Primary anaplastic lymphoma kinase-positive large B-cell lymphoma of the left bulbar conjunctiva: A case report

BACKGROUND Anaplastic lymphoma kinase(ALK)-positive large B-cell lymphoma(LBCL)is an aggressive and rare variant of diffuse LBCL.Herein,we report an uncommon case of stage IE extranodal ALK-positive LBCL initially originating in the bulbar con-junctiva.CASE SUMMARY A 63-year-old woman presented with a mass in the left bulbar conjunctiva that had persisted for six months,accompanied by swelling and pain that had per-sisted for 3 d.Eye examination revealed an 8 mm slightly elevated pink mass in the lower conjunctival sac of the left eye.Microscopically,the tumor was com-posed of large immunoblastic and plasmablastic large lymphoid cells with scattered anaplastic or multinucleated large cells.Immunophenotypically,the neoplastic cells were positive for ALK,CD10,CD138,Kappa,MUM1,BOB.1,OCT-2,CD4,CD45,EMA,CD79a,CD38,and AE1/AE3,and negative for CD20,PAX5,Lambda,BCL6,CD30 and all other T-cell antigens.The results of gene rearrangement tests showed monoclonal IGH/IGK/IGL and TCRD rearran-gements.Fluorescence in situ hybridization studies did not reveal any BCL2,BCL6 or MYC rearrangements.Furthermore,Epstein-Barr virus was not detected by in situ hybridization in the lesions.Based on the histopathological and imaging examinations,the neoplasm was classified as stage IE ALK-positive LBCL.No further treatments were administered.At the 6,15,and 21 mo postoperative follow-up visits,the patient was in good condition,without obvious discomfort.This case represents the first example of primary extranodal ALK-positive LBCL presenting as a bulbar conjunctival mass,which is extremely rare and shares morphological and immunohistochemical features with a variety of other neo-plasms that can result in misdiagnosis.CONCLUSION Awareness of the condition presented in this case report is necessary for early and accurate diagnosis and appropriate treatment.

Role of Cyclin D1b in Inducing Macrophages Toward a Tumor-associated Macrophage-like Phenotype in Murine Breast Cancer

Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TAM activators.Cyclin D1b is a highly oncogenic splice variant of cyclin D1.We previously reported that cyclin D1b enhances the invasiveness of breast cancer cells by inducing EMT.However,the role of cyclin D1b in inducing macrophage differentiation toward tumor-associated macrophage-like cells remains unknown.This study aimed to explore the relationship between breast cancer cells overexpressing cyclin Dlb and TAMs.Methods:Mouse breast cancer 4T1 cells were transfected with cyclin D1b variant and co-cultured with macrophage cells in a Transwell coculture system.The expression of characteristic cytokines in differentiated macrophages was detected using qRT-PCR,ELISA and zymography assay.Tumor-associated macrophage distribution in a transplanted tumor was detected by immunofluorescence staining.The proliferation and migration ability of breast cancer cells was detected using the cell counting kit-8(CCK-8)assay,wound healing assay,Transwell invasion assay,and lung metastasis assay.Expression levels of mRNAs were detected by qRT-PCR.Protein expression levels were detected by Western blotting.The integrated analyses of The Cancer Genome Atlas(TCGA)datasets and bioinformatics methods were adopted to discover gene expression,gene coexpression,and overall survival in patients with breast cancer.Results:After co-culture with breast cancer cells overexpressing cyclin D1b,RAW264.7 macrophages were differentiated into an M2 phenotype.Moreover,differentiated M2-like macrophages promoted the proliferation and migration of breast cancer cells in turn.Notably,these macrophages facilitated the migration of breast cancer cells in vivo.Further investigations indicated that differentiated M2-like macrophages induced EMT of breast cancer cells accompanied with upregulation of TGF-β1 and integrinβ3 expression.Conclusion:Breast cancer cells transfected with cyclin D1b can induce the differentiation of macrophages into a tumor-associated macrophage-like phenotype,which promotes tumor metastasis in vitro and in vivo.

Insulin-like growth factor binding protein-7 induces activation and transdifferentiation of hepatic stellate cells in vitro

AIM:To investigate the role of insulin-like growth factor binding protein-7 (IGFBP-7) in the activation and transdifferentiation of hepatic stellate cells (HSC) in vitro.METHODS:Rat HSC-T6 cells were cultured in separate dishes and treated with various concentration of transforming growth factor (TGF)-β1,IGFBP-7 or antiIGFBP-7 antibody for 24 h.The supernatant or a cytoplasm suspension was obtained from cultured HSC,followed by transfer of cells to form cell-coated dishes.Immunocytochemistry and Western blotting were used to analyze the expression of IGFBP-7 induced by TGF-β1 and the level of fibronectin,collagen and α-smooth muscle actin (SMA).The pro-apoptotic effect of antiIGFBP-7 antibody was determined by flow cytometry.RESULTS:Immunocytochemistry and Western blotting revealed that the expression of IGFBP-7 in TGF-β1 treated HSC was significantly up-regulated compared to that in the control group.In addition,fibronectin,collagen and α-SMA also showed enhanced expression in accordance with the transdifferentiation process in a dose-dependent manner to some extent.Moreover,flow cytometry suggested that anti-IGFBP-7 antibody induced apoptosis of activated HSC,which is responsible for the development of liver fibrosis,and may represent a novel pathway and target for therapeutic intervention.CONCLUSION:IGFBP-7 showed increased expression in activated HSC and played an important role in the activation and transdifferentiation process of HSC.AntiIGFBP-7 antibody may ameliorate liver fibrogenesis.

Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic ?brosis via the regulation of MMPs/TIMPs in mice

Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue inhibitors of metalloproteinases(TIMP) play an essential role in hepatic fibrogenesis by regulating homeostasis and remodeling of the extracellular matrix(ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis. Methods: Hepatic fibrosis was induced by thioacetamide(TAA) in mice. Knockdown of IGFBPrP1 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition of the Hedgehog(Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, α-smooth muscle actin( α-SMA), transforming growth factor β 1(TGF β1), collagen I, MMPs/TIMPs, Sonic Hedgehog(Shh), and glioblastoma family transcription factors(Gli1) were investigated by immunohistochemical staining and Western blotting analysis. Results: We found that hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance. Conclusions: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGF β1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance.

老年睑板腺功能障碍蠕形螨感染率及茶树精油联合氟米龙的疗效

目的:研究老年睑板腺功能障碍(MGD)蠕形螨感染率及茶树精油联合氟米龙的疗效。方法:回顾性病例对照研究。选择2017-09/2018-03在宁波市眼科医院门诊就诊的老年MGD患者59例118眼。将睫毛蠕形螨镜检为阳性的38例患者76眼进行症状评分、蠕形螨数量、泪膜破裂时间(BUT)、角膜荧光素染色(FL)、Schirmer I试验(SIaT)等检查,并按不同治疗方法分成3组,A组使用0.02%氟米龙滴眼液滴眼24眼;B组使用茶树精油(TTO)湿巾敷眼26眼;C组用0.02%氟米龙滴眼液滴眼联合TTO湿巾敷眼26眼,随访4wk。结果:118眼中76眼(64.4%)睫毛蠕形螨镜检为阳性。睫毛蠕形螨阳性的三组患者治疗后的主观症状评分均较治疗前有改善(P<0.05)。治疗后A组蠕形螨数量较治疗前无显著差异(P=0.11);B、C组较治疗前明显减少(均P<0.01)。三组患者BUT治疗前后比较,A组BUT无显著差异(P=0.22);B、C组BUT明显延长(均P<0.05)。治疗后C组的BUT较A、B组明显延长(均P<0.05)。三组患者治疗前后的FL评分均较治疗前明显改善(P<0.05)。结论:老年MGD患者睫毛蠕形螨感染率较高,睑板腺热疏通后TTO湿巾联合0.02%氟米龙滴眼液能有效驱螨、缓解MGD患者局部症状。

IGFBPrP1 induces liver fibrosis by inducing hepatic stellate cell activation and hepatocyte apoptosis via Smad2/3 signaling

AIM:To investigate the role and mechanism of insulinlike growth factor binding protein-related protein 1(IGFBPrP1)in the development of liver fibrosis.METHODS:An in vitro model using hepatic stellate cell(HSC)-T6 cells and an in vivo model of rat liver overexpressing IGFBPrP1 were established using an IGFBPrP1-expressing recombinant adenovirus.The expression of IGFBPrP1 was examined by immunofluorescence,and the expression of collagen?Ⅰ?and fibronectin was mea-sured by real-time reverse transcription-polymerase chain reaction and Western blot analysis.The expression of Smad2/3 and p-Smad2/3 was examined by Western blot and immunohistochemistry.A shSmad3-expressing recombinant adenovirus(AdshSmad3)was designed and used to knockdown the Smad3 gene in HSC-T6 cells and rat liver fibrosis transfected with IGFBPrP1.The expression of collagen?Ⅰ,fibronectin,andα-smooth muscle actin(α-SMA)was determined by Western blot analysis and immunohistochemistry.Hepatocyte apoptosis was assessed using TUNEL assay.RESULTS:IGFBPrP1 overexpression induced collagen deposition and up-regulated the expression ofα-SMA and p-Smad2/3,and AdshSmad3 inhibited IGFBPrP1-stimulated p-Smad2/3 activation and the expression ofα-SMA,collagen?Ⅰ?and fibronectin in HSC-T6 cells.Similarly,increased hepatocyte apoptosis(38.56%±3.42%vs 0.24%±0.03%,P<0.05),α-SMA positive stained cells(29.84%±1.36%vs 5.83%±1.47%,P<0.05),and increased numbers of Smad3(35.88%±2.15%vs10.24%±1.31%,P<0.05)and p-Smad2/3 positive cells(28.87%±2.73%vs 8.23%±0.98%,P<0.05)were detected in the livers of IGFBPrP1-overexpressing rats compared with the control group.Moreover,AdshSmad3 reduced IGFBPrP1-stimulated Smad3 expression and attenuatedα-SMA expression(29.84%±1.36%vs 8.23%±1.28%,P<0.05),hepatocyte apoptosis(38.56%±3.42%vs 6.75%±0.52%,P<0.05),and both collagen?Ⅰ?and fibronectin deposition in the livers of AdIGFBPrP1-treated rats.CONCLUSION:IGFBPrP1 induces liver fibrosis by mediating the activation of hepatic stellate cells and hepatocyte apoptosis in a Smad3-dependent mechanism.

Interaction between insulin-like growth factor binding protein-related protein 1 and transforming growth factor beta 1 in primary hepatic stellate cells

BACKGROUND:We previously showed that insulin-like growth factor binding protein-related protein 1(IGFBPrP1) is a novel mediator in liver fibrosis.Transforming growth factor beta 1(TGFβ1) is known as the strongest effector of liver fibrosis.Therefore,we aimed to investigate the detailed interaction between IGFBPrP1 and TGFβ1 in primary hepatic stellate cells(HSCs).METHODS:We overexpressed TGFβ1 or IGFBPrP1 and inhibited TGFβ1 expression in primary HSCs for 6,12,24,48,72,and 96 hours to investigate their interaction and observe the accompanying expressions of α-smooth muscle actin(α-SMA),collagen I,fibronectin,and phosphorylated-mothers against decapentaplegic homolog 2/3(p-Smad2/3).RESULTS:We found that the adenovirus vector encoding the TGFβ1 gene(Ad TGFβ1) induced IGFBPrP1 expression while that of α-SMA,collagen I,fibronectin,and TGFβ1 increased gradually.Concomitantly,Ad IGFBPrP1 upregulated TGFβ1,α-SMA,collagen I,fibronectin,and p-Smad2/3 in a time-dependent manner while IGFBPrP1 expression was decreased at 96 hours.Inhibition of TGFβ1 expression reduced the IGFBPrP1-stimulated expression of α-SMA,collagen I,fibronectin,and p-Smad2/3.CONCLUSIONS:These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGFβ1,which likely accelerates liver fibrosis progression.Furthermore,IGFBPrP1 likely participates in liver fibrosis in a TGFβ1-depedent manner,and may act as an upstream regulatory factor of TGFβ1 in the Smad pathway.

Cryogenic system design for HIAF iLinac

A helium cryogenic system is designed by the Institute of Modern Physics,Chinese Academy of Sciences,to supply different cooling powers to the cryomodules of ion-Linac(iLinac)accelerator,which serves as the injector of the High Intensity Heavy-Ion Accelerator Facility project.The iLinac is a superconducting heavy-ion accelerator approximately 100 m long and contains 13 cryomodules cooled by superfluid helium.This article describes the cryogenic system design of the iLinac accelerator.The requirements of the cryogenic system,such as cooling mode,refrigeration temperature,operating pressure and pressure stability,are introduced and described in detail.In addition,heat loads from different sources are analyzed and calculated quantitatively.An equivalent cooling capacity of 10 kW at 4.5 K was determined for the cryogenic system according to the total heat load.Furthermore,a system process design was conducted and analyzed in detail.Further,the system layout and the main equipment are presented.

Effect on rabbits’intraocular structure by cross-linked hyaluronic formations as vitreous substitute

AIM:To develop a new material for retina filling and to investigate its effect on intraocular structure and histocompatibility in rabbit eyes.METHODS:The polymer-derived hyaluronic acid(HA)was formed by UV light cross-linked with N-vinyl-pyrrolidone.Vitrectomy was performed in the rabbits,and then crosslinked HA hydrogels at different concentrations were injected.Intraocular pressure measurements,cornea check-up,and B-ultrasound examination were performed during the follow-up period.After six weeks’follow-up,the rabbits were sacrificed,and both eyes were removed for hematoxylin-eosin(HE)staining,and the polymer materials were observed under electron microscopy.RESULTS:The particle size of the cross-linked HA hydrogels was mainly around at 100 nm.After vitrectomy and injection into vitreous cavity optical coherence tomography showed that the polymeric material HA had no significant effect on the overall thickness of the retina.The intraocular pressure returned to the normal level gradually at week 4.B-ultrasound results revealed that there is no significant change in the eye tissue given to HA material.The pathological and transmission electron microscopy results showed no obvious pathological change in the primary cells and rod cells under the retina tissue.CONCLUSION:HA-based cross-linked biopolymers has good biocompatibility in rabbit eyes,showing a promising potential as vitreous substitutes.

Percutaneous transforaminal endoscopic decompression combined with percutaneous vertebroplasty in treatment of lumbar vertebral body metastases:A case report

BACKGROUND Percutaneous endoscopic lumbar discectomy(PTED)is a procedure that is commonly used to treat lumbar disc herniation and spinal stenosis.Despite its less invasiveness,this surgery is rarely used to treat spinal metastases.Percutaneous vertebroplasty(PVP)has been utilized to treat lumbar vertebral body metastases but it has not proven useful in treating sciatic patients.CASE SUMMARY A 68-year-old woman presented with low back pain and radicular symptoms.She couldn't straighten her legs because of severe pain.Computed tomography(CT)showed a mass lesion in the lung and bone destruction in the L4 vertebrae.The biopsy of the lung lesion revealed adenocarcinoma and the biopsy for L4 vertebrae revealed metastatic adenocarcinoma.PTED paired with PVP was performed on the patient due to the patient's poor overall physical state and short survival time.Transcatheter arterial embolization of vertebral tumors was performed before surgical resection to reduce excessive blood loss during the operation.The incision was scaled up with the TESSY technology.The pain was obviously relieved following the operation and no serious complications occurred.Postoperative CT showed that the decompression around the nerve root was successful,polymethyl methacrylate filling was satisfactory and the tumor tissue around the nerve root was obviously removed.During the 1-year follow-up period,the patient was in a stable condition.CONCLUSION PTED in combination with PVP is an effective and safe treatment for Lumbar single-level Spinal Column metastases with radicular symptoms.Because of the small sample size and short followup time,the long-term clinical efficacy of this method needs to be further confirmed.