Stability bearing capacity of concrete filled steel tubular columns subjected to long-term load.

Concrete-filled steel tube (CFST) are commonly used in modern building and bridge applications. Despite their popularity, studies on the investigation of the influence of long-term load on the stability bearing capacity of such elements are scarce. This study investigates how the key parameters including slenderness ratio (λ), axial load ratio (m), and eccentricity ratio (e/r) affect the stability bearing capacity of a CFST column under sustained load. Twenty three CFST columns were fabricated to investigate the effect of long-term load on the stability bearing capacity. Fourteen specimens were subjected to constant compressive loading for 462 days and then tested for failure. The remaining 9 were companion load-free specimens. A three-stage finite element method was used to predict the stability bearing capacity after creep. The results indicate that the stability bearing capacity of CFST columns decrease after being subjected to long-term load. Both the experimental and numerical results indicated that the load of steel tube for long-term load specimens reaching up to the elastic-plastic and plastic process was lower than that of the load-free specimens. Moreover, the corresponding strain of the creep specimens was greater than that of the load-free specimens when the member reached the maximum load. Benchmarking analyses have shown that the creep reduction coefficient (kcr) proposed for CFST columns can be used to predict the reduction of stability bearing capacity after creep. Furthermore, a collected database comprising 49 CFST specimens subjected to long-term load was used to investigate the proposed formulae for kcr. The results show that the formulae were consistent with the experiment results.

Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway.

RNA binding proteins (RBPs) contributes to cancer progression, but the underlying mechanism reminds unclear. Here, we find that DDX21, a representative RBP, is highly expressed in colorectal cancer (CRC), which leads to CRC cell migration and invasion in vitro, and CRC to liver metastasis and lung metastasis in vivo. This effect of DDX21 on CRC metastasis is correlated to the activation of Epithelial-mesenchymal transition (EMT) pathway. Moreover, we reveal that DDX21 protein is phase separated in vitro and in CRC cells, which controls CRC metastasis. Phase-separated DDX21 highly binds on MCM5 gene locus, which is markedly reduced when phase separation is disrupted by mutations on its intrinsically disordered region (IDR). The impaired metastatic ability of CRC upon DDX21 loss is restored by ectopic expression of MCM5, indicating MCM5 is a key downstream target of DDX21 for CRC metastasis. Furthermore, co-higher expressions of DDX21 and MCM5 is significantly correlated with poor survival outcomes of stage III and IV CRC patients, indicating the importance of this mechanism in CRC late and metastatic stage. Altogether, our results elucidate a new model of DDX21 in regulating CRC metastasis via phase separation.

Self-Assembly of a Multifunction DNA Tetrahedron for Effective Delivery of Aptamer PL1 and Pcsk9 siRNA Potentiate Immune Checkpoint Therapy for Colorectal Cancer.

Compared with the traditional single therapy, nanomedicine has promoted a multimodal combination treatment for various carcinomas, especially the development of corresponding intelligent multifunctional biomaterials based on advanced DNA nanotechnology has great potential in cancer combination therapy. Herein, we describe a strategy to "backpack" aptamer PL1, which specifically binds to PD-L1 and Pcsk9 siRNA on well-defined DNA tetrahedral nanoparticles (TDNs) via DNA hybridization, which collectively contributes to the effective therapy for colorectal cancer (CRC). In addition, we designed a targeted TDN upon folic acid (FA) recognition, limiting its release to the sites of tumors where folic acid receptor (FAR) is encountered. Our results demonstrated that the TDN-FA/PL1/Pcsk9-siRNA could free immune cells to target CRC cells and attenuate 83.48% tumor growth in mouse models of CT26 CRC. Mechanically, the cancer-targeting FA guided TDN-FA/PL1/Pcsk9-siRNA into tumor cells, thereby ensuring that the aptamer PL1 could choke the mutual effects between PD-1 and PD-L1, followed by a 1.69-fold increase in T cell number and a 1.9-fold suppression of T cell activity by the PD-1/PD-L1 pathway, while Pcsk9 siRNA decreased Pcsk9 expression averagely to the extent of 65.13% and then facilitated intratumoral infiltration of cytotoxic T cells robustly with IFN-γ and Granzyme B expression. Our results reveal that the multifunctional TND-FA/PL1/Pcsk9-siRNA is effective and safe for CRC therapy, thereby expanding the application of DNA nanotechnology for innovative therapies of various cancers.

Pathological and Prognostic Characterization of Craniopharyngioma Based on the Expression of TrkA, ß-Catenin, Cell Cycle Markers, and BRAF V600E Mutation.

We collected 61 craniopharyngioma (CP) specimens to investigate the expression of TrkA, ß-catenin, BRAF gene mutation, and NTRK1 fusion in CP. There were 37 male and 24 female individuals with a median age of 34 years (range, 4-75 years). Histologically, there were 46 cases of adamantinomatous craniopharyngioma (ACP), 14 cases of papillary craniopharyngioma (PCP), and 1 case with a mixed adamantinomatous and papillary pattern. By immunohistochemistry, we found that moderate/high TrkA expression was detected in 47% (28/60) CP and was significantly higher in adult patients (p = 0.018). Interestingly, TrkA is more expressed in "whorled epithelium" cells in ACP, similar to the localization of abnormal ß-catenin. The abnormal expression rate of ß-catenin was 70% (43/61), and the medium/high cyclin D1 expression rate was 73% (44/60), both of which were significantly higher in ACP than in PCP. Of the CP, 41% (21/51) had a moderate/strong P16-positive signal; 58% (34/59) showed a high Ki-67 expression, and there was a significant correlation between high Ki-67 L.I. and high tumor recurrence (p = 0.021). NTRK1 fusion was not found in CP by fluorescence in situ hybridization (FISH). By PCR, 26% (15/58) CP showed BRAF V600E gene mutation, which mainly occurred in PCP (100%, 14/14) except one case of mixed CP. Moreover, TrkA expression was negatively correlated with Ki-67 index and positively correlated with P16 expression. There was a significantly negative correlation between BRAF V600E mutation and abnormal ß-catenin expression. Our results demonstrate for the first time that TrkA expression might occur in CP, especially in adult CP patients, and suggest that cyclin D1 could be used for ACP histological classification in addition to ß-catenin and BRAF V600E mutation, while Ki-67 could be used as a marker to predict CP recurrence.

Pan-cancer analysis of oncogenic role of Programmed Cell Death 2 Like (PDCD2L) and validation in colorectal cancer.

BACKGROUND: Programmed Cell Death 2 Like (PDCD2L) correlates with cell proliferation, apoptosis and mouse embryonic development. However, the role of PDCD2L in human cancers is unclear. METHODS: Multiple bioinformatic methods, in vitro function experiments and validation were performed to clarify the oncogenic role of PDCD2L in human cancers. RESULTS: Our study found that PDCD2L was aberrantly expressed in multiple types of human cancers, and associated with clinical stage and molecular subtype. Furthermore, overexpression of PDCD2L predicted poor overall survival in adrenocortical carcinoma(ACC), kidney chromophobe(KICH), acute myeloid leukemia(LAML), brain lower grade glioma(LGG),liver hepatocellular carcinoma(LIHC), mesothelioma(MESO), uveal melanoma(UVM) and poor diseases free survival in ACC, bladder urothelial carcinoma(BLCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), kidney renal clear cell carcinoma(KIRC), kidney renal papillary cell carcinoma(KIRP), LGG, LIHC, and UVM. PDCD2L expression was negatively associated with cancer associated fibroblast in breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), sarcoma (SARC), stomach adenocarcinoma (STAD) and testicular germ cell tumors (TGCT). Mechanically, we found that PDCD2L expression was associated with apoptosis, invasion and cell cycle by investigating single cell sequencing data. For further validation, PDCD2Lwas highly expressed in colorectal cancer (CRC) cell lines and tissue samples compared with the normal colon cell line and non-tumor adjacent colorectal mucosa tissues. PDCD2L knockdown induced the apoptosis and proliferation of CRC cells. CONCLUSIONS: Our study shows that the oncogenic role of PDCD2L in various cancers and PDCD2L could be served as a biomarker of CRC.

A Prognosis Marker SLC2A3 Correlates With EMT and Immune Signature in Colorectal Cancer.

SLC2A3 is a membrane transporter that belongs to the solute carrier family, whose function includes transmembrane transport and glucose transmembrane transport activity. To clarify the expression and role of SLC2A3 in colorectal cancer (CRC), we analyzed the TCGA and GEO databases and found that SLC2A3 mRNA levels were significantly higher in CRC tissues than that in adjacent non-tumor tissues. Furthermore, high expression of SLC2A3 predicted poor overall survival and disease free survival for CRC patients. For validation, we collected 174 CRC samples and found that SLC2A3 expression was higher in CRC tissues than that in adjacent non-tumor colorectal mucosa tissues by immunohistochemistry staining. Further study showed that high expression of SLC2A3 was enriched in epithelial-mesenchymal transition (EMT) classical pathway, interferon-γ pathway by GSEA analysis enrichment, indicating that SLC2A3 may play a key role in the progression of CRC through EMT and immune response, which also has been validated by the global gene expression profiling of human CRC cell lines. The expression of SLC2A3 was positively correlated with CD4 and CD8+T cells by using TIMER and EPIC algorithm, respectively. SLC2A3 knockdown suppressed migration and inhibited the expression of Vimentin and MMP9 in CRC cell line SW480 and RKO. Meanwhile, PD-L1 expression was also significantly attenuated in SW480 and RKO cells transfected with SLC2A3 siRNA. The result suggests that SLC2A3 may be involved in the immune response of CRC by regulating PD-L1 immune checkpoint. In our series, SLC2A3 and PD-L1 positive expression was 74% (128/174) and 22% (39/174) of CRC, respectively. SLC2A3 expression was significantly associated with perineural invasion in CRC patients. In conclusion, SLC2A3 may play an important role in progression of CRC by regulating EMT and PD-L1 mediated immune responses.

A novel HDGF-ALCAM axis promotes the metastasis of Ewing sarcoma via regulating the GTPases signaling pathway.

Ewing sarcoma (ES) is a type of highly aggressive pediatric tumor in bones and soft tissues and its metastatic spread remains the most powerful predictor of poor outcome. We previously identified that the transcription factor hepatoma-derived growth factor (HDGF) promotes ES tumorigenesis. However, the mechanisms underlying ES metastasis remain unclear. Here, we show that HDGF drives ES metastasis in vitro and in vivo, and HDGF reduces metastasis-free survival (MFS) in two independent large cohorts of human ES patients. Integrative analyses of HDGF ChIP-seq and gene expression profiling in ES cells reveal that HDGF regulates multiple metastasis-associated genes, among which activated leukocyte cell adhesion molecule (ALCAM) emerges as a major HDGF target and a novel metastasis-suppressor in ES. HDGF down-regulates ALCAM, induces expression and activation of the downstream effectors Rho-GTPase Rac1 and Cdc42, and promotes actin cytoskeleton remodeling and cell-matrix adhesion. In addition, repression of ALCAM and activation of Rac1 and Cdc42 are required for the pro-metastatic functions of HDGF in vitro. Moreover, analyses in murine models with ES tumor orthotopic implantation and experimental metastasis, as well as in human ES samples, demonstrate the associations among HDGF, ALCAM, and GTPases expression levels. Furthermore, high HDGF/low ALCAM expression define a subgroup of patients harboring the worst MFS. These findings suggest that the HDGF/ALCAM/GTPases axis represents a promising therapeutic target for limiting ES metastasis.

Hemangioblastoma: clinicopathologic study of 42 cases with emphasis on TFE3 expression.

Hemangioblastomas (HBs) histologically overlap with TFE3 rearrangement-associated tumors, which present as alveolar architecture and clear or eosinophilic granular cytoplasm. However, whether TFE3 is expressed in HBs remains unexplored. Herein, we analyzed the clinicopathologic features of 42 HBs emphasizing studies of TFE3 expression. Of 42 cases, 38 were sporadic and 4 were regarded as a part of von Hippel-Lindau (VHL) syndrome according to clinical presentation. Nineteen patients were male and 23 were female. Patient age ranged from 17 to 70 years (median 43). Tumor size ranged from 0.4 to 4.8 cm (mean 2.2 cm). Follow-up ranged from 1 to 60 months and 6 patients developed recurrence. Immunohistochemistry staining showed that 36 (86%) of 42 HBs expressed TFE3 in nuclei of tumor cells, of which 21 were evaluated as high TFE3 expression levels. Increased TFE3 expression was significantly associated with older ages (P=0.018) and larger tumor size (P=0.001). Seventeen HBs with high TFE3 expression were negative for rearrangement and amplification of TFE3 by FISH analysis, 3 of which including 2 sporadic and 1 VHL-related HBs demonstrated trisomies or tetrasomies of X-chromosome in 7%~18% of tumor cells. All 3 cases occurred in female, presented with a larger tumor size and displayed a similar morphologic appearance with high cellularity and hyperchromatic nuclei. Our study first reports TFE3 expression and its clinicopathological relevance in HBs. We hypothesize that TFE3 might be involved in the pathogenesis of non-VHL-related HBs. Furthermore, HBs with strong TFE3 expression should be differentiated from brain-metastatic TFE3-rearranged tumors.

BCOR-CCNB3 fusion and BCOR internal tandem duplication in undifferentiated round cell sarcoma: a pathologic and molecular study of 5 cases.

Undifferentiated round cell sarcomas (URCSs) usually remained unclassified due to lack of known genetic abnormalities. Herein, we retrospectively collected 5 cases of URCSs and sought to investigate their unique clinicopathologic and molecular features for providing more accurate classification. There were 2 males and 3 females with age ranged from 7 months to 17 years. The tumors were respectively located in the sacrum, fibula, neck, perineum or groin. Microscopically, all 5 tumors were composed of small-to-medium sized cells with primitive morphology and variable cellularity, distributed within loose myxoid or collagenized fibroid stroma. These tumors lacked specific immunophenotypes and known gene rearrangements. However, the expression levels of CD99 and cyclin D1 were variable. RNA-sequencing data identified one BCOR-CCNB3 gene fusion-positive sarcoma occurring in the sacrum of a 17-year-old male patient. Whole genome sequencing analysis detected BCOR exon 15-internal tandem duplication (BCOR-ITD) in the tumor arising in the groin of one 7-month-old female infant. No specific gene abnormalities were found in the other 3 cases. Interestingly, a morphological and immunohistochemical overlap existed between BCOR-rearrangement tumor and BCOR-ITD-positive tumor, including areas with hypercellularity alternating with hypocellularity, a mixture of round cells and focal spindle cells, pale nuclear chromatin, inconspicuous nucleoli and abundant myxoid matrix, diffuse strong cyclin D1 expression, relatively strong expression of CD99 but lower than that in Ewing sarcoma, and a low Ki-67 proliferation index of about 10%. Our findings demonstrated a significant link between genetic aberration and histopathologic appearances, thus supporting the crucial role of genetic characteristics in accurate clinicopathological classification.

Transplantation of in vitro cultured endothelial progenitor cells repairs the blood-brain barrier and improves cognitive function of APP/PS1 transgenic AD mice.

To date, the pathogenesis of Alzheimer's disease (AD) remains unclear. It is well-known that excessive deposition of Aß in the brain is a crucial part of the pathogenesis of AD. In recent years, the AD neurovascular unit hypothesis has attracted much attention. Impairment of the blood-brain barrier (BBB) leads to abnormal amyloid-ß (Aß) transport, and chronic cerebral hypoperfusion causes Aß deposition throughout the onset and progression of AD. Endothelial progenitor cells (EPCs) are the universal cells for repairing blood vessels. Our previous studies have shown that a reduced number of EPCs in the peripheral blood results in cerebral vascular repair disorder, cerebral hypoperfusion and neurodegeneration, which might be related to the cognitive dysfunction of AD patients. This study was designed to confirm whether EPCs transplantation could repair the blood-brain barrier, stimulate angiogenesis and reduce Aß deposition in AD. The expression of ZO-1, Occludin and Claudin-5 was up-regulated in APP/PS1 transgenic mice after hippocampal transplantation of EPCs. Consistent with previous studies, EPC transplants also increased the microvessel density. We observed that Aß senile plaque deposition was decreased and hippocampal cell apoptosis was reduced after EPCs transplantation. The Morris water maze test showed that spatial learning and memory functions were significantly improved in mice transplanted with EPCs. Consequently, EPCs could up-regulate the expression of tight junction proteins, repair BBB tight junction function, stimulate angiogenesis, promote Aß clearance, and decrease neuronal loss, ultimately improve cognitive function. Taken together, these data demonstrate EPCs may play an important role in the therapeutic implications for vascular dysfunction in AD.

The clinicopathological significance of ZNF10 in invasive ductal carcinoma of the breast.

The aim of this study was to clarify the clinicopathological features and role of zinc finger protein 10 (ZNF10) in breast invasive ductal cancer (IDC). Our data first showed that ZNF10 expression was higher in 8 pairs of fresh breast IDC and breast cancer cell lines compared with their respective adjacent non-tumor breast tissues. ZNF10 expression was significantly higher in IDC compared with DCIS and fibroadenoma of the breast. ZNF10 expression was significantly associated with patients' age, tumor stage, and breast cancer molecular subtype. ZNF10 knockdown inhibited breast cancer cell proliferation, colony formation, cell cycle progression, cell migration, and invasion but induced apoptosis. ZNF10 knockdown also suppressed the tumorigenicity of breast cancer in vivo. The underlying mechanism study showed that ZNF10 regulated the ß-catenin signaling pathway in breast cancer. ZNF10 might bind to the region (nucleotides -300 to +100) of the ß-catenin promoter. In conclusion, our results first suggest that ZNF10 promotes the carcinogenesis and progression of breast IDC via the ß-catenin signaling pathway. Targeting ZNF10 might be a novel treatment strategy for breast cancer.

miR-203a-3p promotes colorectal cancer proliferation and migration by targeting PDE4D.

Colorectal cancer (CRC) is a major worldwide health problem due to its high prevalence and mortality rate. microRNA has been reported playing an important role in a variety of cancers including colorectal cancer. miR-203a-3p has been found up-regulated in CRC tissues compare with the adjacent normal tissues. But, how miR-203a-3p regulates CRC development remains to be elucidated. In this study, gain and loss-of-function assays showed that miR-203a-3p promotes colorectal cancer cell proliferation, colony formation and migration and invasion by targeting PDE4D. And miR-203a-3p/ß-catenin/Cyclin D1/c-Myc signaling pathway is involved in the CRC. In summary, this study highlights an onco-miRNA role for miR-203a-3p by regulating PDE4D in CRC and suggests that miR-203a-3p may be a novel molecular therapeutic target for CRC.

GALNT6 suppresses progression of colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Invasion and metastasis are the main cause of mortality in most CRC patients. Polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6) regulated glycosylation, which is frequently altered in cancers, and play an important role in cancer development. However, the role of GALNT6 in CRC remains unknown. To investigate the role of GALNT6 in CRC, first we studied correlation of GALNT6 expression levels with outcomes of CRC patients and found CRC patients with higher expression of GALNT6 had a better overall survival than those with lower expression. In addition, GALNT6 expression were significantly associated with tumor size, histological differentiation and lymph node metastasis. In vitro, GALNT6 overexpression dramatically inhibited cellular colony formation, migration, and invasion, and promoted the apoptosis of CRC cells. In vivo, CRC with GALNT6 overexpression showed reduced pulmonary metastasis in recipient mice compared with the controls. GALNT6 expression was significantly increased in SW480 and SW1116 cells cultured in hypoxic condition, and decreased in HT29 and LOVO cells with oxidative stress. Affimetrix microarray analysis showed that GALNT6 overexpression induced 279 genes up-regulated and 215 genes down-regulated in CRC. GALNT6 overexpression dramatically suppressed AKT and activated CD28 signaling pathway in CRC. AKT rescue experiment found that AKT was involved in GALNT6-induced CRC cell migration and invasion. In conclusion, our results first suggest that GALNT6 plays an important role in development and progression of CRC as a tumor suppressor gene.

Long-Term Kinetics of Immunologic Components and Neurological Deficits in Rats Following Repetitive Mild Traumatic Brain Injury.

BACKGROUND Despite growing awareness of repetitive mild traumatic brain injury (rmTBI), understanding of the involvement of long-term kinetics of immunologic components in the central and peripheral immune system took part remains incomplete. The present study aimed to provide a quantitative assay for certain immune system parameters in rmTBI rats. MATERIAL AND METHODS Neurological functions were assessed by modified Neurological Severity Score (mNSS) and Morris Water Maze (MWM), immunologic components from brain and peripheral blood were analyzed by flow cytometry (FCM), and concentrations of inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were measure by enzyme-linked immunosorbent assay (ELISA). RESULTS Neurological functions of rmTBI rats were seriously impaired. In the brain, T cells were up-regulated and peaked at week 1. The percentage of CD4+ T cells decreased from week 1 to week 4, while CD8+ T cells notably decreased at week 1, then increased until week 4. The infiltration proportion of Treg cells was reduced at week 1 and peaked at week 2. CD86+/CD11b+ M1 peaked at week 4 and CD206+/CD11b+ M2 rose at week 1. IL-6/IL-10 showed a similar pattern, whose rise corresponded to the decrease in TNF-α at week 2 after rmTBI. FCM demonstrated peripheral immune dysfunction after rmTBI. CONCLUSIONS mNSS and MWM demonstrated neuronal deficits in rmTBI rats, and central and peripheral immune systems were implicated in the pathophysiological processes of rmTBI. Long-term immune response may play dual roles in injury and repair of rmTBI.

The accumulation of brain injury leads to severe neuropathological and neurobehavioral changes after repetitive mild traumatic brain injury.

Traumatic brain injury (TBI) is a major public health problem with long-term neurobehavioral sequela. The evidences have revealed that TBI is a risk factor for later development of neurodegenerative disease and both the single and repetitive brain injury can lead to the neurodegeneration. But whether the effects of accumulation play an important role in the neurodegenerative disease is still unknown. We utilized the Sprague Dawley (SD) rats to develop the animal models of repetitive mild TBI and single mild TBI in order to detect the neurobehavioral changes. The results of neurobehavioral test revealed that the repetitive mild TBI led to more severe behavioral injuries than the single TBI. There were more activated microglia cells and astrocytes in the repetitive mild TBI group than the single TBI group. In consistent with this, the levels of TNF-α and IL-6 were higher and the expression of IL-10 was lower in the repetitive mild TBI group compared with the single TBI group. The expression of amyloid precursor protein (APP) increased in the repetitive TBI group detected by ELISA and western blot. But the levels of total tau (Tau-5) and P-tau (ser202) seem no different between the two groups in most time point. In conclusion, repetitive mild TBI could lead to more severe neurobehavioral impairments and the effects of accumulation may be associated with the increased inflammation in the brain.

[Surgical treatment of hilar cholangiocarcinoma:experience of 53 cases].

OBJECTIVE: To summarize the experience of surgical treatment of the hilar cholangiocarcinoma and explore the factors influencing the operative effect. METHODS: Fifty-three cases of hilar cholangiocarcinoma performed operation from January 1998 to January 2008 were divided into two groups: Group I included cases treated from January 1998 to December 2002 (totally 22 cases); Group II included cases treated from January 2003 to January 2008 (totally 31 cases). Comparative study was carried out between these two groups. RESULTS: Surgical resection [radical resection (R(0)) + palliative resection (R(1))] rate in group I was lower than that in group II (40.9% vs. 71.0%, P = 0.029). Hepatic lobectomy rate in group I was lower than that in group II (30.0% vs. 64.5%, P = 0.016). The resection rate was positively correlated with the hepatic lobectomy rate (r = 0.985, P < 0.01). The median survival time of the patients underwent R(0) resection was longer than that in the patients underwent R(1) resection and palliative bile duct drainage [(27.0 +/- 4.5) months vs. (10.0 +/- 0.7) months vs. (4.0 +/- 0.5) months, respectively, P < 0.01]. CONCLUSIONS: Early diagnosis and radical resection are important to improve the prognosis for patients with hilar cholangiocarcinoma. But for the patients could only receive palliative resection or with positive celiac trunk lymph nodes, combined liver lobe resection could not improve the survival.