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Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death. High recurrence rates after curative resection and the lack of specific biomarkers for intrahepatic metastases are major clinical problems. Recently, exosomal microRNAs (miRNAs) have been reported to have a role in the formation of the pre‐metastatic niche and as promising biomarkers in patients with malignancy. Here we aimed to clarify the molecular mechanisms of intrahepatic metastasis and to identify a novel biomarker miRNA in patients with HCC. A highly intrahepatic metastatic cell line (HuH‐7M) was established by in vivo selection. HuH‐7M showed increased proliferative ability and suppression of apoptosis and anoikis. HuH‐7M and the parental cell (HuH‐7P) showed the similar expression of epithelial‐mesenchymal transition markers and cancer stem cell markers. In vivo, mice treated with exosomes derived from HuH‐7M showed increased tumorigenesis of liver metastases. Exosomes from HuH‐7M downregulated endothelial cell expression of vascular endothelial‐cadherin (VE‐cadherin) and zonula occludens‐1 (ZO‐1) in non‐cancerous regions of liver and increased the permeability of FITC‐dextran through the monolayer of endothelial cells. The miRNAs (miR‐638, miR‐663a, miR‐3648, and miR‐4258) could attenuate endothelial junction integrity by inhibiting VE‐cadherin and ZO‐1 expression. In patients with HCC, higher serum exosomal miR‐638 expression was associated with tumor recurrence. In conclusion, the miRNAs secreted from a highly metastatic cancer cell can promote vascular permeability via downregulation of endothelial expression of VE‐cadherin and ZO‐1. Serum exosomal miR‐638 expression holds potential for serving as a significant and independent prognostic marker in HCC. miR‐638, miR‐663a, miR‐3648, and miR‐4258 downregulate VE‐cadherin and ZO‐1 expression in HUVECs.

Herein, we detail our experience with a unique patient with concomitant multiple sclerosis (MS) and idiopathic thrombocytopenic purpura (ITP) treated with ofatumumab, which resulted in stable disease activity and platelet count normalization. A 21-year-old Japanese woman presented with medial longitudinal fasciculus syndrome and was subsequently diagnosed with MS. She was treated with methylprednisolone pulse therapy (1,000 mg/day for 5 days). During her first hospitalization, her platelet count was low (40 × 10 /L). Based on investigations, serologic findings, and bone marrow aspiration, she was diagnosed with ITP. Following methylprednisolone treatment, oral prednisolone was initiated and gradually tapered. Glatiramer acetate was used as a disease-modifying drug (DMD). As prednisolone was tapered off, the platelet count decreased correspondingly. The clinical course included two MS relapses, each of which was treated with a methylprednisolone pulse and DMD adjustments (the DMT was sequentially switched from glatiramer acetate to dimethyl fumarate, then fingolimod, and finally natalizumab). Despite an initial recovery of the platelet count following these interventions, the platelet count declined correspondingly with the prednisolone dose reduction. Finally, the DMD was switched to ofatumumab, an anti-CD20 monoclonal antibody with pharmacological similarities to rituximab, a second-line treatment for ITP. After the initiation of ofatumumab, the patient remained clinically stable with no further MS relapses, and her platelet count stabilized over 2 years. Herein, we report our experience with a novel case of MS concomitant with ITP that was safely treated with ofatumumab. Considering the pharmacological similarities of ofatumumab to rituximab (a second-line treatment for ITP), anti-CD20 monoclonal antibodies such as ofatumumab could be a promising treatment option for cases of MS concomitant with ITP.

CXCL9, an IFN‐γ inducible chemokine, has been reported to play versatile roles in tumor‐host interrelationships. However, little is known about its role in intrahepatic cholangiocarcinoma (iCCA). Here, we aimed to elucidate the prognostic and biological implications of CXCL9 in iCCA. Endogenous CXCL9 expression and the number of tumor‐infiltrating lymphocytes were immunohistochemically assessed in resection specimens. These data were validated in mice treated by silencing CXCL9 with short hairpin RNA. In addition, the induction of endogenous CXCL9 and the effects of CXCL9 on tumor biological behaviors were evaluated in human cholangiocarcinoma cell lines. Immunohistochemical analyses revealed that high CXCL9 expression was closely correlated with prolonged postoperative survival and a large number of tumor‐infiltrating natural killer (NK) cells. In fact, due to the trafficking of total and tumor necrosis factor‐related apoptosis‐inducing ligand‐expressing NK cells into tumors, CXCL9‐sufficient cells were less tumorigenic in the liver than CXCL9‐deficient cells in mice. Although CXCL9 involvement in tumor growth and invasion abilities differed across cell lines, it did not exacerbate these abilities in CXCL9‐expressing cell lines. We showed that CXCL9 was useful as a prognostic marker. Our findings also suggested that CXCL9 upregulation might offer a therapeutic strategy for treating CXCL9‐expressing iCCA by augmenting anti–tumor immune surveillance. CXCL9, an IFN‐γ inducible chemokine, plays versatile roles in the tumor‐host interrelationship. In this study, we demonstrated that elevated intratumoral CXCL9 expression was associated with a large number of tumor‐infiltrating NK cells, leading to favorable postoperative survival in patients with intrahepatic cholangiocarcinoma. Upregulation of CXCL9 might be an immunotherapeutic approach for treating intrahepatic cholangiocarcinoma.

Background Interactions between tumor and microenvironment determine individual response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors (ICIs). Aspartate β-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. Methods Subcutaneous HCC and orthotopic TNBC murine models were established in immunocompetent BALB/c mice with injection of BNL-T3 and 4 T1 cells, respectively. Immunohistochemistry, immunofluorescence, H&E, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. Results The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based λ phage vaccine targeting ASPH was administrated to mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In control, autocrine chemokine ligand 13 (CXCL13)-C-X-C chemokine receptor type 5 (CXCR5) axis promoted tumor development and progression in HCC and TNBC. Interactions between PD-L1 + cancer cells and PD-1 + T cells resulted in T cell exhaustion and apoptosis, causing immune evasion of cancer cells. In contrast, combination therapy (Vaccine+PD-1 inhibitor) significantly suppressed primary hepatic or mammary tumor growth (with distant pulmonary metastases in TNBC). Adaptive immune responses were attributed to expansion of activated CD4 + T helper type 1 (Th1)/CD8 + cytotoxic T cells (CTLs) that displayed enhanced effector functions, and maturation of plasma cells that secreted high titers of ASPH-specific antibody. Combination therapy significantly reduced tumor infiltration of immunosuppressive CD4 + /CD25 + /FOXP3 + Tregs. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH + cancer cells recruited CXCR5 + /CD8 + T lymphocytes to tertiary lymphoid structures (TLSs), comprising effector and memory CTLs, T follicular helper cells, B cell germinal center, and follicular dendritic cells. TLSs facilitate activation and maturation of DCs and actively recruit immune subsets to tumor microenvironment. These CTLs secreted CXCL13 to recruit more CXCR5 + immune cells and to lyse CXCR5 + cancer cells. Upon combination treatment, formation of TLSs predicts sensitivity to ICI blockade. Combination therapy substantially prolonged overall survival of mice with HCC or TNBC. Conclusions Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH, an ideal TAA, combined with ICIs, inhibits tumor growth and progression of TNBC and HCC.

The continual development of surgical technology has led to a demand for surgical simulators for evaluating and improving the surgical technique of surgeons. To meet these needs, simulators must incorporate a sensing function into the organ model for evaluating the surgical techniques. However, it is difficult to incorporate a temperature sensor into the conventional cardiac training model. In this study, we propose a heart model for surgical training of cardiac catheter ablation made from hydrogel, which has temperature memory properties. The heart model consists of a photo-crosslinkable hydrogel mixed with an irreversible temperature indicator that exhibits a color change from magenta to colorless at 55 °C. The Young’s modulus, electrical resistivity, thermal conductivity, and specific heat capacity of the hydrogel material were evaluated and compared with those of human heart. Furthermore, temperature calibration based on the color of the hydrogel material confirmed that the temperature measurement accuracy of the material is ±0.18 °C (at 56 °C). A heart model for catheter ablation was fabricated using the hydrogel material and a molding method, and the color change due to temperature change was evaluated.

INTRODUCTION: Transmesocolic hernia of the ascending colon is an extremely rare cause of small bowel obstruction. Due to its rarity and nonspecific clinical features, preoperative diagnosis of internal hernia is challenging.CASE PRESENTATION: We report the case of a 95-year-old female patient (body mass index: 19.5) without a history of abdominal surgery, who presented with vomiting and abdominal pain. The patient had a medical history of cerebral infarction, pneumonectomy, hypertension, hyperlipidemia, and dementia. Laboratory test results revealed leukocytosis and mild inflammation. Abdominal CT revealed closed-loop ileus on the left side of the ascending colon with localized small bowel dilatation. Chest CT indicated aspiration pneumonia. Based on these findings, a preoperative diagnosis of an internal hernia with strangulated ileus and aspiration pneumonia was made, necessitating an emergency surgery. Intraoperatively, a segment of the jejunum located 50–70 cm from the ligament of Treitz was herniated through a congenital defect in the ascending mesocolon. The ischemic jejunal bowel was resected and the mesenteric defect was closed. The operative time was 81 min with minimal blood loss. The patient experienced no surgical complications and was discharged on postoperative day 50, following treatment for aspiration pneumonia.CONCLUSIONS: Although transmesocolic hernias of the ascending colon are extremely rare, they should be considered in the differential diagnosis of small bowel obstruction, particularly in older, thin female patients without a history of abdominal surgery. Early diagnosis and timely surgical intervention are essential for achieving favorable outcomes.

Circulating fibrocytes have been reported to migrate into the injured lungs, and contribute to fibrogenesis via CXCL12-CXCR4 axis. In contrast, we report that imatinib mesylate prevented bleomycin (BLM)-induced pulmonary fibrosis in mice by inhibiting platelet-derived growth factor receptor (PDGFR), even when it was administered only in the early phase. The goal of this study was to test the hypothesis that platelet-derived growth factor (PDGF) might directly contribute to the migration of fibrocytes to the injured lungs. PDGFR expression in fibrocytes was examined by flow cytometry and RT-PCR. The migration of fibrocytes was evaluated by using a chemotaxis assay for human fibrocytes isolated from peripheral blood. The numbers of fibrocytes triple-stained for CD45, collagen-1, and CXCR4 were also examined in lung digests of BLM-treated mice. PDGFR mRNA levels in fibrocytes isolated from patients with idiopathic pulmonary fibrosis were investigated by real-time PCR. Fibrocytes expressed both PDGFR-α and -β, and migrated in response to PDGFs. PDGFR inhibitors (imatinib, PDGFR-blocking antibodies) suppressed fibrocyte migration in vitro, and reduced the number of fibrocytes in the lungs of BLM-treated mice. PDGF-BB was a stronger chemoattractant than the other PDGFs in vitro, and anti-PDGFR-β-blocking antibody decreased the numbers of fibrocytes in the lungs compared with anti-PDGFR-α antibody in vivo. Marked expression of PDGFR-β was observed in fibrocytes from patients with idiopathic pulmonary fibrosis compared with healthy subjects. These results suggest that PDGF directly functions as a strong chemoattractant for fibrocytes. In particular, the PDGF-BB-PDGFR-β biological axis might play a critical role in fibrocyte migration into the fibrotic lungs.

Interleukin‐33 (IL‐33), an alarmin released during tissue injury, facilitates the development of cholangiocarcinoma (CCA) in a murine model. However, it is unclear whether IL‐33 is associated with human CCA. The aim of this study was to support the following hypothesis: IL‐33 is released during hepatectomy for CCA, subsequently facilitating the development of subclinical CCA and eventually leading to recurrent disease. IL‐33 expression was assessed in various samples from both humans and mice including resected liver and paired plasma samples collected at hepatectomy and after surgery, and its influences on recurrent disease and patient prognosis were determined. Homogenized human liver samples with high or low IL‐33 expression were added to the culture medium of human CCA cells, and the changes in proliferation and migration were evaluated. To examine the effects of inhibiting the IL‐33 release induced by hepatectomy, syngraft transplantation of murine CCA cells was performed in C57BL/6J mice with or without IL‐33 blockade. The amount of IL‐33 released into the plasma during hepatectomy correlated with the background liver expression. High expression of IL‐33 in the liver was an independent risk factor for recurrence. Homogenized liver tissue strongly expressing IL‐33 increased both the proliferation and migration of tumor cells. Mice who underwent hepatectomy exhibited CCA progression in the remnant liver, whereas blockade of IL‐33 during hepatectomy inhibited tumor progression. Thus, we concluded that surgery for CCA with curative intent paradoxically induced IL‐33 release, which facilitated CCA recurrence, and anti–IL‐33 therapy during hepatectomy might reduce the risk of CCA recurrence. Hepatic interleukin‐33 (IL‐33) is released during hepatectomy, increasing hepatic IL‐33 expression in the remnant liver and facilitating cholangiocarcinoma (CCA) recurrence following surgery by changing the environment. Our results suggest that anti–IL‐33 therapy during hepatectomy reduces the risk of CCA recurrence following surgery.

Background A unique patient with MELAS syndrome, who initially masqueraded as having acute encephalitis and was eventually diagnosed with MELAS syndrome harboring a mtDNA 14453G → A mutation, is described. Case presentation A 74-year-old Japanese man was admitted to another hospital due to acute onset of cognitive impairment and psychosis. After 7 days he was transferred to our hospital with seizures and deteriorating psychosis. The results of primary ancillary tests that included EEG, CSF findings, and brain MRI supported the diagnosis of an acute encephalitis. HSV-DNA and antibodies against neuronal surface antigens in the CSF were all negative. With the assistance of the lactate peak on the brain lesions in the magnetic resonance spectroscopy image and genetic analysis of the biopsied muscle, he was eventually diagnosed with MELAS syndrome harboring mtDNA 14453G → A mutation in the ND6 gene. Conclusions This case provides a caveat that MELAS syndrome can manifest in the symptoms and ancillary tests masquerading as an acute encephalitis caused by infection or autoimmunity. This is the first adult patient seen to harbor the mtDNA14453G → A with a unique onset, which broadens the phenotypic spectrum of MELAS syndrome associated with ND6 gene mutation.

Amino acids play key roles in the function of the central nervous system and their alterations are implicated in psychiatric disorders. In the search for a biomarker for major depressive disorder (MDD), we used high-performance liquid chromatography to measure amino acids and related molecules in the cerebrospinal fluid (CSF) of 52 patients with MDD (42 depressed and 10 remitted; DSM-IV) and 54 matched controls. Significant differences were found in four amino acid concentrations between the depressed patients and controls. After Bonferroni correction, only ethanolamine (EA) levels remained significantly reduced in depressed patients (nominal P = 0.0000011). A substantial proportion of the depressed patients (40.5%) showed abnormally low CSF EA levels (<12.1 μM) ( P = 0.000033; OR = 11.6, 95% CI: 3.1–43.2). When patients with low EA and those with high EA levels were compared, the former had higher scores for overall depression severity ( P = 0.0033) and ‘Somatic Anxiety’ symptoms ( P = 0.00026). In unmedicated subjects, CSF EA levels showed a significant positive correlation with levels of homovanillic acid ( P = 0.0030) and 5-hydroxyindoleacetic acid ( P = 0.019). To our knowledge, this is the first study showing that patients with MDD have significantly lower CSF EA concentrations compared with control subjects. CSF EA could be a state-dependent biomarker for a subtype of MDD.