GDI2 deletion alleviates neurodegeneration and memory loss in the 5xFAD mice model of Alzheimer's disease.

Accumulation of insoluble deposits of amyloid ß-peptide (Aß), derived from amyloid precursor protein (APP) processing, represents one of the major pathological hallmarks of Alzheimer's disease (AD). Perturbations in APP transport and hydrolysis could lead to increased Aß production. However, the precise mechanisms underlying APP transport remain elusive. The GDP dissociation inhibitor2 (GDI2), a crucial regulator of Rab GTPase activity and intracellular vesicle and membrane trafficking, was investigated for its impact on AD pathogenesis through neuron-specific knockout of GDI2 in 5xFAD mice. Notably, deficiency of GDI2 significantly ameliorated cognitive impairment, prevented neuronal loss in the subiculum and cortical layer V, reduced senile plaques as well as astrocyte activation in 5xFAD mice. Conversely, increased activated microglia and phagocytosis were observed in GDI2 ko mice. Further investigation revealed that GDI2 knockout led to more APP co-localized with the ER rather than the Golgi apparatus and endosomes in SH-SY5Y cells, resulting in decreased Aß production. Collectively, these findings suggest that GDI2 may regulate Aß production by modulating APP intracellular transport and localization dynamics. In summary, our study identifies GDI2 as a pivotal regulator governing APP transport and process implicated in AD pathology; thus highlighting its potential as an attractive pharmacological target for future drug development against AD.

Postoperative plasma presepsin as a biomarker of postoperative infectious complications in different surgical departments: A meta-analysis and systematic review.

BACKGROUND: High rates of postoperative infection persist after different surgical procedures, encompassing surgical site infections (SSIs), remote infections, sepsis, and septic shock. Our aim was to assess presepsin's diagnostic accuracy for postoperative infections in patients across surgical procedures. METHOD: We conducted a comprehensive search in seven databases, extracting data independently. Using STATA 14.0, we calculated pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and Under the receiver operator curve and 95 â€‹% confidence interval (AUC, 95 â€‹% CI) as primary outcomes, with secondary outcomes involving sensitivity and specificity in subgroup analyses. RESULTS: This meta-analysis of 14 studies (1891 cases) evaluated presepsin's diagnostic value for postoperative infectious complications. Results include sensitivity of 77 â€‹% (70-83), specificity of 81 â€‹% (71-88), DOR of 14 (8-26), AUC of 84 (80-87), PLR of 4 (3-6), and NLR of 0.28 (0.21-0.38). Presepsin exhibits promise as a diagnostic tool for postoperative infections. CONCLUSION: In summary, compared to conventional markers like C-reactive protein (CRP) and procalcitonin (PCT), presepsin demonstrated superior sensitivity and specificity for detecting postoperative infectious complications across various surgical procedures.

Application of combined preoperative indocyanine green lymphography and ultrasonography for low-pressure vein localization in secondary lymphedema surgery for breast cancer.

BACKGROUND: This study aimed to investigate the value of preoperative indocyanine green (ICG) lymphography combined with ultrasonography for low-pressure vein localization in secondary lymphedema surgery for breast cancer. METHODS: A total of 29 patients who were admitted to the breast surgery department of our hospital from July 2019 to May 2021 were included in this study. All patients received preoperative reverse lymphography and ultrasonography for low-pressure vein in lymphedema surgery. Three arm circumferences were measured before surgery, 6 months after surgery, and 12 months after surgery for comparison with the healthy limb at the same time. RESULTS: Arm circumference at 12 months after surgery was significantly different from those at the preoperative period and 6 months after surgery (P < 0.05). However, this parameter after surgery was still significantly higher than that of the healthy limb (P < 0.05). CONCLUSIONS: The application of preoperative ICG lymphography combined with ultrasonography for low-pressure vein localization before surgery can greatly shorten operation duration by reducing the number of ineffective incisions and improving the probability of vein-lymphatic vessel matching, while ensuring the postoperative efficacy for patients.

Diagnostic Accuracy of Procalcitonin for Infection After Adult Liver Transplantation: A Meta-Analysis and Systematic Review.

Background: Post-operative infection remains a major cause of morbidity and mortality in adults early after liver transplantation (LT). Procalcitonin (PCT) may be a good test method for early diagnosis of post-operative infection and determining its severity. This study was performed to assess the diagnostic accuracy of PCT as a biomarker for infection after LT. Patients and Methods: A meta-analysis and systematic review was conducted for studies reporting diagnostic performance of PCT for infection in adults after LT. Observational studies were evaluated for their reporting of diagnostic accuracy, relevance, and quality. Results: Ten eligible studies assessing 730 patients were included in this meta-analysis and systematic review summarizing the diagnostic value of PCT for post-operative infection in adult liver transplantation. Pooled sensitivity and specificity with corresponding 95% confidence interval were 69% (95% confidence interval [CI], 54-81; heterogeneity I2 = 82.4%) and 88% (95% CI, 82-92; I2 = 52.7%), respectively. The diagnostic odd ratio (DOR) was 16 (95% CI, 10-25; I2 = 76.4%). The summary receiver operator characteristic (SROC) of PCT for post-operative infection was 0.88. There was a wide range of variability in the cutoff values, ranging from 0.22 to 42.80 ng/mL. Heterogeneity was reduced by excluding studies that focused on pediatric LT recipients. Conclusions: Procalcitonin is a moderately accurate diagnostic marker for post-operative infection in adult LT. Additionally, the diagnostic performance can be improved by combining it with other inflammatory biomarkers. This article provides the research direction for post-operative infection control.

Highly tumoricidal efficiency of non-oxidized MXene-Ti3C2Tx quantum dots on human uveal melanoma.

Uveal melanoma (UM) is a highly malignant intraocular tumor with poor prognosis. Current topical ophthalmic therapies purpose to conserve the eye and useful vision. Due to the risks and limited clinical benefits, the topical treatments of UM remain challenging and complex. In this study, newly developed non-oxidized MXene-Ti3C2Tx quantum dots (NMQDs-Ti3C2Tx) are proposed for UM treatment. Surprisingly, NMQDs-Ti3C2Tx shows significant tumor-killing effects on UM cells in a dose-dependent manner and causes severe necrosis near the injection site on the xenograft UM tumor model. Moreover, NMQDs-Ti3C2Tx exhibits excellent biocompatibility with normal retina pigment epithelium (RPE) cells and does not cause any damage in C57BL/6 mice eyes. Mechanistically, NMQDs-Ti3C2Tx inhibits the proliferation, invasion, and migration of UM cells via its desirable reactive oxygen species (ROS) generation ability, which causes lipid peroxidation and mitophagy, triggering cell ferroptosis. Furthermore, NMQDs-Ti3C2Tx is detected accumulating in autolysosomes which exacerbates cell death. This work provides new light on the topical treatment of UM.

Postoperative serum myoglobin as a predictor of early allograft dysfunction after liver transplantation.

Background: Early allograft dysfunction (EAD) is a common postliver transplant complication that has been associated with graft failure and risk for poor prognosis. There are many risk factors for the incidence of EAD after liver transplantation (LT). This study investigated whether elevated postoperative myoglobin (Mb) increases the incidence of EAD in liver transplanted recipients. Methods: A total of 150 adult recipients who measured Mb within 3 days after liver transplantation between June 2019 and June 2021 were evaluated. Then, all patients were divided into two groups: the EAD group and the non-EAD group. Univariate and multivariate logistic regression analyses were performed, and receiver operating characteristic curves (ROCs) were constructed. Results: The incidence of EAD was 53 out of 150 patients (35.3%) in our study. Based on the multivariate logistic analysis, the risk of EAD increased with elevated postoperative Mb (OR = 1.001, 95% CI 1.000-1.001, P = 0.002). The Mb AUC was 0.657, and it was 0.695 when combined with PCT. When the subgroup analysis was conducted, the AUC of serum Mb prediction was better in patients whose preoperative model for end-stage liver disease score ≤ 15 or operative time ≥ 10 h (AUC = 0.751, 0.758, respectively, or 0.760, 0.800 when combined with PCT). Conclusion: Elevated Mb significantly increased the risk of postoperative EAD, suggesting that postoperative Mb may be a novel predictor of EAD after liver transplantation.The study was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2100044257, URL: http://www.chictr.org.cn).

Discovering Innate Driver Variants for Risk Assessment of Early Colorectal Cancer Metastasis.

Metastasis is the main fatal cause of colorectal cancer (CRC). Although enormous efforts have been made to date to identify biomarkers associated with metastasis, there is still a huge gap to translate these efforts into effective clinical applications due to the poor consistency of biomarkers in dealing with the genetic heterogeneity of CRCs. In this study, a small cohort of eight CRC patients was recruited, from whom we collected cancer, paracancer, and normal tissues simultaneously and performed whole-exome sequencing. Given the exomes, a novel statistical parameter LIP was introduced to quantitatively measure the local invasion power for every somatic and germline mutation, whereby we affirmed that the innate germline mutations instead of somatic mutations might serve as the major driving force in promoting local invasion. Furthermore, via bioinformatic analyses of big data derived from the public zone, we identified ten potential driver variants that likely urged the local invasion of tumor cells into nearby tissue. Of them, six corresponding genes were new to CRC metastasis. In addition, a metastasis resister variant was also identified. Based on these eleven variants, we constructed a logistic regression model for rapid risk assessment of early metastasis, which was also deployed as an online server, AmetaRisk (http://www.bio-add.org/AmetaRisk). In summary, we made a valuable attempt in this study to exome-wide explore the genetic driving force to local invasion, which provides new insights into the mechanistic understanding of metastasis. Furthermore, the risk assessment model can assist in prioritizing therapeutic regimens in clinics and discovering new drug targets, and thus substantially increase the survival rate of CRC patients.

Long non-coding RNA NORAD promotes the prostate cancer cell extracellular vesicle release via microRNA-541-3p-regulated PKM2 to induce bone metastasis of prostate cancer.

BACKGROUND: Bone metastasis is the leading cause of mortality and reduced quality of life in patients with metastatic prostate cancer (PCa). Long non-coding RNA activated by DNA damage (NORAD) has been observed to have an abnormal expression in various cancers. This article aimed to explore the molecular mechanism underlying the regulatory role of NORAD in bone metastasis of PCa. METHODS: NORAD expression in clinical PCa tissues and cell lines was detected with the application of qRT-PCR. Cancer cells were then transfected with plasmids expressing NORAD, after which Transwell assay and CCK-8 assay were carried out to detect proliferation, migration, and bone metastasis of PCa. NORAD downstream target molecules were screened through bioinformatics analysis, followed by further verification using dual luciferase assay. Extracellular vesicles (EVs) were labeled with PKH67 and interacted with bone marrow stromal cells. The gain- and loss-function method was applied to determine the internalization and secretion of PCa cells-derived EVs under the intervention of downstream target molecules or NORAD. RESULTS: PCa tissues and cell lines were observed to have a high expression of NORAD, particularly in tissues with bone metastasis. NORAD knockdown resulted in reduced secretion and internalization of EVs, and suppressed proliferation, migration, and bone metastasis of PCa cells. It was indicated that NORAD interacted with miR-541-3p, leading to the upregulation of PKM2. Forced expression of PKM2 promoted the transfer of PKH67-labeled EVs to bone marrow stromal cells. CONCLUSIONS: NORAD might serve as a ceRNA of miR-541-3p to promote PKM2 expression, thereby enhancing the development of bone metastasis in PCa by promoting internalization and transfer of EVs of cancer cells, providing an insight into a novel treatment for the disorder.

Resection and reconstruction of a giant primitive neuroectodermal tumour of the abdominal wall with an ultra-long lateral circumflex femoral artery musculocutaneous flap: a case report.

BACKGROUND: Primitive neuroectodermal tumours are clinically rare. Here, we report a case of a large peripheral primitive neuroectodermal tumour of the abdominal wall. The defect was reconstructed with the longest lateral circumflex femoral artery musculocutaneous flap reported to date. CASE PRESENTATION: A 15-year-old male suffered rupture and bleeding of an abdominal wall mass with a volume of approximately 23*18*10 cm3, involving the whole layer of the abdominal wall. Pathological examination revealed a peripheral primitive neuroectodermal tumour. The tumour was removed via oncologic resection, and the abdominal wall was reconstructed with a bilateral 44*8 cm2 lateral circumflex femoral artery musculocutaneous flap combined with a titanium polypropylene patch. The patient had smooth recovery postoperative, and the functions of the donor and recipient areas of the flap were not significantly affected. CONCLUSION: In this case report, we describe a rare primitive neuroectodermal tumour of the abdominal wall, which invaded almost the entire abdominal wall due to delay of treatment. After thoroughly removing the tumour, we immediately reconstructed the abdominal wall with an ultra-long lateral circumflex femoral artery musculocutaneous flap and achieved better appearance and function after the operation. This case suggests that we should adopt an integrated scheme of surgery combined with radiotherapy and chemotherapy in the treatment of peripheral primitive neuroectodermal tumours. Under the premise of determining the blood supply, the lateral circumflex femoral artery musculocutaneous flap can be cut to a sufficient length.

Lower serum nicotinamide N-methyltransferase levels in patients with bipolar disorder during acute episodes compared to healthy controls: a cross-sectional study.

BACKGROUND: Nicotinamide N-methyltransferase (NNMT) has been implicated in the pathogenesis of neuropsychiatric diseases. Bipolar disorder (BD) is associated with metabolic abnormalities and NNMT regulates energy metabolism and may also exert a causal role in metabolic disorders. The present study aimed to determine serum NNMT levels in patients with BD and compared the results with that of healthy controls, to explore the correlation between NNMT and clinical and metabolic characteristics. METHODS: The NNMT levels of 80 patients having a manic episode of BD and 65 non-psychiatric control individuals were measured using enzyme-linked immunosorbent assay. Metabolic parameters were evaluated using standard laboratory methods. RESULTS: The serum NNMT levels of bipolar mania patients were significantly lower than that of non-psychiatric controls. Furthermore, the serum levels of NNMT were found to be negatively correlated with Young Mania Rating Scale (YMRS) scores and the duration of the illness. Moreover, lower NNMT serum levels were found in patients with a history of antipsychotic medication and dyslipidemia. Our results also demonstrated the different patterns of correlation that exist between the study groups. Serum NNMT levels were found to be negatively correlated with triglyceride, cholesterol, and apolipoprotein B levels in the BD group, while the same was found to be negatively associated only with high-density lipoprotein cholesterol in the control group. CONCLUSIONS: These findings support the suggestion that lower NNMT serum levels are significantly associated with BD and that serum NNMT has the potential to regulate lipid metabolism in BD patients.

Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer.

The acquisition of ectopic fibroblast growthfactor receptor 1 (FGFR1) expression is well documented in prostate cancer progression. How it contributes to prostate cancer progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here, we report that FGFR1 tyrosine kinase reprograms the energy metabolism of prostate cancer cells by regulating the expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. LDHA depletion compromised, whereas LDHB depletion enhanced the tumorigenicity of prostate cancer cells. Furthermore, FGFR1 overexpression and aberrant LDH isozyme expression were associated with short overall survival and biochemical recurrence times in patients with prostate cancer. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of prostate cancer cells, representing a hallmark change in prostate cancer progression.Significance: FGF signaling drives the Warburg effect through differential regulation of LDHA and LDHB, thereby promoting the progression of prostate cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4459/F1.large.jpg Cancer Res; 78(16); 4459-70. ©2018 AACR.

Plasma levels of microRNA-24, microRNA-320a, and microRNA-423-5p are potential biomarkers for colorectal carcinoma.

BACKGROUND: MicroRNAs are stable and easy to detect in plasma. The plasma levels of microRNAs are often changed in disease conditions, including cancer. This makes circulating microRNAs a novel class of biomarkers for cancer diagnosis. Analyses of online microRNA data base revealed that expression level of three microRNAs, microRNA-24 (miR-24), microRNA-320a (miR-320a), and microRNA-423-5p (miR-423-5p) were down-regulated in colorectal cancer (CRC). However, whether the plasma level of these three microRNAs can serve as biomarkers for CRC diagnosis and prognosis is not determined. METHODS: Plasma samples from 223 patients with colorectal related diseases (111 cancer carcinoma, 59 adenoma, 24 colorectal polyps and 29 inflammatory bowel disease) and 130 healthy controls were collected and subjected to reverse transcription-quantitative real time PCR (RT-qPCR) analyses for the three microRNAs. In addition, plasma samples from 43 patients were collected before and after surgical treatment for the same RT-qPCR analyses. RESULTS: The concentrations of plasma miR-24, miR-320a and miR-423-5p were all decreased in patients with CRC and benign lesions (polyps and adenoma) compared with healthy controls, but increased in inflammatory bowel disease (IBD). The sensitivity of miR-24, miR-320a and miR-423-5p for early stage of CRC were 77.78 %, 90.74 %, and 88.89 %, respectively. Moreover, the plasma concentration of the three microRNAs was increased in patients after the surgery who had clinical improvement. CONCLUSIONS: The plasma levels of miR-24, miR-320a, and miR-423-5p have promising potential to serve as novel biomarkers for CRC detection, especially for early stage of CRC, which are superior to the currently used clinical biomarkers for CRC detection, such as CEA and CA19-9. Further efforts to develop the three microRNAs as biomarkers for early CRC diagnosis and prediction of surgical treatment outcomes are warrant.

Type 2 Fibroblast Growth Factor Receptor Signaling Preserves Stemness and Prevents Differentiation of Prostate Stem Cells from the Basal Compartment.

Prostate stem cells (P-SCs) are capable of giving rise to all three lineages of prostate epithelial cells, which include basal, luminal, and neuroendocrine cells. Two types of P-SCs have been identified in both human and mouse adult prostates based on prostasphere or organoid cultures, cell lineage tracing, renal capsule implantation, and expression of luminal- and basal-specific proteins. The sphere-forming P-SCs are from the basal cell compartment that express P63, and are therefore designated as basal P-SCs (P-bSCs). Luminal P-SCs (P-lSCs) express luminal cytokeratins and Nkx3.1. Herein, we report that the type 2 FGF receptor (FGFR2) signaling axis is crucial for preserving stemness and preventing differentiation of P-bSCs. FGFR2 signaling mediated by FGFR substrate 2α (FRS2α) is indispensable for formation and maintenance of prostaspheres derived from P63(+) P-bSCs. Ablation of Fgfr2 in P63(+) cells in vitro causes the disintegration of prostaspheres. Ablation of Fgfr2 in vivo reduces the number of P63-expressing basal cells and enriches luminal cells. This suggests a basal stem cell-to-luminal cell differentiation. In addition, ablation of Fgfr2 in P63(+) cells causes defective postnatal development of the prostate. Therefore, the data indicate that FGFR2 signaling is critical for preserving stemness and preventing differentiation of P-bSCs.

Prostate Sphere-forming Stem Cells Are Derived from the P63-expressing Basal Compartment.

Prostate stem cells (P-SCs) are capable of giving rise to all three lineages of prostate epithelial cells, including basal, luminal, and neuroendocrine cells. Multiple methods have been used to identify P-SCs in adult prostates. These include in vivo renal capsule implantation of a single epithelial cell with urogenital mesenchymal cells, in vitro prostasphere and organoid cultures, and lineage tracing with castration-resistant Nkx3.1 expression (CARN), in conjunction with expression of cell type-specific markers. Both organoid culture and CARN tracing show the existence of P-SCs in the luminal compartment. Although prostasphere cells predominantly express basal cell-specific cytokeratin and P63, the lineage of prostasphere-forming cells in the P-SC hierarchy remains to be determined. Using lineage tracing with P63(CreERT2), we show here that the sphere-forming P-SCs are P63-expressing cells and reside in the basal compartment. Therefore we designate them as basal P-SCs (P-bSCs). P-bSCs are capable of differentiating into AR(+) and CK18(+) organoid cells, but organoid cells cannot form spheres. We also report that prostaspheres contain quiescent stem cells. Therefore, the results show that P-bSCs represent stem cells that are early in the hierarchy of overall prostate tissue stem cells. Understanding the contribution of the two types of P-SCs to prostate development and prostate cancer stem cells and how to manipulate them may open new avenues for control of prostate cancer progression and relapse.

Myricetin suppresses differentiation of 3 T3-L1 preadipocytes and enhances lipolysis in adipocytes.

Myricetin (MyR), a naturally occurring flavonol widely distributed in fruits, vegetables, and medicinal plants, has anticancer, anti-inflammatory, antihyperlipidaemic, and antiobesity activities. In the present study, we hypothesized that the antiobesity property of MyR is mediated via suppression of differentiation of preadipocytes into adipocytes and promotion of lipolysis of mature adipocytes, which effectively decrease the intracellular triglyceride concentration of adipocytes. Accordingly, the aim of this work was to investigate the effects of MyR on adipocyte differentiation and lipolysis in differentiated 3 T3-L1 adipocytes. Our results showed that MyR inhibited differentiation of 3 T3-L1 preadipocytes in a concentration-dependent manner. Myricetin downregulated the mRNA and protein levels of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ, both of which are major adipogenic transcription factors. Furthermore, the mRNA levels of other adipogenesis-related transcription factors, namely, CCAAT/enhancer-binding protein ß, sterin regulatory element binding protein 1-c, peroxisome proliferator-activated receptor γ coactivator-1, adipocyte protein 2, lipoprotein lipase and glucose transporter 4, were also reduced by MyR treatment. Moreover, MyR significantly inhibited the phosphorylation of extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 during the differentiation process. On the other hand, MyR induced a dose-dependent increase in glycerol release in fully differentiated adipocytes, indicating its stimulatory effect on adipocyte lipolysis. Furthermore, MyR downregulated mRNA level of perilipin A and enhanced the phosphorylation level of extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 during lipolysis. Taken together, these findings indicate that MyR exerts antiobesity activity in adipocytes.

Overexpression of DEK gene is correlated with poor prognosis in hepatocellular carcinoma.

The oncogene DEK was originally identified as one of the parts of the DEK­CAN fusion gene, arising from the translocation (6;9) in a subtype of acute myeloid leukemia. Since then, DEK has been shown to promote tumorigenesis in a variety of cancer cell types through its roles in inhibiting cell differentiation, senescence and apoptosis. Certain studies have established that DEK is dysregulated in several types of cancer, including hepatocellular carcinoma (HCC). However, its clinical significance in human HCC remains unknown. In this study, the expression of DEK mRNA and protein was examined in 55 surgical HCC specimens and matched non­tumorous tissues. In addition, the correlation between DEK expression and clinicopathological characteristics and prognosis was analyzed. mRNA and protein levels of DEK were found to be significantly overexpressed in the majority of HCC tumors when compared with matched normal hepatic tissues (P<0.05). In addition, the expression pattern of DEK was closely correlated with differentiation status, portal venous invasion and tumor size (P<0.05). Kaplan­Meier curves demonstrated that patients with higher DEK expression levels had significantly poorer survival than those with lower DEK expression levels (P=0.003). In addition, Cox regression analysis demonstrated that the level of DEK expression may be a valuable prognostic factor (P<0.05). These results suggested that DEK may play a significant role in hepatocyte differentiation and may serve as a useful prognostic marker and biomarker for the staging of HCC.

Autophagy defects suggested by low levels of autophagy activator MAP1S and high levels of autophagy inhibitor LRPPRC predict poor prognosis of prostate cancer patients.

MAP1S (originally named C19ORF5) is a widely distributed homolog of neuronal-specific MAP1A and MAP1B, and bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. Mitochondrion-associated protein LRPPRC functions as an inhibitor for autophagy initiation to protect mitochondria from autophagy degradation. MAP1S and LRPPRC interact with each other and may collaboratively regulate autophagy although the underlying mechanism is yet unknown. Previously, we have reported that LRPPRC levels serve as a prognosis marker of patients with prostate adenocarcinomas (PCA), and that patients with high LRPPRC levels survive a shorter period after surgery than those with low levels of LRPPRC. MAP1S levels are elevated in diethylnitrosamine-induced hepatocelular carcinomas in wildtype mice and the exposed MAP1S-deficient mice develop more malignant hepatocellular carcinomas. We performed immunochemical analysis to evaluate the co-relationship among the levels of MAP1S, LRPPRC, P62, and γ-H2AX. Samples were collected from wildtype and prostate-specific PTEN-deficient mice, 111 patients with PCA who had been followed up for 10 years and 38 patients with benign prostate hyperplasia enrolled in hospitals in Guangzhou, China. The levels of MAP1S were generally elevated so the MAP1S-mediated autophagy was activated in PCA developed in either PTEN-deficient mice or patients than their respective benign tumors. The MAP1S levels among patients with PCA vary dramatically, and patients with low MAP1S levels survive a shorter period than those with high MAP1S levels. Levels of MAP1S in collaboration with levels of LRPPRC can serve as markers for prognosis of prostate cancer patients.

Elevated levels of mitochondrion-associated autophagy inhibitor LRPPRC are associated with poor prognosis in patients with prostate cancer.

BACKGROUND: Autophagy has recently been found to play important roles in tumorigenesis and leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) has been identified as an inhibitor that suppresses autophagy and mitophagy and maintains mitochondrial activity. The authors hypothesized that LRPPRC levels can be used as a biomarker for the diagnosis and prognosis of prostate cancer. METHODS: Immunochemistry analysis was performed to evaluate the levels of LRPPRC in 112 samples collected from patients with prostate adenocarcinoma (PCa) and 38 samples from patients with benign prostatic hyperplasia (BPH) who were enrolled in hospitals in Guangzhou City, China and were followed for 10 years. RESULTS: Significantly higher levels of LRPPRC were found in PCa samples compared with BPH samples. Greater than 75% of patients with PCa demonstrated high levels of LRPPRC whereas only 10% of patients with BPH were found to have similar levels of LRPPRC. The levels of LRPPRC were found to be positively correlated with tumor grade, metastasis, and serum prostate-specific antigen level, but were negatively correlated with hormone therapy sensitivity after 2 years of surgery and overall survival. The association between high levels of LRPPRC and late-stage PCa or hormone therapy insensitivity was confirmed in tissue samples collected from prostate-specific phosphatase and tensin homolog (PTEN)(-/-) mice or hormone-dependent and hormone-independent PCa cell lines. CONCLUSIONS: LRPPRC levels may be used as an independent biomarker for patients with PCa at a late stage with poor prognosis.

A novel role of proteasomal ß1 subunit in tumorigenesis.

p27Kip1 is a key cell-cycle regulator whose level is primarily regulated by the ubiquitin-proteasome degradation pathway. Its ß1 subunit is one of seven ß subunits that form the ß-ring of the 20S proteasome, which is responsible for degradation of ubiquitinated proteins. We report here that the ß1 subunit is up-regulated in oesophageal cancer tissues and some ovarian cancer cell lines. It promotes cell growth and migration, as well as colony formation. ß1 binds and degrades p27Kip1directly. Interestingly, the lack of phosphorylation at Ser158 of the ß1 subunit promotes degradation of p27Kip1. We therefore propose that the ß1 subunit plays a novel role in tumorigenesis by degrading p27Kip1.

Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress.

BACKGROUND: FGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury. METHODS: In this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases. RESULTS: We found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects. CONCLUSION: FGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans.