Publications by authors named "Fuchen Liu"

44 Publications

Impact of preoperative TACE on incidences of microvascular invasion and long-term post-hepatectomy survival in hepatocellular carcinoma patients: A propensity score matching analysis.

Cancer Med 2021 03 1;10(6):2100-2111. Epub 2021 Mar 1.

The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.

Background: To study the influence of preoperative transcatheter arterial chemoembolization (TACE) on the incidence of microvascular invasion (MVI) and long-term survival outcomes in hepatocellular carcinoma (HCC) patients.

Methods: Between January 1, 2010 and December 1, 2014, consecutive HCC patients who underwent curative liver resection were enrolled in this study. Univariable and multivariable regression analyses were used to identify independent predictive factors of MVI. Propensity score matching (PSM) was used to compare the incidences of MVI and prognosis between patients who did and did not receive preoperative TACE. Factors associated with Disease-Free Survival (DFS) and Overall survival (OS) were identified using Cox regression analyses.

Results: Of 1624 patients, 590 received preoperative TACE. The incidence of MVI was significantly lower in patients with preoperative TACE than those without preoperative TACE (39.15% vs. 45.36%, p = 0.015). After PSM, the incidences of MVI were similar in the two groups (38.85% vs. 41.10%, p = 0.473). Multivariable regression analysis revealed preoperative TACE to have no impact on the incidence of MVI. Before PSM, survival of patients with preoperative TACE was significantly worse than those without preoperative TACE (p = 0.032 for DFS and p = 0.027 for OS). After PSM, the difference became insignificant (p = 0.465 for DFS and p = 0.307 for OS). After adjustment for other prognostic variables in the propensity-matched cohort, preoperative TACE was still found not to be associated with DFS and OS after HCC resection. Both before and after PSM, the prognosis of patients was not significantly different between the two groups for BCLC stages 0, A, and B.

Conclusions: Preoperative TACE did not influence the incidence of MVI and prognosis of patients with HCC who underwent 'curative' liver resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957201PMC
March 2021

ONX0912, a selective oral proteasome inhibitor, triggering mitochondrial apoptosis and mitophagy in liver cancer.

Biochem Biophys Res Commun 2021 Apr 17;547:102-110. Epub 2021 Feb 17.

Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, 200040, China. Electronic address:

Proteasome inhibitors represent effective anti-tumor drugs. ONX0912 is a novel oral proteasome inhibitor that selectively targets the chymotrypsin-like activity of 20S proteasome subunits β5 and LMP7 (Low molecular mass polypeptide-7). It has been shown to be effective in hematologic malignancies. However, its anti-tumor effect in solid tumors remains unclear. Here, we discovered that ONX0912 suppressed the expansion of liver cancer cells. ONX0912 treatment led to an increased level of mitochondrial membrane potential collapse and mitochondrial ROS in tumor cells in a concentration- and exposure time-dependent manner, indicating ONX0912 triggers apoptosis through the intrinsic mitochondrial pathway. ONX0912 also induced mitophagy by activating Parkin/Pink pathway. Silencing mitophagy receptor protein, p62, aggravated the ONX0912-mediated apoptosis, which implied a new mechanism for the conversion between autophagy and apoptosis. Furthermore, we found that the ONX0912 target protein, LMP7 was overexpressed in liver cancer tissues compared to their adjacent tissues and increased level of LMP7 predicted worse clinical characteristics and poorer prognosis. In conclusion, we demonstrated that ONX0912 suppressed liver cancer cell expansion by inducing apoptosis and mitophagy. Our data also revealed ONX0912 as a potential clinical therapeutic drug for liver cancer therapy, and inhibition of mitophagy may sensitize the anti-tumor effect of ONX0912.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2021.02.037DOI Listing
April 2021

A mitochondrial myopathy-associated tRNA 7453G>A mutation alters tRNA metabolism and mitochondrial function.

Mitochondrion 2021 03 3;57:1-8. Epub 2020 Dec 3.

Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong 266035 China; Brain Science Research Institute, Shandong University, Jinan, Shandong 250012, China. Electronic address:

Background: Mitochondrial disorders are a group of heterogeneous diseases characterized by biochemical disturbances in oxidative phosphorylation (OXPHOS). Mutations in mitochondrial transfer RNA (mt-tRNA) genes are the most frequently in mitochondrial disease. However, few studies have detailed the molecular mechanisms behind these mutations.

Methods: We performed clinical evaluation, genetic analysis, muscle histochemistry, and molecular and biochemical investigations in muscle tissue and proband-derived cybrid cell lines.

Results: We found a mitochondrial tRNA mutation (m.7453G>A) in a 15-year-old patient with severe mitochondrial myopathy. We demonstrated that this mutation caused impairment of mitochondrial translation, respiratory deficiency, overproduction of reactive oxygen species (ROS), and decreased mitochondrial membrane potential (MMP), which ultimately led to severe mitochondrial myopathy.

Conclusion: Our findings offer valuable new insights into the tRNA m.7453G>A mutation for both the pathogenic mechanism and functional consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mito.2020.11.015DOI Listing
March 2021

Reversible Neuropsychiatric Disturbances Caused by Nitrous Oxide Toxicity: Clinical, Imaging and Electrophysiological Profiles of 21 Patients with 6-12 Months Follow-up.

Neuropsychiatr Dis Treat 2020 23;16:2817-2825. Epub 2020 Nov 23.

Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan City, People's Republic of China.

Purpose: Nitrous oxide (NO) abuse has become an increasingly severe problem in China. The aim of the study was to summarize the features of NO-induced neurology and enhance the awareness of this disease among physicians.

Patients And Methods: We retrospectively reviewed the clinical, imaging, electrophysiological characteristics and the prognosis of patients with NO neurotoxicity in our hospital from January 2016 to August 2019.

Results: Twenty-one patients (average age: 22.6±4.6 years) were collected. Eighty-six percent (18/21) patients presented with acute or subacute neurological disorders as their initial symptoms. The remaining fourteen percent (3/21) had psychiatric symptoms as the earliest symptoms. With progression, movement dysfunction appeared in ninety percent (19/21) of the patients with fifty-three percent (10/19) presented with weakness limited to both lower extremities. Sixty-two percent (13/21) of the patients presented with subjective sensory deficit. Seventy-one percent (15/21) had vibration sense impairment and positive Romberg's sign. Sixty-seven percent of the patients had hyporeflexia or areflexia. Fourteen percent (3/21) showed positive Babinski's sign. Seventy-eight percent (14/18) showed significantly increased homocysteine (HCY) level and only seventeen percent (3/18) showed decreased serum vitamin B level. T hyperintensity involving the posterior columns and lateral columns with inverted V sign in cervical spinal MRI had been observed in forty-seven percent (8/17) of the patients. Axonal peripheral neuropathy occurred in eighty-five percent (17/20) of the patients. The level of serum vitamin B and HCY, as well as imaging findings, were rapidly recovered after supplementation of Vitamin B.

Conclusion: The NO-induced neuropsychiatric disturbances mainly occurred in the young groups and should be recognized by clinicians. The prognosis of NO intoxication is relatively good.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/NDT.S270179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695601PMC
November 2020

Effect of menopausal status on the survival and recurrence of sex-classified hepatocellular carcinoma after liver resection: a case-matched study with propensity score matching.

Aging (Albany NY) 2020 11 24;12(24):25895-25915. Epub 2020 Nov 24.

The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.

Objective: To investigate the impact of menopausal status on the prognosis for sex-classified Hepatocellular carcinoma (HCC) and to establish prognostic nomograms for patients after liver resection.

Results: After propensity score matching (PSM), statistically significant differences in both overall survival (OS) and recurrence-free survival (RFS) were found between men and women HCC patients. Based on Cox regression analysis, these differences were evident in the normal menstruation (N) group expanded with male patients, but not in either the expanded postmenopausal (P) or intermediate (I) groups. Sex disparity was also apparent in the recurrence-free survival (RFS) of the total HCC patients. Integrated with independent factors, nomograms for the OS and RFS of the expanded N group showed higher C-indices of 0.773 and 0.724, respectively, than those of nomograms for the total patients and BCLC stage (P<0.001).

Conclusion: Sex disparity appears to affect both the survival and recurrence of HCC only in normal menstruation women and their matched men. For predicting survival, prognostic nomograms derived from the expanded N group of HCC patients were more accurate for patients with the same clinical conditions.

Methods: The patients (390 females and 1920 males), who underwent curative liver resection for HCC during 2008 to 2012, were screened. The 390 women were divided into three groups: normal menstruation, intermediate, and postmenopausal. To overcome selection bias, the three groups of females were matched with males at a ratio of 1:2, using propensity score matching. Based on further Cox regression analysis, independent factors were integrated into nomograms for OS and RFS by R rms. The accuracy and discrimination of the nomograms were evaluated by the C-index, calibration curve, and decision curve analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.202155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803575PMC
November 2020

Postoperative adjuvant TACE-associated nomogram for predicting the prognosis of resectable Hepatocellular Carcinoma with portal vein Tumor Thrombus after Liver Resection.

Int J Biol Sci 2020 23;16(16):3210-3220. Epub 2020 Oct 23.

The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Navy Medical University, Shanghai 200438, China.

To explore the effects of postoperative adjuvant transarterial chemoembolization (PA-TACE) on the prognosis of HCC patients with Portal Vein Tumor Thrombus (PVTT) undergoing resection, and to develop a PA-TACE-related nomogram for predicting survival individually. Two hundred and ninety-three consecutive HCC patients with PVTT under R0 hepatectomy were recruited. Forty-seven cases had recurrence within one month after surgery. The remaining 246 cases consisted of 90 PA-TACE and 156 non-PA-TACE cases. COX regression analysis was performed for overall survival (OS) or recurrence-free survival (RFS) of these 246 cases, allowing the derivation of independent factors that were integrated into the nomogram. C-index, calibration curves, and risk stratification were performed to evaluate the performance and discriminative power of the nomograms. In 246 patients without recurrence within one month after surgery, the OS and RFS for the PA-TACE group were significantly better than those for the non-PA-TACE group (P<0.0001, P<0.0001, respectively). After Cox regression analysis of OS or RFS, PA-TACE-related nomogram models were constructed. The C-index of the PA-TACE-related nomogram for OS and RFS was 0.72 and 0.73, respectively. Calibration curves revealed a good agreement between predictions and observations for the nomograms. Based on the nomogram-related risk stratification, Kaplan-Meier curves showed powerful discriminative ability. PA-TACE therapy improved the survival of HCC patients with PVTT undergoing hepatectomy. Accurate nomogram models were developed for predicting the individual survival and recurrence of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/ijbs.46896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645989PMC
October 2020

Distal myopathy due to TCAP variants in four unrelated Chinese patients.

Neurogenetics 2021 03 6;22(1):1-10. Epub 2020 Aug 6.

Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.

Distal myopathies are a group of clinically and genetically heterogeneous hereditary muscle disorders characterized by progressive muscular weakness starting in the distal parts of the limbs. The most common subtype of distal myopathy is GNE myopathy, a rare muscle disease with autosomal recessive inheritance. Limb-girdle muscular dystrophy 2G (LGMD2G) is a rare autosomal recessive subtype of LGMDs caused by TCAP variant. Patients with LGMD2G can present with distal myopathy and rimmed vacuoles on muscle pathology. Thus far, the most reported TCAP mutations related to LGMD2G were recessive frameshift or nonsense variants. Here, we described four Chinese patients from unrelated families with LGMD2G due to TCAP mutations. The clinical symptoms of our patients were similar to those previously reported in LGMD2G patients. Three different pathogenic TCAP variants were identified in these patients, including two frameshift variants and one intronic variant. Autophagolysosomes have been observed in one patient by electron microscopy. Our research expands the genetic spectrum of TCAP mutations in China, indicating c.165-166insG is likely the common pathogenic variant. We also provide evidences that autophagy may be involved in the pathophysiology of LGMD2G.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-020-00623-4DOI Listing
March 2021

A novel m.11406 T > A mutation in mitochondrial ND4 gene causes MELAS syndrome.

Mitochondrion 2020 09 10;54:57-64. Epub 2020 Jul 10.

Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, Shandong 266035, China; Brain Science Research Institute, Shandong University, Jinan, Shandong 250012, China. Electronic address:

Pathogenic point mutations of mitochondrial DNA (mtDNA) are associated with a large number of heterogeneous diseases involving multiple systems with which patients may present with a wide range of clinical phenotypes. In this study, we describe a novel heteroplasmic missense mutation, m.11406 T > A, of the ND4 gene encoding the subunit 4 of mitochondrial complex I in a 32-year-old woman with recurrent epileptic seizure, headache and bilateral hearing loss. Skeletal muscle histochemistry demonstrated that approximately 20% of fibers were cytochrome C oxidase (COX) deficient with increased activity of succinate dehydrogenase (SDH). Further investigations in muscle specimens showed significantly reduced level of ND4 protein. It is interesting that the subunits of complex I (ND1 and NDFUB8) and complex IV(CO1) were also remarkably decreased. These findings indicate that ND1, NDFUB8 and CO1 are more susceptible than other subunits to mutations in the mitochondrial ND4 gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mito.2020.06.011DOI Listing
September 2020

Functional connectome fingerprinting accuracy in youths and adults is similar when examined on the same day and 1.5-years apart.

Hum Brain Mapp 2020 Oct 11;41(15):4187-4199. Epub 2020 Jul 11.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Pioneering studies have shown that individual correlation measures from resting-state functional magnetic resonance imaging studies can identify another scan from that same individual. This method is known as "connectotyping" or functional connectome "fingerprinting." We analyzed a unique dataset of 12-30 years old (N = 140) individuals who had two distinct resting state scans on the same day and again 12-18 months later to assess the sensitivity and specificity of fingerprinting accuracy across different time scales (same day, ~1.5 years apart) and developmental periods (youths, adults). Sensitivity and specificity to identify one's own scan was high (average AUC = 0.94), although it was significantly higher in the same day (average AUC = 0.97) than 1.5-years later (average AUC = 0.91). Accuracy in youths (average AUC = 0.93) was not significantly different from adults (average AUC = 0.96). Multiple statistical methods revealed select connections from the Frontoparietal, Default, and Dorsal Attention networks enhanced the ability to identify an individual. Identification of these features generalized across datasets and improved fingerprinting accuracy in a longitudinal replication data set (N = 208). These results provide a framework for understanding the sensitivity and specificity of fingerprinting accuracy in adolescents and adults at multiple time scales. Importantly, distinct features of one's "fingerprint" contribute to one's uniqueness, suggesting that cognitive and default networks play a primary role in the individualization of one's connectome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hbm.25118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502841PMC
October 2020

Mitochondrial encephalopathy Due to a Novel Pathogenic Mitochondrial tRNA m.4349C>T Variant.

Ann Clin Transl Neurol 2020 06;7(6):980-991

Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan, Shandong, 250000, China.

Objective: Mitochondrial diseases are a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA, among which, mutations in mitochondrial tRNA genes possessing prominent status. In most of the cases, however, the detailed molecular pathogenesis of these tRNA gene mutations remains unclear.

Methods: We performed the clinical emulation, muscle histochemistry, northern blotting analysis of tRNA levels, biochemical measurement of respiratory chain complex activities and mitochondrial respirations in muscle tissue and cybrid cells.

Results: We found a novel m.4349C>T mutation in mitochondrial tRNA gene in a patient present with encephalopathy, epilepsy, and deafness. We demonstrated molecular pathomechanisms of this mutation. This mutation firstly disturbed the translation machinery of mitochondrial tRNA and impaired mitochondrial respiratory chain complex activities, followed by remarkable mitochondrial dysfunction and ROS production.

Interpretation: This study illustrated the pathogenicity of a novel m.4349C>T mutation and provided a better understanding of the phenotype associated with mutations in mitochondrial tRNA gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318088PMC
June 2020

"Myo-neuropathy" is commonly associated with mitochondrial tRNA mutation.

J Neurol 2020 Nov 23;267(11):3319-3328. Epub 2020 Jun 23.

Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Shandong University, Jinan, 250000, Shandong, China.

The mitochondrial tRNA (mt-tRNA) mutation is initially associated with myoclonic epilepsy and ragged-red fibers (MERRF). The clinical, laboratory, morphologic and molecular findings from 22 mt-tRNA mutation carriers from local database in East China were analyzed retrospectively. We identified 13 symptomatic and 9 asymptomatic individuals with a known pathogenic mitochondrial tRNA mutation. The most common mutations were m.8344 A>G (81.8%), m.8363G>A (9.1%), m.8356 T>C (4.5%) and m.8356 T>G (4.5%). The degree of mutation heteroplasmy in blood was high both in symptomatic (mean 64.5%, range 41-82%) and asymptomatic individuals (mean 53.1%, range 21-78%). Age at onset ranged from 6 year-old to the age of 66 years (mean 35.8 ± 16.4 years old). The most frequent symptoms were muscle weakness (76.9%), exercise intolerance (76.9%), elevated creatine kinase levels (61.5%), peripheral neuropathy (69.2%) and cerebellar ataxia (61.5%), while myoclonus was only present in 23.1% of symptomatic patients. A diagnosis of mitochondrial myopathy (MM) and neuropathy ataxia and retinitis pigmentosa (NARP/NARP-like) syndrome was made in 77% of symptomatic patients, whereas the classic syndrome of myoclonic epilepsy with ragged-red fibers (MERRF) was rare (23%). In this cohort of patients with mt-tRNA mutation, more than one third of our patients did not develop signs and symptoms of central nervous system involvement even in later stages of the disease, indicating the necessity to investigate the mt-tRNA gene in 'pure' mitochondrial 'myo-neuropathy'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-10017-zDOI Listing
November 2020

Idebenone Protects against Atherosclerosis in Apolipoprotein E-Deficient Mice Via Activation of the SIRT3-SOD2-mtROS Pathway.

Cardiovasc Drugs Ther 2020 Jun 17. Epub 2020 Jun 17.

Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital, Shandong University, Jinan, 25000, Shandong, China.

Purpose: Atherosclerosis, a chronic disease of the arteries, results from pathological processes including the accumulation and aggregation of oxidized low-density lipoprotein (oxLDL) in the vessel walls, development of neointima, formation of a fibrous cap, and migration of immune cells to damaged vascular endothelium. Recent studies have shown that mitochondrial dysfunction is closely associated with the development and progression of atherosclerosis. Idebenone, a short-chain benzoquinone similar in structure to coenzyme Q10, can effectively clear oxygen free radicals as an electron carrier and antioxidant. In the present study, we aim to investigate weather idebenone protects against atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice.

Methods: apoE-/- mice receiving a high-fat diet (HFD) were treated with idebenone for 16 weeks. A total of 60 mice were randomized into the following four groups: (1) HFD, (2) HFD and low-dose idebenone (100 mg/kg/d), (3) HFD and medium-dose idebenone (200 mg/kg/d), and (4) HFD and high-dose (400 mg/kg/d). Proteomic analysis was performed between the HFD and idebenone-high-dose group. Plaque analysis was carried out by histological and immunohistochemical staining. Western blot, TUNEL staining, and MitoSOX assays were performed in human umbilical vein endothelial cells (HUVECs) to investigate the SIRT3-SOD2-mtROS pathway.

Results: Histological and morphological analysis demonstrated that idebenone significantly reduced plaque burden and plaque size. Idebenone treatment effectively stabilized the atherosclerotic plaques. In mice treated with idebenone, 351 up-regulated and 379 down-regulated proteins were found to be significantly altered in proteomic analysis. In particular, the expression of SIRT3, SOD2, and NLRP3 was significantly regulated in the idebenone treatment groups compared with the HFD group both in vivo and in vitro. We further confirmed that idebenone protected against endothelial cell damage and inhibited the production of mitochondrial reactive oxygen species (mtROS) in cholesterol-treated HUVECs.

Conclusions: We demonstrated that idebenone acted as a mitochondrial protective agent by inhibiting the activation of NLPR3 via the SIRT3-SOD2-mtROS pathway. Idebenone may be a promising therapy for patients with atherosclerosis by improving mitochondrial dysfunction and inhibiting oxidative stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10557-020-07018-5DOI Listing
June 2020

Preresidency Publication Productivity of U.S. Neurosurgery Interns.

World Neurosurg 2020 05 31;137:e291-e297. Epub 2020 Jan 31.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA.

Background: Research experience is believed to be an important component of the neurosurgery residency application process. One measure of research productivity is publication volume. The preresidency publication volume of U.S. neurosurgery interns and any potential association between applicant publication volume and the match results of top-ranked residency programs have not been well characterized.

Objective: In this study, we sought to characterize the preresidency publication volume of U.S. neurosurgery residents in the 2018-2019 intern class using the Scopus database.

Methods: For each intern, we recorded the total number of publications, total number of first or last author publications, total number of neuroscience-related publications, mean number of citations per publication, and mean impact factor of the journal per publication. Preresidency publication volumes of interns at the top-25 programs (based on a composite ranking score according to 4 different ranking metrics) were compared with those at all other programs.

Results: We found that 82% of neurosurgery interns included in the analysis (190 interns from 95 programs) had at least 1 publication. The average number of publications per intern among all programs was 6 ± 0.63 (mean ± standard error of the mean). We also found that interns at top-25 neurosurgery residency programs tended to have a higher number of publications (8.3 ± 1.2 vs. 4.8 ± 0.7, P = 0.0137), number of neuroscience-related publications (6.8 ± 1.1 vs. 4.1 ± 0.7, P = 0.0419), and mean number of citations per publication (9.8 ± 1.7 vs. 5.7 ± 0.8, P = 0.0267) compared with interns at all other programs.

Conclusions: Our results provide a general estimate of the preresidency publication volume of U.S. neurosurgery interns and suggest a potential association between publication volume and matching in the top-25 neurosurgery residency programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2020.01.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202965PMC
May 2020

Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis.

EBioMedicine 2019 Sep 5;47:114-127. Epub 2019 Sep 5.

Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China. Electronic address:

Background: There are many reports of the anti-tumour effects of exogenous adenosine in gastrointestinal tumours. Gemcitabine, a first line agent for patients with poor performance status, and adenosine have structural similarities. For these reasons, it is worth exploring the therapeutic efficacy of adenosine and its underlying mechanism in pancreatic cancer.

Methods: Tumour volumes and survival periods were measured in a patient-derived xenograft (PDX) model of pancreatic cancer. The Akt-p21 signalling axis was blocked by p21 silencing or by the Akt inhibitor GSK690693. The combined effect of GSK690693 and adenosine was calculated by the Chou-Talalay equation and verified by measuring fluorescent areas in orthotopic models.

Findings: Among the PDX mice, the tumour volume in the adenosine treatment group was only 61% of that in the saline treatment group. Adenosine treatment in combination with the Akt inhibitor, GSK690693, or the silencing of p21 to interfere with the Akt-p21 axis can switch the senescence-to-apoptosis signal and alleviate drug resistance. A GSK690693-adenosine combination caused 37.4% further reduction of tumour fluorescent areas in orthotopic models compared with that observed in adenosine monotherapy.

Interpretation: Our data confirmed the therapeutic effect of adenosine on pancreatic cancer, and revealed the potential of Akt inhibitors as sensitization agents in this treatment. FUND: The work is supported by grants from the National Natural Science Foundation of China to Dongqin Yang (81572336, 81770579) and Jie Liu (81630016, 81830080), and jointly by the Development Fund for Shanghai Talents (201660).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2019.08.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796568PMC
September 2019

MAT2B mediates invasion and metastasis by regulating EGFR signaling pathway in hepatocellular carcinoma.

Clin Exp Med 2019 Nov 6;19(4):535-546. Epub 2019 Sep 6.

Department of Digestive Diseases of Huashan Hosptial, Fudan University, Shanghai, 200040, China.

The poor prognosis of hepatocellular carcinoma (HCC) patients is mainly due to cancer metastasis. Methionine adenosyltransferase 2β (MAT2B) encodes a regulatory subunit (β) for methionine adenosyltransferase. Previous studies reveal that MAT2B provides a growth advantage for HCC, but its role in metastasis is unknown. This study showed that both in the xenograft zebra fish model and in the lung metastasis model in nude mice, the stable inhibition of MAT2B could suppress the metastasis of HCC cancer cells. Silencing of MAT2B in HCC cell lines could remarkably inhibit migration and invasion. By analysis of human phospho-kinase array membranes, we found several differentially expressed proteins, including phosphor-AKT, phospho-EGFR, phospho-Src family, phospho-FAK, phospho-STAT3 and phospho-ERK. We further confirmed the change of these EGFR pathway-related proteins was in accordance with MAT2B expression pattern through immunoblotting test. Finally, we found that MAT2B was overexpressed in HCC caner tissues and correlated with poor prognosis for HCC patients in clinical manifestation. Our study demonstrated that silencing of MAT2B could suppress liver cancer cell migration and invasion through the inhibition of EGFR signaling, which suggested that MAT2B might serve as a new prognostic marker and therapeutic target for HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10238-019-00579-2DOI Listing
November 2019

Resting-State Functional Network Organization Is Stable Across Adolescent Development for Typical and Psychosis Spectrum Youth.

Schizophr Bull 2020 02;46(2):395-407

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA.

Background: Resting-state functional neuroimaging captures large-scale network organization; whether this organization is intact or disrupted during adolescent development across the psychosis spectrum is unresolved. We investigated the integrity of network organization in psychosis spectrum youth and those with first episode psychosis (FEP) from late childhood through adulthood.

Methods: We analyzed data from Philadelphia Neurodevelopmental Cohort (PNC; typically developing = 450, psychosis spectrum = 273, 8-22 years), a longitudinal cohort of typically developing youth (LUNA; N = 208, 1-3 visits, 10-25 years), and a sample of FEP (N = 39) and matched controls (N = 34). We extracted individual time series and calculated correlations from brain regions and averaged them for 4 age groups: late childhood, early adolescence, late adolescence, adulthood. Using multiple analytic approaches, we assessed network stability across 4 age groups, compared stability between controls and psychosis spectrum youth, and compared group-level network organization of FEP to controls. We explored whether variability in cognition or clinical symptomatology was related to network organization.

Results: Network organization was stable across the 4 age groups in the PNC and LUNA typically developing youth and PNC psychosis spectrum youth. Psychosis spectrum and typically developing youth had similar functional network organization during all age ranges. Network organization was intact in PNC youth who met full criteria for psychosis and in FEP. Variability in cognitive functioning or clinical symptomatology was not related to network organization in psychosis spectrum youth or FEP.

Discussion: These findings provide rigorous evidence supporting intact functional network organization in psychosis risk and psychosis from late childhood through adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/schbul/sbz053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442350PMC
February 2020

ASB3 knockdown promotes mitochondrial apoptosis via activating the interdependent cleavage of Beclin1 and caspase-8 in hepatocellular carcinoma.

Sci China Life Sci 2019 Dec 15;62(12):1692-1702. Epub 2019 Apr 15.

Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, 200040, China.

Apoptosis and autophagy are distinct cellular processes that can be highly interconnected. The cross talk between the two processes is indispensable in determining the overall cell fate. Although the apoptosis-promoting effect of caspases has been demonstrated, the roles of autophagy-related proteins and even autophagy itself in regulating apoptosis remain poorly understood. In our present study, we found that downregulation of ubiquitin E3 ligase ASB3 led to enhanced mitochondrial apoptosis as well as autophagy, which synergistically promoted cell death in hepatocellular carcinoma (HCC). We observed the activation of caspase-8 and decrease of autophagy protein Beclin1 in apoptotic cells that were depleted of ASB3. Beclin1 was mainly cleaved by activated caspase-8 and active Beclin1 initiated mitochondrial apoptosis via locating its C-terminal fragment to mitochondria. In addition, knocking down of Beclin1 markedly blocked the apoptosis, indicating its essential role in the process. Notably, our study indicated that enhanced autophagy level might be involved in the activation of caspase-8 and promote the apoptosis. Taken together, our results demonstrated that ASB3 can regulate mitochondrial pathway of apoptosis by controlling caspase-8 mediated cleavage of Beclin1 in HCC. Therefore, ASB3 may potentially serve as a novel target for HCC therapy, especially when combined with autophagy agonist.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11427-018-9505-0DOI Listing
December 2019

A Gene-Related Nomogram for Preoperative Prediction of Lymph Node Metastasis in Colorectal Cancer.

J Invest Surg 2020 Sep 24;33(8):715-722. Epub 2019 Mar 24.

The First Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.

: To develop and validate a gene-related nomogram for predicting the risk of lymph node (LN) metastasis preoperatively in patients with colorectal cancer (CRC). : RNA-seq data of 581 CRC and 51 normal cases with clinical features were downloaded from TCGA database. In the evaluation cohort with 381 CRC cases, the LASSO regression was used to reduce dimensionality of gene signatures extracted to build gene score. A gene-related nomogram was performed based on the multivariable logistic regression analysis. The performance of the nomogram was assessed by the discrimination, calibration, and clinical usefulness not only in the evaluation, but also in the validation cohort with 200 CRC cases. : A total of 12,590 differentially expressed genes were selected, in which 59 candidates associated with LN metastasis in differentially expressed genes set were screened by LASSO to form the gene score. Based on the analysis of multivariate logistic regression, the gene-related nomogram showed good calibration and discrimination not only in the evaluation cohort (concordance-index 0.93; 95%CI 0.91-0.96), but also in the validation cohort (concordance-index 0.70; 95%CI 0.63-0.78). The decision curve analysis of the gene-related nomogram also provides constructive guidance for the design of operation plan, preoperatively. : The presented genes nomogram may predict the LN metastasis in CRC patients, preoperatively. And 59 hub genes were defined related to LN metastasis of CRC, which can serve as treatment targets for the further study. Preoperative biopsy and gene analysis are needed to develop the operation plan in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08941939.2019.1569738DOI Listing
September 2020

Transcriptome and epigenome landscape of human cortical development modeled in organoids.

Science 2018 12;362(6420)

Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aat6720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426303PMC
December 2018

Hierarchical segmentation using equivalence test (HiSET): Application to DCE image sequences.

Med Image Anal 2019 01 28;51:125-143. Epub 2018 Oct 28.

Université Paris Descartes, Université Sorbonne Paris Cité (USPC), France; Faculté de Pharmacie de Paris - EA bioSTM, France. Electronic address:

Dynamical contrast enhanced (DCE) imaging allows non invasive access to tissue micro-vascularization. It appears as a promising tool to build imaging biomarkers for diagnostic, prognosis or anti-angiogenesis treatment monitoring of cancer. However, quantitative analysis of DCE image sequences suffers from low signal to noise ratio (SNR). SNR may be improved by averaging functional information in a large region of interest when it is functionally homogeneous. We propose a novel method for automatic segmentation of DCE image sequences into functionally homogeneous regions, called DCE-HiSET. Using an observation model which depends on one parameter a and is justified a posteriori, DCE-HiSET is a hierarchical clustering algorithm. It uses the p-value of a multiple equivalence test as dissimilarity measure and consists of two steps. The first exploits the spatial neighborhood structure to reduce complexity and takes advantage of the regularity of anatomical features, while the second recovers (spatially) disconnected homogeneous structures at a larger (global) scale. Given a minimal expected homogeneity discrepancy for the multiple equivalence test, both steps stop automatically by controlling the Type I error. This provides an adaptive choice for the number of clusters. Assuming that the DCE image sequence is functionally piecewise constant with signals on each piece sufficiently separated, we prove that DCE-HiSET will retrieve the exact partition with high probability as soon as the number of images in the sequence is large enough. The minimal expected homogeneity discrepancy appears as the tuning parameter controlling the size of the segmentation. DCE-HiSET has been implemented in C++ for 2D and 3D image sequences with competitive speed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.media.2018.10.007DOI Listing
January 2019

Carbon Defect-Induced Reversible Carbon-Oxygen Interfaces for Efficient Oxygen Reduction.

ACS Appl Mater Interfaces 2018 Nov 8;10(46):39735-39744. Epub 2018 Nov 8.

Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Institute of Functional Nano and Soft Materials (FUNSOM) , Soochow University , Suzhou 215123 , China.

It is a great challenge to fabricate a metal-free oxygen reduction reaction (ORR) electrocatalyst that can operate well in the acidic medium and fuel cells system. Here, a metal-free carbon material C-900 with abundant defect sites is fabricated by a self-sacrificed template and a solid-state reaction strategy. C-900 shows a superior performance to 20% Pt/C in alkaline medium and a performance closer to 20% Pt/C in acidic condition. It can thus be applied in air-breathing fuel cell (without extra operation pressure) as the cathode catalyst, which shows a high performance (1160 W L; ∼62% of 20% Pt/C) with excellent stability. By using oxygen temperature-programmed desorption, the strong selective chemisorption of O on C-900 has been revealed. The excellent chemisorption property of C-900 may originate from the large amounts of carbon defect sites, which have been confirmed by synchrotron radiation-based X-ray absorption spectroscopy. The rich defect sites and excellent chemisorption property can thus induce reversible carbon-oxygen interface for the excellent ORR activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.8b14323DOI Listing
November 2018

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development.

Cell 2018 11;175(4):1088-1104.e23

Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry, Yale School of Medicine, New Haven, CT 06510, USA; Departments of Genetics and of Comparative Medicine, Program in Cellular Neuroscience, Neurodegeneration and Repair, and Yale Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:

Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene's contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2018.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459420PMC
November 2018

ETFDH Mutations and Flavin Adenine Dinucleotide Homeostasis Disturbance Are Essential for Developing Riboflavin-Responsive Multiple Acyl-Coenzyme A Dehydrogenation Deficiency.

Ann Neurol 2018 11 19;84(5):659-673. Epub 2018 Oct 19.

Research Institute of Neuromuscular and Neurodegenerative Disease, Department of Neurology, Qilu Hospital, Shandong University, Jinan, China.

Objective: Riboflavin-responsive multiple acyl-coenzyme A dehydrogenation deficiency (RR-MADD) is an inherited fatty acid metabolism disorder mainly caused by genetic defects in electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). The variant ETF:QO protein folding deficiency, which can be corrected by therapeutic dosage of riboflavin supplement, has been identified in HEK-293 cells and is believed to be the molecular mechanism of this disease. To verify this hypothesis in vivo, we generated Etfdh knockin (KI) mice.

Methods: Tissues from these mice as well as muscle biopsies and fibroblasts from 7 RR-MADD patients were used to examine the flavin adenine dinucleotide (FAD) concentration and ETF:QO protein amount.

Results: All of the homozygous KI mice (Etfdh , KI/KI) were initially normal. After being given a high-fat and vitamin B -deficient (HF-B D) diet for 5 weeks, they developed weight loss, movement ability defects, lipid storage in muscle and liver, and elevated serum acyl-carnitine levels, which are clinically and biochemically similar to RR-MADD patients. Both ETF:QO protein and FAD concentrations were significantly decreased in tissues of HF-B D-KI/KI mice and in cultured fibroblasts from RR-MADD patients. After riboflavin treatment, ETF:QO protein increased in proportion to elevated FAD concentrations, but not related to mRNA levels. These results were further confirmed in cultured fibroblasts from RR-MADD patients.

Interpretation: For the first time, we successfully developed a RR-MADD mice model and confirmed that FAD homeostasis disturbances played a crucial role on the pathomechanism of RR-MADD in this mouse model and culture cells from patients. Supplementation of riboflavin may stabilize variant ETF:QO protein by rebuilding FAD homeostasis. Ann Neurol 2018;84:667-681.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25338DOI Listing
November 2018

Human neuroepithelial stem cell regional specificity enables spinal cord repair through a relay circuit.

Nat Commun 2018 08 24;9(1):3419. Epub 2018 Aug 24.

Cellular Neuroscience, Neurodegeneration and Repair (CNNR) Program, Yale School of Medicine, New Haven, CT, 06536, USA.

Traumatic spinal cord injury results in persistent disability due to disconnection of surviving neural elements. Neural stem cell transplantation has been proposed as a therapeutic option, but optimal cell type and mechanistic aspects remain poorly defined. Here, we describe robust engraftment into lesioned immunodeficient mice of human neuroepithelial stem cells derived from the developing spinal cord and maintained in self-renewing adherent conditions for long periods. Extensive elongation of both graft and host axons occurs. Improved functional recovery after transplantation depends on neural relay function through the grafted neurons, requires the matching of neural identity to the anatomical site of injury, and is accompanied by expression of specific marker proteins. Thus, human neuroepithelial stem cells may provide an anatomically specific relay function for spinal cord injury recovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-05844-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109094PMC
August 2018

Targeting of the C-Jun/BCL-XL/P21 Axis Accelerates the Switch from Senescence to Apoptosis Upon ROC1 Knockdown in Gastric Cancer Cells.

Cell Physiol Biochem 2018 24;48(3):1123-1138. Epub 2018 Jul 24.

Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.

Background/aims: Regulator of cullins-1 (ROC1) is a pivotal component of cullin-RING E3 ubiquitin ligases, which help to regulate distinct cellular processes by governing the degradation of various substrates. Because the role of ROC1 in gastric cancer is largely uncharacterized, we investigated the relationship between ROC1 expression and the prognosis of gastric cancer patients and explored the biological function of ROC1 and its underlying mechanisms in gastric cancer.

Methods: Kaplan-Meier and multivariate Cox regression analyses were used to evaluate the correlation between the carcinogenesis of gastric cancer and ROC1. SA-β-gal staining and the senescence-associated secretory phenotype (SASP) were used to assess ROC1 silencing-induced cellular senescence. A xenograft zebrafish model was used to evaluate the effects of BCL-XL and ROC1 co-silencing on tumor formation in vivo.

Results: High ROC1 expression was correlated with poor prognosis and a low 5-year survival rate of gastric cancer patients. ROC1 depletion significantly inhibited the growth of gastric cancer cells by sequentially inducing p21-mediated cellular senescence and mitochondrial-dependent apoptosis. Functional studies revealed successive upregulation of c-Jun, BCL-XL, and p21 upon ROC1 knockdown. BCL-XL suppression via RNA interference or a BH3 mimetic (ABT-737 or ABT-263) efficiently enhanced the anti-tumor effects of ROC1 knockdown. Equally as important, BCL-XL silencing strengthened ROC1 knockdown-induced apoptosis by blocking p21-mediated senescence.

Conclusions: The c-Jun/BCL-XL/p21 axis promotes senescence to resist ROC1 knockdown-induced apoptosis in gastric cancer cells. Targeted inactivation of BCL-XL could sensitize gastric cancer cells to ROC1 knockdown in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000491979DOI Listing
September 2018

Targeting CAND1 promotes caspase-8/RIP1-dependent apoptosis in liver cancer cells.

Am J Transl Res 2018 15;10(5):1357-1372. Epub 2018 May 15.

Department of Digestive Diseases of Huashan Hospital, Fudan University Shanghai 200040, China.

Cullin-associated NEDD8-dissociated 1 (CAND1) plays a vital role in regulating the activity of Cullin-RING ubiquitin ligases (CRLs), which are frequently dysregulated in cancer. However, the role of CAND1 in hepatocellular carcinoma (HCC) remains unknown. Here, we found that CAND1 was overexpressed in HCC tissues compared to corresponding adjacent liver tissues (71.7% vs 16.7%); high expression of CAND1 was associated with poor overall survival (40.7 vs 57.3 months, P=0.0013); and CAND1 was an independent risk factor for the prognosis of HCC patients (N=138, P=0.018). Functional studies revealed that CAND1 knockdown efficiently suppressed the proliferation of liver cancer cells by activating caspase-8-dependent mitochondrial apoptosis. We also observed a mutual activation loop between caspase-8 and Receptor Interacting Protein 1 (RIP1), which amplified CAND1 knockdown-induced apoptotic signals in the cells. Furthermore, RIP1 inhibitor Necrostatin-1 eliminated the activation of caspase-8. In conclusion, our study pioneered in reporting high CAND1 expression as a predictor of poor prognosis for HCC patients. CAND1 silencing suppressed HCC cell proliferation by inducing caspase-8/RIP1-dependent apoptosis. These findings supported that CAND1 could be a new therapeutic target for liver cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992550PMC
May 2018

Cleavage of potassium channel Kv2.1 by BACE2 reduces neuronal apoptosis.

Mol Psychiatry 2018 07 27;23(7):1542-1554. Epub 2018 Apr 27.

Otolaryngology Key Lab of the Ministry of Health, Qilu Hospital, Shandong University, 107 Wenhuaxi Rd, 250012, Jinan, China.

Potassium channel Kv2.1 regulates potassium current in cortical neurons and potassium efflux is necessary for cell apoptosis. As a major component of delayed rectifier current potassium channels, Kv2.1 forms clusters in the membrane of hippocampal neurons. BACE2 is an aspartyl protease to cleave APP to prevent the generation of Aβ, a central component of neuritic plaques in Alzheimer's brain. We now identified Kv2.1 as a novel substrate of BACE2. We found that BACE2 cleaved Kv2.1 at Thr376, Ala717, and Ser769 sites and disrupted Kv2.1 clustering on cell membrane, resulting in decreased I of Kv2.1 and a hyperpolarizing shift in primary neurons. Furthermore, we discovered that the BACE2-cleaved Kv2.1 forms, Kv2.1-1-375, Kv2.1-1-716, and Kv2.1-1-768, depressed the delayed rectifier I surge and reduced neuronal apoptosis. Our study suggests that BACE2 plays a neuroprotective role by cleavage of Kv2.1 to prevent the outward potassium currents, a potential new target for Alzheimer's treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-018-0060-2DOI Listing
July 2018

Overexpression of RHEB is associated with metastasis and poor prognosis in hepatocellular carcinoma.

Oncol Lett 2018 Mar 10;15(3):3838-3845. Epub 2018 Jan 10.

The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China.

Aberrant expression of Ras homolog enriched in brain (RHEB) has been observed in a variety of cancer tissues and is closely associated with clinicopathological features. However, the expression profile of RHEB in patients with hepatocellular carcinoma (HCC) and its clinical signature with underlying mechanisms have not been explored thus far. To analyze the association between RHEB expression and clinicopathological features, the RHEB expression levels were determined in the present study using gene microarrays, immunohistochemistry and western blotting in 60 liver cancer tissues and 35 normal liver tissues. Downregulation of RHEB expression in liver cancer cell lines was achieved by RNA interfering technology to explore its biological function in HCC. RHEB expression was high in liver cancer tissues, with an increase of 2.00±0.19-fold compared with normal tissues and of 2.00±0.27-fold compared with adjacent non-cancer tissues. RHEB expression increased along with the clinical staging of HCC, and the overall survival and mortality of patients were closely correlated to RHEB levels, micro-vascular invasion, hepatitis B virus-DNA titer, tumor differentiation and pathological satellites (P<0.05). After knocking down RHEB in SMMC-7721 cells, the growth of liver cancer cells was significantly reduced. The majority of cells were blocked in S-phase, and their colony-forming and proliferating abilities significantly decreased (P<0.05). , upon downregulation of RHEB expression, the tumorigenic ability of HCC significantly decreased (P<0.05). These data suggest that RHEB expression is a significant prognostic factor and may be important in HCC cell growth. The present study highlights the importance of RHEB as a novel prognostic marker of HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ol.2018.7759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796355PMC
March 2018

Global spectral clustering in dynamic networks.

Proc Natl Acad Sci U S A 2018 01 16;115(5):927-932. Epub 2018 Jan 16.

Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA 15213;

Community detection is challenging when the network structure is estimated with uncertainty. Dynamic networks present additional challenges but also add information across time periods. We propose a global community detection method, persistent communities by eigenvector smoothing (PisCES), that combines information across a series of networks, longitudinally, to strengthen the inference for each period. Our method is derived from evolutionary spectral clustering and degree correction methods. Data-driven solutions to the problem of tuning parameter selection are provided. In simulations we find that PisCES performs better than competing methods designed for a low signal-to-noise ratio. Recently obtained gene expression data from rhesus monkey brains provide samples from finely partitioned brain regions over a broad time span including pre- and postnatal periods. Of interest is how gene communities develop over space and time; however, once the data are divided into homogeneous spatial and temporal periods, sample sizes are very small, making inference quite challenging. Applying PisCES to medial prefrontal cortex in monkey rhesus brains from near conception to adulthood reveals dense communities that persist, merge, and diverge over time and others that are loosely organized and short lived, illustrating how dynamic community detection can yield interesting insights into processes such as brain development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1718449115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798376PMC
January 2018

Molecular and cellular reorganization of neural circuits in the human lineage.

Science 2017 11;358(6366):1027-1032

Yale Center for Genomic Analysis, Yale School of Medicine, New Haven, CT, USA.

To better understand the molecular and cellular differences in brain organization between human and nonhuman primates, we performed transcriptome sequencing of 16 regions of adult human, chimpanzee, and macaque brains. Integration with human single-cell transcriptomic data revealed global, regional, and cell-type-specific species expression differences in genes representing distinct functional categories. We validated and further characterized the human specificity of genes enriched in distinct cell types through histological and functional analyses, including rare subpallial-derived interneurons expressing dopamine biosynthesis genes enriched in the human striatum and absent in the nonhuman African ape neocortex. Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels, with relevance for brain function and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aan3456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776074PMC
November 2017