A review of emerging bone tissue engineering via PEG conjugated biodegradable amphiphilic copolymers.

Defects in bones can be caused by a plethora of reasons, such as trauma or illness, and in many cases, it poses challenges to the current treatment approaches for bone repair. With increasing demand of bone bioengineering in tissue transplant, there is a need to source for sustainable solutions to induce bone regeneration. Polymeric biomaterials have been identified as a promising approach due to its excellent biocompatibility and controllable biodegradability. Specifically, poly(ethylene glycol) (PEG) is one of the most commonly investigated polymer for use in bio-related application due to its bioinertness and versatility. Furthermore, the hydrophilic nature enables it to be incorporated with hydrophobic but biodegradable polymers like, polylactide (PLA) and polycaprolactone (PCL), to create an amphiphilic polymer. This article reviews the recent synthetic strategies available for the construction of PEG conjugated polymeric system, analysis of PEG influence on the material properties, and provides an overview of its application in bone engineering.

Autocrine hGH stimulates oncogenicity, epithelial-mesenchymal transition and cancer stem cell-like behavior in human colorectal carcinoma.

Tumor derived human growth hormone (hGH) has been implicated in cancer development and progression. However, the specific functional role of autocrine/paracrine hGH in colorectal cancer (CRC) remains largely to be determined. Herein, we demonstrated a crucial oncogenic role of autocrine hGH in CRC progression. Elevated hGH expression was detected in CRC compared to normal colorectal tissue, and hGH expression in CRC was positively associated with tumor size and lymph node metastasis. Forced expression of hGH stimulated cell proliferation, survival, oncogenicity and epithelial to mesenchymal transition (EMT) of CRC cells, and promoted xenograft growth and local invasion in vivo. Autocrine hGH expression in CRC cells stimulated the activation of the ERK1/2 pathway, which in turn resulted in increased transcription of the mesenchymal marker FIBRONECTIN 1 and transcriptional repression of the epithelial marker E-CADHERIN. The autocrine hGH-stimulated increase in CRC cell proliferation, cell survival and EMT was abrogated upon ERK1/2 inhibition. Furthermore, autocrine hGH-stimulated CRC cell migration and invasion was dependent on the ERK1/2-mediated increase in FIBRONECTIN 1 expression and decrease in E-CADHERIN expression. Forced expression of hGH also enhanced CSC-like behavior of CRC cells, as characterized by increased colonosphere formation, ALDH-positive population and CSC marker expression. Autocrine hGH-enhanced cancer stem cell (CSC)-like behavior in CRC cells was also observed to be E-CADHERIN-dependent. Thus, autocrine hGH plays a critical role in CRC progression, and inhibition of hGH could be a promising targeted therapeutic approach to limit disease progression in metastatic CRC patients.

Release of HER2 repression of trefoil factor 3 (TFF3) expression mediates trastuzumab resistance in HER2+/ER+ mammary carcinoma.

HER2+/ER+ breast cancer, a subset of the luminal B subtype, makes up approximately 10% of all breast cancers. The bidirectional crosstalk between HER2 and estrogen receptor (ER) in HER2+/ER+ breast cancer contributes to resistance towards both anti-estrogens and HER2-targeted therapies. TFF3 promotes breast cancer progression and has been implicated in anti-estrogen resistance in breast cancer. Herein, we investigated the cross-regulation between HER2 and estrogen-responsive TFF3, and the role of TFF3 in mediating trastuzumab resistance in HER2+/ER+ breast cancer. TFF3 expression was decreased by HER2 activation, and increased by inhibition of HER2 with trastuzumab in HER2+/ER+ breast cancer cells, partially in an ERα-independent manner. In contrast, the forced expression of TFF3 activated the entire HER family of receptor tyrosine kinases (HER1-4). Hence, HER2 negatively regulates its own signalling through the transcriptional repression of TFF3, while trastuzumab inhibition of HER2 results in increased TFF3 expression to compensate for the loss of HER2 signalling. In HER2+/ER+ breast cancer cells with acquired trastuzumab resistance, TFF3 expression was markedly upregulated and associated with a corresponding decrease in HER signalling. siRNA mediated depletion or small molecule inhibition of TFF3 decreased the survival and growth advantage of the trastuzumab resistant cells without re-sensitization to trastuzumab. Furthermore, TFF3 inhibition abrogated the enhanced cancer stem cell-like behaviour in trastuzumab resistant HER2+/ER+ breast cancer cells. Collectively, TFF3 may function as a potential biomarker and therapeutic target in trastuzumab resistant HER2+/ER+ breast cancer.

Autocrine Human Growth Hormone Promotes Invasive and Cancer Stem Cell-Like Behavior of Hepatocellular Carcinoma Cells by STAT3 Dependent Inhibition of CLAUDIN-1 Expression.

Despite progress in diagnosis and treatment of hepatocellular carcinoma (HCC), the clinical outcome is still unsatisfactory. Increased expression of human growth hormone (hGH) in HCC has been reported and is associated with poor survival outcome in HCC patients. Herein, we investigated the mechanism of the oncogenic effects of hGH in HCC cell lines. In vitro functional assays demonstrated that forced expression of hGH in these HCC cell lines promoted cell proliferation, cell survival, anchorage-independent growth, cell migration, and invasion, as previously reported. In addition, forced expression of hGH promoted cancer stem cell (CSC)-like properties of HCC cells. The increased invasive and CSC-like properties of HCC cells with forced expression of hGH were mediated by inhibition of the expression of the tight junction component CLAUDIN-1. Consistently, depletion of CLAUDIN-1 expression increased the invasive and CSC-like properties of HCC cell lines. Moreover, forced expression of CLAUDIN-1 abrogated the acquired invasive and CSC-like properties of HCC cell lines with forced expression of hGH. We further demonstrated that forced expression of hGH inhibited CLAUDIN-1 expression in HCC cell lines via signal transducer and activator of transcription 3 (STAT3) mediated inhibition of CLAUDIN-1 transcription. Hence, we have elucidated a novel hGH-STAT3-CLAUDIN-1 axis responsible for invasive and CSC-like properties in HCC. Inhibition of hGH should be considered as a therapeutic option to hinder progression and relapse of HCC.

Trefoil factor 3 mediation of oncogenicity and chemoresistance in hepatocellular carcinoma is AKT-BCL-2 dependent.

The efficacious treatment of hepatocellular carcinoma (HCC) remains a challenge, partially being attributed to intrinsic chemoresistance. Previous reports have observed increased TFF3 expression in HCC. Herein, we investigated the functional role of TFF3 in progression of HCC, and in both intrinsic and acquired chemoresistance. TFF3 expression was observed to be upregulated in HCC and associated with poor clinicopathological features and worse patient survival outcome. Functionally, forced expression of TFF3 in HCC cell lines increased cell proliferation, cell survival, anchorage-independent and 3D matrigel growth, cell invasion and migration, and in vivo tumor growth. In contrast, depleted expression of TFF3 decreased the oncogenicity of HCC cells as indicated by the above parameters. Furthermore, forced expression of TFF3 decreased doxorubicin sensitivity of HCC cells, which was attributed to increased doxorubicin efflux and cancer stem cell-like behavior of Hep3B cells. In contrast, depletion of TFF3 increased doxorubicin sensitivity and decreased cancer stem cell-like behavior of Hep3B cells. Correspondingly, TFF3 expression was markedly increased in Hep3B cells with acquired doxorubicin resistance, while the depletion of TFF3 resulted in re-sensitization of the Hep3B cells to doxorubicin. The increased doxorubicin efflux and enhanced cancer stem cell-like behavior of the doxorubicin-resistant Hep3B cells was observed to be dependent on TFF3 expression. In addition, we determined that TFF3-stimulated oncogenicity and chemoresistance in HCC cells was mediated by AKT-dependent expression of BCL-2. Hence, therapeutic inhibition of TFF3 should be considered to hinder HCC progression and overcome intrinsic and acquired chemoresistance in HCC.

An assessment of the risks of carcinogenicity associated with polyhydroxyalkanoates through an analysis of DNA aneuploid and telomerase activity.

Polyhydroxyalkanoates (PHA) are aliphatic polyesters synthesized by many bacteria. Because of their flexible mechanical strengths, superior elastic property, biodegradability and biocompatibility, PHA have been developed for applications as medical implants, drug delivery matrices, and devices to support cell growth. Lots of studies showed that PHA matrices improved cell proliferation and tissue regeneration. However, the possibility of whether rapid cell proliferation on PHA matrices will induce tumor formation is unclear. Here we confirmed that proliferating rat osteoblasts grown on films of various PHA including PHB, PHBV, P3HB4HB, PHBHHx and PHBVHHx did not lead to cancer induction at least for p8th. Cell proliferation was evaluated by the incorporation of 5-bromodeoxyuridine (BrdU), the transcript expression of cancer related genes Ki67, p53 and c-Fos was monitored by quantitative Real-time PCR, the results showed the cells proliferating on the PHA films were under normal cell cycle regulation. Moreover, DNA aneuploid and telomerase activity were only detected in the positive control UMR-108 cells; compared with cells grown on films, UMR-108 cells had longer telomeres, further demonstrated the normal status of cells proliferating on the PHA films. It indicated that the above PHA family members could be used to support cell growth without indication of susceptibility to tumor induction. These results will be important for promoting the application of PHA as new members of biomaterials.

Differentiation of human bone marrow mesenchymal stem cells grown in terpolyesters of 3-hydroxyalkanoates scaffolds into nerve cells.

Polyhydroxyalkanoates, abbreviated as PHA, have been studied for medical applications due to their suitable mechanical properties, blood and tissue tolerance and in vivo biodegradability. As a new member of PHA family, terpolyester of 3-hydroxybutyrate, 3-hydroxyvalerate and 3-hydroxyhexanoate, abbreviated as PHBVHHx, was compared with polylactic acid (PLA), copolyester of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx) for their respective functions leading to differentiation of human bone marrow mesenchymal stem cell (hBMSC) into nerve cells. Results indicated that 3D scaffolds promoted the differentiation of hBMSC into nerve cells more intensively compared with 2D films. Smaller pore sizes of scaffolds increased differentiation of hBMSC into nerve cells, whereas decreased cell proliferation. PHBVHHx scaffolds with pore sizes of 30-60 microm could be used in nerve tissue engineering for treatment of nerve injury. The above results were supported by scanning electron microscope (SEM) and confocal microscopy observation on attachment and growth of hBMSCs on PLA, PHBHHx and PHBVHHx, and by CCK-8 evaluation of cell proliferation. In addition, expressions of nerve markers nestin, GFAP and beta-III tubulin of nerve cells differentiated from hBMSC grown in PHBVHHx scaffolds were confirmed by real-time PCR.

Diagnosis and Treatment of Malignant Brain Tumor in Children / 实用儿科临床杂志

Objective To explore the diagnosis,treatment and pathology of malignant brain tumor in children.Methods The clinical data of 61 children with malignant brain tumor were reviewed,including their age distribution,diagnosis,operation route(according to the position of the brain tumors),chemotherapy [using bischloro-nitrosourea(BCNU),teniposide(VM-26) and temozolomide]and radiotherapy (part and whole brain irradiation,three diamensions conformal therapy,gamma knife and X-kinfe).Results Of 61 cases,which including 37 boys and 24 girls whose mean age was 11.3 years,24 cases were supratentorial tumors and 37 cases were infratentorial.Forty-five tumors received total or subtotal recession,10 cases with major recession,and 6 cases with partial recession.After operation,39 cases (63.9%) received radiotherapy,and 29 cases (47.5%) with chemotherapy.Follow-up of 49 cases were achieved,in which 22 cases died and 27 cases survived.Conclusions Surgical removal is still the chief treatment for malignant brain tumor in children.The exairesis profect should be formulated according to the specificity of each case.Radiotherapy methods should be related to post-operational images(CT or MRI).And it was different from the brain tumors in adult.It is good to prolong survival duration for some chosen cases with optimal chemotherapy.