The new models reflected the wide range of patho-biological features and genetic alterations that characterize human pancreatic cancer and may be used collectively or selectively as a markedly improved in vivo tool for preclinical and molecular studies of pancreatic cancer.

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, and is currently the third-leading cause of cancer death among males in Japan. 1 The high incidence of recurrence is the most crucial prognostic factor for patients with HCC. 2 Through a combination of pathologic and genetic approaches, recurrence of HCC has been divided into 2 types: multicentric occurrence of new tumors 3-5 and intrahepatic metastasis of the original HCC. Several clinicopathologic studies have shown that the incidence of intrahepatic metastasis is higher in HCC with an infiltrative growth pattern than in HCC with an expansive growth pattern. 6 In a previous study, a high incidence of loss of heterozygosity of chromosome 16 was reported in HCC with intrahepatic metastasis. 7

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The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the ensuing worldwide pandemic. The spread of the virus has had global effects such as activity restriction, economic stagnation, and collapse of healthcare infrastructure. Severe SARS-CoV-2 infection induces a cytokine storm, leading to acute respiratory distress syndrome (ARDS) and multiple organ failure, which are very serious health conditions and must be mitigated or resolved as soon as possible. Mesenchymal stem cells (MSCs) and their exosomes can affect immune cells by inducing anti-inflammatory macrophages, regulatory T and B cells, and regulatory dendritic cells, and can inactivate T cells. Hence, they are potential candidate agents for treatment of severe cases of COVID-19. In this review, we report the background of severe cases of COVID-19, basic aspects and mechanisms of action of MSCs and their exosomes, and discuss basic and clinical studies based on MSCs and exosomes for influenza-induced ARDS. Finally, we report the potential of MSC and exosome therapy in severe cases of COVID-19 in recently initiated or planned clinical trials of MSCs (33 trials) and exosomes (1 trial) registered in 13 countries on ClinicalTrials.gov.

Pancreatic cancer has the worst prognosis among cancers due to the difficulty of early diagnosis and its aggressive behavior. To characterize the aggressiveness of pancreatic cancers on gene expression, pancreatic cancer xenografts transplanted into severe combined immunodeficient mice served as a panel for gene-expression profiling. As a result of profiling, the adenylate cyclase-associated protein 1 (CAP1) gene was shown to be overexpressed in all of the xenografts. The expression of CAP1 protein in all 73 cases of pancreatic cancer was recognized by immunohistochemical analyses. The ratio of CAP1-positive tumor cells in clinical specimens was correlated with the presence of lymph node metastasis and neural invasion, and also with the poor prognosis of patients. Immunocytochemical analyses in pancreatic cancer cells demonstrated that CAP1 colocalized to the leading edge of lamellipodia with actin. Knockdown of CAP1 by RNA interference resulted in the reduction of lamellipodium formation, motility, and invasion of pancreatic cancer cells. This is the first report demonstrating the overexpression of CAP1 in pancreatic cancers and suggesting the involvement of CAP1 in the aggressive behavior of pancreatic cancer cells. Pancreatic cancer is a leading cause of cancer death worldwide. 1,2 Only about 20% of pancreatic cancer can be surgically resected with curative intent at the time of diagnosis. 3 Mainly due to the difficulty in early detection and frequent metastatic dissemination, the 5-year survival rate for pancreatic cancer patients remains below 5%. 3,4 Considering that vascular involvement, lymph node metastasis, and neural invasion have been proposed as prognostic factors, 5-7 it seems that metastasis is responsible for the aggressive behavior of pancreatic cancer. Pancreatic cancer appears to acquire genetic aberrations with successive alteration of genes involved in the regulation of cell proliferation. The alterations include activating mutations of the KRAS gene 8,9 that occur early in the stage of pancreatic carcinogenesis, and inactivations by the deletion and mutation of the CDKN2A, 10 TP53, 11 and SMAD4 genes. 12 In addition to cell proliferation, cell motility is one of the factors associated with cancer metastasis; however, no alteration of such genes has been revealed in pancreatic cancer. Therefore, alteration of the expression level of genes by epigenetic or transcriptional manner may be a cue to elucidate the mechanism of cancer metastasis.Recent developments in the technology of human genome research enabled us to obtain genome-wide gene-expression profiles, and vast numbers of marker molecule candidates for pancreatic cancer have been proposed. [13][14][15][16][17][18] In this study, xenografts of clinical specimens orthotopically transplanted into severe combined immunodeficient (SCID) mice 19 were utilized as a panel for gene-expression profiling of pancreatic cancer. Among commonly overexpressed genes in pancreatic cancer xenografts, we further evaluated the adenylate cyclaseassociated pr...

Liver-intestine (LI) cadherin represents a novel type of cadherin within the cadherin superfamily, and is distinguished from other cadherins by specific structural and functional features. Among normal tissues, LI-cadherin is known to be expressed in the intestinal mucosa, while its expression in cancerous tissue has not been investigated to date, except in gastric carcinoma. In the present study we investigated LI-cadherin expression immunohistochemically using our newly established monoclonal antibody in a large set (n = = = =102) of tumor specimens from patients with ductal adenocarcinoma of the pancreas, and correlated the findings with the patients' survival. LI-cadherin expression was seen focally in normal pancreatic ducts. In carcinoma, well-differentiated carcinoma cases strongly expressed LI-cadherin, whereas less differentiated areas and poorly differentiated carcinoma cases expressed less or were negative. Kaplan-Meier analysis for all patients demonstrated that high LI-cadherin expression ( > > > >25% of cells stained positive) correlated with good survival (P < ancreatic carcinoma is one of the most lethal malignancies worldwide, and its incidence has been increasing in industrialized countries.<1, 2) Most patients with pancreatic carcinoma are diagnosed at an advanced stage because of the aggressiveness of this disease and the lack of early symptoms, and the 5-year survival rate is only 10-26% even after curative surgical resection.3-5) A number of studies have been done to date to reveal the pathological and biological prognostic factors in pancreatic carcinoma, 6) but the precise reason for the biological aggressiveness of this disease has not yet been elucidated.Cadherins are a family of Ca 2+ -dependent homotypic cellcell adhesion molecules that are involved in the maintenance of tissue structure and morphogenesis. 7,8) It is known that all members of this family share common structural features, with some exceptions, having an amino-terminal extracellular region characterized by a unique domain called the cadherin repeat, a single transmembrane domain, and a cytoplasmic domain at the carboxyl terminus.9) A large number of cadherin superfamily members have been identified to date, and are expressed in different tissues of a variety of multicellular organisms. There is increasing evidence that cadherin-mediated cell adhesion additionally plays a crucial role in carcinoma cell behavior. 10,11) LI-cadherin, which is also called human peptide transporter-1 (HPT-1), is a structurally unique member of the cadherin superfamily.12, 13) Whereas the so-called classic cadherins, such as E-, N-and P-cadherin, have five cadherin repeats within the extracellular domain, LI-cadherin consists of seven cadherin repeats. LI-cadherin has only 20 amino acids in the cytoplasmic domain, although classic cadherins have a highly conserved cytoplasmic domain which consists of 150 to 160 amino acids. The expression of LI-cadherin differs by species. In the rat, LIcadherin is expressed in the liver and intestinal epithe...

The clinical implementation of ARFI provides noninvasive repeated evaluations of liver stiffness at an arbitrary position, which has the potential to shed new light on NASH management.

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