The tumor microenvironment (TME) is a complex system characterized by low oxygen, low pH, high pressure, and numerous growth factors and protein hydrolases that regulate a wide range of biological behaviors in the tumor and have a profound impact on cancer progression. Immunotherapy is an innovative approach to cancer treatment that activates the immune system, resulting in the spontaneous killing of tumor cells. However, the therapeutic efficacy of these clinically approved cancer immunotherapies (e.g., immune checkpoint blocker (ICB) therapies and chimeric antigen receptor (CAR) T-cell therapies) is far from satisfactory due to the presence of immunosuppressive TMEs created in part by tumor hypoxia, acidity, high levels of reactive oxygen species (ROS), and a dense extracellular matrix (ECM). With continuous advances in materials science and drug-delivery technologies, biomaterials hold considerable potential for targeting the TME. This article reviews the advances in biomaterial-based targeting of the TME to advance our current understanding on the role of biomaterials in enhancing tumor immunity. In addition, the strategies for remodeling the TME offer enticing advantages; however, the represent a double-edged sword. In the process of reshaping the TME, the risk of tumor growth, infiltration, and distant metastasis may increase.

In view of their low immunogenicity, biomimetic internal environment, tissue- and organ-like physicochemical properties, and functionalization potential, decellularized extracellular matrix (dECM) materials attract considerable attention and are widely used in tissue engineering. This review describes the composition of extracellular matrices and their role in stem-cell differentiation, discusses the advantages and disadvantages of existing decellularization techniques, and presents methods for the functionalization and characterization of decellularized scaffolds. In addition, we discuss progress in the use of dECMs for cartilage, skin, nerve, and muscle repair and the transplantation or regeneration of different whole organs (e.g., kidneys, liver, uterus, lungs, and heart), summarize the shortcomings of using dECMs for tissue and organ repair after refunctionalization, and examine the corresponding future prospects. Thus, the present review helps to further systematize the application of functionalized dECMs in tissue/organ transplantation and keep researchers up to date on recent progress in dECM usage.

Fibrotic diseases result in organ remodelling and dysfunctional failure and account for one-third of all deaths worldwide. There are no ideal treatments that can halt or reverse progressive organ fibrosis, moreover, organ transplantation is complicated by problems with a limited supply of donor organs and graft rejection. The development of new approaches, especially induced pluripotent stem cell (iPSC)-based therapy, is becoming a hot topic due to their ability to self-renew and differentiate into different cell types that may replace the fibrotic organs. In the past decade, studies have differentiated iPSCs into fibrosis-relevant cell types which were demonstrated to have anti-fibrotic effects that may have the potential to inform new effective precision treatments for organ-specific fibrosis. In this review, we summarize the potential of iPSC-based cellular approaches as therapeutic avenues for treating organ fibrosis, the advantages and disadvantages of iPSCs compared with other types of stem cell-based therapies, as well as the challenges and future outlook in this field.

Mesenchymal stem cells (MSCs) play a pivotal role in tissue engineering and regenerative medicine, with their clinical application often hindered by cell senescence during ex vivo expansion. Recent studies suggest that MSC-deposited decellularized extracellular matrix (dECM) offers a conducive microenvironment that fosters cell proliferation and accentuates stem cell differentiation. However, the ability of this matrix environment to govern lineage differentiation of tissue-specific stem cells remains ambiguous. This research employs human adipose-derived MSCs (ADSCs) and synovium-derived MSCs (SDSCs) as models for adipogenesis and chondrogenesis differentiation pathways, respectively. Genetically modified dECM (GMdECM), produced by SV40LT-transduced immortalized cells, was studied for its influence on cell differentiation. Both types of immortalized cells displayed a reduction in chondrogenic ability but an enhancement in adipogenic potential. ADSCs grown on ADSC-deposited dECM showed stable chondrogenic potential but increased adipogenic capacity; conversely, SDSCs expanded on SDSC-generated dECM displayed elevated chondrogenic capacity and diminished adipogenic potential. This cell-dependent response was confirmed through GMdECM expansion, with SDSCs showing enhanced chondrogenesis. However, ADSCs did not exhibit improved chondrogenic potential on GMdECM, suggesting that the matrix microenvironment does not dictate the final differentiation path of tissue-specific stem cells. Potential molecular mechanisms, such as elevated basement membrane protein expression in GMdECMs and dynamic TWIST1 expression during expansion and chondrogenic induction, may underpin the strong chondrogenic differentiation of GMdECM-expanded SDSCs.

Ground-glass opacity (GGO)-associated pulmonary nodules have been known as a radiologic feature of early-stage lung cancers and exhibit an indolent biological behavior. However, the correlation between driver genes and radiologic features as well as the immune microenvironment remains poorly understood. We performed a custom 1021-gene panel sequencing of 334 resected pulmonary nodules presenting as GGO from 262 Chinese patients. A total of 130 multiple pulmonary nodules were sampled from 58 patients. Clinical-pathologic and radiologic parameters of these pulmonary nodules were collected. Immunohistochemistry (IHC) and multiplex immunofluorescent staining (mIF) were applied to analyze proliferation and immune cell markers of GGO-associated pulmonary nodules. Compared with pure GGO nodules, mixed GGO nodules were enriched for invasive adenocarcinoma (IAC) (182/216 vs 73/118, P < .001). Eighty-eight percent (294/334) of GGO-associated nodules carried at least one mutation in EGFR/ERBB2/BRAF/KRAS/MAP2K1 of the RTK/RAS signaling pathway, and the alterations in these driver genes were mutually exclusive. The analysis of multifocal pulmonary nodules from the same patient revealed evidence of functional convergence on RTK/RAS pathways. Nodules with ERBB2/BRAF/MAP2K1 mutations tended to be more indolent than those with EGFR and KRAS mutations. IHC and mIF staining showed that KRAS-mutant GGO nodules displayed higher infiltration of CD4+ T cell and CD8+ T cell as well as stronger proliferation and immune inhibitory signals. Our study demonstrates a driver landscape of radiologically detectable GGO-associated pulmonary nodules in Chinese patients and supports that different driver patterns in RTK/RAS pathway are corresponding to different radiologic features.

Interaction between stromal cells and acute myeloid leukemia (AML) cells in bone marrow (BM) is known to contribute importantly to chemoresistance and disease recurrence. Therefore, disruption of a crosstalk between AML cells and BM microenvironment may offer a promising therapeutic strategy for AML treatment. Here, we demonstrate that in a niche-like co-culture system, AML cells took up functional mitochondria from bone marrow stromal cells (BMSCs) and inhibition of such mitochondrial transfer by metformin, the most commonly prescribed drug for type 2 diabetes mellitus, significantly enhanced the chemosensitivity of AML cells co-cultured with BMSCs. The chemo-sensitizing effect of metformin was acted through reducing the mitochondrial transfer and mitochondrial oxidative phosphorylation (OXPHOS) in the recipient AML cells. In addition, metformin potentiated the antitumor efficacy of cytarabine (Ara-C) in vivo in an NCG immunodeficient mouse xenograft model by inhibiting the mitochondrial transfer and OXPHOS activity in the engrafted human AML cells. Altogether, this study identifies a potential application of metformin in sensitizing AML cells to chemotherapy and unveils a novel mechanism by which metformin executes such effect via blocking the mitochondrial transfer from stromal cells to AML cells.

Adipogenesis of bone marrow mesenchymal stem cells (MSCs) promotes chemoresistance of acute myeloid leukaemia (AML) cells. MSCs from AML patients (AML-MSCs) display enhanced adipogenesis compared with bone marrow MSCs from healthy donors. However, the precise molecular mechanism by which adipogenesis of MSCs from AML marrow differs from normal counterparts remains obscure. We found that METTL3 significantly inhibits MSC adipogenesis. Here, we aimed to identify the molecular mechanism linking METTL3 and MSC adipogenesis. Analysis of m6 A epigenetic changes in MSCs determined via RIP-qPCR and MeRIP-qPCR indicated that METTL3 affects AKT protein expression in MSCs by mediating m6 A modification of AKT1-mRNA. Downregulated METTL3 expression in AML-MSCs induced an increase in AKT protein, resulting in enhanced MSC adipogenesis, thereby contributing to chemoresistance in AML cells. Therefore, targeting AKT regulation by mRNA modification in MSC adipogenesis might provide a novel therapeutic strategy to overcome AML chemoresistance.

We report sternoclavicular joint and sternal reconstruction using 3-dimensional carbon-fiber prosthesis. Commentary: Rigid Chest Wall Reconstruction—Innovation With Functional ImprovementsSeminars in Thoracic and Cardiovascular SurgeryVol. 32Issue 1PreviewChest wall reconstruction can be particularly challenging for anterior chest wall resections that involve the sternum along with sternoclavicular joints or multiple anterior ribs. The reconstruction options often require rigid fixation due to vulnerability of the underlying heart and lung and the potential for paradoxical movement of the chest wall which can be functionally and cosmetically undesirable. Materials that have been historically considered include polypropylene (Marlex) mesh sandwiched around methyl methacrylate resin or polytetrafluoroethylene mesh of 2-mm thickness. Full-Text PDF

Background Bone marrow stromal cells (BMSCs) are known to promote chemoresistance in acute myeloid leukemia (AML) cells. However, the molecular basis for BMSC-associated AML chemoresistance remains largely unexplored. Methods The mitochondrial oxidative phosphorylation (OXPHOS) levels of AML cells were measured by a Seahorse XFe24 cell metabolic analyzer. The activity of total or mitochondrial signal transducer and transcription activator 3 (STAT3) in AML cells was explored by flow cytometry and Western blotting. Real-time quantitative PCR, Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to analyze expression of interleukin 6 (IL-6) in the human BMSC line HS-5, and IL-6 was knocked out in HS-5 cells by CRISPR/Cas9 system. Results In this study, we observed that co-culturing with BMSCs heightened OXPHOS levels in AML cells, thus promoting chemoresistance in these cells. HS-5 cell-induced upregulation of OXPHOS is dependent on the activation of STAT3, especially on that of mitochondrial serine phosphorylated STAT3 (pS-STAT3) in AML cells. The relationship among pS-STAT3, OXPHOS, and chemosensitivity of AML cells induced by BMSCs was demonstrated by the STAT3 activator and inhibitor, which upregulated and downregulated the levels of mitochondrial pS-STAT3 and OXPHOS, respectively. Intriguingly, AML cells remodeled HS-5 cells to secrete more IL-6, which augmented mitochondrial OXPHOS in AML cells and stimulated their chemoresistance. IL-6 knockout in HS-5 cells impaired the ability of these cells to activate STAT3, to increase OXPHOS, or to promote chemoresistance in AML cells. Conclusions BMSCs promoted chemoresistance in AML cells via the activation of the IL-6/STAT3/OXPHOS pathway. These findings exhibit a novel mechanism of chemoresistance in AML cells in the bone marrow microenvironment from a metabolic perspective.

Relapse of minimal residual disease (MRD) is a major problem after conventional chemotherapy in patients with acute myeloid leukemia (AML). The bone marrow stroma can protect AML cells from insults of chemotherapy, partly contributing to AML relapse. Arsenic trioxide (ATO) is the main component of arsenical traditional Chinese medicines and has been widely used for the treatment of hematologic malignancies particularly acute promyelocytic leukemia over the past three decades. ATO acts through a direct arsenic binding to cysteine residues in zinc fingers located in promyelocytic leukemia protein (PML), thus killing the leukemia stem cells (LSCs). Our prior study has demonstrated that adhesion to stroma cells could render AML cells resistant to ATO but the detailed mechanism remains to be explored. Here, we report that the adhesion-induced resistance to ATO is related to the up-regulation of myeloid cell leukemia-1 (Mcl-1). Homoharringtonine (HHT) can potentiate the anti-leukemia effects of ATO on adhered AML cells by suppressing Mcl-1 through glycogen synthase kinase-3β (GSK3β). Furthermore, a potentiating effect of HHT on ATO was also observed in primary AML cells and AML xenografted tumors. Thus, these data indicate that HHT could enhance ATO anti-leukemia activity both in vitro and in vivo.

Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits multiple myeloma (MM) cells both in vitro and in vivo. Our prior study demonstrated that the potency of HHT in MM cells was compromised significantly when myeloma cells were co-cultured with BM stromal cells. This study aimed to investigate whether PI3K/Akt inhibitor LY294002 could potentiate the antimyeloma activity of HHT against MM cells adhered to BM stromal cells and in vivo xenograft models. A co-culture system composed of MM cells and human stromal cells was employed to mimic MM cells in bone marrow niche. The inhibitory and pro-apoptotic effect of HHT and LY294002 was determined by CCK-8 assay or flow cytometry. Expression of PI3K/Akt signaling molecules and anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) was assessed by western blot analysis and/or reverse transcription real-time quantitative PCR (RT-qPCR). MM xenografts were used to evaluate antitumor effect of combined therapy with HHT and LY294002. Adhesion to BM stromal cells rendered MM cells resistant to HHT whereas silencing Mcl-1 partly reversed the resistance. LY294002 induced apoptosis in MM cells and potentiated the antimyeloma effects of HHT by inhibiting the PI3K/Akt signal pathway which was abnormally activated during adhesion. LY294002 also enhanced the antimyeloma effect of HHT in in vivo xenograft models. These findings suggest that activation of PI3K/Akt signal pathway was responsible for the resistance to HHT in MM cells adhered to stromal cells. LY294002 can potentiate the antimyeloma activity of HHT both in vitro and in vivo, which may represent a new clinical treatment in MM.

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. AML cells secrete angiogenic factors to remodel vasculature and acquire chemoresistance; however, antiangiogenic drugs are often ineffective in AML treatment. Cancer cell-derived exosomes can induce angiogenesis, but their role in vascular remodeling during AML is unclear. Here, we found that exosomes secreted by AML cells promoted proliferation and migration and tube-forming activity of human umbilical vein endothelial cells (HUVECs), whereas HUVECs conferred chemoresistance to AML cells. AML cell-derived exosomes contained vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) messenger RNA and induced VEGFR expression in HUVECs. Furthermore, they enhanced glycolysis, which correlated with HUVEC proliferation, tube formation, and resistance to apoptosis. Thus, AML cells secrete VEGF/VEGFR-containing exosomes that induce glycolysis in HUVECs leading to vascular remodeling and acquisition of chemoresistance. These findings may contribute to the development of novel therapeutic strategies targeting exosomes in AML.

Central MessageConventional implanted prostheses for PPS therapy are easily deformed and liable to shift out of position. 3D carbon fiber–printed implants may be a better option for PPS surgery.See Editorial Commentary page e139. Conventional implanted prostheses for PPS therapy are easily deformed and liable to shift out of position. 3D carbon fiber–printed implants may be a better option for PPS surgery. See Editorial Commentary page e139. An 18-year-old woman presented with a more than 6-month history of recurrent dyspnea, wheezing, recurring right bronchopneumonia, and tachycardia after left pneumonectomy 2 years previously for an adenoid cystic carcinoma of the left main-stem bronchus. Thoracic computed tomography revealed a shift of mediastinal contents and parts of the right lung into the left hemithorax (Figure 1, A and B). The heart abutted the left lateral rib cage, and the vena cava and pulmonary vessels were compressed (Figure 1, B). The most serious effect was that the narrow lower trachea and intermediate bronchus had been compressed by the vertebral column and adjacent viscera (Figure 1, A and B). The preoperative minimal minor axes of the lower trachea and the intermediate bronchus were 2.9 mm and 2.7 mm, respectively. Bronchoscopy confirmed dynamic severe narrowing of the bronchus. The clinical signs and imaging indicated a diagnosis of postpneumonectomy syndrome (PPS). To shift the mediastinal contents, especially the trachea, back into their native positions and relieve the compression on the bronchus, a tridimensional (3D) carbon fiber–printed prosthesis was proposed and approved by a multidisciplinary committee. First, a 3D electron model of the thoracic structure, including the organs and ribcage, was created by MIMICS software (Materialise Magics; Materialise Software, Leuven, Belgium) with computed tomography data analysis. The mediastinal shifts and structural improvement of the implant were then performed in the 3D electron model (Figure 1, C). A custom implant was manufactured with the carbon fiber 3D sintering printing technique (Yakang Biotech, Changsha, China) (Figure 1, D). After surgically removing the chest adhesions, the prosthesis was placed in the left hemithorax, cushioned by Teflon patches (Figure 2, A). The mediastinal anatomy shifted back into a normal position (Video 1). Intraoperative bronchoscopy showed a patent right bronchus without narrowing.Figure 2A, The custom prosthesis implanted into the left hemithorax cushioned by Teflon patches. B and D, Computed tomography scan of the thorax 12 months after surgery. Arrow indicates the custom implant. B, 3D reconstruction of the intrathoracic structure. C, Normal positioning of the mediastinal contents and right lung. The compressed lower trachea has returned to its normal anatomic position. D, The compressed intermediate bronchus has been relieved.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The PPS symptoms completely disappeared after surgery, and the patient was discharged 2 weeks later. She remained asymptomatic during 1-year follow-up. Radiographic results showed that the carbon fiber prosthesis had allowed significant reduction of the mediastinal contents and right lung (Figure 2, B and D), compression of the lower trachea, and relief of intermediate bronchus (Figure 2, C and D). The institutional review board of The Second Xiangya Hospital approved the study. The patient gave informed written consent to report her case. PPS is a rare complication of pneumonectomy that is more commonly seen in adolescent patients.1Valji A.M. Maziak D.E. Shamji F.M. Matzinger F.R. Postpneumonectomy syndrome: recognition and management.Chest. 1998; 114: 1766-1769Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar The preferred treatment strategy for patients with PPS is to shift the displaced mediastinal contents back into their normal positions with a prostheses. Conventional prosthetic implants for PPS therapy are silicone breast implants,2Wasserman K. Jamplis R.W. Lash H. Brown H.V. Cleary M.G. Lafair J. Post-pneumonectomy syndrome. Surgical correction using Silastic implants.Chest. 1979; 75: 78-81Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar saline breast implants, and tissue expanders.3McRae M.C. Detterbeck F.C. Narayan D. Correction of postpneumonectomy syndrome using a custom implant.BMJ Case Rep. 2011; : 2011Google Scholar, 4Lloyd M.S. Wallis C. Muthialu N. Elliott M. Bulstrode N.W. Treatment of postpneumonectomy syndrome with tissue expanders: the Great Ormond Street Hospital experience.J Plast Reconstr Aesthet Surg. 2014; 67: 725-728Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Because of their lack of rigidity, however, these traditional, flexible material prostheses are easily deformed and liable to shift out of position. It is difficult to maintain stable or reliable support in the mediastinum. The extrusion of contents also may lead to implant failure.3McRae M.C. Detterbeck F.C. Narayan D. Correction of postpneumonectomy syndrome using a custom implant.BMJ Case Rep. 2011; : 2011Google Scholar Conventional rigid implants, although not easily deformed, are difficult to fit in the thoracic cavity during surgery. In addition, most of the implants are too heavy. The development of the 3D printing technic and individual therapy have provided a novel solution for PPS surgery: a custom-made 3D printed prosthesis. With better rigidity and strength, the custom 3D carbon fiber–printed prosthesis maintains its form within the chest. With a customized 3D printed adjoining plane, the prosthesis perfectly fits the mediastinal anatomy (especially the ventricular wall) (Figures 1, D, and 2, B). Although the 3D printed implant's adjoining plane makes the prosthesis perfectly fit the mediastinum, we covered the carbon fiber prosthesis with Teflon patches to offer better cushioning. We also applied fixed Teflon patches to the chest wall before implantation, which avoided a shift of the prosthesis after the operation. The prosthesis did not cause any subjective discomfort or show any signs of erosion. We will continue to follow the patient to confirm the long-term effect. The relatively low density of the material (1.5 g/cm3) and hollow structure provided a prosthesis for our patient with a weight of 48.6 g, and yet completely relieved the burden of the displaced mediastinal contents. Furthermore, the carbon fiber implant will not interfere with the postoperative imaging around the implants, block the radiation therapy, or decrease the computational accuracy of the therapeutic dose, which may be caused by a metal prosthesis. We report the first case of PPS surgery with a customized 3D carbon fiber–printed prosthesis. This is a novel individual treatment for PPS with satisfactory results.

Although melatonin has been shown to exert marked antitumor effects against a variety of cancers, the underlying mechanisms remain to be fully elucidated. It has been hypothesized that the anticancer properties of melatonin are associated with its ability to suppress epithelial-to-mesenchymal transition (EMT) of cancer cells. In the present study, melatonin effectively suppressed interleukin (IL)-1 beta-induced EMT in human gastric adenocarcinoma (GA) cells. Sequential treatment of GA cells with melatonin after IL-1 beta challenge markedly reversed the IL-1 beta-induced morphological changes, reduced cell invasion and migration, increased beta-catenin and E-cadherin expression, and downregulated fibronectin, vimentin, Snail, matrix metalloproteinase (MMP)2 and MMP9 expression. Moreover, IL-1 beta-induced activation of NF-kappa B was attenuated following treatment with melatonin. Knockdown of NF-kappa B significantly reduced the IL-1 beta-induced EMT in GA cells. Taken together, these findings indicate that melatonin may act by suppressing EMT and tumor progression by inhibiting NF-kappa B activity.

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasia characterized by the presence of the Philadelphia (Ph) chromosome in hematopoietic cells (HCs). As one of the most important components of the bone marrow microenvironment (BMM), bone mesenchymal stromal cells (BMSCs) are critical in the development of leukemia and essential in the regulation of hematopoiesis. However, little is known regarding the alterations of BMSCs in CML. The current study performed Cell Counting Kit-8 and colony-forming unit fibroblast assays to evaluate the proliferative ability of BMSCs. The percentage of senescent BMSCs was evaluated by a senescence-associated β-galactosidase staining assay. Subsequently, a long-term culture-initiating cell assay was designed to explore the HC-supporting capacity of the BMSCs. Furthermore, cytogenetics were detected by conventional cytogenetic analysis and fluorescence in situ hybridization analysis. The current results revealed that CML-BMSCs exhibited decreased cell proliferation and impaired HC-support capacity, as well as increased susceptibility to senescence. No chromosomal aberrations, including the absence of the Ph chromosome, were noted in all CML-BMSCs. In conclusion, the current study demonstrated functional inhibition of CML-BMSCs; however, no signs of chromosomal aberrations were observed, thereby providing insight into the changes occurring in the CML-BMM.

Although melatonin has been shown to exert marked antitumor effects against a variety of cancers, the underlying mechanisms remain to be fully elucidated. It has been hypothesized that the anticancer properties of melatonin are associated with its ability to suppress epithelial‑to‑mesenchymal transition (EMT) of cancer cells. In the present study, melatonin effectively suppressed interleukin (IL)‑1β‑induced EMT in human gastric adenocarcinoma (GA) cells. Sequential treatment of GA cells with melatonin after IL‑1β challenge markedly reversed the IL‑1β‑induced morphological changes, reduced cell invasion and migration, increased β‑catenin and E‑cadherin expression, and downregulated fibronectin, vimentin, Snail, matrix metalloproteinase (MMP)2 and MMP9 expression. Moreover, IL‑1β‑induced activation of NF‑κB was attenuated following treatment with melatonin. Knockdown of NF‑κB significantly reduced the IL‑1β‑induced EMT in GA cells. Taken together, these findings indicate that melatonin may act by suppressing EMT and tumor progression by inhibiting NF‑κB activity.

Although vascular implantation has been used as an effective treatment for cardiovascular disease for many years, off-the-shelf and regenerable vascular scaffolds are still not available. Tissue engineers have tested various materials and methods of surface modification in the attempt to develop a scaffold that is more suitable for implantation. Extracellular matrix-based natural materials and biodegradable polymers, which are the focus of this review, are considered to be suitable materials for production of tissue-engineered vascular grafts. Various methods of surface modification that have been developed will also be introduced, their impacts will be summarized and assessed, and challenges for further research will briefly be discussed.

Background Cell therapy is a promising strategy for tissue regeneration. Key to this strategy is mobilization and recruitment of exogenous or autologous stem/progenitor cells by cytokines. However, there is no effective cytokine delivery system available for clinic application, in particular for myocardial regeneration. The aim of this study was to develop a novel cytokine delivery system that is stable in solution at physiological pH. Methods Four groups of self-assembled chitosan oligosaccharide/heparin (CSO/H) nanoparticles were prepared with various volume ratios of chitosan oligosaccharide to heparin (5:2, 5:4, 4:15, 1:5) and characterized by laser diffraction, particle size analysis, and transmission electron microscopy. The encapsulation efficiency and loading content of two cytokines, ie, stromal cell-derived factor (SDF)-1α and vascular endothelial growth factor (VEGF) were quantified using an enzyme-linked immunosorbent assay. The biological activity of the loaded SDF-1α and VEGF was evaluated using the transwell migration assay and MTT assay. The dispersion profiles for the cytokine-loaded nanoparticles were quantified using fluorescence molecular tomography. Results CSO/H nanoparticles were prepared successfully in solution with physiological pH. The particle sizes in the four treatment groups were in the range of 96.2–210.5 nm and the zeta potential ranged from −29.4 mV to 24.2 mV. The loading efficiency in the CSO/H nanoparticle groups with the first three ratios was more than 90%. SDF-1α loaded into CSO/H nanoparticles retained its migration activity and VEGF loaded into CSO/H nanoparticles continued to show proliferation activity. The in vivo dispersion test showed that the CSO/H nanoparticles enabled to VEGF to accumulate locally for a longer period of time. Conclusion CSO/H nanoparticles have a high cytokine loading capacity and allow cytokines to maintain their bioactivity for longer, are stable in an environment with physiological pH, and may be a promising cytokine delivery system for tissue regeneration.

Objective To investigate the expression and significance of UbcH10 in gastric cancer.Methods The expression of UbcH10 in 117 cases of gastric carcinoma tissues,who were followed up postoperatively,were detected by using immunohistochemistry; The expression among different histological grades and clinical stages are analyzed by statistics; Real-time polymerase chain reaction (Rt PCR) and Western blot method were used to detect the expressions of UbcH10 mRNA and protein in 43 cases of gastric carcinoma tissues and the cancer adjacent normal tissues.Results In paraffin fixed blocks of gastric cancer,positive rate of UbcH10 protein expression was higher than normal gastric tissues (83％ vs 55％,Rs =-0.397,P＜0.01).The difference of UbcH10 expression was not significant in gender,age,tumor site and size of the tumor(Rs =0.369,-0.378,-0.276,0.421,P ＜ 0.05),while it was significantly correlated to tumor differentiation,invasive depth,lymphatic metastasis and clinical stage (Rs =0.369,-0.378,-0.276,0.421,P ＜0.05).UbcH10 and Ki-67 protein and HER-2 expression were in significantly positive correlation (Rs =0.834,Rs =0.281,P ＜ 0.01).UbcH10 mRNA and protein expression in fresh gastric carcinoma tissues was higher than that in their corresponding adjacent normal tissues(ACt =32.2±5.19,4.69 ±1.26,t =26.8,P＜0.01),(0.74±0.45,0.11 ±0.04,t =8.09,P＜0.01).The -5 year patient's survival rate in UbcH10 highly-expressed gastric cancer was higher compared to those with UbcH10 low-expression(x2 =13.116,P ＜0.01).Conclusions UbcH10 is upregulated in gastric cancer,and expression of UbcH10 is closely related to the prognosis of patients with gastric cancer.