Pathological and Biological Significance of the Specific Glycan, TRA-1-60, on Aggressive Gastric Adenocarcinoma.

The glycans form a unique complex on the surface of cancer cells and play a pivotal role in tumor progression, impacting proliferation, invasion, and metastasis. TRA-1-60 is a glycan that was identified as a critical marker for the establishment of fully reprogrammed inducible pluripotent stem cells. Its expression has been detected in multiple cancer tissues, including embryonal carcinoma, prostate cancer, and pancreatic cancer, but the biological and pathological characterization of TRA-1-60-expressing tumor cells remains unclear within various types of malignancies. Here, we report the biological characteristics of TRA-1-60-expressing gastric cancer cells, especially those with its cell surface expression, and the therapeutic significance of targeting TRA-1-60. The cells with cell membrane expression of TRA-1-60 were mainly observed in the invasive area of patient gastric cancer tissues and correlated with advanced stages of the disease based on histopathological and clinicopathological analyses. In vitro analysis using a scirrhous gastric adenocarcinoma line, HSC-58, which highly expresses TRA-1-60 on its plasma membrane, revealed increased stress-resistant mechanisms, supported by the upregulation of glutathione synthetase and NCF-1 (p47phox) via lipid-ROS regulatory pathways, as detected by RNA-seq analysis followed by oxidative stress gene profiling. Our in vivo therapeutic study using the TRA-1-60-targeting antibody-drug conjugate, namely, Bstrongomab-conjugated monomethyl auristatin E, showed robust efficacy in a mouse model of peritoneal carcinomatosis induced by intraperitoneal xenograft of HSC-58, by markedly reducing massive tumor ascites. Thus, targeting the specific cell surface glycan, TRA-1-60, shows a significant therapeutic impact in advanced-stage gastric cancers.

A Fatal Case of Concurrent Disseminated Tuberculosis, Pneumocystis Pneumonia, and Bacterial Septic Shock in a Patient with Rheumatoid Arthritis Receiving Methotrexate, Glucocorticoid, and Tocilizumab: An Autopsy Report.

Recently, treatment for rheumatoid arthritis has dramatically improved but increases the risk of bacterial and opportunistic infections. Herein, we report a fatal case of concurrent disseminated tuberculosis, pneumocystis pneumonia, and septic shock due to pyelonephritis caused by extended-spectrum ß-lactamase-producing Escherichia coli in a patient with rheumatoid arthritis who received methotrexate, glucocorticoid, and tocilizumab. Despite undergoing intensive treatment, the patient developed respiratory failure and died after 7 days of admission. An autopsy indicated that pulmonary tuberculosis were the ultimate causes of death, while pyelonephritis was controlled.

PLOD2-driven IL-6/STAT3 signaling promotes the invasion and metastasis of oral squamous cell carcinoma via activation of integrin ß1.

We previously reported that high expression of procollagen­lysine 2­oxoglutarate 5­dioxygenase 2 (PLOD2) leads to stabilization and plasma membrane translocation of integrin ß1 to promote the invasion and metastasis of oral squamous cell carcinoma (SCC). The present study aimed to further understand the relationship between PLOD2­integrin ß1 signaling and the tumor microenvironment. This study provided further advanced insights indicating that elevated interleukin (IL)­6 in the tumor microenvironment acts as a key molecule that triggers PLOD2­integrin ß1 axis­derived acceleration of tumor invasion and metastasis. It was found using the dual­luciferase reporter assay system that signal transducer and activator of transcription 3 (STAT3) activation by IL­6 was essential for increasing the expression levels of PLOD2 through direct activation of the PLOD2 promoter in oral SCC, whereas IL­6 stimulation did not contribute to integrin ß1 expression or the subsequent maturation process towards a functional form on the plasma membrane. Furthermore, the expression of IL­6 in oral SCC tissues was mainly observed in the tumor stroma. Finally, with double immunofluorescence staining, it was found that IL­6 expression occurred in CD163­positive M2 macrophages distributed around the tumor nest. These results combined with our previous results indicate that as IL­6 significantly increases STAT3­mediated PLOD2 promoter activity, IL­6 released by M2­type tumor­associated macrophages is a crucial factor that promotes PLOD2­integrin ß1 axis­enhanced invasion and metastasis of oral SCC cells.

Syndrome of inappropriate secretion of antidiuretic hormone associated with angiotensin-converting enzyme inhibitor therapy in the perioperative period.

INTRODUCTION:: Angiotensin-converting enzyme (ACE) inhibitors are one of the most commonly used medications for hypertension. Rarely, ACE inhibitors have the potential to cause a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). CASE PRESENTATION:: A 70-year-old woman with > 10 years ACE inhibitor therapy with normonatremia suddenly developed severe SIADH when she took a liquid diet in the uneventful perioperative period, with hemodynamic stability and no surgical complications. She promptly recovered from SIADH subsequent to discontinuing the ACE inhibitor therapy and changing her diet. Therefore, it was assumed that excess antidiuretic hormone secretion due to an ACE inhibitor and free water load from the liquid diet contributed to hyponatremia in our patient. CONCLUSION:: Patients treated with an ACE inhibitor can latently experience inappropriate secretion of antidiuretic hormone, and rapidly develop severe hyponatremia together with additional factors affecting water or salt homeostasis regardless of the length of the administration duration. Clinicians should monitor serum sodium levels in such patients not only just after the initiation of ACE inhibitors but also upon the appearance of those factors.

Cathepsin S degrades arresten and canstatin in infarcted area after myocardial infarction in rats.

The basement membrane surrounding cardiomyocytes is mainly composed of α1 and α2 chain of type IV collagen. Arresten and canstatin are fragments of non-collagenous C-terminal domain of α1 and α2 chain, respectively. We previously reported that the expression of canstatin was decreased in infarcted area 2 weeks after myocardial infarction in rats. In the present study, we investigated the regulatory mechanism for expression of arresten and canstatin. Myocardial infarction model rats were produced by ligating left anterior descending artery. Western blotting and immunohistochemical staining were performed to determine the protein expression and distribution. Arresten and canstatin were highly expressed in the heart. One day and three days after myocardial infarction, the expression of arresten and canstatin in infarcted area was lower than that in non-infarcted area. The expression of cathepsin S, which is known to degrade arresten and canstatin, was increased in the infarcted area. A knockdown of cathepsin S gene using small interference RNA suppressed the decline of arresten and canstatin in the infarcted area 3 days after myocardial infarction. This study for the first time revealed that arresten and canstatin are immediately degraded by cathepsin S in the infarcted area after myocardial infarction. These findings present a novel fundamental insight into the pathogenesis of myocardial infarction through the turnover of basement membrane-derived endogenous factors.