Removal of gemcitabine-induced senescent cancer cells by targeting glutaminase1 improves the therapeutic effect in pancreatic ductal adenocarcinoma

Insufficient cancer treatment can induce senescent cancer cell formation and treatment resistance. The characteristics of induced senescent cancer (iSnCa) cells remain unclear. Pancreatic ductal adenocarcinoma (PDAC) has a low and nondurable response rate to current treatments. Our study aimed to analyze the properties of iSnCa cells and the relationship between cellular senescence and prognosis in PDAC. We evaluated the characteristics of gemcitabine-induced senescent cancer cells and the effect of senescence-associated secretory phenotype (SASP) factors released by iSnCa cells on surrounding PDAC cells. The relationship between cellular senescence and the prognosis was investigated in 50 patients with PDAC treated with gemcitabine-based neoadjuvant chemotherapy. Exposure to 5 ng/mL gemcitabine-induced senescence, decreased proliferation and increased senescence-associated β-galactosidase-cell staining without cell death in PDAC cells; the expression of glutaminase1 (GLS1) and SASP factors also increased and caused epithelial-mesenchymal transition in surrounding PDAC cells. iSnCa cells were selectively removed by the GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) through apoptosis induction. Cellular senescence was induced in PDAC cells via insufficient gemcitabine in subcutaneous tumor model mice. GLS1 expression was an independent prognostic factor in patients with PDAC who received gemcitabine-based neoadjuvant chemotherapy. This is the first study to identify the relationship between senescence and GLS1 in PDAC. Low-dose gemcitabine-induced senescence and increased GLS1 expression were observed in PDAC cells. Cellular senescence may contribute to treatment resistance of PDAC, hence targeting GLS1 in iSnCa cells may improve the therapeutic effect.     

An Autopsy Case of Antibody-negative Immune-mediated Necrotizing Myopathy with Severe Cardiac Involvement

A 41-year-old man was admitted with a chief complaint of dyspnea. Echocardiography showed diffuse severe hypokinesis in the left ventricle. Although his heart failure improved, high creatine kinase levels persisted. A muscle biopsy of the biceps brachii showed necrotic and regenerating fibers along with positive findings for major histocompatibility complex class I and membrane attack complex. He was diagnosed with antibody-negative immune-mediated necrotizing myopathy (IMNM). Steroid therapy was started, but he died due to ventricular fibrillation. Autopsy findings revealed CD68-positive macrophages in the myocardium and quadriceps. To our knowledge, this is the first case of antibody-negative IMNM with cardiac involvement.     

Concomitant Pulmonary and Cerebral Tumor Embolism and Intracardiac Metastasis from Bladder Cancer

An 82-year-old woman with a history of bladder cancer presented with dyspnea and loss of consciousness. Contrast-enhanced computed tomography revealed pulmonary embolism, and emergency thrombus aspiration therapy was performed, but the thrombus was not aspirated. Echocardiography showed mobile masses in the heart and a right-to-left shunt due to a patent foramen ovale (PFO). Magnetic resonance imaging showed multiple cerebral infarctions. Surgical thrombectomy and PFO closure were performed, and the patient was diagnosed with intracardiac metastasis of bladder cancer based on intraoperative histopathology. This is a rare case of concomitant pulmonary and cerebral tumor embolism and intracardiac metastasis from bladder cancer.     

Mutational analysis of the cardiac actin gene in familial and sporadic dilated cardiomyopathy

Dilated cardiomyopathy (DCM) results in part from genetic disorders. Recently, missense mutations of the cardiac actin gene have been reported to cause DCM. We studied 136 Japanese DCM cases to elucidate how frequently the gene mutations are involved in its pathogenesis. Genomic DNA samples were obtained from 136 DCM cases (107 males, 29 females), containing 30 familial DCM (5 confirmed and 25 suspected). All six exons of the cardiac actin gene were analyzed by polymerase chain reaction, single-strand conformation polymorphism, and sequencing. We detected no mutations of the disease causation previously reported (G867A or A1014G) but two silent mutations (G979C and C1018T) in exon 6 and one point mutation (T1080A) in the 3′-untranslated region. As a result of screening 128 healthy subjects, these novel silent mutations were found to be mere genetic polymorphisms, not responsible for the disease. Although some genetic polymorphisms exist in the cardiac actin gene, mutations of the gene are rarely responsible for DCM, at least in the Japanese patients. Am. J. Med. Genet. 86:325–327, 1999. © 1999 Wiley-Liss, Inc.     

Comparison of stapler and electrocautery for division of the intersegmental plane in lung segmentectomy

BackgroundWe retrospectively compared the use of a stapler and electrocautery for division of the intersegmental plane during pulmonary segmentectomy.MethodsWe enrolled 156 patients who underwent pulmonary segmentectomy in our department between March 2006 and August 2020. The patients were divided into electrocautery (n=62) and stapler (n=94) groups based on the device used to divide the intersegmental plane. Patient characteristics, perioperative outcomes, and ratios of actual (calculated using software) to predicted (calculated by counting the resected segments) lung volumes were compared between the two groups. Additionally, we used multivariate analysis to identify the factors that contributed to the incidence of postoperative air leakage after cut-off value was set by receiver operating characteristic (ROC) curve analysis. Moreover, a subset analysis was performed based on the type of segmentectomy (common or uncommon). Common segmentectomies included resection of the basilar or superior segment of the lower lobe, or lingular or upper division of the left upper lobe; all other segmentectomies were classified as uncommon.ResultsCompared to the electrocautery group, the stapler group had shorter operative times (P=0.0027), duration of postoperative drainage (P=0.00037), and duration of postoperative hospitalization (P=0.0021). Moreover, incidence of postoperative ≥3 days drainage was significantly reduced in the stapler group (P=0.003). There were no significant differences between the stapler and electrocautery groups in the actual:predicted lung volumes at 6 months (1.01 and 1.04, respectively; P=0.28) or 12 months (1.06 and 1.07, respectively; P=0.68) after surgery. Preoperative lung volume was significantly correlated with preoperative vital capacity (VC) (γ=0.69; P<0.001) and forced expiratory volume in 1 second (FEV₁) (γ=0.48; P<0.001). The multivariate analysis indicated that the use of stapler for division of intersegmental plane was the only factor that contributed to reducing the incidence of postoperative ≥3 days drainage (P=0.0027, odds ratio: 0.23, 95% CI: 0.086–0.597). In a subset analysis of uncommon segmentectomy, there were no significant differences among the groups in most perioperative results.ConclusionsCompared to electrocautery, the use of a stapler for division of the intersegmental plane was associated with better perioperative outcomes, especially reduction of postoperative drainage time, and similar postoperative remnant lung volumes and function.