A Strain Transfer Model for Detection of Pitting Corrosion and Loading Force of Steel Rebar with Distributed Fiber Optic Sensor.

Steel rebar corrosion is one of the predominant factors influencing the durability of marine and offshore reinforced concrete structures, resulting in economic loss and the potential threat to human safety. Distributed fiber optic sensors (DFOSs) have gradually become an effective method for structural health monitoring over the past two decades. In this work, a strain transfer model is developed between a steel rebar and a DFOS, considering pitting-corrosion-induced strain variation in the steel rebar. The Gaussian function is first adopted to describe the strain distribution near the corrosion pit of the steel rebar and then is substituted into the governing equation of the strain transfer model, and the strain distribution in the DFOS is analytically obtained. Tensile tests are also conducted on steel rebars with artificially simulated corrosion pits, which are used to validate the developed model. The results show that the Gaussian function can be used to describe the strain variation near a corrosion pit with a depth less than 50% of the steel rebar diameter, and the strain distribution in the DFOS analytically determined based on the developed strain transfer model agrees well with the tensile test results. The corrosion pit depth and loading force in the steel rebars estimated based on the proposed model agree well with the actual values, and therefore, the developed strain transfer model is effective in detecting pitting corrosion and loading force in steel rebars.

Research Progress of Preparation Technology of Ion-Exchange Resin Complexes.

As insoluble polymer materials, ion-exchange resins (IERs) can exchange their own ions with desirable charged ions in the solution. According to the affinity of active moieties for soluble counterions, IERs could be categorized into the following four types: strongly acidic cation, weakly acidic cation, strongly basic anion, and weakly basic anion exchange resins. Due to their relative safety and high drug-loading capacity, IERs have garnered extensive attention in the pharmaceutical field since the 1950s. As numerous investigations combine drugs with IERs, this article summarizes the technologies employed in these studies from four aspects: IER screening principles, combining technologies, characterization methods, and in vitro and in vivo release of drug-resinate complexes. In addition, the advantages and disadvantages of various technologies and their scope are expounded. The article provides new insights on the preparation of ion-exchange resin complexes.

[Stability research of Xiaoer Ganmaoning Oral Liquid based on chromatographic peak matching and image sensory evaluation].

The high performance liquid chromatography(HPLC) characteristic chromatogram of Xiaoer Ganmaoning Oral Liquid(oral liquid for short) was established. The medicinal materials corresponding to characteristic peaks, their index components and ranges of similarity with the reference chromatograms were clarified. The similarity between the characteristic chromatograms of 10 batches of the oral liquid and the reference chromatogram was higher than 0.994. Eighteen characteristic peaks were identified, which were derived from different medicinal materials including Scutellariae Radix, Arctii Fructus, Lonicerae Japonicae Flos, Gardeniae Fructus and Forsythiae Fructus. Further, 11 characteristic peaks were assigned by the comparison with reference substances as chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid, isochlorogenic acid A, isochlorogenic acid C, baicalin, baicalein, wogonin, scutellarin, forsythiaside A and arctiin. Also, the characteristic chromatogram of precipitate in the oral liquid was established, and the similarity between characteristic chromatograms of 10 batches of the precipitate and the reference chromatogram was higher than 0.940. The 14 characteristic peaks originating from the precipitate and those from the oral liquid were consistent in retention time, and the content of all index components in the precipitate was lower than 5% of that in the oral liquid. Moreover, the stability of precipitate during the accelerated stability test was explored with filtration and Matlab-based image sensory evaluation. The precipitate mass and precipitation degree both increased over the stability test duration significantly. The stability of the oral liquid was used as a model system in this study to establish the integrated quality control system which related to medicinal materials, preparations and precipitate with HPLC characteristic chromatograms and image sensory evaluation, which lays a foundation for the exploration of the quantity value transfer of the oral liquid.

Preliminary study on the safety and efficacy of a new polymyxin B-immoblized resin column in treatment of LPS-induced sepsis beagles.

BACKGROUND: This study aims to assess the safety and efficacy of direct hemoperfusion using a new polymyxin B-immobilized resin column (disposable endotoxin adsorber, KCEA) in an endotoxin/ lipopolysaccharide (LPS)-induced sepsis model. METHODS: Eighteen beagles were randomized into 1 intervention group (KCEA group, n = 6) and 2 control groups (sham group and model group, n = 6 each). Sepsis was induced by continuous intravenous application of 0.5 mg/kg body weight of endotoxin for 60 min. An extracorporeal hemoperfusion device made with KCEA for endotoxin adsorption was used. Model group beagles received standard treatment with fluids and vasoactive drugs, KCEA group beagles received standard treatment and direct hemoperfusion of KCEA for 2 h, and sham group beagles were treated with standard treatment and direct hemoperfusion of a sham column for 2 h. RESULTS: Good blood compatibility of KCEA was confirmed by assessing clinical parameters. Blood endotoxin peak levels in the KCEA group were significantly lower, resulting in a significant suppression of IL-6, TNF-α and procalcitonin, which improved mean arterial pressure and significantly lowered vasopressor demand, thereby protecting organ function and improving survival time and rate. In the KCEA group, MAP was significantly higher over 6 h than those recorded both in the sham group and model group. The 7-day survival rates of the KCEA, sham and model groups were 50%, 0% and 0%, respectively. CONCLUSION: KCEA hemoadsorption was effective at detoxifying circulatory endotoxin and inflammatory mediators and contributed to the decreased mortality rate in the sepsis beagles.

An antitumor peptide RS17-targeted CD47, design, synthesis, and antitumor activity.

BACKGROUND: CD47 is a widely expressed transmembrane protein located on the surface of somatic cells. It mediates a variety of cellular processes including apoptosis, proliferation, adhesion, and migration. An important role for CD47 is the transmission of a "Don't eat me" signal by interacting with SIRPα on the macrophage surface membrane, thereby preventing the phagocytosis of normal cells. However, cancer cells can take advantage of this autogenous signal to protect themselves from phagocytosis, thus enabling immune escape. Blocking the interaction between CD47 and SIRPα has proven to be effective in removing cancer cells. The treatment of various cancers with CD47 monoclonal antibodies has also been validated. METHODS: We designed and synthesized a peptide (RS17), which can specifically bind to CD47 and block CD47-SIRPα signaling. The affinity of RS17 for CD47-expressing tumor cells was determined, while the inhibition of CD47-SIRPα signaling was evaluated in vitro and in vivo. RESULTS: The results indicated that RS17 significantly promotes the phagocytosis of tumor cells by macrophages and had a similar therapeutic effect compared with a positive control (CD47 monoclonal antibodies). In addition, a cancer xenograft mouse model was established using CD47-expressing HepG2 cells to evaluate the effect of RS17 on tumor growth in vivo. Using ex vivo and in vivo mouse models, RS17 demonstrated a high inhibitory effect on tumor growth. CONCLUSIONS: Based on our results, RS17 may represent a novel therapeutic peptide for cancer therapy.

Enhanced Safety and Antitumor Efficacy of Switchable Dual Chimeric Antigen Receptor-Engineered T Cells against Solid Tumors through a Synthetic Bifunctional PD-L1-Blocking Peptide.

Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) therapy has an excellent efficacy in cancer treatment, especially its impressive results in hematological malignancies. Unfortunately, its application on solid tumors is challenged by the off-target effects caused by lacking of tumor specific antigens and the immunosuppression caused by the tumor microenvironment. We constructed a switchable dual receptor CAR-T cell (sdCAR-T) whose activity relied upon double antigens (mesothelin and fluorescein isothiocyanate) and was strictly controlled by a "switch" (FPBM) consisting of a PD-L1 blocking peptide conjugated to fluorescein isothiocyanate. SdCAR-T cells were activated only when FPBM and cognate tumor cells expressing both PD-L1 and mesothelin coexist. Importantly, long-term proliferation experiments in vitro and the pharmacodynamic study in vivo showed a stronger antitumor activity of this system compared to the second generation mesothelin CAR-T cells. In view of this novel treatment paradigm being safer and more effective than traditional CAR-T cells, it may become a new strategy for the treatment of solid tumors.

Antisense oligonucleotides targeting lncRNA AC104041.1 induces antitumor activity through Wnt2B/ß-catenin pathway in head and neck squamous cell carcinomas.

Long non-coding RNAs (lncRNAs) contribute to the initiation and progression of various tumors, including head and neck squamous carcinoma (HNSCC), which is a common malignancy with high morbidity and low survival rate. However, the mechanism of lncRNAs in HNSCC tumorigenesis remains largely unexplored. In this work, we identified a novel lncRNA AC104041.1 which is highly upregulated and correlated with poor survival in HNSCC patients. Moreover, AC104041.1 overexpression significantly promoted tumor growth and metastasis of HNSCC in vitro and in vivo. Mechanistically, AC104041.1 mainly located in the cytoplasm and could function as ceRNA (competing endogenous RNA) for miR-6817-3p, thereby stabilized Wnt2B, and consequently inducing ß-catenin nuclear translocation and activation. Moreover, we demonstrate that salinomycin, which as a highly effective antibiotic in the elimination of cancer stem cells through the Wnt/ß-catenin signaling, could enhance the inhibition of tumor growth by antisense oligonucleotides (ASO) targeting AC104041.1 in HNSCC cells and PDXs (patient-derived xenograft) model. Thus, our data provide preclinical evidence to support a novel strategy of ASOs targeting AC104041.1 in combination with salinomycin and may as a beneficial treatment approach for HNSCC.

NK cell-derived exosomes carry miR-207 and alleviate depression-like symptoms in mice.

BACKGROUND: Depression is a common mental disease that mainly manifests as bad mood, decreased interest, pessimism, slow thinking, lack of initiative, poor diet and sleep. Patients with severe depression have suicidal tendencies. Exosomes are small vesicles released by the fusion of a multivesicular body and membranes, and they contain specific proteins, nucleic acids, and lipids related to the cells from which they originate. MicroRNAs (miRNAs) are 20-24 nt RNAs that can be packaged into exosomes and can play important regulatory roles. Astrocytes are the most abundant cell population in the central nervous system and have a close link to depression. Astrocyte activation could result in the release of inflammatory cytokines, including IL-1ß, IL-6, and TNF-α, which could promote the symptoms of depression. In previous research, our team confirmed that NK cells regulate depression in mice. Here, we propose that miRNA in the exosomes from NK cells performs this antidepressant function. METHODS: Exosomes from NK cells were shown by in vivo and in vitro experiments to alleviate symptoms of chronic mild stress in mice and decrease pro-inflammatory cytokines release from astrocytes. The production of pro-inflammatory cytokines was assessed by ELISA. Microarray analysis was used to identify critical miRNAs. Luciferase reporter assays, qPCR, and other experiments were used to prove that exosomal miR-207 has an important role in alleviating the symptoms of stress in mice. RESULTS: MiRNA-containing exosomes from NK cells could alleviate symptoms of chronic mild stress in mice. In vivo experiments showed that these exosomes decreased the levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) released by astrocytes. By microarray analysis of exosome miRNA profiles, miR-207 was found to be overexpressed in exosomes derived from unstressed mice. Experiments confirmed that miR-207 directly targets TLR4 interactor with leucine-rich repeats (Tril) and inhibits NF-κB signaling in astrocytes. MiR-207 could decrease the release of pro-inflammatory cytokines and inhibit expression of Tril in vitro. In vivo experiments revealed that exosomes with low miR-207 levels showed decreased antidepressant activity. CONCLUSION: Collectively, our findings revealed that exosomal miR-207 alleviated symptoms of depression in stressed mice by targeting Tril to inhibit NF-κB signaling in astrocytes.

[Corrigendum] In vitro and in vivo activities of an antitumor peptide HM-3: A special dose-efficacy relationship on an HCT­116 xenograft model in nude mice.

After the publication of the article, the authors have realized that Figs. 3 and 7 in their paper were published with errors; in the first instance, regarding Fig. 3, panels 'C' and 'D' contained partially overlapping data and were derived from the same original source, where these images were intended to show the effect of 2 ng/ml sunitinib and 2 µg/ml HM­3, respectively, on cell migration. Likewise, in Fig. 7, panels 'C' and 'D' also contained partially overlapping data derived from the same original source, even though these images were intended to show representative images for sections of tumor tissue from the HM­3 (3 mg/kg) and HM­3 (48 mg/kg) treatment groups. These errors arose inadvertently, as a consequence of the authors' mishandling of their data. The revised versions of Figs. 3 and 7, featuring the corrected data panels for panels 'C' and 'D' in both Figures, are shown opposite. The revised data shown for these Figures do not affect the overall conclusions reported in the paper. The authors apologize to the Editor of Oncology Reports and to the readership for any inconvenience caused. [the original article was published in Oncology Reports 36: 2951­2959, 2016; DOI: 10.3892/or.2016.5077].

Tumor-Derived EV-Encapsulated miR-181b-5p Induces Angiogenesis to Foster Tumorigenesis and Metastasis of ESCC.

Pathological angiogenesis is necessary for tumor development and metastasis. Tumor-derived extracellular vesicles (EVs) play an important role in mediating the crosstalk between cancer cells and vascular endothelial cells. To date, whether and how microRNAs (miRNAs) encapsulated in tumor-derived EVs affect angiogenesis in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we showed that miR-181b-5p, an angiogenesis-promoting miRNA of ESCC, can be transferred from ESCC cells to vascular endothelial cells via EVs. In addition, ESCC-derived EVs-miR-181b-5p dramatically induced angiogenesis by targeting PTEN and PHLPP2, and thereby facilitated tumor growth and metastasis. Moreover, miR-181b-5p was highly expressed in ESCC tissues and serum EVs. High miR-181b-5p expression level in ESCC patients was well predicted for poor overall survival. Our work suggests that intercellular crosstalk between tumor cells and vascular endothelial cells is mediated by tumor-derived EVs. miR-181b-5p-enriched EVs secreted from ESCC cells are involved in angiogenesis that control metastasis of ESCC, providing a potential diagnostic biomarker or drug target for ESCC patients.

Retraction Note: Receptor tyrosine kinase inhibitor Sunitinib and integrin antagonist peptide HM-3 show similar lipid raft dependent biphasic regulation of tumor angiogenesis and metastasis.

The authors have retracted this article [1] because the bands shown in Fig. 5 panel D for GTP-RhoA/Control, GTP-RhoA/Sunitinib (2 and 64 nM) and GTP-RhoA/HM-3 (4.5 and 72 uM) are not data generated as part of this study. All authors agree to this retraction.

The intraperitoneal administration of MOTS-c produces antinociceptive and anti-inflammatory effects through the activation of AMPK pathway in the mouse formalin test.

The activation of the AMP activated protein kinase (AMPK) exerts antinociceptive effects in acute and neuropathic pain models. Mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c), a mitochondrial-derived peptide, regulates many biological activities via activating AMPK. However, the role of MOTS-c in the formalin-induced inflammatory nociception remains unclear. In this study, we investigated the role of MOTS-c in the formalin-induced inflammatory nociception. The antinociceptive effect of MOTS-c was assessed by recording the time spent licking paw. The anti-inflammatory effect of MOTS-c was evaluated by detecting the inflammatory cytokine level changes in the mouse serum. Western blot was used to detect the changes of protein phosphorylation levels in the mouse spinal cord. Changes of c-fos expression in the spinal cord were assessed by immunohistochemistry. Our results showed that the intraperitoneal administration of MOTS-c reduced the time spent on licking in phase 2 in a dose-dependent manner in the formalin test. The antinociceptive effects of MOTS-c (50 mg/kg, i.p.) were attenuated by the AMPK antagonist compound C (10 mg/kg, i.p.). MOTS-c (50 mg/kg, i.p.) significantly reduced pro-inflammatory cytokine levels and elevated the level of anti-inflammatory cytokine in mouse serum. In addition, MOTS-c treatment significantly increased AMPKα phosphorylation level and suppressed formalin-induced extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinases (JNK), and P38 activation and c-fos expression in the mouse spinal cord. These results suggest that systemic administration of MOTS-c exerts antinociceptive and anti-inflammatory effects, at least partially, through activating AMPK pathway and inhibiting MAP kinases-c-fos signaling pathway in the mouse formalin test.

A novel arthritis model induced by wind, damp, cold and heat in female rats.

Animal models are in constant development to benefit scientific research. Rheumatoid arthritis (RA) is considered a very complex disease due to its complicated pathogenesis, and patients with rheumatic disease around the world are still unable to obtain effective, simple and curable treatment. In order to obtain a clear insight into the pathogenesis of RA, a rat model was established based on the concept of Bi syndrome in Traditional Chinese Medicine by simulating the conditions of RA as much as possible via the change in the physical conditions wind, damp, cold and heat (WDCH). For the first time, a new WDCH-induced RA model in female rats was successfully established and evaluated by body-weight change, paw swelling, blood cells analysis, spleen and thymus coefficients, autoantibodies and serum cytokine changes and histopathology. This model is characterised by its objectivity, no exogenous induction, short modelling time, extremely elevated expression level of autoantibodies and obvious histopathological change. The establishment of such a new model may provide more benefits in the research of the pathogenesis of RA.

CD200-CD200R1 signalling attenuates imiquimod-induced psoriatic inflammation by inhibiting the activation of skin inflammatory macrophages.

Psoriasis is an autoimmune skin disease caused by interactions between keratinocytes and immune cells, such as macrophages. CD200 is expressed on the surface of various cell types, and its receptor, CD200R1, belongs to a family of immunosuppressive receptors that are mainly expressed on myeloid cells. CD200/CD200R1 signalling is associated with the prevention of autoimmune diseases; however, the role of CD200/CD200R1 signalling in the pathogenesis of psoriasis remains unknown. In this study, we detected in vivo effect of the CD200 protein on psoriasis and in vitro effects of CD200 on macrophages and keratinocytes co-cultured with macrophages were also evaluated. Our data showed that the expression of CD200 and CD200R1 was decreased and the expression of macrophage-related pro-inflammatory factors (IL-6, IL-1ß, TNF-α) was increased in IMQ-induced psoriasis-like skin of mice. After subcutaneous injection of CD200, the symptoms were alleviated, local expression of CD200R1 was markedly induced, infiltrated CD68+ cells were significantly reduced and the expression levels of IL-6, IL-1ß, and TNF-α were strongly downregulated. In in vitro experiments, CD200 suppressed the migration of macrophages, induced CD200R1 expression on the surface of macrophages, and decreased the levels of pro-inflammatory factors. Western blot (WB) data showed that the CD200-CD200R1 reaction controlled the activation of inflammatory macrophages by inhibiting the NF-κB signalling pathway. These results demonstrate that CD200-CD200R1 signalling can reduce IMQ-induced psoriasis-like skin inflammation by inhibiting the activation of macrophages.

Receptor tyrosine kinase inhibitor Sunitinib and integrin antagonist peptide HM-3 show similar lipid raft dependent biphasic regulation of tumor angiogenesis and metastasis.

BACKGROUND: Anti-angiogenesis remains an attractive strategy for cancer therapy. Some anti-angiogenic reagents have bell-shape dose-response curves with higher than the effective doses yielding lower anti-angiogenic effects. In this study, two different types of anti-angiogenic reagents, a receptor tyrosine kinase inhibitor Sunitinib and an integrin antagonist peptide HM-3, were selected and their effects on tumor angiogenesis and metastasis were compared. The involved molecular mechanisms were investigated. METHODS: The effect of high dose Sunitinib and HM-3 on tumor angiogenesis and metastasis was investigated with two animal models: metastasis of B16F10 cells in syngeneic mice and metastasis of human MDA-MB-231 cells in nude mice. Furthermore, mechanistic studies were performed with cell migration and invasion assays and with biochemical pull-down assays of intracellular RhoGTPases. Distribution of integrin αvß3, α5ß1, VEGFR2 and the complex of integrin αvß3 and VEGFR2 inside or outside of lipid rafts was detected with lipid raft isolation and Western-blot analysis. RESULTS: Both Sunitinib and HM-3 showed a bell-shape dose-response curve on tumor angiogenesis and metastasis in both animal models. The effects of Sunitinib and HM-3 on endothelial cell and tumor cell proliferation and migration were characterized. Activation of intracellular RhoGTPases and actin stress fiber formation in endothelial and cancer cells following Sunitinib and HM-3 treatment correlated with cell migration analysis. Mechanistic studies confirmed that HM-3 and Sunitinib regulated distribution of integrin αvß3, α5ß1, VEGFR2 and αvß3-VEGFR2 complexes, both inside and outside of the lipid raft regions to regulate endothelial cell migration and intracellular RhoGTPase activities. CONCLUSIONS: These data confirmed that a general non-linear dose-effect relationship for these anti-angiogenic drugs exists and their mechanisms are correlative. It also suggests that the effective dose of an anti-angiogenic drug may have to be strictly defined to achieve its optimal clinical effects.

Anti-Tumor Activity and Pharmacokinetics of AP25-Fc Fusion Protein.

AP25 is an anti-tumor peptide with a high affinity for integrins. It exerts its anti-tumor activity by inhibiting angiogenesis and by directly inhibiting the growth of tumor cells. Its half-life time in vivo is only about 50 minutes, which limits its clinical application. In order to prolong the half-life time of AP25 while preserving its anti-tumor activity, several fusion proteins of AP25 and IgG4 Fc were designed and expressed; their anti-tumor activity and pharmacokinetics properties were evaluated. Firstly, four AP25-Fc fusion protein sequences were designed, and the corresponding proteins were expressed and purified. Based on the results of HUVEC migration inhibition assay, HUVEC and tumor cell proliferation inhibition assay and yields of expression by HEK293 cells, the fusion protein designated PSG4R was selected for further evaluation. The anti-tumor effect of PSG4R was then evaluated in vivo on HCT-116 nude mice xenograft model. And the pharmacokinetics properties of PSG4R were investigated in rats. The results showed that PSG4R could inhibit the growth of xenografts of human colon cancer cell line HCT-116 in nude mice by intravenous administration of 40 mg/kg once every two days. The half-life time of PSG4R was 56.270 ± 15.398 h. This study showed that the construction of AP25-Fc fusion protein could significantly prolong the half-life of AP25 while retaining its anti-tumor activity, which provides a new direction for new drug development of AP25.

Peptide PD29 treats bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß/smad signaling pathway.

Pulmonary fibrosis (PF) is an end-stage change in lung disease characterized by fibroblast proliferation, massive extracellular matrix (ECM) aggregation with inflammatory damage, and severe structural deterioration. PD29 is a 29-amino acid peptide which has the potential to alleviate PF pathogenesis via three mechanisms: anti-angiogenesis, inhibition of matrix metalloproteinase activities, and inhibition of integrins. In this study, fibrotic lung injuries were induced in SD rats by a single intratracheal instillation of 5 mg/kg bleomycin (BLM). Then, these rats were administered 7.5, 5, or 2.5 mg/kg PD29 daily for 30 days. BLM induced-syndromes including structure distortion, excessive deposition of ECM, excessive inflammatory infiltration, and pro-inflammatory cytokine release were used to evaluate the protective effect of PD-29. Oxidative stress damage in lung tissues was attenuated by PD29 in a dose-dependent manner. The expression of TGF-ß1 and the phosphorylation of Smad-2/-3-its downstream targets-were enhanced by BLM and weakened by PD29. In vitro, PD29 inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) and transformation in A549 cells and mouse primary fibroblasts into myofibroblasts. In summary, PD29 reversed EMT and transformation of fibroblasts into myofibroblasts in vitro and prevented PF in vivo possibly by suppressing the TGF-ß1/Smad pathway.

Significantly increased anti-tumor activity of carcinoembryonic antigen-specific chimeric antigen receptor T cells in combination with recombinant human IL-12.

BACKGROUND AIMS: Chimeric antigen receptor T cells (CAR-T cells) have been successfully used in treatments of hematological tumors, however, their anti-tumor activity in solid tumor treatments was limited. As IL-12 increases T-cell immune functions, we designed carcinoembryonic antigen (CEA) specific CAR-T (CEA-CAR-T) cells and, for the first time, used them in combination with recombinant human IL-12 (rhIL-12) to treat several types of solid tumors. METHODS: In vitro anti-tumor activity of CEA-CAR-T cells in combination with rhIL-12 was confirmed by evaluation of CEA-CAR-T cell activation, proliferation, and cytotoxicity after co-incubation with CEA-positive or CEA-negative human tumor cells. In vivo anti-tumor activity of CEA-CAR-T cells in combination with rhIL-12 was confirmed in a xenograft model in nude mice for treatments of several types of solid tumors. RESULTS: In vitro experiments confirmed that rhIL-12 significantly increased the activation, proliferation, and cytotoxicity of CEA-CAR-T cells. Similarly, in vivo experiments found that CEA-CAR-T cells in combination with rhIL-12 had significantly enhanced anti-tumor activity than CEA-CAR-T cells in growth inhibition of newly colonized colorectal cancer cell HT-29, pancreatic cancer cell AsPC-1, and gastric cancer cell MGC803. CONCLUSIONS: These works confirmed that simultaneous use of cytokines, for example, rhIL-12, can increase the anti-tumor activity of CAR-T cells, especially for treatments of several types of solid tumors.

Shedding New Light on The Role of ανß3 and α5ß1 Integrins in Rheumatoid Arthritis.

ανß3 and α5ß1 are essential glycoproteins involved in the pathogenesis of rheumatoid arthritis (RA). Understanding of the role these integrins play in disease have been analyzed via description of cells-expressing ανß3 and α5ß1 and their mediators to trigger inflammation. ανß3 and α5ß1 facilitate cells-ECM and cell-cell communication, producing pro-inflammatory factors. Pro-inflammatory factors are essential for the building of undesirable new blood vessels termed angiogenesis which can further lead to destruction of bones and joints. Despite many attempts to target these glycoproteins, there are still some problems, therefore, there is still interest in understanding the synergistic role these integrins play in the pathogenesis of RA. The purpose of this review is to gain insights into the biological effects of ανß3 and α5ß1 in synovial tissues that are relevant to pathogenesis and therapy of RA.

Design and Synthesis of A PD-1 Binding Peptide and Evaluation of Its Anti-Tumor Activity.

Immune-checkpoint blockades, suchas PD-1 monoclonal antibodies, have shown new promising avenues to treat cancers. Failure responsesof many cancer patients to these agents have led to a massive need for alternative strategies to optimize tumor immunotherapy. Currently, new therapeutic developments involve peptide blocking strategies, as they have high stability and low immunogenicity. Here, we have designed and synthesized a new peptide FITC-YT-16 to target PD-1. We have studied FITC-YT-16 by various experiments, including Molecular Operating Environment MOE modeling, purification testing by HPLC and LC mass, peptide/PD-1 conjugation and affinity by microscale thermophoresis (MST), and T cell immune-fluorescence imaging by fluorescence microscopy and flow cytometry. The peptide was tested for its ability to enhanceT cell activity against tumor cell lines, including TE-13, A549, and MDA-MB-231. Lastly, we assessed T cell cytotoxicity under peptide treatment. YT-16⁻PD-1 interaction showed a high binding affinity as a low energy complex that was confirmed by MOE. Furthermore, the peptide purity and molecular weights were 90.96% and 2344.66, respectively. MST revealed that FITC-YT-16 interacted with PD-1 at a Kd value of 17.8 ± 2.6 nM. T cell imaging and flow cytometry revealed high affinity of FITC-YT-16 to PD-1. Interestingly, FITC-YT-16 efficiently blocked PD-1 signaling pathways and promoted T cell inflammatory responses by elevating IL-2 and INF-γ levels. Moreover, FITC-YT-16 has the ability to activate T cell cytotoxicity. Therefore, FITC-YT-16 significantly enhanced T cell anti-tumor activity by blocking PD-1⁻PD-L1 interactions.