Identification of RNF213 as a potential suppressor of local invasion in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a lethal cancer with poor survival especially when it spreads. The histopathology of its rare intraductal papillary neoplasm of the bile duct type (IPNB) characteristically shows cancer cells originating within the confined bile duct space. These cells eventually invade and infiltrate the nearby liver tissues, making it a good model to study the mechanism of local invasion, which is the earliest step of metastasis. To discover potential suppressor genes of local invasion in ICC, we analyzed the somatic mutation profiles and performed clonal evolution analyses of the 11 pairs of macrodissected IPNB tissues with local invasion (LI-IPNB) and IPNB tissues without local invasion from the same patients. We identified a protein-truncating variant (PTV) in an E3 ubiquitin ligase, RNF213 (c.6967C>T; p.Gln2323X; chr17: 78,319,102 [hg19], exon 29), as the most common PTV event in LI-IPNB samples (4/11 patients). Knockdown of RNF213 in HuCCT1 and YSCCC cells showed increased migration and invasion, and reduced vasculogenic mimicry, but maintained normal proliferation. Transcriptomic analysis of the RNF213-knockdown versus control cells was then performed in the HuCCT1, YSCCC, and KKU-100 cells. Gene Ontology (GO) enrichment analysis of the common differentially expressed genes revealed significantly altered cytokine and oxidoreductase-oxidizing metal ions activities, as confirmed by western blotting. Gene Set Enrichment Analysis (GSEA) identified the most enriched pathways being oxidative phosphorylation, fatty acid metabolism, reactive oxygen species, adipogenesis, and angiogenesis. In sum, loss of function of RNF213 is a common genetic alteration in LI-IPNB tissues. RNF213 knockdown leads to increased migration and invasion of ICC cells, potentially through malfunctions of the pathways related inflammation, and energy metabolisms.

Long-term follow-up of efficacy and safety in elderly patients with chronic myeloid leukemia treated with intermittent low dose dasatinib therapy.

Intermittent low dose dasatinib therapy brought about a beneficial effect in elderly patients with chronic-phase chronic myeloid leukemia (CML-CP) without inducing severe adverse events (AEs). An 85-year-old male patient, who received twice-weekly, thrice-weekly, or four-times-weekly administration of 20 mg/day dasatinib after once-weekly administration, achieved a major molecular response two years after the start of dasatinib treatment and later sometimes achieved a deep molecular response, maintaining the efficacy for 11 years. The mean daily dose ranged from 5.7 mg to 11.4 mg. Furthermore, a 79-year-old male patient, who received thrice-weekly or every other day administration of 20 mg/day dasatinib after once-weekly administration, achieved a deep molecular response at four and half years after the start of dasatinib treatment. The mean daily dose is 8.6 mg. Intermittent low dose dasatinib therapy appears to be feasible in elderly patients with CML-CP. The goal of treatment in elderly patients with CML-CP appears to be different from that in younger patients, since they often suffer from serious AEs in the case of standard dose tyrosine kinase inhibitor therapy, followed by the dose reduction or cessation of treatment.

Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.

One CD4+TCR and One CD8+TCR Targeting Autochthonous Neoantigens Are Essential and Sufficient for Tumor Eradication.

PURPOSE: To achieve eradication of solid tumors, we examined how many neoantigens need to be targeted with how many T-cell receptors (TCR) by which type of T cells. EXPERIMENTAL DESIGN: Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). TCR-therapy used CD8+ T-cell subsets engineered with TCRs isolated from CD8+ T cells (CD8+TCR-therapy), CD4+ T-cell subsets engineered with TCRs isolated from CD4+ T cells (CD4+TCR-therapy), or combinations of both. The targeted tumors were established for at least 3 weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans. RESULTS: Relapse was common with CD8+TCR-therapy even when targeting multiple different autochthonous neoantigens on heterogeneous solid tumors. CD8+TCR-therapy was only effective against homogenous tumors artificially derived from a cancer cell clone. In contrast, a combination of CD8+TCR-therapy with CD4+TCR-therapy, each targeting one neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4+TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8+TCR-therapy was essential for cure. In vitro data were consistent with elimination of cancer cells requiring a four-cell cluster composed of TCR-engineered CD4+ and CD8+ T cells together with antigen-presenting cells and cancer cells. CONCLUSIONS: Two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous targets. We demonstrate that simplifications to adoptive TCR-therapy are possible without compromising efficacy.

Gastric type III heterotopic pancreas presenting as adenomyoma in the antrum of the stomach: a case report.

Although heterotopic pancreas usually occurs in the stomach and rarely presents as a submucosal tumor, an accurate preoperative diagnosis is often difficult because of the variety of clinical symptoms and findings depending on the size and location of the lesion. We experienced a case of gastric type III heterotopic pancreas presenting as a gastric adenomyoma in the antrum of the stomach. A 62-year-old woman visited a local hospital for epigastric discomfort. An esophagogastroduodenoscopy study indicated a submucosal tumor in the greater curvature of the gastric antrum. The patient underwent surgical resection of the tumor because it was enlarged. The histological sections of the resected specimen showed that the tumor was composed of ductular structures lined by tall columnar epithelia and a prominent smooth muscle stroma with no atypical cells. The tumor was compatible with Heinrich's type III heterotopic pancreas, which presented as an adenomyoma of the stomach. These findings provide useful histological features and some insight into a better understanding of the embryonic origin and development of adenomyoma and heterotopic pancreas in the antrum of the stomach.

Droplet size affects the degree of separation between fluorescence-positive and fluorescence-negative droplet populations in droplet digital PCR.

In droplet digital polymerase chain reaction (ddPCR) tests, a single sample solution is divided into many water-in-oil droplets. At the endpoint of PCR amplification, individual droplets are classified as either fluorescence-positive (FL(+)) or fluorescence-negative (FL(-)) droplets based upon their fluorescence amplitudes. Populations of FL(+) and FL(-) droplets can be seen in the histogram of fluorescence amplitude. The absolute copy number of a target molecule can be calculated from the fraction of FL(+) droplets relative to the total droplet number analyzed using Poisson statistics. It is crucial that the population of FL(+) droplets can be distinctly separated from that of the FL(-) droplets for accurately estimating the FL(+) droplet fraction and the absolute copy number. However, the distinct separation of the two populations is often impaired in actual ddPCR tests. Although many factors have been suggested to affect population separation, no study has addressed whether the droplet size influences the degree of separation. In this study, we compared the degrees of separation for ddPCR runs with three different droplet sizes. The experimental results showed an increasing degree of separation with decreasing droplet size. This discovery will potentially guide researchers to use smaller droplets in ddPCR to achieve higher accuracy and precision.

Pseudomonas otitidis bacteremia in an immunocompromised patient with cellulitis: case report and literature review.

BACKGROUND: Pseudomonas otitidis belongs to the genus Pseudomonas and causes various infections, including ear, skin, and soft tissue infections. P. otitidis has a unique susceptibility profile, being susceptible to penicillins and cephalosporins but resistant to carbapenems, due to the production of the metallo-ß-lactamase called POM-1. This revealed genetic similarities with Pseudomonas aeruginosa, which can sometimes lead to misidentification. CASE PRESENTATION: We report the case of a 70-year-old Japanese male who developed cellulitis and bacteremia during chemotherapy for multiple myeloma. He was initially treated with meropenem, but blood culture later revealed gram-negative bacilli identified as P. otitidis using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Carbapenem resistance was predicted from previous reports; therefore, we switched to dual therapy with levofloxacin and cefepime, and favorable treatment results were obtained. CONCLUSION: This is the first reported case of P. otitidis cellulitis and bacteremia in an immunocompromised patient. Carbapenems are typically used in immunocompromised patients and P. otitidis is often resistant to it. However, its biochemical properties are similar to those of Pseudomonas aeruginosa; therefore, its accurate identification is critical. In the present study, we rapidly identified P. otitidis using MALDI-TOF MS and switched from carbapenems to an appropriate antimicrobial therapy, resulting in a successful outcome.

Post-Coronavirus Disease 2019 Syndrome in Japan: An Observational Study Using a Medical Database.

Introduction: In Japan, the clinical information on post-COVID-19 syndrome, including nursing care requirements, is limited. The present study investigated the incidence of acute and post-COVID-19 symptoms, including nursing care requirements, when different SARS-CoV2 strains were prevalent and vaccination statuses changed to mass vaccination programs in Japan. Methods: Electronic health records of 122,045 patients diagnosed with COVID-19 between January 1, 2020, and June 30, 2022, were obtained from the Tokushukai Group Medical Database. Patient data was divided into three observation periods. Using the International Statistical Classification of Diseases and Related Health Problems 10 codes, typical symptoms of acute (within two weeks after diagnosis) and post-COVID-19 (2-12 weeks after diagnosis) were extracted. Moreover, the nursing care requirements of patients who visited the hospital before and after the COVID-19 diagnosis were examined. Results: Original and alpha strains were prevalent in Period 1, wherein most of the population was unvaccinated. The delta strain was prevalent in Period 2, wherein approximately 70% of the population was vaccinated. The omicron strain was prevalent in Period 3, wherein approximately 70% of the population completed the two vaccination doses. Headache, malaise/fatigue, depression, and disuse syndrome were detected in acute and post-COVID-19. The incidence of depression and disuse syndrome in post-COVID-19 increased with age, with the highest incidence in the 60-85-year group. Moreover, increased high-level nursing care requirements were observed after COVID-19 in the 60-85-year-age group. Conclusions: A lower incidence of acute and post-COVID-19 symptoms in Japan is linked to increased population vaccination coverage. However, differences in viral strains may be involved. Moreover, a reduction in long-term quality of life exists in older adult patients after COVID-19. These data provide fundamental information for preventing and treating post-COVID-19 syndrome in Japan.

Randomized phase I/II study of vascular endothelial growth factor receptor peptide vaccines for patients with hepatocellular carcinoma.

AIM: We evaluated the safety and efficacy of vascular endothelial growth factor receptor (VEGFR)-targeted peptide vaccines for the immunization of patients with unresectable hepatocellular carcinoma (HCC) who had responded to transarterial chemoembolization. METHODS: Twenty-two patients were randomized 1:1 to receive VEGFR-targeted peptides or placebo. The primary end-point was the safety assessment of the immunization. The secondary end-points were evaluation of immunological responses and clinical outcomes. RESULTS: No severe adverse events were induced by the study agents. Among the 12 patients in the vaccine group, a VEGFR1-specific cytotoxic T lymphocyte (CTL) response was induced in eight (66.7%) patients and a VEGFR2-specific CTL response was induced in 10 (83.3%). The median progression-free survival (PFS) and overall survival (OS) rates were 4.8 and 52.0 months, respectively, in the vaccine group, and 2.7 and 21.8 months, respectively, in the placebo group. No statistically significant differences were found between the two groups (PFS p = 0.925, OS p = 0.190). When divided into two groups according to immunoreactivity, the median PFS of patients with and without a strong immune response to VEGFR1 were 7.4 and 2.7 months, and that to VEGFR2 were 10.6 and 2.7 months, respectively; there were significant differences according to the immune response. CONCLUSIONS: Immunotherapy with peptide vaccines targeting VEGFR1 and VEGFR2 was well tolerated with no serious adverse events. It also effectively induced peptide-specific CTLs in patients with unresectable HCC.

Head-to-head comparison of three chelates reveals DOTAGA promising for 225 Ac labeling of anti-FZD10 antibody OTSA101.

To select the most suitable chelate for 225 Ac radiolabeling of the anti-FZD10 antibody OTSA101, we directly compared three chelates: S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2,2',2″-(10-(1-carboxy-4-((4-isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (p-SCN-Bn-DOTAGA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DO3A-NHS-ester). We evaluated the binding affinity of the chelate-conjugated OTSA101 antibodies, as well as the labeling efficiency and stability in murine serum of 225 Ac-labeled OTSA101 as in vitro properties. The biodistribution, intratumoral distribution, absorbed doses, and therapeutic effects of the chelate-conjugated OTSA101 antibodies were assessed in the synovial sarcoma mouse model SYO-1. Of the three conjugates, DOTAGA conjugation had the smallest impact on the binding affinity (p < 0.01). The labeling efficiencies of DOTAGA-OTSA101 and DO3A-OTSA101 were 1.8-fold higher than that of DOTA-OTSA101 (p < 0.01). The stabilities were similar between 225 Ac-labeled DOTA-OTSA101, DOTAGA-OTSA101, and DO3A-OTSA101in serum at 37 and 4°C. The dosimetric analysis based on the biodistribution revealed significantly higher tumor-absorbed doses by 225 Ac-labeled DOTA-OTSA101 and DOTAGA-OTSA101 compared with 225 Ac-DO3A-OTSA101 (p < 0.05). 225 Ac-DOTAGA-OTSA101 exhibited the highest tumor-to-bone marrow ratio, with bone marrow being the dose-limiting tissue. The therapeutic and adverse effects were not significantly different between the three conjugates. Our findings indicate that among the three evaluated chelates, DOTAGA appears to be the most promising chelate to produce 225 Ac-labeled OTSA101 with high binding affinity and high radiochemical yields while providing high absorbed doses to tumors and limited absorbed doses to bone marrow.

Immunological analysis of hybrid neoantigen peptide encompassing class I/II neoepitope-pulsed dendritic cell vaccine.

Neoantigens/ are tumor-specific antigens that evade central immune tolerance mechanisms in the thymus. Long-term tumor-specific cytotoxic T lymphocyte activity maintenance requires class II antigen-reactive CD4+ T cells. We had previously shown that intranodal vaccination with class I neoantigen peptide-pulsed dendritic cells (DCs) induced a robust immune response in a subset of patients with metastatic cancer. The present study aimed to perform a detailed ex vivo analysis of immune responses in four patients receiving an intranodal hybrid human leukocyte antigen class II neoantigen peptide encompassing a class I neoantigen epitope (hybrid neoantigen)-pulsed DC vaccine. After vaccination, strong T-cell reactions against the hybrid class II peptide and the class I-binding neoantigen peptide were observed in all four patients. We found that hybrid class II neoantigen peptide-pulsed DCs stimulated CD4+ T cells via direct antigen presentation and CD8+ T cells via cross-presentation. Further, we demonstrated that hybrid class II peptides encompassing multiple class I neoantigen epitope-pulsed DCs could present multiple class I peptides to CD8+ T cells via cross-presentation. Our findings provide insight into the mechanisms underlying hybrid neoantigen-pulsed DC vaccine therapy and suggest future neoantigen vaccine design.

Changes in Peripheral Blood Eosinophil Counts and Risk of Eosinophilic Granulomatosis with Polyangiitis Onset after Initiation of Dupilumab Administration in Adult Patients with Asthma.

BACKGROUND: The purpose of this study is to clarify the changes in peripheral blood eosinophil (PBE) counts and eosinophilic granulomatosis with polyangiitis (EGPA) onset in patients with asthma who were treated with dupilumab in clinical practice. METHODS: The primary outcome of this study is to determine the onset of EGPA in patients whose PBE counts continued to rise within 6 months of dupilumab initiation (rising group) and in patients whose PBE counts peaked and subsequently declined within 6 months (peaked and declined group). As a secondary outcome, the incidence of developing EGPA in patients with PBE counts greater than 1500 cells/µL at 3 or 6 months after dupilumab administration is investigated. RESULTS: A total of 37 individual were enrolled (male/female = 14/23, median age = 57.0 years old). The development of EGPA was significantly more frequent in the rising group compared with the peaked and declined group (p = 0.042, effect size = 0.455, moderate association). Patients with PBE counts greater than 1500 cells/µL showed a significantly higher risk of developing EGPA (p = 0.017, effect size = 0.678, strong association). CONCLUSIONS: Physicians should check for the onset of EGPA by monitoring the elevation of eosinophils within 6 months after dupilumab administration, especially in patients with PBE counts greater than 1500 cells/µL at 3 months.

Transcutaneous gas monitoring is a useful tool to detect respiratory depression during bronchoscopy performed under propofol sedation.

BACKGROUND: Bronchoscopy is a relatively invasive procedure where patients are often sedated. However, adequate sedation is not always achieved. Propofol is often used for difficult-to-sedate patients undergoing bronchoscopy despite a potential risk of respiratory depression. Transcutaneous carbon dioxide (tcpCO2) monitoring, introduced recently, is recognized as a convenient surrogate method for continuous monitoring of the partial pressure of arterial carbon dioxide (PaCO2). This study examined the safety of switching to propofol during bronchoscopy by using transcutaneous carbon dioxide monitoring. METHODS: Patients in whom transcutaneous gas monitoring had been performed during bronchoscopy were included in this study. The participants were divided into two groups: 1) the midazolam + fentanyl group (MF group), and 2) the group in which midazolam was switched to propofol owing to inadequate sedation obtained with midazolam + fentanyl (MFP group). We retrospectively analyzed the transcutaneous gas measurement data collected in patients under propofol sedation for bronchoscopy. RESULTS: This study included 61 (MF, n = 41; MFP, n = 20) patients. The duration of elevated tcpCO2 (>50 mm Hg) was greater in the MFP group (MF 8.5 min vs. MFP 22.1 min, p = 0.042). CONCLUSION: Switching midazolam to propofol during bronchoscopy was significantly associated with a higher risk of elevated tcpCO2, which is indicative of respiratory depression. Therefore, continuous tcpCO2 monitoring is required to ensure the safety of patients under propofol sedation for bronchoscopy.

A Protective Effect of Pirfenidone in Lung Fibroblast-Endothelial Cell Network via Inhibition of Rho-Kinase Activity.

Pulmonary fibrosis is a life-threatening disease that has been attributed to several causes. Specifically, vascular injury is thought to be involved in the pathogenesis of fibrosis. The effects of the antifibrotic drug pirfenidone on angiogenesis have not been fully elucidated. This study aimed to investigate the effects of pirfenidone in human lung fibroblast-endothelial cell co-culture network formation and to analyze the underlying molecular mechanisms. Human lung fibroblasts were co-cultured with human umbilical vein endothelial cells to establish a co-culture network cell sheet. The influence of pirfenidone was evaluated for protective effect on the endothelial network in cell sheets stimulated with transforming growth factor ß (TGF-ß). Results indicated that TGF-ß disrupted the network formation. Pirfenidone and Y27632 (Rho-associated coiled-coil containing protein kinase [Rho-kinase or ROCK] inhibitor) protected against the TGF-ß-induced endothelial network disruption. TGF-ß activated Rho-kinase signaling in cells composing the co-culture cell sheet, whereas pirfenidone and Y27632 inhibited these effects. In conclusion, TGF-ß-induced Rho-kinase activation and disrupted endothelial network formation. Pirfenidone suppressed TGF-ß-induced Rho-kinase activity in cell sheets, thereby enabling vascular endothelial cells networks to be preserved in the cell sheets. These findings suggest that pirfenidone has potential vascular network-preserving effect via inhibiting Rho-kinase activity in vascular injury, which is a precursor to pulmonary fibrosis.

SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.

Cancers often display immune escape, but the mechanisms are incompletely understood. Herein, we identify SMYD3 as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab. SMYD3 depletion induces upregulation of multiple type I interferon (IFN) response and antigen presentation machinery genes in HNSCC cells. Mechanistically, SMYD3 binds to and regulates the transcription of UHRF1, encoding for a reader of H3K9me3, which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1, and silences their expression. SMYD3 further maintains the repression of immune-related genes through intragenic deposition of H4K20me3. In vivo, Smyd3 depletion induces influx of CD8+ T cells and increases sensitivity to anti-programmed death 1 (PD-1) therapy. SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC.

Treatment satisfaction with molidustat in CKD-related anemia in non-dialysis patients: a post-hoc analysis of two clinical trials.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the standard treatment for patients with renal anemia to increase hemoglobin (Hb) levels and reduce the need for blood transfusions. However, treatments targeting high Hb levels require high doses of ESAs administered intravenously, which is associated with an elevated risk of adverse cardiovascular events. Furthermore, there have been some problems such as hemoglobin variability and low achievement of target hemoglobin due to the shorter half-lives of ESAs. Consequently, erythropoietin-promoting medications, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, have been developed. This study aimed to evaluate changes in the Treatment Satisfaction Questionnaire for Medicine version II (TSQM-II) domain scores relative to baseline in each trial, to assess patient satisfaction with molidustat versus darbepoetin alfa. METHODS: This post-hoc analysis of two clinical trials compared treatment satisfaction with an HIF-PH inhibitor, molidustat, versus a standard ESA, darbepoetin alfa, as part of therapy in patients with non-dialysis chronic kidney disease (CKD) and renal anemia. RESULTS: Exploratory outcome data using the TSQM-II showed that both arms in both trials had enhanced treatment satisfaction over the course of the study period, as well as improvements in most TSQM-II domains at week 24 of treatment. Molidustat was associated with convenience domain scores at multiple time points depending on the trial. More patients were highly satisfied with the convenience of molidustat than that of darbepoetin alfa. Patients treated with molidustat had increased global satisfaction domain scores compared with those treated with darbepoetin alfa; however, the differences in global satisfaction domain scores were not significant. CONCLUSION: These patient-reported satisfaction outcomes support the use of molidustat as a patient-centered treatment option for CKD-related anemia. REGISTRATION OF CLINICAL TRIALS: ClinicalTrials.gov Identifier: NCT03350321 (November 22, 2017). CLINICALTRIALS: gov Identifier: NCT03350347 (November 22, 2017).

Current Trends in Neoantigen-Based Cancer Vaccines.

Cancer immunotherapies are treatments that use drugs or cells to activate patients' own immune systems against cancer cells. Among them, cancer vaccines have recently been rapidly developed. Based on tumor-specific antigens referred to as neoantigens, these vaccines can be in various forms such as messenger (m)RNA and synthetic peptides to activate cytotoxic T cells and act with or without dendritic cells. Growing evidence suggests that neoantigen-based cancer vaccines possess a very promising future, yet the processes of immune recognition and activation to relay identification of a neoantigen through the histocompatibility complex (MHC) and T-cell receptor (TCR) remain unclear. Here, we describe features of neoantigens and the biological process of validating neoantigens, along with a discussion of recent progress in the scientific development and clinical applications of neoantigen-based cancer vaccines.

Cellular and Molecular Control of Lipid Metabolism in Idiopathic Pulmonary Fibrosis: Clinical Application of the Lysophosphatidic Acid Pathway.

Idiopathic pulmonary fibrosis (IPF) is a representative disease that causes fibrosis of the lungs. Its pathogenesis is thought to be characterized by sustained injury to alveolar epithelial cells and the resultant abnormal tissue repair, but it has not been fully elucidated. IPF is currently difficult to cure and is known to follow a chronic progressive course, with the patient's survival period estimated at about three years. The disease occasionally exacerbates acutely, leading to a fatal outcome. In recent years, it has become evident that lipid metabolism is involved in the fibrosis of lungs, and various reports have been made at the cellular level as well as at the organic level. The balance among eicosanoids, sphingolipids, and lipid composition has been reported to be involved in fibrosis, with particularly close attention being paid to a bioactive lipid "lysophosphatidic acid (LPA)" and its pathway. LPA signals are found in a wide variety of cells, including alveolar epithelial cells, vascular endothelial cells, and fibroblasts, and have been reported to intensify pulmonary fibrosis via LPA receptors. For instance, in alveolar epithelial cells, LPA signals reportedly induce mitochondrial dysfunction, leading to epithelial damage, or induce the transcription of profibrotic cytokines. Based on these mechanisms, LPA receptor inhibitors and the metabolic enzymes involved in LPA formation are now considered targets for developing novel means of IPF treatment. Advances in basic research on the relationships between fibrosis and lipid metabolism are opening the path to new therapies targeting lipid metabolism in the treatment of IPF.