[Dendritic Cell Therapy with Neoantigens and Oncoantigens].

We treated 3,164 patients with advanced cancer with dendritic cell therapy between July 2005 and March 2020. The effective rate in patients treated with dendritic cell therapy more than 3 times was 19.0%. Among them, we treated 133 cancer patients with a combination of immune checkpoint inhibitors and dendritic cell therapy between June 2015 and March 2020. The effective rate in these patients was 54.1%. We treated 98 cancer patients with dendritic cell therapy with neoantigens between March 2018 and March 2020. The effective rate in these patients treated with neoantigens was 38.7%. The effective rate in patients treated without neoantigens was 18.3%. Dendritic cell therapy with neoantigens enhanced the effective rate. The effective rate of dendritic cell therapy with both immune checkpoint inhibitors and neoantigens was 60.7%.

[Combination of Immunotherapy and Hyperthermia].

We treated 123cancer patients with a combination of immune checkpoint inhibitor and dendritic cell therapy between June 2015 and April 2019. The effective rate of cases administered for B3times was 51.5%. Hyperthermia was found to enhance the effects of radiotherapy, chemotherapy, and immunotherapy. In addition, hyperthermia enhanced the effects of combined immunotherapy. In clinical cases and animal models, immunohistochemical staining showed that the expression of PD-L1 and MHC classⅠ and invasion of CD8 cells were increased after hyperthermia.

[Effects of Immune Checkpoint Inhibitor Combined with Dendritic Cell Therapy and Hyperthermia].

In this study, 97cancer patients were treated with combined immune checkpoint inhibitor therapy and dendritic cell thera- py between June 2015 and April 2018. We administered nivolumab with 2-3mg/kg bw every 2-3weeks. The rate of progress in cases where nivolumab was administered more than 3 times was 55.2%. Dendritic cell therapy enhanced the immune checkpoint inhibitor therapy. In cases where the effect of combined immune checkpoint inhibitor therapy and dendritic cell therapy was restricted, hyperthermia and radiation therapy are useful for the recovery of combined therapy.

Feasibility of a new approach for creating a preperitoneal space in transabdominal preperitoneal repair inguinal hernia repair: using a sandwich approach.

PURPOSE: In Japan, transabdominal preperitoneal (TAPP) inguinal hernia repair is performed by firmly pulling the peritoneum inwards to lift it from the underlying deep layer of subperitoneal fascia. It decreases the postoperative pain and discomfort in the inguinal area. The aim of this study was to evaluate the feasibility of the sandwich approach, which is a new technique for creating a preperitoneal space. METHODS: The operation was performed via the sandwich approach. We made sure to protect the preperitoneal fascia areolar layer when making the preperitoneal space. RESULTS: We performed TAPP in 745 patients (876 hernias) treated between October 2006 and April 2015 at Himeji Medical Center and Kurashiki Central Hospital. Before October 2010, we did not use the sandwich approach, and recurrence was observed in three patients. From October 2010, we always used the sandwich approach and never experienced any cases of recurrence. Clavien-Dindo classification Grade 3 or higher postoperative complications occurred in 6 patients (0.8%) between October 2006 and April 2015. Mesh-related ileus was the most frequently observed morbidity. There were no cases of vas differentia or spermatic vessel injury, postoperative chronic pain, or urinary retention. CONCLUSION: The sandwich approach is feasible as another standard dissective procedure for TAPP.

[Administration of Immune Checkpoint Inhibitor for Cancer except for Melanoma and Lung Cancer].

We treated 19 cancer patients with cancer types other than melanoma and lung cancer with immune checkpoint inhibitors, between June 2015 and April 2016. We administered nivolumab at 2-3mg/kg bw every 2-3 weeks. One patient received 14 doses, 5 received 6 doses, 3 received 5 doses, 3 received 4 doses, and 3 received 3 doses. Three remarkably effective responses were seen in cases of pancreatic cancer, esophageal cancer, and brain malignant lymphoma. In every effective case, dendritic cell therapy was administered prior to nivolumab.

Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11.

Recently, various approaches for controlling the embryonic stem (ES) cell microenvironment have been developed for regulating cellular fate decisions. It has been reported that the lineage specific differentiation could be affected by the size of ES cell colonies and embryoid bodies (EBs). However, much of the underlying biology has not been well elucidated. In this study, we used microengineered hydrogel microwells to direct ES cell differentiation and determined the role of WNT signaling pathway in directing the differentiation. This was accomplished by forming ES cell aggregates within microwells to form different size EBs. We determined that cardiogenesis was enhanced in larger EBs (450 microm in diameter), and in contrast, endothelial cell differentiation was increased in smaller EBs (150 microm in diameter). Furthermore, we demonstrated that the EB-size mediated differentiation was driven by differential expression of WNTs, particularly noncanonical WNT pathway, according to EB size. The higher expression of WNT5a in smaller EBs enhanced endothelial cell differentiation. In contrast, the increased expression of WNT11 enhanced cardiogenesis. This was further validated by WNT5a-siRNA transfection assay and the addition of recombinant WNT5a. Our data suggest that EB size could be an important parameter in ES cell fate specification via differential gene expression of members of the noncanonical WNT pathway. Given the size-dependent response of EBs to differentiate to endothelial and cardiac lineages, hydrogel microwell arrays could be useful for directing stem cell fates and studying ES cell differentiation in a controlled manner.

Low-positive antibody titer against Helicobacter pylori cytotoxin-associated gene A (CagA) may predict future gastric cancer better than simple seropositivity against H. pylori CagA or against H. pylori.

BACKGROUND: To investigate the IgG antibody titer against Helicobacter pylori CagA as a risk factor for future noncardia gastric cancer. METHODS: A nested case-control study was done in the longitudinal cohort of atomic bomb survivors using stored sera before diagnosis (mean, 2.3 years). Enrolled were 299 cancer cases and 3 controls per case selected from cohort members matched on age, gender, city, and time and type of serum storage and countermatched on radiation dose. RESULTS: H. pylori IgG seropositive with CagA IgG low titer was the strongest risk factor for noncardia gastric cancer [relative risk (RR), 3.9; 95% confidence interval (95% CI), 2.1-7.0; P < 0.001], especially for intestinal-type tumor (RR, 9.9, 95% CI, 3.5-27.4; P < 0.001), compared with other risk factors, H. pylori IgG seropositive with CagA IgG negative (RR, 2.2; 95% CI, 1.3-3.9; P = 0.0052), H. pylori IgG seropositive with CagA IgG high titer (RR, 2.0; 95% CI, 1.3-3.2; P = 0.0022), chronic atrophic gastritis (RR, 2.4; 95% CI, 1.8-3.3; P < 0.001), current smoking (RR, 2.3; 95% CI, 1.4-3.5; P < 0.001), or radiation dose (RR, 2.1; 95% CI, 1.2-3.1; P = 0.00193). Current smoking showed significantly higher risk for diffuse-type than intestinal-type tumors (P = 0.0372). Radiation risk was significant only for nonsmokers, all noncardia, and diffuse-type gastric cancers. CONCLUSIONS: A low CagA IgG titer is a useful biomarker to identify a high-risk group and it also provides a clue to understanding host-pathogen interaction.

Influence of novel resin monomer on viability of L-929 mouse fibroblasts in vitro.

We have previously synthesized a novel acrylic resin monomer, methacryloyloxyethyl methyl succinate (TA). The aim of this in vitro study, therefore, was to examine its influence on cell viability using L-929 mouse fibroblasts and then compare the results with MMA, EMA, and LMA. Medium containing each monomer was changed every 15 minutes as some monomers were volatile. After one hour of exposure, these mediums were replaced with a normal medium and cells were further incubated for 72 hours. IC50 value for each monomer was determined, and chronological cell viability and cytomorphologic observation were evaluated. Viability was impaired in a dose-dependent manner. All monomers, except TA, tended to correlate between molecular weight and cell viability. On the other hand, TA showed excellent viability and did not impair growth abruptly. These results thus demonstrated that cellular damage by TA was much lower than that by other monomers.

Relation between QT duration and mortality in an elderly Japanese population.

The effects of prolonged QTc intervals on mortality were investigated in about 3,500 elderly Japanese patients followed for approximately 8.8 years. Prolonged QTc was found to be a marker for risk for all-cause mortality and mortality from heart disease or from coronary heart disease (CHD) after adjusting for other CHD risk factors. Even in Japanese subjects, who have a lower coronary heart disease rate than that of Caucasians, the careful observation of subjects with a prolonged QTc is believed to be necessary.

Mitochondrial DNA heteroplasmy in wheat, Aegilops and their nucleus-cytoplasm hybrids.

A mitochondrial (mt) transcriptional unit, nad3-orf156, was studied in the nucleus-cytoplasm hybrids of wheat with D/D2 plasmons from Aegilops species and their parental lines. A comparative RFLP analysis and sequencing of the random PCR clones revealed the presence of seven sequence types and their polymorphic sites were mapped. All the hybrids possessed the paternal copies besides the maternal copies. More paternal copies were present in the D2 plasmon hybrids, whereas more maternal copies were present in the D plasmon hybrids. Two major copies were present with different stoichiometries in the maternal Aegilops parents. However, only a major D plasmon copy was detected in the hybrids, irrespective of their plasmon types. The hexaploid wheat parent (AABBDD genome) possessed the major D plasmon copy in approximately 5% stoichiometry, while no D plasmon-homologous copies were detected in the tetraploid wheat parent (AABB genome). The results suggest that the observed mtDNA heteroplasmy is due to paternal contribution of mtDNA. The different copy stoichiometry suggests differential amplification of the heteroplasmic copies among the hybrids and the parental lines. All editing sites and their editing frequencies were conserved among the lines, and only the maternal pattern of editing occurred in the hybrids.