Oncolytic vaccinia virus reinvigorates peritoneal immunity and cooperates with immune checkpoint inhibitor to suppress peritoneal carcinomatosis in colon cancer

BackgroundPeritoneal carcinomatosis (PC) is a common and devastating manifestation of colon cancer and refractory to conventional anticancer therapeutics. During the peritoneal dissemination of colon cancer, peritoneal immunity is nullified by various mechanisms of immune evasion. Here, we employed the armed oncolytic vaccinia virus mJX-594 (JX) to rejuvenate the peritoneal antitumor immune responses in the treatment of PC.MethodsPC model of MC38 colon cancer was generated and intraperitoneally treated with JX and/or anti-programmed cell death protein 1 (PD-1) antibody. The peritoneal tumor burden, vascular leakage, and malignant ascites formation were then assessed. Tumors and peritoneal lavage cells were analyzed by flow cytometry, multiplex tissue imaging, and a NanoString assay.ResultsJX treatment effectively suppressed peritoneal cancer progression and malignant ascites formation. It also restored the peritoneal anticancer immunity by activating peritoneal dendritic cells (DCs) and CD8+ T cells. Moreover, JX selectively infected and killed peritoneal colon cancer cells and promoted the intratumoral infiltration of DCs and CD8+ T cells into peritoneal tumor nodules. JX reinvigorates anticancer immunity by reprogramming immune-related transcriptional signatures within the tumor microenvironment. Notably, JX cooperates with immune checkpoint inhibitors (ICIs), anti-programmed death-1, anti-programmed death-ligand 1, and anti-lymphocyte-activation gene-3 to elicit a stronger anticancer immunity that eliminates peritoneal metastases and malignant ascites of colon cancer compared with JX or ICI alone.ConclusionsIntraperitoneal immunotherapy with JX restores peritoneal anticancer immunity and potentiates immune checkpoint blockade to suppress PC and malignant ascites in colon cancer.

Unilateral Pseudo-Ainhum in Liver Cirrhosis

BACKGROUND: Pseudo-ainhum is defined as any case of auto‐amputation not associated with the classic spontaneous ainhum seen in Africans with unknown etiology. CASE PRESENTATION: A severely ill 58-year-old male patient presented with a painless constricting circular band on his left second toe. His medical history was remarkable for severe alcoholic liver cirrhosis with ascites formation leading to dyspnea. He had a hypoalbuminemia and a pronounced peripheral sensory neuropathy. CONCLUSION: Here we present the second case of pseudo-ainhum associated with liver cirrhosis.

Sorafenib-loaded PAMAM dendrimer attenuates liver fibrosis and its complications in bile-duct-ligated rats

We assessed the effect of sorafenib-loaded polyamidoamine (PAMAM) dendrimer on liver fibrosis induced by bile duct ligation (BDL). Male Wistar rats were divided into 9 groups: intact, sham, DMSO + BDL, BDL, sorafenib (30 mg/kg), sorafenib (60 mg/kg), PAMAM + BDL, sorafenib (30 mg/kg) + PAMAM + BDL, sorafenib (60 mg/kg) + PAMAM + BDL. BDL was induced and then rats were treated daily with sorafenib and (or) PAMAM for 4 weeks. Improvement of liver was detected via assessment of ascites formation, collagen deposition, liver blood flow, vascular endothelial growth factor level, and blood cells count. Sorafenib-loaded PAMAM dendrimer in both 30 and 60 mg/kg doses reduced ascites formation, reduced collagen deposition, and improved drug-induced hematological side effects of sorafenib alone in comparison with sorafenib-alone treatment. Sorafenib-loaded PAMAM dendrimer increased liver blood flow compared with sorafenib-received groups. Sorafenib-loaded PAMAM dendrimer reduced BDL-induced liver injury compared with sorafenib-received groups. Moreover, sorafenib-loaded PAMAM dendrimer decreased vascular endothelial growth factor level in serum and liver tissue in comparison with sorafenib-received groups. Sorafenib-loaded PAMAM dendrimer profoundly improved the therapeutic effects of sorafenib in BDL rats.

A comparative study of serum ascitic fluid albumin gradient with ascitic fluid total protein in evaluating the etiology of ascites

Background: The traditional method of classification of ascites by AFTP offers little insight into the pathophysiology of ascites formation and it has many drawbacks. In order to overcome it, the classification of ascites based on SAAG has emerged. Even SAAG has some draw backs like non correlation with ascites due to non-alcoholic cirrhosis and difficulty in identifying the ascites due to mixed etiology. This study is conducted to compare the diagnostic accuracies of SAAG and AFTP in identifying the pathophysiology of ascites.Methods: A total of fifty patients who were admitted with ascites were included in the study. Ascitic fluid total protein and SAAG were calculated. They were classified on the basis of SAAG into High SAAG and Low SAAG and on the basis of AFTP into Transudate and Exudate. After the etiology of ascites evaluated by various diagnostic procedures, the sensitivity, specificity and diagnostic accuracy of SAAG and AFTP in identifying the pathophysiology of ascites calculated sepereately. The diagnostic accuracies of SAAG and AFTP were compared statistically.Results: The sensitivity of SAAG was found to be 86.84% and that of AFTP 60%. The specificity of SAAG was found to be 83.33% and that of AFTP was found to be 60%. The diagnostic accuracy of SAAG was found to be 86% and that of AFTP was found to be 60%. The diagnostic accuracy of SAAG and AFTP for individual etiologies of ascites were found and compared. SAAG was found to be superior to AFTP with a P value of <0.01 which was statistically significant.Conclusions: The sensitivity and specificity of SAAG was superior to AFTP in identifying the etiology of ascites.

LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.