Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice.

Rationale: Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal interstitial lung disease lacking specific therapeutics. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage biosynthesis pathway and a cytokine, has been previously reported as a biomarker for lung diseases; however, the role of NAMPT in pulmonary fibrosis has not been elucidated. Methods: We identified the NAMPT level changes in pulmonary fibrosis by analyzing public RNA-Seq databases, verified in collected clinical samples and mice pulmonary fibrosis model by Western blotting, qRT-PCR, ELISA and Immunohistochemical staining. We investigated the role and mechanism of NAMPT in lung fibrosis by using pharmacological inhibition on NAMPT and Nampt transgenic mice. In vivo macrophage depletion by clodronate liposomes and reinfusion of IL-4-induced M2 bone marrow-derived macrophages (BMDMs) from wild-type mice, combined with in vitro cell experiments, were performed to further validate the mechanism underlying NAMPT involving lung fibrosis. Results: We found that NAMPT increased in the lungs of patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis. NAMPT inhibitor FK866 alleviated BLM-induced pulmonary fibrosis in mice and significantly reduced NAMPT levels in bronchoalveolar lavage fluid (BALF). The lung single-cell RNA sequencing showed that NAMPT expression in monocytes/macrophages of IPF patients was much higher than in other lung cells. Knocking out NAMPT in mouse monocytes/macrophages (Namptfl/fl;Cx3cr1CreER) significantly alleviated BLM-induced pulmonary fibrosis in mice, decreased NAMPT levels in BALF, reduced the infiltration of M2 macrophages in the lungs and improved mice survival. Depleting monocytes/macrophages in Namptfl/fl;Cx3cr1CreER mice by clodronate liposomes and subsequent pulmonary reinfusion of IL-4-induced M2 BMDMs from wild-type mice, reversed the protective effect of monocyte/macrophage NAMPT-deletion on lung fibrosis. In vitro experiments confirmed that the mechanism of NAMPT engaged in pulmonary fibrosis is related to the released NAMPT by macrophages promoting M2 polarization in a non-enzyme-dependent manner by activating the STAT6 signal pathway. Conclusions: NAMPT prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice. Targeting the NAMPT of monocytes/macrophages is a promising strategy for treating pulmonary fibrosis.

Inhibition of PI3K/AKT signaling pathway prevents blood-induced heterotopic ossification of the injured tendon.

Objective: It is a common clinical phenomenon that blood infiltrates into the injured tendon caused by sports injuries, accidental injuries, and surgery. However, the role of blood infiltration into the injured tendon has not been investigated. Methods: A blood-induced rat model was established and the impact of blood infiltration on inflammation and HO of the injured tendon was assessed. Cell adhesion, viability, apoptosis, and gene expression were measured to evaluate the effect of blood treatment on tendon stem/progenitor cells (TSPCs). Then RNA-seq was used to assess transcriptomic changes in tendons in a blood infiltration environment. At last, the small molecule drug PI3K inhibitor LY294002 was used for in vivo and in vitro HO treatment. Results: Blood caused acute inflammation in the short term and more severe HO in the long term. Then we found that blood treatment increased cell apoptosis and decreased cell adhesion and tenonic gene expression of TSPCs. Furthermore, blood treatment promoted osteochondrogenic differentiation of TSPCs. Next, we used RNA-seq to find that the PI3K/AKT signaling pathway was activated in blood-treated tendon tissues. By inhibiting PI3K with a small molecule drug LY294002, the expression of osteochondrogenic genes was markedly downregulated while the expression of tenonic genes was significantly upregulated. At last, we also found that LY294002 treatment significantly reduced the tendon HO in the rat blood-induced model. Conclusion: Our findings indicate that the upregulated PI3K/AKT signaling pathway is implicated in the aggravation of tendon HO. Therefore, inhibitors targeting the PI3K/AKT pathway would be a promising approach to treat blood-induced tendon HO.

Butyrate facilitates immune clearance of colorectal cancer cells by suppressing STAT1-mediated PD-L1 expression.

OBJECTIVE: Immunotherapy has been proven to improve the prognosis of patients with advanced malignancy but has shown limited efficacy in patients with Colorectal Cancer (CRC). Increasing evidence suggests that butyrate, a bacterial metabolite, enhances the efficacy of cancer therapies by modulating immune responses. Here, the effect and the mechanism of butyrate on anti-PD-L1 therapy were investigated in CRC. METHODS: The expression of PD-L1 and STAT1, and the lysine acetylation of STAT1 in CRC cells were observed after treatment with butyrate (2, 5, and 10 mM) for 24h or butyrate (5 mM) for 8, 16, and 24h. Site-directed mutations of STAT1 (K410R or K413R) were introduced to determine the role of STAT1 acetylation in modulating PD-L1 expression. The effect of butyrate on the cytotoxicity of CD8+ T-cells against CRC cells with or without PD-L1 overexpression was explored in vitro and in vivo. RESULTS: Butyrate could suppress IFN-γ-induced PD-L1 up-regulation in CRC cells in a dose- and time-dependent way. Butyrate promoted the lysine acetylation of STAT1 to reduce STAT1 expression. Non-acetylated mutant STAT1 not only ameliorated butyrate-induced suppression of lysine acetylation and nuclear translocation of STAT1 but also blocked the effect of butyrate on PD-L1. Butyrate attenuated the IFN-γ-induced impairment of CD8+ T-cell cytotoxicity against CRC cells. Meanwhile, butyrate suppressed CRC tumor growth by enhancing CD8+ T-cell infiltration. However, directly overexpressing PD-L1 in CRC cells could abolish the effect of butyrate. CONCLUSION: Butyrate strengthens the immune response to CRC cells by suppressing PD-L1 expression via acetylation of STAT1.

3D-printed biomimetic scaffolds with precisely controlled and tunable structures guide cell migration and promote regeneration of osteochondral defect.

Untreated osteochondral defects will develop into osteoarthritis, affecting patients' quality of life. Since articular cartilage and subchondral bone exhibit distinct biological characteristics, repairing osteochondral defects remains a major challenge. Previous studies have tried to fabricate multilayer scaffolds with traditional methods or 3D printing technology. However, the efficacy is unsatisfactory because of poor control over internal structures or a lack of integrity between adjacent layers, severely compromising repair outcomes. Therefore, there is a need for a biomimetic scaffold that can simultaneously boost osteochondral defect regeneration in both structure and function. Herein, an integrated bilayer scaffold with precisely controlled structures is successfully 3D-printed in one step via digital light processing (DLP) technology. The upper layer has both 'lotus- and radial-' distribution pores, and the bottom layer has 'lotus-' pores to guide and facilitate the migration of chondrocytes and bone marrow mesenchymal stem cells, respectively, to the defect area. Tuning pore sizes could modulate the mechanical properties of scaffolds easily. Results show that 3D-printed porous structures allow significantly more cells to infiltrate into the area of 'lotus- and radial-' distribution pores during cell migration assay, subcutaneous implantation, andin situtransplantation, which are essential for osteochondral repair. Transplantation of this 3D-printed bilayer scaffold exhibits a promising osteochondral repair effect in rabbits. Incorporation of Kartogenin into the upper layer of scaffolds further induces better cartilage formation. Combining small molecules/drugs and precisely size-controlled and layer-specific porous structure via DLP technology, this 3D-printed bilayer scaffold is expected to be a potential strategy for osteochondral regeneration.

Butyrate facilitates immune clearance of colorectal cancer cells by suppressing STAT1-mediated PD-L1 expression

Abstract Objective Immunotherapy has been proven to improve the prognosis of patients with advanced malignancy but has shown limited efficacy in patients with Colorectal Cancer (CRC). Increasing evidence suggests that butyrate, a bacterial metabolite, enhances the efficacy of cancer therapies by modulating immune responses. Here, the effect and the mechanism of butyrate on anti-PD-L1 therapy were investigated in CRC. Methods The expression of PD-L1 and STAT1, and the lysine acetylation of STAT1 in CRC cells were observed after treatment with butyrate (2, 5, and 10 mM) for 24h or butyrate (5 mM) for 8, 16, and 24h. Site-directed mutations of STAT1 (K410R or K413R) were introduced to determine the role of STAT1 acetylation in modulating PD-L1 expression. The effect of butyrate on the cytotoxicity of CD8+ T-cells against CRC cells with or without PD-L1 overexpression was explored in vitro and in vivo. Results Butyrate could suppress IFN-γ-induced PD-L1 up-regulation in CRC cells in a dose- and time-dependent way. Butyrate promoted the lysine acetylation of STAT1 to reduce STAT1 expression. Non-acetylated mutant STAT1 not only ameliorated butyrate-induced suppression of lysine acetylation and nuclear translocation of STAT1 but also blocked the effect of butyrate on PD-L1. Butyrate attenuated the IFN-γ-induced impairment of CD8+ T-cell cytotoxicity against CRC cells. Meanwhile, butyrate suppressed CRC tumor growth by enhancing CD8+ T-cell infiltration. However, directly overexpressing PD-L1 in CRC cells could abolish the effect of butyrate. Conclusion Butyrate strengthens the immune response to CRC cells by suppressing PD-L1 expression via acetylation of STAT1.

Msx1+ stem cells recruited by bioactive tissue engineering graft for bone regeneration.

Critical-sized bone defects often lead to non-union and full-thickness defects of the calvarium specifically still present reconstructive challenges. In this study, we show that neurotrophic supplements induce robust in vitro expansion of mesenchymal stromal cells, and in situ transplantation of neurotrophic supplements-incorporated 3D-printed hydrogel grafts promote full-thickness regeneration of critical-sized bone defects. Single-cell RNA sequencing analysis reveals that a unique atlas of in situ stem/progenitor cells is generated during the calvarial bone healing in vivo. Notably, we find a local expansion of resident Msx1+ skeletal stem cells after transplantation of the in situ cell culture system. Moreover, the enhanced calvarial bone regeneration is accompanied by an increased endochondral ossification that closely correlates to the Msx1+ skeletal stem cells. Our findings illustrate the time-saving and regenerative efficacy of in situ cell culture systems targeting major cell subpopulations in vivo for rapid bone tissue regeneration.

Laparoscopic ultrasonography-guided cryoablation of locally advanced pancreatic cancer: a preliminary report.

OBJECTIVE: To evaluate safety and feasibility of laparoscopic ultrasonography (LUS)-guided cryoablation of locally advanced pancreatic cancer (LAPC). PATIENTS AND METHODS: From April 2018 to December 2018, ten patients (five women, five men; mean age 58.2 ± 9.4 years) with LAPC underwent the operation. LUS was used to guide the cryoablation. Computed tomography (CT) imaging, biochemical analysis and pain score analysis by numeric rating scale (NRS) were used to assess treatment outcomes at 1 week and 3 months after the operation. RESULTS: Cryoablation was performed by the operation in all cases. Seven patients received complete ablation and the success rate of operation was 70%. Two cryoablation cycles and an average of 1.4 ± 0.5 cryoprobes were used. The average freezing time and operation time were 23.8 ± 1.0 and 110.5 ± 24.7 min, respectively. The mean blood loss was 52.0 ± 16.6 ml. No major complications were observed after the operation. The mean maximum tumor diameter determined by CT decreased from 4.9 ± 0.7 cm before the operation to 4.7 ± 1.0 cm at 1 week and 4.6 ± 1.3 cm at 3 months, with P values of 0.53 and 0.51 (relative to the preoperative values), respectively. Postoperative CT imaging results suggested tumor necrosis in cryoablation-treated areas. The mean CA19-9 levels decreased from 347.5 ± 345.7 U/mL before operation to 190.4 ± 153.8 U/mL at 1 week and 182.7 ± 165.6 U/mL at 3 months, with P values of 0.15 and 0.14 (relative to the preoperative values), respectively. The average pain scores declined from 6.9 ± 1.1 before operation to 1.3 ± 1.2 at 1 week and 2.0 ± 0.8 at 3 months, with both P values of < 0.01 (relative to the preoperative values). CONCLUSION: This preliminary study suggested that LUS-assisted cryoablation was a safe and feasible treatment for LAPC.

Long Intergenic Nonprotein Coding RNA 173 Inhibits Tumor Growth and Promotes Apoptosis by Repressing Sphingosine Kinase 1 Protein Expression in Pancreatic Cancer.

Pancreatic cancer is a common malignant tumor worldwide. Extensive studies have been conducted on the functional role of long noncoding RNAs in pancreatic cancer. In this study, long intergenic nonprotein coding RNA 173 (LINC00173) was highly expressed in pancreatic cancer tissues. In vitro functional experiments showed that LINC00173 overexpression inhibited the proliferation and invasion of pancreatic cancer cells and promoted cell apoptosis in MIA PaCa-2 and PANC-1 cells. RNA sequencing analysis and Western blot assays demonstrated that LINC00173 reduced the expression of sphingosine kinase 1 (SPHK1) and then inhibited the protein expression of activated phospho-protein kinase B (AKT) and NF-κB. In vivo functional assays also revealed that LINC00173 inhibited the growth of pancreatic cancer xenografts, repressed cell proliferation, promoted cell apoptosis, and inhibited SPHK1 expression. The combined results of this study indicate that LINC00173 inhibits pancreatic cancer progression by repressing SPHK1 expression. Improving LINC00173 may represent a therapeutic strategy for pancreatic cancer in the future.

[Evolvement of a five-way translocation t(5;9;22;6;17) from a four-way Philadelphia translocation t(5;9;22;6) in a rare case of chronic myeloid leukemia].

OBJECTIVE: To trace a rare case of chronic myeloid leukemia (CML) with a four-way Philadelphia chromosome variant by cytogenetic analysis in order to provide a basis for the selection of treatment. METHODS: Bone marrow morphology, chromosomal karyotyping, fluorescence in situ hybridization (FISH) and real-time quantitative PCR (RQ-PCR) were used for the diagnosis and staging of the disease. Point mutations in the tyrosine kinase domain of ABL1 gene were detected by Sanger sequencing. RESULTS: The patient was initially diagnosed as CML in chronic phase (CML-CP) with a chromosomal karyotype of 46,XX,t(5;9;22;6)(q13;q34;q11;q25), while FISH revealed presence of a variant Philadelphia chromosome translocation. Clonal evolution has occurred after 38 months of tyrosine kinase inhibitor (TKI) treatment, when cytogenetic analysis revealed coexisting t(5;9;22;6)(q13;q34;q11;q25) and t(5;9;22;6;17)(q13;q34;q11;q25;q11). After 57 months of TKIs treatment, only the t(5;9;22;6;17) clone was detected. Three months later, hyperdiploidy with additional abnormalities were detected in addition to t(5;9;22;6;17). Three mutations, including p.Tyr253Phe, p.Thr315Ile and p.Gly250Glu, were identified in the tyrosine kinase domain of the ABL1 gene during the course of disease. The patient did not attain cytogenetic and molecular response to TKIs. CONCLUSION: The four-way variant translocation may be genetically unstable. Clonal evolution and genetic mutations are likely to occur during TKIs treatment, resulting in poor response to drug therapy. This observation, however, needs to be confirmed by large-scale studies.

Metformin Increases the Chemosensitivity of Pancreatic Cancer Cells to Gemcitabine by Reversing EMT Through Regulation DNA Methylation of miR-663.

BACKGROUND: Pancreatic cancer is a devastating malignancy with poor prognosis. Metformin, a classic anti-diabetes drug, seems to improve survival of pancreatic cancer patients in some studies. METHODS: Cell counting kit-8 assay was used to detect the BxPC-3 and MIAPaCa-2 cell viability after treatment with gemcitabine only or with different concentrations of metformin. The methylation state and expression level of miR-663 were detected by methylation analysis and RT-PCR. Dual-luciferase reporter gene analysis, Western blot and RT-PCR were used to confirm the target of miR-663. Moreover, xenograft experiment was also performed to validate the role of metformin in chemosensitivity in vivo. RESULTS: We found that metformin increased the chemosensitivity of pancreatic cancer cells to gemcitabine, and epithelial-mesenchymal transition (EMT) progress caused by gemcitabine was suppressed by metformin. We further explored the possible molecular mechanisms and it was demonstrated that CpG islands of miR-663 were hypomethylated and relative expression level of miR-663 was up-regulated after treatment of metformin. miR-663, an important cancer suppressor miRNA, was confirmed to increase the chemosensitivity of pancreatic cancer cells by reversing EMT directly targeted TGF-ß1. Moreover, we identified that metformin increased the chemosensitivity through up-regulating expression of miR-663. CONCLUSION: We demonstrated that metformin increased the chemosensitivity of pancreatic cancer cells to gemcitabine by reversing EMT through regulation DNA methylation of miR-663.

Comparative peptidome profiling reveals critical roles for peptides in the pathology of pancreatic cancer.

BACKGROUNDS/AIMS: Pancreatic cancer is a digestive system tumour disease with a notably poor prognosis and a 5-year survival rate of less than 10 %. In recent years, peptide drugs have shown great clinical value in antitumour applications. We aim to identify differentially expressed peptides by using peptidomics techniques to explore the mechanisms involved in the development and pathology of pancreatic cancer. METHODS: We performed peptidomic analysis of pancreatic cancer and paired paracancerous tissues by using ITRAQ labelling technology and conducted in-depth bioinformatics analysis and functional studies on differentially expressed peptides. RESULTS: A total of 2,881 peptides were identified, of which 133 were differentially expressed (116 were upregulated and 17 were downregulated). By using GO analysis, the differentially expressed peptides were found to be closely related to the tumour microenvironment and extracellular matrix. KEGG enrichment analysis revealed that precursor proteins were closely related to the T2DM and RAS signalling pathways. The endogenous peptide P1DG can significantly inhibit the proliferation, migration and invasion of pancreatic cancer cells. CONCLUSION: P1DG and its precursor GAPDH may be closely related to the proliferation, migration and invasion of pancreatic cancer. Peptidomics can aid in understanding the pathogenesis of pancreatic cancer more comprehensively.

Multifunctional gap-enhanced Raman tags for preoperative and intraoperative cancer imaging.

Multi-modality imaging agents are desirable for tumor diagnosis because they can provide more alternative and reliable information for accurate detection and therapy of diseases than single imaging technique. However, most reported conventional imaging agents have not been found to successfully overcome the disadvantages of traditional diagnoses such as sensitivity, spatial resolution, short half-decay time and complexity. Therefore, exploring a multifunctional nanocomposite with the combination of their individual modality characteristics has great impact on preoperative imaging and intraoperative diagnosis of cancer. In our study, mesoporous silica gadolinium-loaded gap-enhanced Raman tags (Gd-GERTs) specifically for preoperative and intraoperative imaging are designed and their imaging capability and biosafety are examined. They exhibit strong attenuation property for computed X-ray tomography (CT) imaging, high T1 relaxivity for magnetic resonance (MR) imaging capability and surface-enhanced Raman spectroscopy (SERS) signal with good dispersity and stability, which presents CT/MR/SERS multi-mode imaging performance of the tumor of mice within a given time. Furthermore, in vivo biodistribution and long-term toxicity studies reveal that the Gd-GERTs have good biocompatibility and bio-safety. Therefore, Gd-GERTs are of great potential as a multifunctional nanoplatform for accurate preoperative CT/MRI diagnosis and intraoperative Raman imaging-guide resection of cancers. STATEMENT OF SIGNIFICANCE: Recent advances in molecular imaging technology have provided a myriad of opportunities to prepare various nanomaterials for accurate diagnosis and response evaluation of cancer via different imaging modalities. However, single bioimaging modality is still challenging to overcome the issues such as sensitivity, spatial resolution, imaging speed and complexity for clinicians. In this work, we designed a kind of unique multifunctional nanoprobes with computed X-ray tomography/magnetic resonance/surface-enhanced Raman spectroscopy (CT/MR/SERS) triple-modal imaging capabilities. Multifunctional nanotags offer the capabilities of preoperative noninvasive CT/MR imaging for identification of tumors as well as intraoperative real-time SERS imaging for guidance of complete resection of tumors. These multifunctional nanoprobes show critical clinical significance on the improvement of tumor diagnosis and therapy.

Ultrabright gap-enhanced Raman tags for high-speed bioimaging.

Surface-enhanced Raman spectroscopy (SERS) is advantageous over fluorescence for bioimaging due to ultra-narrow linewidth of the fingerprint spectrum and weak photo-bleaching effect. However, the existing SERS imaging speed lags far behind practical needs, mainly limited by Raman signals of SERS nanoprobes. In this work, we report ultrabright gap-enhanced Raman tags (GERTs) with strong electromagnetic hot spots from interior sub-nanometer gaps and external petal-like shell structures, larger immobilization surface area, and Raman cross section of reporter molecules. These GERTs reach a Raman enhancement factor beyond 5 × 109 and a detection sensitivity down to a single-nanoparticle level. We use a 370 µW laser to realize high-resolution cell imaging within 6 s and high-contrast (a signal-to-background ratio of 80) wide-area (3.2 × 2.8 cm2) sentinel lymph node imaging within 52 s. These nanoprobes offer a potential solution to overcome the current bottleneck in the field of SERS-based bioimaging.

Thermosensitive drug-loading system based on copper sulfide nanoparticles for combined photothermal therapy and chemotherapy in vivo.

A phase-change material (PCM) is an efficient energy storage material, but its poor thermal conductivity has limited its application in nanomedicine research. In this study, we used the photothermal material copper sulfide (CuS) to tackle this challenge. The designed CuS-DOX-MBA@PCM nanoparticles (NPs) were prepared by a nanoprecipitation method, and were composed of CuS, the anticancer drug (DOX), and near-infrared (NIR) dyes (MBA) encapsulated with stearic acid and lauric acid, which are characterized by a low eutectic point close to human physiological temperature. Because the CuS-DOX-MBA@PCM NPs could release the drug quickly in physiological conditions, it implied that they could have potential as a promising drug-loading system. CuS-DOX-MBA@PCM NPs were utilized as an imaging-guided photothermal agent for photothermal therapy (PTT) combined with chemotherapy in cells and in a mice model. In vitro fluorescence imaging indicated the high uptake of CuS-DOX-MBA@PCM NPs in tumor cells due to enhanced permeability and retention effects, while in vivo experiments showed that the tumor growth in tumor-bearing mice models could be inhibited by the CuS-DOX-MBA@PCM NPs. Such an evident enhanced tumor inhibition could be attributed to the synergistic effect of the DOX chemotherapy and the photothermal therapy with a safe laser irradiation at 808 nm with a power density of 1.0 W cm-2. Furthermore, this combined therapy offers the possibility to lower the dosage of DOX in anticancer therapy, which would thus decrease the toxic effects on cancer patients. The results from this study confirmed the effect of CuS-DOX-MBA@PCM NPs for use as a chemo-photothermal therapy and the clinical value of the designed thermosensitive drug-loading system in the field of combined cancer therapy.

Chronic pancreatitis with multiple pseudocysts and pancreatic panniculitis: A case report.

RATIONALE: Pancreatic pseudocyst can present single or multiple, inside or outside the pancreas. Pancreatic panniculitis is a rare skin lesion in pancreatic disease patients. The purpose of this study is to report a case of chronic pancreatitis coexisting with multiple pseudocysts and pancreatic panniculitis. PATIENT CONCERNS: A 46-year-old man with chronic pancreatitis presented multiple small cystic lesions inside the head of the pancreas and two large cystic lesions adjacent to the tail of the pancreas. The patient also developed subcutaneous nodules involving upper and lower limbs, hands, and lower abdomen bilaterally. DIAGNOSIS: The patient was diagnosed with pancreatic pseudocyst and pancreatic panniculitis resulted from chronic pancreatitis. INTERVENTIONS: Bile duct stent and pancreatic duct stent placement was performed endoscopicly. OUTCOMES: Panniculitis faded three weeks later and the pancreatic pseudocysts disappeared six weeks later. LESSONS: Clinicians should be aware of the manifestation of multiple pancreatic pseudocyst and pancreatic panniculitis, and endoscopic transpapillary drainage may be a effective way in this scenario.

Systemic lupus erythematosus with intestinal perforation: A case report.

Systemic lupus erythematosus (SLE) is a systemic autoimmune inflammatory disease, which can affect almost all systems and organs. Gastrointestinal disorder is one of the most noteworthy complications of patients with SLE. However, gastrointestinal disorder with intestinal perforation is rare, but potentially life-threatening if not treated promptly. The present study reported a case of SLE with intestinal perforation, where surgical intervention was performed and a crevasse (~3 cm in diameter) was detected in the ileum, ~60 cm from the ileocecal valve. Following surgery, the patient suffered from difficult ventilator weaning, septic shock and intestinal obstruction. The patient was successfully treated and discharged from the hospital after ~4 months of treatment. Intestinal perforation in SLE patients is potentially life-threatening; early diagnosis and prompt treatment are crucial to the management of this rare complication of SLE.

Carcinoid tumor of the appendix: A case report.

Carcinoid tumors are the most common neoplasm of the appendix. The clinical presentation of these lesions is often similar to that of acute appendicitis, or the tumors are asymptomatic. The carcinoids are commonly found incidentally during histopathological examination of the resected appendix following appendectomy or other abdominal procedures. Appendiceal carcinoids usually behave as benign tumors and appendicectomy alone is a sufficient treatment in the majority of cases, while for larger lesions, right colectomy should be performed. The prognosis of patients with local appendiceal carcinoids is excellent. The present study reports the case of a 22-year-old female patient that presented with recurrent right lower abdominal pain of a three-year duration. The patient underwent successful appendectomy and recovered four days later. Subsequently, an appendiceal carcinoid tumor located at the tip of the appendix was diagnosed by histopathological examination. Follow-up examination one year after surgery revealed that the patient was well with no discomfort.

Vasohibin 2 decreases the cisplatin sensitivity of hepatocarcinoma cell line by downregulating p53.

Hepatocellular carcinoma (HCC) is a prevalent problem worldwide. Chemotherapy, especially cisplatin (CDDP)-based systemic chemotherapy, is the best option for advanced liver cancer. However, CDDP resistance is becoming common and hindering the clinical application of CDDP. Meanwhile, no consensus has been reached regarding the chemotherapeutic use of vasohibin 2 (VASH2), which promotes the angiogenesis and proliferation of cancer cells. In this work, a tissue microarray was used to observe VASH2 and its possible role in cancer treatment. Results showed that VASH2 was highly expressed in HCC tissues and was significantly correlated with cancer differentiation. To further investigate the efficacy and mechanism of the combination of VASH2 with anti-cancer drugs in liver cancer cells, we stably built VASH2 overexpression and knockdown cell lines. We found that VASH2 can influence the CDDP sensitivity and that the cell overexpression of VASH2 had a higher cell viability and lower apoptosis rate after CDDP exposure. We also observed that VASH2 overexpression downregulated wild-type p53, as well as suppressed the expression of the pro-apoptotic protein BCL2-associated X protein (Bax) and cleaved caspase-3 (CC-3) after treatment by CDDP. Conversely, the knockdown of VASH2 significantly inhibited these effects. In an in vivo chemosensitivity study, nude mice were subcutaneously injected with tumor cells and received CDDP treatment through intraperitoneal administration every 3 days. We found that VASH2 knockdown markedly limited the tumor growth and enhanced the CDDP toxicity and apoptosis of tumor cells. Western blot analysis revealed that tumor cells with downregulated VASH2 had a higher expression of wild-type p53, Bax, and CC-3 than control cells. Overall, our results indicated the novel roles of VASH2 in the chemoresistance of hepatocarcinoma cells to CDDP and suggested that VASH2 may be a promising anticancer target.

IL-17 neutralization significantly ameliorates hepatic granulomatous inflammation and liver damage in Schistosoma japonicum infected mice.

IL-17 is a signature cytokine of Th17 cells implicated in the induction and progression of chronic inflammatory diseases. Several studies in C57BL/6 mice, immunized with soluble schistosome egg Ags (SEA) in complete Freund's adjuvant (CFA), and subsequently infected with Schistosoma mansoni (S. mansoni) have shown that severe hepatic granulomatous inflammation is correlated with high levels of IL-17. Here, using a Schistosoma japonicum (S. japonicum) larvae infection model in C57BL/6 mice, we analyzed the dynamic expression of IL-17 in infected livers by RT-qPCR and ELISA. Our results showed that IL-17 expression was elevated during the course of infection. The temporal expression of IL-17 and cytokines/chemokines involved in the induction and effector function of Th17 cells was paralleled with hepatic granulomatous inflammation. Treatment of S. japonicum infected mice with IL-17-neutralizing mAb resulted in significant downmodulation of granulomatous inflammation and hepatocyte necrosis. The protection was associated with lower expression of proinflammatory cytokines/chemokines, such as IL-6, IL-1ß, CXCL1, and CXCL2 and a reduced number of infiltrating neutrophils. Anti-IL-17 mAb significantly ameliorated hepatic granulomatous inflammation, partly through the downregulation of proinflammatory cytokines/chemokines and recruitment of neutrophils. Our data indicate a pathogenic role of Th17/IL-17 in hepatic immunopathology in S. japonicum infected mice.