Long-term activation of anti-tumor immunity in pancreatic cancer by a p53-expressing telomerase-specific oncolytic adenovirus.

BACKGROUND: Pancreatic cancer is an aggressive, immunologically "cold" tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702). METHODS: We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps). RESULTS: First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection. CONCLUSION: OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer.

Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles.

Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. In this study, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and they showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.

[A Case of Primary Acinic Cell Carcinoma(ACC)of the Breast].

A49 -year-old woman presented with a 3.5 cm mass in her right breast. Mammography revealed a lobular mass with poorly defined margins and no microcalcification. Ultrasonography showed a hypoechoic mass with an irregular margin. The tumor was diagnosed as breast carcinoma using a core needle biopsy. The patient underwent a modified radical mastectomy with sentinel lymph node biopsy, and received adjuvant chemotherapy. The tumor consisted of 2 types of carcinoma. The center of the tumor was solid-tubular carcinoma, and the periphery was acinic cell carcinoma(ACC). Histopathologically, the neoplastic cells of the periphery were characterized by widespread acinic cell-like differentiation with a eosinophilic granular or clear cytoplasm, resembling acinic cells of the parotid gland(t3, f[+], ly0, v0, n0, stage II B). Immunohistochemically, the specimens tested positive for salivary gland amylase, and negative for collagen type IV , ER, PgR, and HER2. We administered UFT as adjuvant chemotherapy. Eight months after surgery, local recurrence was observed. ACC of the breast is rare, and has been reported to have a good prognosis. Further investigations are needed to elucidate its true histogenesis the appropriate treatment.

[A Case of Mediastinal Dissection by Video-Assisted Thoracoscopic Surgery (VATS)in a Patient with Mediastinal Nodal Recurrence from Thyroid Carcinoma after Primary Surgery via Median Sternotomy].

A70 's male was diagnosed with advanced papillary thyroid carcinoma and underwent total thyroidectomy with left lymph node dissection(T4a, N1b, M0, stage IV A). Six years after the surgery, subclavicular and mediastinal lymph node recurrence was observed. Radioiodine therapy was not successful for those lesions. Lymph node dissection was performed via the cervical and transsternal approaches. One year after the second surgery, cervical and mediastinal lymph node recurrence was again observed. We removed the cervical lymph nodes via the cervical approach. One month after cervical dissection, we removed the mediastinal lymph nodes via video-assisted thoracoscopic surgery(VATS). The lymph nodes were relatively easily dissected by VATS under excellent surgical views. Repeat mediastinal dissection via median sternotomy could be associated with significant complications. VATS is expected to reduce the risk of reoperation and enhance surgical outcomes.

[A Case of Minimal Thyroid Carcinoma Diagnosed by a Solitary Pulmonary Metastasis].

We report a case of minimal thyroid carcinoma diagnosed by a solitary pulmonary metastasis. A 70's man visited a medical practitioner because of chest discomfort, and there was an abnormality on the chest X-ray. Chest computed tomography(CT) showed a nodule in the right middle lobe of the lung. Positron emission tomography with 18-fluorodeoxyglucose(FDG)-PET revealed increased FDG uptake in that tumor, but did not reveal any other lesion. The tumor was clinically suspected to be a carcinoid tumor, primary lung cancer, metastatic lung cancer, or a benign tumor. Right middle lobe lobectomy was performed, and the tumor was diagnosed as a metastasis from a thyroid papillary carcinoma by pathological diagnosis during surgery. After surgery, we found a tumor in the left lobe of the thyroid by CT and US. Because the patient did not desire 131I therapy, he underwent a left hemithyroidectomy and neck dissection. There was a papillary carcinoma 1.0 cm in the thyroid gland and there were 3 cervical lymph node metastases. There has been no recurrence for 11 years after surgery.

Cell motility and biofilm formation in Bacillus subtilis are affected by the ribosomal proteins, S11 and S21.

Bacillus subtilis differentiates into various cellular states in response to environmental changes. It exists in two states during the exponential growth phase: motile cells and connected chains of sessile cells. Here, we identified new regulators of cell motility and chaining, the ribosomal proteins S21 (rpsU) and S11 (rpsK). Their mutants showed impaired cell motility (observed in a laboratory strain) and robust biofilm formation (observed in an undomesticated strain). The two major operons for biofilm formation, tapA-sipW-tasA and epsA-O, were strongly expressed in the rpsU mutant, whereas the flagellin-encoding hag gene and other SigD-dependent motility regulons were not. Genetic analysis revealed that the mutation of remA, the transcriptional activator of the eps operon, is epistatic to that of rpsU, whereas the mutation of antagonistic regulators of SinR is not. Our studies demonstrate that S11 and S21 participate in the regulation of bistability via the RemA/RemB pathway.

[A case of bone marrow carcinomatosis with disseminated intravascular coagulation arising from breast cancer successfully treated with paclitaxel plus bevacizumab].

We report a case of bone marrow carcinomatosis with disseminated intravascular coagulation (DIC) originating from metastatic breast cancer that was treated with paclitaxel plus bevacizumab. A woman in her 30s was diagnosed with bone marrow carcinomatosis arising from metastatic breast cancer 2 years previously. Pathologically, estrogen receptor (ER) and progesterone receptor(PgR) / -positive and human epidermal growth factor receptor 2(HER2/neu)-negative scirrhous carcinoma was diagnosed. She improved after treatment with paclitaxel plus bevacizumab and zoledronic acid. Subsequently, she was treated with hormonal therapy(tamoxifen plus luteinizing-hormone-releasing hormone [LH-RH]agonist) for 7 months. Because progressive bone metastasis was identified and tumor markers increased, the patient was administered paclitaxel plus bevacizumab again. Fifteen days after chemotherapy was initiated, DIC developed. Chemotherapy was continued without decreasing the dose, and recombinant human soluble thrombomodulin (rTM) was added. The DIC resolved in 5 days. After 6 courses of paclitaxel plus bevacizumab, improvement of tumor markers and bone metastasis was observed. Paclitaxel plus bevacizumab can be effective for treatment of bone marrow carcinomatosis with DIC originating from metastatic breast cancer.

New Gall-Forming Insect Model, Smicronyx madaranus: Critical Stages for Gall Formation, Phylogeny, and Effectiveness of Gene Functional Analysis.

The molecular mechanisms underlying insect gall formation remain unclear. A major reason for the inability to identify the responsible genes is that only a few systems can be experimentally validated in the laboratory. To overcome these problems, we established a new galling insect model, Smicronyx madaranus. Our manipulation experiments using nail polish sealing and insecticide treatment revealed an age-dependent change in gall formation by S. madaranus; adult females and larvae are responsible for gall induction and enlargement, respectively. Furthermore, it has been suggested that substances released during oviposition and larval feeding are involved in each process. Phylogenetic analysis showed that gall-forming weevils, including S. madaranus, belong to two distinct lineages that utilize different host plants. This may indicate that gall-forming traits evolved independently in these Smicronyx lineages. The efficacy of RNA interference (RNAi) in S. madaranus was confirmed by targeting the multicopper oxidase 2 gene. It is expected that the mechanisms of gall formation will be elucidated by a comprehensive functional analysis of candidate genes using RNAi and the S. madaranus galling system in the near future.

Intrahepatic cholangiocarcinoma with a liver abscess due to hepatic actinomycosis.

BACKGROUND: Liver tumors with liver abscesses are unusual and rarely reported. In particular, studies of intrahepatic cholangiocarcinoma with liver abscesses due to hepatic actinomycosis have not been reported. CASE PRESENTATION: A 73-year-old woman presented with swelling of the right hypochondrium. Computed tomography revealed a mass lesion that was continuous with the abdominal wall in the right lobe of the liver, suggesting a liver tumor invading the abdominal wall. A liver biopsy revealed intrahepatic cholangiocarcinoma with a liver abscess. The histopathological specimen contained bacterial masses of actinomycosis, and the cause of the liver abscess was determined to be hepatic actinomycosis. As a result of percutaneous drainage and antibiotic therapy, the part of the tumor attached to the abdominal wall disappeared; therefore, we assumed that most of the lesion was not cholangiocarcinoma but a liver abscess due to hepatic actinomycosis. Radical surgery for residual intrahepatic cholangiocarcinoma was performed after chemotherapy. Currently, the patient is alive without recurrence 2 years and 9 months after the operation. CONCLUSION: We encountered a difficult-to-diagnose case of intrahepatic cholangiocarcinoma with a liver abscess due to hepatic actinomycosis. A needle biopsy allowed early diagnosis and percutaneous drainage was an effective treatment.

A new galling insect model enhances photosynthetic activity in an obligate holoparasitic plant.

Insect-induced galls are microhabitats distinct from the outer environment that support inhabitants by providing improved nutrients, defence against enemies, and other unique features. It is intriguing as to how insects reprogram and modify plant morphogenesis. Because most of the gall systems are formed on trees, it is difficult to maintain them in laboratories and to comprehend the mechanisms operative in them through experimental manipulations. Herein, we propose a new model insect, Smicronyx madaranus, for studying the mechanisms of gall formation. This weevil forms spherical galls on the shoots of Cuscuta campestris, an obligate parasitic plant. We established a stable system for breeding and maintaining this ecologically intriguing insect in the laboratory, and succeeded in detailed analyses of the gall-forming behaviour, gall formation process, and histochemical and physiological features. Parasitic C. campestris depends on host plants for its nutrients, and usually shows low chlorophyll content and photosynthetic activity. We demonstrate that S. madaranus-induced galls have significantly increased CO2 absorbance. Moreover, chloroplasts and starch accumulated in gall tissues at locations inhabited by the weevil larvae. These results suggest that the gall-inducing weevils enhance the photosynthetic activity in C. campestris, and modify the plant tissue to a nutrient-rich shelter for them.