSTRACT

Fluorescent probes have become an indispensable tool in the detection and imaging of biological and disease-related analytes due to their sensitivity and technical simplicity. In particular, fluorescent probes with far-red to near-infrared (FR-NIR) emissions are very attractive for biomedical applications. However, many available FR-NIR fluorophores suffer from small Stokes shifts and sometimes low quantum yields, resulting in self-quenching and low contrast. In this work, we describe the rational design and engineering of FR-NIR 2,4,6-triphenylpyrylium-based fluorophores (TPP-Fluors) with the help of theoretical calculations. Our strategy is based on the appending of electron-donating substituents and fusing groups onto 2,4,6-triphenylpyrylium. In contrast to the parent TPP with short emission wavelength, weak quantum yields, and low chemical stability, the obtained novel TPP-Fluors display some favorable properties, such as long-wavelength emission, large Stokes shifts, moderate to high quantum yields, and chemical stability. TPP-Fluors demonstrate their biological value as mitochondria-specific labeling reagents due to their inherently positive nature. In addition, TPP-Fluors can also be applied to develop ratiometric fluorescent probes, as the electron-donating ability of the 2,6-phenyl substituents is closely correlated with their emission wavelength. A proof-of-concept ratiometric probe has been developed by derivatizing the amino groups of TPP-Fluor for the detection and imaging of nitroreductase in vitro and in hypoxic cells.

8.
Int Orthop ; 43(3): 719-726, 2019 03.
Article in English | MEDLINE | ID: mdl-30083845

ABSTRACT

BACKGROUND: The optimal strategy for shepherd's crook deformity correction remains technically challenging. In particular, it is difficult to perform an accurate osteotomy based on the pre-operative correction plan. Moreover, the choice of ideal hardware remains unclear. In addition, when combined with the deformity of knee joint, the sequence of deformity correction is another overlooked factor when making a correction strategy. METHODS: From February 2012 to March 2014, we retrospectively examined a cases series in our department involving the creation of three-dimensional (3D) printing osteotomy templates and inner fixation for shepherd's crook deformity in fibrous dysplasia. RESULTS: A total of ten patients of shepherd's crook deformity were enrolled in this study. The neck shaft angle was corrected from a mean value of 88.1° (range, 73-105°) pre-operatively to a mean value of 128.5° (range, 120-135°) post-operatively; no marked loss in the value was observed (mean, 123.7°; range, 115-130°) at the final follow-up. In addition, compared with patients using dynamic hip screw (DHS), longer operation time and additional blood loss were recorded in patients using intramedullary nail (IN). Moreover, after correction of shepherd's crook deformity, two patients were observed more predominant on their pre-existing valgus knee deformity. CONCLUSIONS: 3D printing osteotomy templates facilitate the correction of shepherd's crook deformity. Dynamic hip screw (DHS), combined with polymethylmethacrylate (PMMA) augmentation, yields excellent outcomes and ensures easy placement and non-intramedullary manipulation, lower bleeding volume, and reduced operation time. Prior to the correction of shepherd's crook deformity, the mechanical axis of the lower limb should be carefully examined, and any evidence of valgus knee deformity should be addressed in advance.


Subject(s)
Bone Malalignment/surgery , Femur/surgery , Fibrous Dysplasia of Bone/surgery , Osteotomy/methods , Printing, Three-Dimensional , Adult , Bone Malalignment/etiology , Female , Femur/diagnostic imaging , Fibrous Dysplasia of Bone/complications , Fracture Fixation, Internal/methods , Humans , Male , Middle Aged , Retrospective Studies
9.
Int J Mol Sci ; 20(17)2019 Aug 29.
Article in English | MEDLINE | ID: mdl-31470507

ABSTRACT

Imbalance of lipid metabolism is a main cause of metabolic syndrome leading to life-threatening metabolic diseases. Angiopoietin-like protein 8 (Angptl8) was recently identified as a liver and adipose tissue-released hormone that is one of the molecules involved in triglyceride metabolism. However, the regulatory mechanism of Angptl8 is largely unknown. A high fat diet (HFD)-fed mouse model, which showed high cholesterol, high triglyceride, and high insulin in the blood, revealed the upregulation of hepatic and plasma Angptl8 and the downregulation of hepatic glycine N-methyltransferase (GNMT). The inverse correlation of hepatic Angptl8 and GNMT expression in the livers of HFD-fed mice was also confirmed in a publicly available microarray dataset. The mechanistic study using primary hepatocytes showed that the Angptl8 expression could be induced by insulin treatment in a dose- and time-dependent manner. Inhibition of PI3K/Akt pathway by the specific inhibitors or the dominant-negative Akt blocked the insulin-induced Angptl8 expression. Moreover, knockout of GNMT promoted the Akt activation as well as the Angptl8 expression. These results suggested that GNMT might be involved in insulin-induced Angptl8 expression in HFD-mediated metabolic syndrome.


Subject(s)
Angiopoietin-like Proteins/genetics , Diet, High-Fat/adverse effects , Gene Expression Regulation/genetics , Glycine N-Methyltransferase/genetics , Liver/metabolism , Metabolic Syndrome/genetics , Angiopoietin-Like Protein 8 , Angiopoietin-like Proteins/blood , Angiopoietin-like Proteins/metabolism , Animals , Cells, Cultured , Gene Expression Regulation/drug effects , Glycine N-Methyltransferase/blood , Glycine N-Methyltransferase/metabolism , Hepatocytes/metabolism , Insulin/pharmacology , Lipids/blood , Liver/enzymology , Male , Metabolic Syndrome/etiology , Metabolic Syndrome/metabolism , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction/genetics
10.
Cancer Sci ; 109(10): 3105-3114, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30099830

ABSTRACT

Lung cancer patients with human immunodeficiency virus (HIV) have a poorer prognosis than do patients without HIV infection. HIV1 Tat is a secreted viral protein that penetrates the plasma membrane and interacts with a number of proteins in non-HIV-infected cells. The loss of function of Tat-interacting protein 30 (TIP30) has been linked to metastasis in non-small cell lung cancer (NSCLC). However, it is unknown how the interaction of HIV1 Tat with TIP30 regulates the metastasis of NSCLC cells. In this study, the overexpression of TIP30 decreased tumor growth factor-ß-induced epithelial-to-mesenchymal transition (EMT) and invasion of NSCLC cells, whereas the knockdown of TIP30 promoted EMT, invasion and stemness. Exposure to recombinant HIV1 Tat proteins promoted EMT and invasion. A mechanistic study showed that the interaction of HIV1 Tat with TIP30 blocked the binding of TIP30 to importin-ß, which is required for the nuclear translocation of Snail. Indeed, the loss of TIP30 promoted the nuclear translocation of Snail. In vivo studies demonstrated that the overexpression of TIP30 inhibited the metastasis of NSCLC cells. In contrast, the coexpression of HIV1 Tat and TIP30 diminished the inhibitory effect of TIP30 on metastasis. Immunohistochemistry confirmed that TIP30 overexpression reduced the nuclear localization of Snail, whereas the coexpression of HIV1 Tat and TIP30 increased nuclear Snail in metastatic tumors. In conclusion, the binding of HIV1 Tat to TIP30 enhanced EMT and metastasis by regulating the nuclear translocation of Snail. Targeting Tat-interacting proteins may be a potential therapeutic strategy to prevent metastasis in NSCLC patients with HIV infection.


Subject(s)
Acetyltransferases/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , HIV Infections/pathology , Lung Neoplasms/pathology , Snail Family Transcription Factors/metabolism , Transcription Factors/metabolism , tat Gene Products, Human Immunodeficiency Virus/metabolism , Acetyltransferases/genetics , Animals , Carcinoma, Non-Small-Cell Lung/virology , Cell Line, Tumor , Cell Nucleus/metabolism , Epithelial-Mesenchymal Transition , Gene Knockdown Techniques , HEK293 Cells , HIV/metabolism , HIV Infections/virology , Humans , Lung Neoplasms/virology , Male , Mice , Mice, Nude , Neoplasm Invasiveness/pathology , RNA, Small Interfering/metabolism , Recombinant Proteins/metabolism , Transcription Factors/genetics , Transforming Growth Factor beta/metabolism , Xenograft Model Antitumor Assays
11.
Int J Med Sci ; 15(13): 1573-1581, 2018.
Article in English | MEDLINE | ID: mdl-30443180

ABSTRACT

Histone deacetylase 6 (HDAC6), a member of the HDAC enzymes, has been reported to play substantial roles in many cellular processes. Evidence shows that deregulation of HDAC6 may be involved in the progression of some cancers, neurodegenerative diseases, and inflammatory disorders. However, little is known regarding the effect of post-translational modification of HDAC6 on cellular localization and biological functions. In the present study, we identified four phosphorylation sites on HDAC6 under normal conditions by mass spectrometry analysis. Two phosphorylation sites, pSer22 and pSer412, are recognized as Pin1 (peptidyl-prolyl cis/trans isomerase NIMA-interacting 1) substrates. Pin1 can interact with HDAC6 and be involved in HDAC6-mediated cell motility. Pin1 depletion abrogates HDAC6-induced cell migration and invasion in H1299 lung cancer cells. The findings of this study suggest that Pin1 might regulate HDAC6-mediated cell motility through alteration of protein conformation and function. Our results indicate the complexity of activity regulation between HDAC6 and Pin1, expanding knowledge regarding the multifunctional roles of Pin1 in tumorigenesis and cancer progression.


Subject(s)
Cell Movement/physiology , Histone Deacetylase 6/metabolism , NIMA-Interacting Peptidylprolyl Isomerase/metabolism , Cell Line, Tumor , Cell Movement/genetics , Histone Deacetylase 6/genetics , Humans , Mass Spectrometry , NIMA-Interacting Peptidylprolyl Isomerase/genetics , Phosphorylation/genetics , Phosphorylation/physiology
12.
Clin Lab ; 64(7): 1145-1151, 2018 Jul 01.
Article in English | MEDLINE | ID: mdl-30146843

ABSTRACT

BACKGROUND: Cystinuria is a rare inherited renal stone disease caused by mutations in the SLC3A1 and SLC7A9 genes. The Chinese cystinuria phenotype and genotype have rarely been reported in the literature. METHODS: For this research, the clinical features and genetic etiology were analyzed in seven children, and the clinical characteristics were summarized. The blood and urine amino acids and acylcarnitine were analyzed. Additionally, the whole coding sequence and exon-intron junctions of the SLC3A1 and SLC7A9 genes were analyzed. RESULTS: These seven patients with cystinuria were from seven unrelated Chinese families, and they were diagnosed between the ages of 1 month and 16 years old. The urinary amino acids, including ornithine, arginine, and threonine, were elevated in these patients. A homozygous c.325G>A mutation in SLC7A9 was identified in two patients, and six SLC3A1 mutations were found in five patients. CONCLUSIONS: The core pedigree analysis showed that most of the parents carried mutations; however, there was no association between the clinical course and the genotype.


Subject(s)
Amino Acid Transport Systems, Basic/genetics , Amino Acid Transport Systems, Neutral/genetics , Cystinuria/genetics , Mutation , Adolescent , Amino Acids/blood , Amino Acids/urine , Asian People/genetics , Carnitine/analogs & derivatives , Carnitine/blood , Carnitine/urine , Child , Child, Preschool , China , Cystinuria/ethnology , Cystinuria/metabolism , Family Health , Female , Humans , Infant , Infant, Newborn , Male
13.
J Pathol ; 237(1): 50-61, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25925728

ABSTRACT

Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up-regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786-0, ACHN and A-498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E-cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter-binding activity of Snail. Snail silencing blocked the ghrelin-mediated effects on E-cadherin repression and cell migration. Snail-E-cadherin regulation was mediated by GHS-R-triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin-induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS-R-PI3K-Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset].


Subject(s)
Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/secondary , Cell Movement , Ghrelin/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Transcription Factors/metabolism , Animals , Antigens, CD , Binding Sites , Cadherins/genetics , Cadherins/metabolism , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/mortality , Cell Line, Tumor , Cell Movement/drug effects , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Ghrelin/genetics , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/mortality , Male , Mice, Inbred NOD , Mice, SCID , Neoplasm Invasiveness , Oligonucleotide Array Sequence Analysis , Phosphatidylinositol 3-Kinase/metabolism , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation , Promoter Regions, Genetic/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Receptors, Ghrelin/genetics , Receptors, Ghrelin/metabolism , Signal Transduction , Snail Family Transcription Factors , Time Factors , Transcription Factors/genetics , Transfection
14.
Zhongguo Dang Dai Er Ke Za Zhi ; 18(1): 67-71, 2016 Jan.
Article in Zh | MEDLINE | ID: mdl-26781416

ABSTRACT

This study reports a boy with psychomotor retardation and epilepsy due to maternal phenylketonuria (PKU). The boy was admitted at the age of 20 months because of psychomotor retardation and epilepsy. He had seizures from the age of 1 year. His development quotient was 43. He presented with microcephaly, normal skin and hair color. Brain MRI scan showed mild cerebral white matter demyelination, broadening bilateral lateral ventricle and foramen magnum stricture. Chromosome karyotype, urine organic acids, blood amino acids and acylcarnitines were normal. His mother had mental retardation from her childhood. She presented with learning difficulties and yellow hair. Her premarriage health examinations were normal. She married a healthy man at age of 26 years. When she visited us at 28 years old, PKU was found by markedly elevated blood phenylalanine (916.54 µmol/L vs normal range 20-120 µmol/L). On her phenylalanine hydroxylase (PAH) gene, a homozygous mutations c.611A>G (p.Y204C) was identified, which confirmed the diagnosis of PAH-deficient PKU. Her child carries a heterozygous mutation c.611A>G with normal blood phenylalanine. Her husband had no any mutation on PAH. It is concluded that family investigation is very important for the etiological diagnosis of the children with mental retardation and epilepsy. Carefully clinical and metabolic survey should be performed for the parents with mental problems to identify parental diseases-associated child brain damage, such as maternal PKU.


Subject(s)
Epilepsy/etiology , Intellectual Disability/etiology , Phenylketonuria, Maternal , Adult , Female , Humans , Infant , Male , Phenylalanine Hydroxylase/genetics , Pregnancy
15.
J Cell Sci ; 126(Pt 21): 4862-72, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-23970419

ABSTRACT

Pin1 was the first prolyl isomerase identified that is involved in cell division. The mechanism by which Pin1 acts as a negative regulator of mitotic activity in G2 phase remains unclear. Here, we found that Aurora A can interact with and phosphorylate Pin1 at Ser16, which suppresses the G2/M function of Pin1 by disrupting its binding ability and mitotic entry. Our results also show that phosphorylation of Bora at Ser274 and Ser278 is crucial for binding of Pin1. Through the interaction, Pin1 can alter the cytoplasmic translocation of Bora and promote premature degradation by ß-TrCP, which results in a delay in mitotic entry. Together with the results that Pin1 protein levels do not significantly fluctuate during cell-cycle progression and Aurora A suppresses Pin1 G2/M function, our data demonstrate that a gain of Pin1 function can override the Aurora-A-mediated functional suppression of Pin1. Collectively, these results highlight the physiological significance of Aurora-A-mediated Pin1 Ser16 phosphorylation for mitotic entry and the suppression of Pin1 is functionally linked to the regulation of mitotic entry through the Aurora-A-Bora complex.


Subject(s)
Aurora Kinase A/metabolism , Cell Cycle Proteins/metabolism , Cells/cytology , G2 Phase , Mitosis , Peptidylprolyl Isomerase/metabolism , Amino Acid Motifs , Animals , Aurora Kinase A/genetics , Cell Cycle Proteins/genetics , Cells/enzymology , Cells/metabolism , Down-Regulation , Gene Expression Regulation , Humans , Mice , Mice, Knockout , NIMA-Interacting Peptidylprolyl Isomerase , Peptidylprolyl Isomerase/genetics , Phosphorylation , Protein Binding
16.
Am J Respir Crit Care Med ; 190(6): 675-87, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-25152164

ABSTRACT

RATIONALE: Metabolic alterations contribute to cancer development and progression. However, the molecular mechanisms relating metabolism to cancer metastasis remain largely unknown. OBJECTIVES: To identify a key metabolic enzyme that is aberrantly overexpressed in invasive lung cancer cells and to investigate its functional role and prognostic value in lung cancer. METHODS: The differential expression of metabolic enzymes in noninvasive CL1-0 cells and invasive CL1-5 cells was analyzed by a gene expression microarray. The expression of target genes in clinical specimens from patients with lung cancer was examined by immunohistochemistry. Pharmacologic and gene knockdown/overexpression approaches were used to investigate the function of the target gene during invasion and metastasis in vitro and in vivo. The association between the target gene expression and clinicopathologic parameters was further analyzed. Bioinformatic analyses were used to discover the signaling pathways involved in target gene-regulated invasion and migration. MEASUREMENTS AND MAIN RESULTS: Squalene synthase (SQS) was up-regulated in CL1-5 cells and in the tumor regions of the lung cancer specimens. Loss of function or knockdown of SQS significantly inhibited invasion/migration and metastasis in cell and animal models and vice versa. High expression of SQS was significantly associated with poor prognosis among patients with lung cancer. Mechanistically, SQS contributed to a lipid-raft-localized enrichment of tumor necrosis factor receptor 1 in a cholesterol-dependent manner, which resulted in the enhancement of nuclear factor-κB activation leading to matrix metallopeptidase 1 up-regulation. CONCLUSIONS: Up-regulation of SQS promotes metastasis of lung cancer by enhancing tumor necrosis factor-α receptor 1 and nuclear factor-κB activation and matrix metallopeptidase 1 expression. Targeting SQS may have considerable potential as a novel therapeutic strategy to treat metastatic lung cancer.


Subject(s)
Farnesyl-Diphosphate Farnesyltransferase/metabolism , Lung Neoplasms/enzymology , Lung Neoplasms/secondary , Membrane Microdomains/metabolism , Neoplasm Invasiveness/physiopathology , Receptors, Tumor Necrosis Factor, Type I/metabolism , Animals , Cell Line, Tumor , Cholesterol/biosynthesis , Disease Models, Animal , Farnesyl-Diphosphate Farnesyltransferase/genetics , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/pathology , Matrix Metalloproteinase 1/metabolism , Prognosis , Up-Regulation
17.
Zhongguo Dang Dai Er Ke Za Zhi ; 17(10): 1103-6, 2015 Oct.
Article in Zh | MEDLINE | ID: mdl-26483233

ABSTRACT

Methylmalonyl CoA mutase deficiency due to MUT gene defect has been known as the main cause of isolated methylmalonic acidemia in Mainland China. This study reported a patient with isolated methylmalonic aciduria (MUT type) characterized as acute brainstem encephalitis and myelitis. The previously healthy girl presented with fever, lethargy and progressive weakness in her extremities at the age of 3 years and 2 months. Three day later, she had respiratory distress and consciousness. Cranial MRI revealed bilateral symmetrical lesion of pallidum, brain stem and spinal cord, indicating acute brainstem encephalitis and myelitis. Her blood propionylcarnitine (6.83 µmol/L vs normal range 1.0 to 5.0 µmol/L) and urinary methylmalonic acid (133.22 mmol/mol creatinine vs normal range 0.2 to 3.6 mmol/mol creatinine) increased significantly. Plasma total homocysteine was normal. On her MUT gene, a reported mutation (c.1630_1631GG>TA) and a novel mutation (c.1663C>T, p.A555T) were identified, which confirmed the diagnosis of methylmalonic aciduria (MUT type). After cobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine, progressive improvement has been observed. The clinical manifestation of patients with methylmalonic aciduria is complex. Metabolic study and gene analysis are keys for the diagnosis and treatment of the disorder.


Subject(s)
Amino Acid Metabolism, Inborn Errors/etiology , Brain Stem/pathology , Encephalitis/etiology , Methylmalonyl-CoA Mutase/genetics , Mutation , Myelitis/etiology , Acute Disease , Child, Preschool , Female , Humans
18.
Zhongguo Dang Dai Er Ke Za Zhi ; 17(2): 172-5, 2015 Feb.
Article in Zh | MEDLINE | ID: mdl-25760844

ABSTRACT

cblB defect is a rare type of methylmalonic aciduria. In this study, a Chinese boy was diagnosed with methylmalonic aciduria cblB type and a novel mutation in the MMAB gene. The clinical presentations, blood acylcarnitines profiles, urine organic acids and genetic features of the patient were reported. The boy presented with fever, feeding difficulty and lethargy at the age of 2 months. Seven days later, he had coma, cold limb, thrombocytopenia, metabolic acidosis and liver damage. His blood propionylcarnitine and urinary methylmalonic acid levels increased significantly, but the plasma total homocysteine level was in the normal range, which supported the diagnosis of isolated methylmalonic aciduria. Gene analysis was performed by direct sequencing. No mutation in the MUT gene was found. However, a reported mutation c.577G>A (p.E193K) and a novel mutation c.562G>A (p.V188M) in the MMAB gene were identified, which confirmed the diagnosis of methylmalonic aciduria cblB type. Progressive clinical and biochemical improvement has been observed after hydroxylcobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine. He is currently 3 years and 11 months old and has a normal development condition. The phenotypes of the patients with cblB defect are nonspecific. Metabolic analysis and MMAB gene analysis are keys for the diagnosis of the disorder.


Subject(s)
Alkyl and Aryl Transferases/genetics , Amino Acid Metabolism, Inborn Errors/genetics , Mutation , Humans , Infant , Male
19.
Zhongguo Dang Dai Er Ke Za Zhi ; 17(9): 965-70, 2015 Sep.
Article in Zh | MEDLINE | ID: mdl-26412180

ABSTRACT

OBJECTIVE: To study the clinical features and treatment outcomes of cardiovascular system involvement in children with methylmalonic aciduria combined with hyperhomocysteinemia (MMACHC). METHODS: The clinical data of 10 children with methylmalonic aciduria combined with hyperhomocysteinemia and who had cardiovascular system involvement were retrospectively analyzed and the treatment outcomes were followed up. RESULTS: In the 10 patients, there were 4 cases with initial presentations of cardiovascular system symptoms such as shortness of breath and dyspnea, 3 cases with urinary tract symptoms such as edema, hematuria and proteinuria, and 3 cases with nervous system symptoms such as developmental retardation and convulsions. The 10 patients had different types and severity of cardiovascular injuries. After 3 months to 8 years of follow-up, the congenital heart defects resolved naturally in 2 cases, and the patient with arrhythmia had no obvious changes. In 5 cases of hypertension, blood pressures recovered to normal in 3 cases, and 1 case was lost to follow-up. In 5 patients with pulmonary hypertension, 2 died, 2 recovered, and 1 case had mildly elevated pulmonary artery pressure. Seven patients underwent MMACHC gene testing, and 5 showed c.80A>G mutations. CONCLUSIONS: Metabolic disease should be taken into account for the children with unexplained pulmonary hypertension and hypertension with the onset of the shortness of breath and dyspnea. The severity of cardiovascular system involvement might be one of the most important factors affecting the prognosis of children with MMACHC. Cardiavascular system involvement of the patients may be related to MMACHC c.80A>G mutations.


Subject(s)
Amino Acid Metabolism, Inborn Errors/complications , Cardiovascular Diseases/etiology , Hyperhomocysteinemia/complications , Amino Acid Metabolism, Inborn Errors/genetics , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Hyperhomocysteinemia/genetics , Infant , Infant, Newborn , Male , Retrospective Studies
20.
Zhongguo Dang Dai Er Ke Za Zhi ; 16(1): 62-6, 2014 Jan.
Article in Zh | MEDLINE | ID: mdl-24461181

ABSTRACT

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. It is known that MTHFR deficiency may result in hyperhomocysteinemia, but MTHFR deficiency-induced schizophrenia has been rarely reported. Here we present the clinical course, biochemical and genetic characteristics of schizophrenia resulted from MTHFR deficiency in a school-age boy. He was 13 years old. He was admitted with a two-year history of fear, auditory hallucination, learning difficulty, sleeping problems, irascibility, drowsing and giggling. At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine. Further DNA sequencing analysis showed 665C>T homozygous mutations in the MTHFR gene. The patient was diagnosed with MTHFR deficiency-associated schizophrenia and treatment with calcium folinate, vitamin B12, vitamin B6, and betaine was initiated. After the treatment for 1 week, his plasma and urine levels of homocysteine were decreased to a normal range and the clinical symptoms were significantly improved. After 3 months of treatment, the patient returned to school. He is now living with normal school life. In summary, children with late-onset MTHFR deficiency and secondary cerebral folate deficiency may lead to schizophrenia. This rare condition can be early diagnosed through analyses of blood and urine total homocysteine, amino acids in blood and folate in blood and cerebral fluid and successfully treated with folinic acid, vitamin B6, vitamin B12 and betaine.


Subject(s)
Homocystinuria/complications , Methylenetetrahydrofolate Reductase (NADPH2)/deficiency , Muscle Spasticity/complications , Schizophrenia/etiology , Adolescent , Base Sequence , Homocystinuria/diagnosis , Homocystinuria/drug therapy , Humans , Male , Molecular Sequence Data , Muscle Spasticity/diagnosis , Muscle Spasticity/drug therapy , Psychotic Disorders/complications , Psychotic Disorders/diagnosis , Psychotic Disorders/drug therapy
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