Comprehensive radiomics nomogram for predicting survival of patients with combined hepatocellular carcinoma and cholangiocarcinoma.

BACKGROUND: Combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (cHCC-CCA) is defined as a single nodule showing differentiation into HCC and intrahepatic cholangiocarcinoma and has a poor prognosis. AIM: To develop a radiomics nomogram for predicting post-resection survival of patients with cHCC-CCA. METHODS: Patients with pathologically diagnosed cHCC-CCA were randomly divided into training and validation sets. Radiomics features were extracted from portal venous phase computed tomography (CT) images using the least absolute shrinkage and selection operator Cox regression and random forest analysis. A nomogram integrating the radiomics score and clinical factors was developed using univariate analysis and multivariate Cox regression. Nomogram performance was assessed in terms of the C-index as well as calibration, decision, and survival curves. RESULTS: CT and clinical data of 118 patients were included in the study. The radiomics score, vascular invasion, anatomical resection, total bilirubin level, and satellite lesions were found to be independent predictors of overall survival (OS) and were therefore included in an integrative nomogram. The nomogram was more strongly associated with OS (hazard ratio: 8.155, 95% confidence interval: 4.498-14.785, P < 0.001) than a model based on the radiomics score or only clinical factors. The area under the curve values for 1-year and 3-year OS in the training set were 0.878 and 0.875, respectively. Patients stratified as being at high risk of poor prognosis showed a significantly shorter median OS than those stratified as being at low risk (6.1 vs 81.6 mo, P < 0.001). CONCLUSION: This nomogram may predict survival of cHCC-CCA patients after hepatectomy and therefore help identify those more likely to benefit from surgery.

The effect and safety of preoperative biliary drainage in patients with hilar cholangiocarcinoma: an updated meta-analysis.

BACKGROUND: The effect and safety of preoperative biliary drainage (PBD) in patients with perihilar cholangiocarcinoma are still controversial; the aim of our study is to evaluate all aspects of PBD. METHODS: All included studies featured PBD versus non-PBD (NPBD) groups were from 1996 to 2019 and were extracted from Cochrane Library, Embase, PubMed, and Science Citation Index Expanded. RESULTS: Sixteen studies met the inclusion criteria and were included in this analysis. PBD may lead to a significantly higher incidence of overall morbidities (OR 0.67, 95% CI 0.53, 0.85; P = 0.0009) and intraoperative transfusions (OR 0.72, 95% CI 0.55, 0.94; P = 0.02); moreover, bile leakage (OR 0.58, 95% CI 0.24, 1.41; P = 0.04), infection (OR 0.31, 95% CI 0.20, 0.47; P < 0.00001), and cholangitis (OR 0.18, 95% CI 0.007, 0.48; P = 0.0007) are also related to PBD. However, NPBD was associated with more frequent hepatic insufficiency (OR 3.09, 95% CI 1.15, 8.31; P = 0.03). In the subgroup meta-analysis, the differences in the outcomes of bile leakage and overall morbidity lost significance between the PBD and NPBD groups when the mean total serum bilirubin (TSB) concentration was above 15 mg/dl. CONCLUSION: Meta-analysis demonstrated that compared to NPBD, PBD is associated with a greater risk of several kinds of infection and morbidities, but its ability to reduce postoperative hepatic insufficiency cannot be ignored. In patients with a high TSB concentration, PBD tends to be a better choice. However, these results need to be confirmed in a future prospective randomized trial with large samples to clarify the effects and find a specific TSB concentration for PBD.

Parenchymal-sparing versus extended hepatectomy for colorectal liver metastases: A systematic review and meta-analysis.

AIMS: To assess the safety and efficacy of parenchymal-sparing hepatectomy (PSH) as a treatment of colorectal liver metastases (CLM). METHODS: A comprehensive medical literature search was performed. Perioperative and long-term survival outcomes were pooled. Subgroup analysis and meta-regression analysis were performed to identify potential sources of heterogeneity. RESULTS: A total of 18 studies comprising 7081 CLM patients were eligible for this study. The PSH was performed on 3974 (56.1%) patients. We found that the OS (overall survival; hazard ratio [HR] = 1.01, 95% confidence interval [CI]: 0.94-1.08) and RFS (recurrence-free survival; HR = 1.00, 95% CI: 0.94-1.07) were comparable between non-PSH and PSH group. The perioperative outcomes were better in PSH than in non-PSH group. Non-PSH group was significantly associated with longer operative time (standard mean difference [SMD] = 1.17, 95% CI: 0.33-2.00), increased estimated blood loss (SMD = 1.36, 95% CI: 0.64-2.07), higher intraoperative transfusion rate (risk ratio [RR] = 2.27, 95% CI: 1.60-3.23), and more postoperative complications (RR = 1.39, 95% CI: 1.16-1.66). Meta-regression analyses revealed that no variable influenced the association between surgical types and the survival outcomes. CONCLUSIONS: This study shows that PSH is associated with better perioperative outcomes without compromising oncological outcomes. Given the increasing incidence of hepatic parenchyma, the PSH treatment offers a greater opportunity of repeat resection for intrahepatic recurrent tumors. It should be considered as an effective surgical approach for CLM.

Long non-coding RNA PlncRNA-1 promotes cell proliferation and hepatic metastasis in colorectal cancer.

Emerging evidence has identified that long non-coding RNAs (lncRNAs) may play an important role in the pathogenesis of many cancer types, including colorectal cancer (CRC). However, the role of PlncRNA-1 in CRC remains unclear. The aim of our present study was to investigate the potential functions of PlncRNA-1 in CRC and to identify the underlying mechanisms of action. We demonstrated that up-regulated PlncRNA-1 in CRC tissues and cells promoted cell proliferation by accelerating cell cycle process and inhibiting cell apoptosis in vitro, enhanced tumor growth and matastasis in vivo and was associated with cell migration and invasion, EMT process of CRC cells. In addition, PlncRNA-1 was a target of miR-204 and enhanced the expression of an endogenous miR-204 target, MMP9 in CRC cells. Furthermore, we found that PlncRNA-1 activates Wnt/ß-catenin pathway through the miR-204 in CRC cells. These results suggest that the PlncRNA-1/miR-204/ Wnt/ß-catenin regulatory network may shed light on tumorigenesis in CRC.

The choose of different surgical therapies of hepatic alveolar echinococcosis: A single-center retrospective case-control study.

The aim of this study was to evaluate different surgical therapies for hepatic alveolar echinococcosis in different clinical stages.We analyze the clinical data of 115 patients who received surgical treatment in West China Hospital from January 2004 to June 2016. Among these patients, 77 cases underwent radical hepatic resection (group A, n = 77); 17 cases underwent palliative resection (group B, n = 17), and 21 cases underwent liver transplantation (group C, n = 21) with 12 cases of orthotopic liver transplantation and 9 cases of liver autotransplantation.The postoperative complication rate of radical hepatic resection group was 13.0% (10/77), which is statistically significant (P < .05) than the rate of palliative resection group 29.4% (5/17) or liver transplantation group 23.8% (5/21). The follow-up period ranged from 1 to 72 months. The overall median survival rate of radical resection was 72/77, higher than the rate of palliative group (12/17) or transplantation group (17/21), which was also statistically significant (P < .01).In our study, we believe in that all stages of hepatic alveolar echinococcosis should take active surgical interventions, and radical hepatic resection should be considered as the first-choice treatment for early stage of alveolar echinococcosis, while palliative surgery is still helpful to relieve symptoms and improve the life quality for advanced patients. Liver transplantation might also be an alternative option for the late-stage hepatic alveolar echinococcosis.

Safety of hepatitis B virus core antibody-positive grafts in liver transplantation: A single-center experience in China.

BACKGROUND: Given the shortage of suitable liver grafts for liver transplantation, proper use of hepatitis B core antibody-positive livers might be a possible way to enlarge the donor pool and to save patients with end-stage liver diseases. However, the safety of hepatitis B virus core antibody positive (HBcAb+) donors has been controversial. Initial studies were mainly conducted overseas with relatively small numbers of HBcAb+ liver recipients, and there are few relevant reports in the population of mainland China. We hypothesized that the safety of HBcAb+ liver grafts is not suboptimal. AIM: To evaluate the safety of using hepatitis B virus (HBV) core antibody-positive donors for liver transplantation in Chinese patients. METHODS: We conducted a retrospective study enrolling 1071 patients who underwent liver transplantation consecutively from 2005 to 2016 at West China Hospital Liver Transplantation Center. Given the imbalance in several baseline variables, propensity score matching was used, and the outcomes of all recipients were reviewed in this study. RESULTS: In the whole population, 230 patients received HBcAb+ and 841 patients received HBcAb negative (HBcAb-) liver grafts. The 1-, 3- and 5-year survival rates in patients and grafts between the two groups were similar (patient survival: 85.8% vs 87.2%, 77.4% vs 81.1%, 72.4% vs 76.7%, log-rank test, P = 0.16; graft survival: 83.2% vs 83.6%, 73.8% vs 75.9%, 70.8% vs 74.4%, log-rank test, P = 0.19). After propensity score matching, 210 pairs of patients were generated. The corresponding 1-, 3- and 5-year patient and graft survival rates showed no significant differences. Further studies illustrated that the post-transplant major complication rates and liver function recovery after surgery were also similar. In addition, multivariate regression analysis in the original cohort and propensity score-matched Cox analysis demonstrated that receiving HBcAb+ liver grafts was not a significant risk factor for long-term survival. These findings were consistent in both HBV surface antigen-positive (HBsAg+) and HBsAg negative (HBsAg-) patients.Newly diagnosed HBV infection had a relatively higher incidence in HBsAg- patients with HBcAb+ liver grafts (13.23%), in which HBV naive recipients suffered most (31.82%), although this difference did not affect patient and graft survival (P = 0.50 and P = 0.49, respectively). Recipients with a high HBV surface antibody (anti-HBs) titer (more than 100 IU/L) before transplantation and antiviral prophylaxis with nucleos(t)ide antiviral agents post-operation, such as nucleos(t)ide antiviral agents, had lower de novo HBV infection risks. CONCLUSION: HBcAb+ liver grafts do not affect the long-term outcome of the recipients. Combined with proper postoperative antiviral prophylaxis, utilization of HBcAb+ grafts is rational and feasible.

Two-stage hepatectomy for multiple giant alveolar echinococcosis.

Alveolar echinococcosis is a chronically progressive and potentially fatal disease. Patients with multiple giant alveolar echinococcosis have a poor prognosis when radical resection cannot be achieved, but curative resection can be limited by low future remnant liver volumes. In these cases, 2-stage liver resection may be a better choice: after a first-stage hepatectomy with partial resection, liver regeneration is allowed in the residual liver before proceeding to the second-stage hepatectomy. In this study, we therefore retrospectively reviewed and evaluated the safety and feasibility of two-stage hepatectomy in patients with multiple giant alveolar echinococcosis.We reviewed the data for all patients who underwent 2-stage hepatectomy for multiple giant alveolar echinococcosis between August 2013 and December 2015 at either the West China Hospital of Sichuan University or the Hospital of Ganzi Tibetan Autonomous Prefecture.We identified 7 patients in whom 2-stage hepatectomy was completed. During the first-stage hepatectomy, 4 patients underwent right-sided hepatectomy and the other 3 underwent left-sided hepatectomy. The second-stage hepatectomies were successfully performed 3 months after the first-stage procedures. All patients had follow-up durations of >1 year; there were no cases of operation-related mortality, and no patients experienced disease recurrence.Two-stage hepatectomy is safe and feasible for patients with multiple giant alveolar echinococcosis.

Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and ß-Arrestin-1-Regulated Lactate Metabolism.

BACKGROUND: Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful. METHODS: We used specific ß-adrenergic agonists, as well as ß2-adrenergic receptor (ß2AR) and arrestin knockout models, to study the effects of adaptive ß2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecular and cell biological approaches to elucidate the signaling subnetworks. RESULTS: We observed that the duration of the adaptive ß2AR activation determines its consequences on learning and memory. Short-term formoterol treatment, for 3 to 5 days, improved cognitive function; however, prolonged ß2AR activation, for more than 6 days, produced harmful effects. We identified the activation of several signaling networks downstream of ß2AR, as well as an essential role for arrestin and lactate metabolism in promoting cognitive ability. Whereas Gs-protein kinase A-cyclic adenosine monophosphate response element binding protein signaling modulated monocarboxylate transporter 1 expression, ß-arrestin-1 controlled expression levels of monocarboxylate transporter 4 and lactate dehydrogenase A through the formation of a ß-arrestin-1/phospho-mitogen-activated protein kinase/hypoxia-inducible factor-1α ternary complex to upregulate lactate metabolism in astrocyte-derived U251 cells. Conversely, long-term treatment with formoterol led to the desensitization of ß2ARs, which was responsible for its decreased beneficial effects. CONCLUSIONS: Our results not only revealed that ß-arrestin-1 regulated lactate metabolism to contribute to ß2AR functions in improved memory formation, but also indicated that the appropriate management of one specific stress pathway, such as through the clinical drug formoterol, may exert beneficial effects on cognitive abilities.

Minimizing tacrolimus decreases the risk of new-onset diabetes mellitus after liver transplantation.

AIM: To investigate the impact of minimum tacrolimus (TAC) on new-onset diabetes mellitus (NODM) after liver transplantation (LT). METHODS: We retrospectively analyzed the data of 973 liver transplant recipients between March 1999 and September 2014 in West China Hospital Liver Transplantation Center. Following the exclusion of ineligible recipients, 528 recipients with a TAC-dominant regimen were included in our study. We calculated and determined the mean trough concentration of TAC (cTAC) in the year of diabetes diagnosis in NODM recipients or in the last year of the follow-up in non-NODM recipients. A cutoff of mean cTAC value for predicting NODM 6 mo after LT was identified using a receptor operating characteristic curve. TAC-related complications after LT was evaluated by χ(2) test, and the overall and allograft survival was evaluated using the Kaplan-Meier method. Risk factors for NODM after LT were examined by univariate and multivariate Cox regression. RESULTS: Of the 528 transplant recipients, 131 (24.8%) developed NODM after 6 mo after LT, and the cumulative incidence of NODM progressively increased. The mean cTAC of NODM group recipients was significantly higher than that of recipients in the non-NODM group (7.66 ± 3.41 ng/mL vs 4.47 ± 2.22 ng/mL, P < 0.05). Furthermore, NODM group recipients had lower 1-, 5-, 10-year overall survival rates (86.7%, 71.3%, and 61.1% vs 94.7%, 86.1%, and 83.7%, P < 0.05) and allograft survival rates (92.8%, 84.6%, and 75.7% vs 96.1%, 91%, and 86.1%, P < 0.05) than the others. The best cutoff of mean cTAC for predicting NODM was 5.89 ng/mL after 6 mo after LT. Multivariate analysis showed that old age at the time of LT (> 50 years), hypertension pre-LT, and high mean cTAC (≥ 5.89 ng/mL) after 6 mo after LT were independent risk factors for developing NODM. Concurrently, recipients with a low cTAC (< 5.89 ng/mL) were less likely to become obese (21.3% vs 30.2%, P < 0.05) or to develop dyslipidemia (27.5% vs 44.8%, P <0.05), chronic kidney dysfunction (14.6% vs 22.7%, P < 0.05), and moderate to severe infection (24.7% vs 33.1%, P < 0.05) after LT than recipients in the high mean cTAC group. However, the two groups showed no significant difference in the incidence of acute and chronic rejection, hypertension, cardiovascular events and new-onset malignancy. CONCLUSION: A minimal TAC regimen can decrease the risk of long-term NODM after LT. Maintaining a cTAC value below 5.89 ng/mL after LT is safe and beneficial.

Endothelial tyrosine kinase receptor B prevents VE-cadherin cleavage and protects against atherosclerotic lesion development in ApoE-/- mice.

Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor (BDNF). In addition to its nervous system functions, TrkB is also expressed in the aortic endothelium. However, the effects of endothelial TrkB signaling on atherosclerosis remained unknown. Immunofluorescence analysis revealed that TrkB expression is downregulated in the endothelium of atherosclerotic lesions from ApoE-/- mice compared with the atheroma-free aorta of WT mice. Endothelial TrkB knockdown led to increased lesion size, lipid deposition and inflammatory responses in the atherosclerotic lesions of the ApoE-/- mice compared with the control mice. Mechanistic studies showed that TrkB activation prevented VE-cadherin shedding by enhancing the interaction between vascular endothelial protein tyrosine phosphatase and VE-cadherin, maintaining VE-cadherin in a dephosphorylated state. Our data demonstrate that TrkB is an endothelial injury-response molecule in atherogenesis. Endothelial BDNF/TrkB signaling reduces VE-cadherin shedding and protects against atherosclerotic lesion development in ApoE-/- mice.

Tyrosine kinase receptor B protects against coronary artery disease and promotes adult vasculature integrity by regulating Ets1-mediated VE-cadherin expression.

OBJECTIVE: Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor. In addition to its nervous system functions, TrkB is also expressed in the cardiovascular system. However, the association of TrkB and coronary artery disease (CAD) remains unknown. We investigated the role of TrkB in the development of CAD and its mechanism. APPROACH AND RESULTS: We performed a case-control study in 2 independent cohort of Chinese subjects and found -69C>G polymorphisms of TrkB gene significantly associated with CAD. TrkB -69C homozygotes, which corresponded to decreased TrkB expression by luciferase reporter assay, showed increased risk for CAD. Immunofluorescence analysis revealed that TrkB was expressed in the aortic endothelium in atherosclerotic lesions in humans and ApoE(-/-) mice. TrkB knockdown in the aortic endothelium resulted in vascular leakage in ApoE(-/-) mice. Mechanistic studies showed that TrkB regulated vascular endothelial cadherin (VE-cadherin) expression through induction and activation of Ets1 transcriptional factor. Importantly, TrkB activation attenuated proatherosclerotic factors induced-endothelial hyperpermeability in human vascular endothelial cells. CONCLUSIONS: Our data demonstrate that TrkB protects endothelial integrity during atherogenesis by promoting Ets1-mediated VE-cadherin expression and plays a previously unknown protective role in the development of CAD.

Blockage of GSK3ß-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease.

It is well established that mitochondrial fragmentation plays a key role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), which is highly expressed in nervous system and regulated by various posttranslational modifications including phosphorylation. We identified glycogen synthase kinase (GSK)3ß-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. Moreover, neurons transfected with Ser(40)Ser(44) phosphomimic Drp1 showed increased mitochondria fragmentation and were more vulnerable to amyloid-ß (Aß)-induced apoptosis. Therefore, blocking GSK3ß-induced Drp1 phosphorylation may be an effective way to protect neurons from Aß toxicity. To address this, we designed and synthesized an artificial polypeptide named TAT-Drp1-SpS, which could specifically block GSK3ß-induced Drp1 phosphorylation. Our results demonstrated that TAT-Drp1-SpS treatment could significantly reduce Aß-induced neuronal apoptosis in cultured neurons. Notably, TAT-Drp1-SpS administration in hippocampus Cornu Ammonis 1 (CA1) region significantly reduced Aß burden and rescued the memory deficits in AD transgenic mice. Although Aß has multiple targets to exert its neurotoxicity, our findings suggested that GSK3ß-induced mitochondrial fragmentation was, at least partially, mediated by Aß toxicity and contribute to the pathogenesis of AD. Taken together, GSK3ß-induced Drp1 phosphorylation provides a novel mechanism for mitochondrial fragmentation in AD, and our findings suggested a novel therapeutic strategy for AD.

Blocking GSK3ß-mediated dynamin1 phosphorylation enhances BDNF-dependent TrkB endocytosis and the protective effects of BDNF in neuronal and mouse models of Alzheimer's disease.

Endocytosis of tropomyosin related kinase B (TrkB) receptors has critical roles in brain-derived neurotrophic factor (BDNF) mediated signal transduction and biological function, however the mechanism that is governing TrkB endocytosis is still not completely understood. In this study, we showed that GSK3ß, a key kinase in neuronal development and survival, could regulate TrkB endocytosis through phosphorylating dynamin1 (Dyn1) but not dynamin2 (Dyn2). Moreover, we found that beta-amyloid (Aß) oligomer exposure could impair BDNF-dependent TrkB endocytosis and Akt activation through enhancing GSK3ß activity in cultured hippocampal neurons, which suggested that BDNF-induced TrkB endocytosis and the subsequent signaling were impaired in neuronal model of Alzheimer's disease (AD). Notably, we found that inhibiting GSK3ß phosphorylating Dyn1 by using TAT-Dyn1SpS could rescue the impaired TrkB endocytosis and Akt activation upon BDNF stimuli under Aß exposure. Finally, TAT-Dyn1SpS could facilitate BDNF-mediated neuronal survival and cognitive enhancement in mouse models of AD. These results clarified a role of GSK3ß in BDNF-dependent TrkB endocytosis and the subsequent signaling, and provided a potential new strategy by inhibiting GSK3ß-induced Dyn1 phosphorylation for AD treatment.

Syntaxin 8 modulates the post-synthetic trafficking of the TrkA receptor and inflammatory pain transmission.

Nerve growth factor (NGF) promotes the survival, maintenance, and neurite outgrowth of sensory and sympathetic neurons, and the effects are mediated by TrkA receptor signaling. Thus, the cell surface location of the TrkA receptor is crucial for NGF-mediated functions. However, the regulatory mechanism underlying TrkA cell surface levels remains incompletely understood. In this study, we identified syntaxin 8 (STX8), a Q-SNARE protein, as a novel TrkA-binding protein. Overexpression and knockdown studies showed that STX8 facilitates TrkA transport from the Golgi to the plasma membrane and regulates the surface levels of TrkA but not TrkB receptors. Furthermore, STX8 modulates downstream NGF-induced TrkA signaling and, consequently, the survival of NGF-dependent dorsal root ganglia neurons. Finally, knockdown of STX8 in rat dorsal root ganglia by recombinant adeno-associated virus serotype 6-mediated RNA interference led to analgesic effects on formalin-induced inflammatory pain. These findings demonstrate that STX8 is a modulator of TrkA cell surface levels and biological functions.

A dietary polyphenol resveratrol acts to provide neuroprotection in recurrent stroke models by regulating AMPK and SIRT1 signaling, thereby reducing energy requirements during ischemia.

Polyphenol resveratrol (RSV) has been associated with Silent Information Regulator T1 (SIRT1) and AMP-activated protein kinase (AMPK) metabolic stress sensors and probably responds to the intracellular energy status. Our aim here was to investigate the neuroprotective effects of RSV and its association with SIRT1 and AMPK signaling in recurrent ischemia models. In this study, elderly male Wistar rats received a combination of two mild transient middle cerebral artery occlusions (tMCAOs) as an in vivo recurrent ischemic model. Primary cultured cortical neuronal cells subjected to combined oxygen-glucose deprivation (OGD) were used as an in vitro recurrent ischemic model. RSV administration significantly reduced infarct volumes, improved behavioral deficits and protected neuronal cells from cell death in recurrent ischemic stroke models in vivo and in vitro. RSV treatments significantly increased the intracellular NAD(+) /NADH ratio, AMPK and SIRT1 activities, decreased energy assumption and restored cell energy ATP level. SIRT1 and AMPK inhibitors and specific small interfering RNA (siRNA) for SIRT1 and AMPK significantly abrogated the neuroprotection induced by RSV. AMPK-siRNA and inhibitor decreased SIRT1 activities; however, SIRT1-siRNA and inhibitor had no impact on phospho-AMPK (p-AMPK) levels. These results indicated that the neuroprotective effects of RSV increased the intracellular NAD(+) /NADH ratio as well as AMPK and SIRT1 activities, thereby reducing energy ATP requirements during ischemia. SIRT1 is a downstream target of p-AMPK signaling induced by RSV in the recurrent ischemic stroke model.

LIM kinase 1 (LIMK1) interacts with tropomyosin-related kinase B (TrkB) and Mediates brain-derived neurotrophic factor (BDNF)-induced axonal elongation.

BDNF/TrkB signaling plays critical roles in axonal outgrowth of neurons, the process of which requires the remodeling of the cytoskeleton structure, including microtubules and filamentous actin. However, the mechanism by which BDNF/TrkB signaling regulates cytoskeleton reorganization is still unclear. Here, we identified a novel interaction between LIMK1 and TrkB, which is required for the BDNF-induced axonal elongation. We demonstrated that BDNF-induced TrkB dimerization led to LIMK1 dimerization and transphosphorylation independent of TrkB kinase activity, which could further enhance the activation and stabilization of LIMK1. Moreover, activated LIMK1 translocated to the membrane fraction and phosphorylated its substrate cofilin, thus promoting actin polymerization and axonal elongation. Our findings provided evidence of a novel mechanism for the BDNF-mediated signal transduction leading to axonal elongation.

Sublocalization of Rab23, a mediator of Sonic hedgehog signaling pathway, in hepatocellular carcinoma cell lines.

The novel member of the Rab family of GTPases, Rab23, is an essential negative regulator of the Sonic hedgehog (Shh) signaling pathway. Loss of function mutation of the Rab23 gene causes abnormal development of the neural tube in mice and in certain human congenital diseases. The aberrant overexpression of Rab23 has been associated with various diseases, such as gastric, hepatocellular and lung cancer. The exact function of Rab23 in hepatocellular carcinomas (HCCs), however, remains unknown. Previously, we reported the abnormal sublocalization of Rab23 in lung cancers. In the current study, we investigated the role of Rab23 in HCCs. We report the distinct sublocalization pattern of Rab23 in HCC cell lines. This difference depends on the GDP/GTP-binding form, and inhibition of the Rab23 cycle decreases the expression and nuclear localization of Gli1.

PI3-kinase/Akt pathway-regulated membrane insertion of acid-sensing ion channel 1a underlies BDNF-induced pain hypersensitivity.

Central neural plasticity plays a key role in pain hypersensitivity. This process is modulated by brain-derived neurotrophic factor (BDNF) and also involves the type 1a acid-sensing ion channel (ASIC1a). However, the interactions between the BDNF receptor, tropomyosin-related kinase B (TrkB), and ASIC1a are unclear. Here, we show that deletion of ASIC1 gene suppressed the sustained mechanical hyperalgesia induced by intrathecal BDNF application in mice. In both rat spinal dorsal horn neurons and heterologous cell cultures, the BDNF/TrkB pathway enhanced ASIC1a currents via phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) cascade and phosphorylation of cytoplasmic residue Ser-25 of ASIC1a, resulting in enhanced forward trafficking and increased surface expression. Moreover, in both rats and mice, this enhanced ASIC1a activity was required for BDNF-mediated hypersensitivity of spinal dorsal horn nociceptive neurons and central mechanical hyperalgesia, a process that was abolished by intrathecal application of a peptide representing the N-terminal region of ASIC1a encompassing Ser-25. Thus, our results reveal a novel mechanism underlying central sensitization and pain hypersensitivity, and reinforce the critical role of ASIC1a channels in these processes.

Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants.

Brain-derived neurotrophic factor (BDNF) plays important roles in cell survival, neural plasticity, learning, and stress regulation. However, whether the recently found human BDNF Val66Met (BDNF(Met)) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between the BDNF(Met) polymorphism and stress are unclear. We found that heterozygous BDNF(+/Met) mice displayed hypothalamic-pituitary-adrenal axis hyperreactivity, increased depressive-like and anxiety-like behaviors, and impaired working memory compared with WT mice after 7 d restraint stress. Moreover, BDNF(+/Met) mice exhibited more prominent changes in BDNF levels and apical dendritic spine density in the prefrontal cortex and amygdala after stress, which correlated with the impaired working memory and elevated anxiety-like behaviors. Finally, the depressive-like behaviors in BDNF(+/Met) mice could be selectively rescued by acute administration of desipramine but not fluoxetine. These data indicate selective behavioral, molecular, and structural deficits resulting from the interaction between stress and the human genetic BDNF(Met) polymorphism. Importantly, desipramine but not fluoxetine has antidepressant effects on BDNF(+/Met) mice, suggesting that specific classes of antidepressant may be a more effective treatment option for depressive symptoms in humans with this genetic variant BDNF.

Quality of life and psychological outcome of donors after living donor liver transplantation.

AIM: To investigate the health related quality of life (HRQoL) and psychological outcome of donors after living donor liver transplantation. METHODS: Participants were 92 consecutive liver transplant donors who underwent hepatectomy without middle hepatic vein at West China Hospital of Sichuan University between January 2007 and September 2010. HRQoL was measured using the Chinese version of the Medical Outcomes Study Short Form-36 (SF-36), and psychological symptoms were measured using the Symptom Checklist-90-Revised (SCL-90-R). Data collected from donors were compared to previously published data from the general population. Clinical and demographic data were collected from medical records and questionnaires. RESULTS: The general health score of the SF-36 was significantly lower in females (59.78 ± 12.25) than in males (75.83 ± 22.09). Donors more than 40 years old scored higher in social functioning (85.71 ± 14.59) and mental health (82.61 ± 20.00) than those younger than 40 (75.00 ± 12.13, 68.89 ± 12.98; social functioning and mental health, respectively). Donors who had surgery more than two years prior to the study scored highest in physical functioning (P = 0.001) and bodily pain (P = 0.042) while those less than one year from surgery scored lowest. The health of the liver recipient significantly influenced the general health (P = 0.042), social functioning (P = 0.010), and role-emotional (P = 0.028) of donors. Donors with full-time employment scored highest in role-physical (P = 0.005), vitality (P = 0.001), social functioning (P = 0.016), mental health (P < 0.001), the physical component summary scale (P < 0.001), and the mental component summary scale (MCS) (P < 0.001). Psychological measures indicated that donors were healthier than the general population in obsessive-compulsive behavior, interpersonal sensitivity, phobic anxiety, and paranoid ideation. The MCS of the SF-36 was significantly correlated with most symptom scores of the SCL-90-R. CONCLUSION: HRQoL and psychological outcome were favorable in living liver transplant donors after donation. Specifically, gender, age, time since operation, recipient health condition, and employment after donation, influenced postoperative quality of life.