CD40 Agonists Alter the Pancreatic Cancer Microenvironment by Shifting the Macrophage Phenotype toward M1 and Suppress Human Pancreatic Cancer in Organotypic Slice Cultures

Background/Aims@#CD40 agonists are thought to generate antitumor effects on pancreatic cancer via macrophages and T cells. We aimed to investigate the role of CD40 agonists in the differentiation of macrophages and treatment of human pancreatic adenocarcinoma. @*Methods@#Immunohistochemistry was performed on paraffin-embedded surgical blocks from patients with pancreatic cancers to evaluate macrophage phenotypes and their relationship with survival. The effects of CD40 agonists on macrophage phenotypes and human pancreatic cancer were evaluated utilizing cell cocultures and organotypic slice cultures. @*Results@#CD163 + (predominant in M2 macrophages) and FOXP3 + (predominant in regulatory T cells) expression levels in the tumors were significantly lower in patients with stage IB pancreatic cancer than in those with stage II or III disease (p=0.002 and p=0.003, respectively). Patients with high CD163 + expression had shorter overall survival than those with low CD163 + expression (p=0.002). In vitro treatment of THP-1 macrophages with a CD40 agonist led to an increase in HLA-DR + (predominant in M1 macrophages) and a decrease in CD163 + expression in THP-1 cells. Cell cocultures showed that CD40 agonists facilitate the suppression of PANC-1 human pancreatic cancer cells by THP-1 macrophages. Organotypic slice cultures showed that CD40 agonists alter the pancreatic cancer microenvironment by shifting the macrophage phenotype toward M1 (increase HLA-DR + and decrease CD163 + expression), decreasing the abundance of regulatory T cells, and increasing tumor cell apoptosis. @*Conclusions@#CD163 is related to advanced human pancreatic cancer stages and shorter overall survival. CD40 agonists alter macrophage phenotype polarization to favor the M1 phenotype and suppress human pancreatic cancer.

Effects of Hydroxychloroquine on the Metabolism of Fas ligand of T cells / 대한류마티스학회지

OBJECTIVE: Hydroxychloroquine (HCQ) is a drug that has been used to treat autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus. However, the specific mechanism for its pharmacologic action has been largely unknown. It has been reported that dysregulation of lymphocytic apoptosis mediated by Fas ligand (FasL) and Fas is associated with the development of autoimmune diseases and HCQ induces apoptosis in peripheral blood lymphocytes. These reports suggest that HCQ may exert its pharmacologic effects through the modulation of FasL and Fas. Therefore, we are intended to investigate the effects of HCQ on the regulation of FasL and Fas. Jurkat cells or peripheral blood mononuclear cells (PBMNC) were treated with varying concentrations of HCQ. Semiquantative reverse transcription- polymerase chain reaction, Western blotting, flow cytometry, and ELISA were used for this study. HCQ at nontoxic concentrations( 50~150 micrometer) caused a dose dependent increase of FasL mRNA expression and FasL in cell lysates. HCQ inhibited the release of intracellular 40 kDa FasL by Jurkat cells which were pulse-stimulated with PHA (50 microgram/ml). Jurkat cells activated with PHA increased membrane bound FasL (mFasL) expression (24.5+/-4.3%), however Jurkat cells pretreated with HCQ(150 micrometer) followed by PHA administration did not further increase mFasL expression (26.8+/-1.6%). Addition of different concentrations of HCQ to the cultured PBMNC stimulated with PHA for 24 hours showed increase of soluble FasL (sFasL). The levels of sFasL treated with HCQ zero, 50, 150 and 300 micrometer for 24 hours were 38.6+/-3.0, 43.4+/-5.1, 77.0+/-3.6(P<0.05) and 72.3+/-8.1pg/ml(P<0.05) respectively. However, fas metabolism was not affected by HCQ. CONCLUSION: These results suggest that HCQ may exhibit its pharmacological effects by upregulation of FasL gene expression and increased production sFasL without any influence on the Fas metabolism of T cells.

A Case of Williams Syndrome Diagnosed by FISH

Williams syndrome was first reported in 1961, it is characterized by distinct facial changes, growth deficiency, mental retardation, congenital heart defect (particularly the supravalvular aortic stenosis), associated at times with infantile hypercalcemia. The diagnosis of this disease relied on phenotype, after recent acknowledgement of its genetic basis on the 7th chromosomal locus q11.23 involving elastin gene on the PCR. Recently, commercial probe of elastin gene for FISH was supplied and diagnosed this disease easier. Using PCR has some benefits concerning whether the origin of the genetic defect is maternal or paternal. The diagnosis of this disease is difficult due to low sensitivity, below 50%. But FISH is widely used because it is faster with high positive predictibility. We report Williams syndrome diagnosed by FISH with a brief review and related literatures.

A Case of Embryonal Carcinoma Developed in a Cryptorchid Testis / 대한비뇨기과학회지

A case of testicular embryonal carcinoma developed in s cryptorchid testis is presented with a review of the literature. According to Campbell's series, the incidence of malignant cryptorchid testis was 11.6%. and his statistical evaluation was similar to Gilbert and Hamilton's series of 7,000 cases of testicular neoplasms where 840 tumors were developed in undescended testes(12%). Both authors agree that the chance of neoplastic development in a cryptorchid testis is approximately 48 times greater then that developing in a normally descended testis. Several cases of testicular tumor were reported sporadically in Korea, but malignant tumors in cryptorchism were rarely seen in the literatures Only two cases of malignant cryptorchid testis were already reported in Korea.