Interferons and systemic lupus erythematosus: Pathogenesis, clinical features, and treatments in interferon-driven disease.

Type I interferons (IFNs) have recently received a lot of attention with the elucidation of the pathogenesis of systemic lupus erythematosus (SLE). Type I IFNs are associated with many SLE symptoms and play a role in the pathogenesis of autoimmune diseases that may occur concurrently with SLE, such as Sjögren's syndrome, antiphospholipid syndrome, myositis, scleroderma, and interferonopathy. Type I IFNs could be the link between these diseases. However, direct measurement of type I IFN levels and the IFN gene signature is currently unavailable in clinical practice. This review discusses type I IFN signalling in SLE, investigates the role of type I IFN in the clinical manifestations and symptoms associated with SLE and other IFN-related diseases, and discusses the clinical tests that can be used to diagnose SLE and measure disease activity. In addition, the role of type I IFN-blocking therapies as potential treatments for SLE is discussed.

Comparative accuracy of the Lilium α-200 portable ultrasound bladder scanner and conventional transabdominal ultrasonography for postvoid residual urine volume measurement in association with the clinical factors involved in measurement errors.

AIM: We examined the comparative accuracy of the portable ultrasound bladder scanner, Lilium α-200, and conventional ultrasonography (CUS) in bladder volume measurement. We also examined factors that could lead to measurement errors. METHODS: Postvoid residual (PVR) volume was measured by Lilium α-200 and CUS with catheterized volume as a comparator in 224 consecutive men, of which 109 were also measured for the serially inflated bladder with saline. The measurement accuracy with respect to the actual volume was evaluated by calculating the error volume (EV), % error volume (%EV), and their absolute values. Absolute %EV of ≤20% was designated as nonerror. The measurement of prostate volume, abdominal thickness, and pelvimetry was performed on magnetic resonance images. RESULTS: PVR volumes measured by CUS are better correlated with actual volumes (r = .779) than those of Lilium α-200 (r = .606). When the measurement accuracy was indicated by absolute values of EV and %EV, CUS provided a more accurate estimate (21 ± 21 ml, 60 ± 42%) than Lilium α-200 (32 ± 45 ml, 91 ± 142%). The frequency of error was significantly increased at lower bladder volumes. Overestimation was associated with larger prostate size for the Lilium α-200, while underestimation was associated with greater bladder flattening for both methods. CONCLUSION: PVR volumes measured by Lilium α-200 were fairly correlated with actual volumes. However, their relative errors were too large to correctly predict the actual volume. Flattened bladder and a large prostate may hinder accurate measurements. Consequently, Lilium α-200 is not superior to CUS and its feasibility is limited to when the precise measurement is not required.

Non-transmissible MV Vector with Segmented RNA Genome Establishes Different Types of iPSCs from Hematopoietic Cells.

Recent advances in gene therapy technologies have enabled the treatment of congenital disorders and cancers and facilitated the development of innovative methods, including induced pluripotent stem cell (iPSC) production and genome editing. We recently developed a novel non-transmissible and non-integrating measles virus (MV) vector capable of transferring multiple genes simultaneously into a wide range of cells through the CD46 and CD150 receptors. The MV vector expresses four genes for iPSC generation and the GFP gene for a period of time sufficient to establish iPSCs from human fibroblasts as well as peripheral blood T cells. The transgenes were expressed differentially depending on their gene order in the vector. Human hematopoietic stem/progenitor cells were directly and efficiently reprogrammed to naive-like cells that could proliferate and differentiate into primed iPSCs by the same method used to establish primed iPSCs from other cell types. The novel MV vector has several advantages for establishing iPSCs and potential future applications in gene therapy.

[A Case of Esophageal Neuroendocrine Carcinoma(NEC)Treated with Collective Treatment].

A 68-year-old man presented to our hospital. An upper gastrointestinal tract endoscopy performed elsewhere revealed an elevated lesion with a circumferential esophageal cancer(identified as small cell carcinoma). Perthe treatment forsmall cell cancer and the standard treatment for esophageal neuroendocrine carcinoma, 7 courses of CBDCA(5mg/m2)plus ETP (100mg/m2)were administered. The lesion shrank and the lymph node swelling disappeared and the patient was deemed to be in partial remission. Nine months later, however, the primary tumor increased in size. A transthoracic subtotal esophagectomy( laparoscope-assisted), 2 area dissection, and gastric tube reconstruction(post-sternal)were performed at 2 years and 10 months afterdiagnosis.

Nrf2 gene mutation and single nucleotide polymorphism rs6721961 of the Nrf2 promoter region in renal cell cancer.

BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in cell proliferation by promotion of metabolic activity. It is also the major regulator of antioxidants and has a pivotal role in tumor cell proliferation and resistance to chemotherapy. Accordingly, we investigated the role of Nrf2 in renal cell carcinoma (RCC). METHODS: In 50 patients who had metastatic RCC and received cytoreductive nephrectomy, we performed Nrf2 gene mutation analysis using targeted next-generation sequencing, as well as investigating a specific single nucleotide polymorphism (SNP; rs6721961) in the Nrf2 promoter region and Nrf2 protein expression. RESULTS: Targeted next-generation sequencing revealed that five tumors had SNPs of Nrf2 associated with amino acid sequence variation, while 11 tumors had SNPs of Kelch-like ECH-associated protein 1 gene, 35 had SNPs of von Hippel-Lindau gene, and none had SNPs of fumarate hydratase gene. The three genotypes of rs6721961 showed the following frequencies: 60% for C/C, 34% for C/A, and 6% for A/A. Nrf2 mutation and the C/A or A/A genotypes were significantly associated with increased Nrf2 protein expression (p = 0.0184 and p = 0.0005, respectively). When the primary tumor showed Nrf2 gene mutation, the C/A or A/A genotype, or elevated Nrf2 protein expression, the response of metastases to vascular endothelial growth factor-targeting therapy was significantly worse (p = 0.0142, p = 0.0018, and p <  0.0001, respectively), and overall survival was significantly reduced (p = 0.0343, p = 0.0421, and p <  0.0001, respectively). Elevated Nrf2 protein expression was also associated with shorter survival according to multivariate Cox proportional analysis. CONCLUSION: These findings suggest an associated between progression of RCC and Nrf2 signaling.

The relationship between peripheral neuropathy and efficacy in second-line chemotherapy for unresectable advanced gastric cancer: a prospective observational multicenter study protocol (IVY).

BACKGROUND: Paclitaxel is used in second-line conventional chemotherapies to manage patients with unresectable advanced gastric cancer (GC). Paclitaxel-induced peripheral neuropathy is a known adverse event leading to treatment discontinuation. Additionally, oxaliplatin which causes irreversible peripheral neuropathy is now commonly used in first-line chemotherapy for advanced GC in Japan. Thus, examining the incidence of peripheral neuropathy with paclitaxel after oxaliplatin is necessary to improve the quality of life and outcomes of patients with advanced GC in the second-line treatment setting. METHODS: This prospective observational multicenter study, (which we named IVY study), will evaluate the degree of chemotherapy-induced peripheral neuropathy (CIPN) and the efficacy of second-line chemotherapy for unresectable advanced GC. A patient neurotoxicity questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) will be used to assess CIPN during the second-line treatment. The key eligibility criteria are as follows: 1) unresectable or recurrent GC histologically confirmed to be primary adenocarcinoma of the stomach, 2) age over 20 years, 3) Eastern Cooperative Oncology Group performance status score of 0-2, 4) written informed consent following full study information is provided to the patient, 5) progression or intolerance for first-line chemotherapy comprising fluorinated pyrimidine and platinum anticancer drugs (cisplatin or oxaliplatin) for advanced GC. 6) presence of evaluable lesions as confirmed using a computed tomography (CT) or magnetic resonance imaging. A total of 200 patients is considered to be appropriate for inclusion in this study. DISCUSSION: The results of this study will provide some information on CIPN with the sequential usage of oxaliplatin as first-line chemotherapy to paclitaxel as second-line chemotherapy in clinical practice. TRIAL REGISTRATION: This trial is registered in the University Hospital Medical Information Network's Clinical Trials Registry with the registration number UMIN000033376 (Registered 11 July 2018).

[Incidence of Catheter-Related Thrombosis in Patients with Long-Term Indwelling Central Venous Port Who Received Chemotherapies for Unresectable Advanced Digestive Cancers].

BACKGROUND: Most patients with unresectable advanced digestive cancers require placement of a fully implantable venous access port to facilitate safe delivery of anti-cancer drugs. Anti-VEGF therapies are commonly used even though they increase the risk of thrombosis. The objective of this study was to assess the incidence of radiologically confirmed catheter-related thrombosis(CRT)in patients with advanced digestive cancers. METHODS: We retrospectively reviewed 88 patients with advanced digestive cancers who had adapted implantable ports placed in our institution for chemotherapy. RESULTS: Thirty-nine patients were diagnosed with colorectal cancer, 26 with gastric cancer, 12 with pancreatic cancer, 8 with esophageal cancer, and 3 with other cancers. During follow-up, 22 patients(25%)received anti-VEGF therapies, while 66 patients(75%)did not. Four out of 88 patients(4.5%)had asymptomatic CRT. The incidence of CRT was the same(4.5%)regardless of whether the patient received anti-VEGF therapy. CONCLUSIONS: In patients with digestive cancers who had implantable venous access ports, the incidence of the CRT was 4.5% with no association with anti-VEGF therapies.

Significance of sarcopenia as a prognostic factor for metastatic urothelial carcinoma patients treated with systemic chemotherapy.

BACKGROUND: Recently, numerous studies have reported an association between sarcopenia and poor outcomes in various kinds of malignancies. We investigated whether sarcopenia predicts the survival of patients with metastatic urothelial carcinoma who underwent systemic chemotherapy. METHODS: We reviewed 87 metastatic urothelial carcinoma patients who underwent chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin for cisplatin-unfit patients) between 2007 and 2015. A computed tomography scan prior to chemotherapy was used for evaluating sarcopenia, and we measured three cross-sectional areas of skeletal muscle at the third lumbar vertebra and calculated the skeletal muscle index (SMI), the paraspinal muscle index (PSMI), and the total psoas area (TPA) of each patient. Predictive values of survival were assessed using Cox regression analysis. RESULTS: The median overall survival (OS) was 16 months (95% CI 13.5-18). Although SMI alone was not a significant predictor of shorter OS (P = 0.117) in univariate analysis, SMI stratified by the value of the body mass index (BMI) was a significant predictor of shorter OS in univariate analysis (P = 0.037) and was also an independent predictor of shorter OS in multivariate analysis (P = 0.026). PSMI and TPA were not significant prognostic factors even when stratified by BMI (P = 0.294 and 0.448), respectively. CONCLUSION: Neither PSMI nor TPA could substitute SMI as a predictor for poor outcomes in metastatic urothelial carcinoma patients treated with systemic chemotherapy in our study. SMI stratified by BMI is a useful predictor of prognosis in these patients.

[Analysis of Fecal Cancer-Specific DNA to Detect Colorectal Neoplasia].

To screen colorectal cancers, fecal occult blood test(FOBT), conducted to detect occult blood present in the feces, has been shown to reduce colorectal cancer mortality in many large-scale colorectal cancer screening programs. However, the sensitivities of FOBT for early-stage colon cancer, colon cancer located at the right colon and colorectal adenoma tend to be low. Additionally, some colorectal cancers which could not detect by repeated FOBT screening are actually existed. Beyond those disadvantages, FOBT is the most promised colorectal cancer screening tool for large-scale cohort. To overcome the weak points of FOBT to screen colorectal tumors, the strategy for capturing and recovering tumor-derived DNA in feces has been developed and applied for clinical usage. In this study, we summarized the series of strategies for capturing and recovering fecal tumor-derived DNA to screen colorectal neoplasia.

[Introduction].

Time has come when oncology has met immunology. Immune checkpoint inhibitors(ICIs)are being approved as standard cancer treatments, day by day. ICIs, however, have serious immune-related adverse events(irAEs)in a diverse manner, requiring the establishment of team-approach system to manage irAEs. Here, irAEs are summarized and their managements are discussed.

Evaluation of pancreatic cancer cell migration with multiple parameters in vitro by using an optical real-time cell mobility assay device.

BACKGROUND: Migration of cancer cell correlates with distant metastasis and local invasion, which are good targets for cancer treatment. An optically accessible device "TAXIScan" was developed, which provides considerably more information regarding the cellular dynamics and less quantity of samples than do the existing methods. Here, we report the establishment of a system to analyze the nature of pancreatic cancer cells using TAXIScan and we evaluated lysophosphatidic acid (LPA)-elicited pancreatic cell migration. METHODS: Pancreatic cancer cell lines, BxPC3, PANC-1, AsPC1, and MIAPaCa-2, were analyzed for adhesion as well as migration towards LPA by TAXIScan using parameters such as velocity and directionality or for the number of migrated cells by the Boyden chamber methods. To confirm that the migration was initiated by LPA, the expression of LPA receptors and activation of intracellular signal transductions were examined by quantitative reverse transcriptase polymerase reaction and western blotting. RESULTS: Scaffold coating was necessary for the adhesion of pancreatic cancer cells, and collagen I and Matrigel were found to be good scaffolds. BxPC3 and PANC-1 cells clearly migrated towards the concentration gradient formed by injecting 1 µL LPA, which was abrogated by pre-treatment with LPA inhibitor, Ki16425 (IC50 for the directionality ≈ 1.86 µM). The LPA dependent migration was further confirmed by mRNA and protein expression of LPA receptors as well as phosphorylation of signaling molecules. LPA1 mRNA was highest among the 6 receptors, and LPA1, LPA2 and LPA3 proteins were detected in BxPC3 and PANC-1 cells. Phosphorylation of Akt (Thr308 and Ser473) and p42/44MAPK in BxPC3 and PANC-1 cells was observed after LPA stimulation, which was clearly inhibited by pre-treatment with a compound Ki16425. CONCLUSIONS: We established a novel pancreatic cancer cell migration assay system using TAXIScan. This assay device provides multiple information on migrating cells simultaneously, such as their morphology, directionality, and velocity, with a small volume of sample and can be a powerful tool for analyzing the nature of cancer cells and for identifying new factors that affect cell functions.

[Current Cancer Immunotherapy Using Activated Lymphocytes - Do Lymphocytes Actually Recognize Cancer Cells ?].

Molecular cloning of interleukin-2(IL-2)has enabled adoptive cell therapy(ACT)to be established by using autologous activated lymphocytes. The low of regenerative medicine will promote the active development of ACT for public use, and ACTs that utilize tumor-infiltrating lymphocytes(TIL), in vitro tumor-sensitized lymphocytes, natural killer T cells, and gammadelta T cells are being evaluated as advanced medical treatments in Japan. In addition, chimeric antigen receptor genemodified T(CAR-T)cells and T cell receptor gene-modified T(TCR-T)cells are available for investigational clinical use. CART and TCR-T cells have been associated with serious adverse events as well as drastic clinical efficacies, indicating the importance of choosing the antigens to be targeted. Presently, it is accurate to state that lymphocytes do recognize cancer cells. Clinical ACT research focusing on TIL and mutated cancer antigens will be initiated for the development of personalized immunotherapy for cancer in the future.

Guidance for peptide vaccines for the treatment of cancer.

Recent progress in fundamental understanding of tumor immunology has opened a new avenue of cancer vaccines. Currently, the development of new cancer vaccines is a global topic and has attracted attention as one of the most important issues in Japan. There is an urgent need for the development of guidance for cancer vaccine clinical studies in order to lead to drug development. Peptide vaccines characteristically have the effect of indirectly acting against cancer through the immune system - a mechanism of action that clearly differs from anticancer drugs that exert a direct effect. Thus, the clinical development of cancer peptide vaccines should be planned and implemented based on the mechanism of action, which differs significantly from conventional anticancer drug research. The Japanese Society for Biological Therapy has created and published Guidance for peptide vaccines for the treatment of cancer as part of its mission and responsibilities towards cancer peptide vaccine development, which is now pursued globally. We welcome comments from regulators and business people as well as researchers in this area.

The Rho-kinase inhibitor HA-1077 suppresses proliferation/migration and induces apoptosis of urothelial cancer cells.

BACKGROUND: Activation of Rho, one of the small GTPases, and its major downstream target Rho-kinase (ROCK) promotes the development and metastasis of cancer. We previously showed that elevation of Rho and ROCK expression was associated with tumor invasion, metastasis, and an unfavorable prognosis in patients with urothelial cancer of the bladder or upper urinary tract. METHODS: We investigated the effects of a ROCK inhibitor on the growth, migration, and apoptosis of bladder cancer cells. We also examined phosphorylation of RhoA (RhoA activity) by measuring its GTP-bound active form and assessed the expression of ROCK to explore the underlying molecular mechanisms. RESULTS: Lysophosphatidic acid (LPA) and geranylgeraniol (GGOH) induced an increase of cell proliferation and migration in association with promotion of RhoA activity and upregulation of ROCK expression. The ROCK inhibitor fasudil (HA-1077) suppressed cell proliferation and migration, and also induced apoptosis in a dose-dependent manner. HA-1077 dramatically suppressed the expression of ROCK-I and ROCK-II, but did not affect RhoA activity. CONCLUSIONS: These findings suggest that ROCK could be a potential molecular target for the treatment of urothelial cancer.

Imatinib plasma levels during successful long-term treatment of metastatic-gastrointestinal stromal tumors.

BACKGROUND/AIMS: To investigate whether imatinib dosage correlated with effective plasma levels and clinical characteristics for Japanese patients undergoing long-term (≥2 years) imatinib therapy for GISTs. METHODOLOGY: Twenty-five patients who received imatinib for a metastatic pathologically diagnosed GISTs at our hospital were enrolled. Imatinib response was assessed according to Choi's criteria. Blood samples were collected 22­26 h after the previous imatinib dose before the next scheduled dose. Results: Fourteen patients were male and the median age was 65 years. The median duration of imatinib therapy was 3.8 years (range, 2.0­11.5 years). The median plasma level of imatinib was 1098 ng/ml and the minimal plasma level after ≥5 years of therapy was 789 ng/ml. Imatinib dosage was significantly correlated with history of gastrectomy. The minimum body surface area of patients who received 400-mg/day imatinib dosage was 1.560 m2. CONCLUSIONS: The minimum level in all patients showing response for ≥5 years of treatment was 789 ng/ml, suggesting an effective plasma imatinib level of ≥800 ng/ml. Our results suggest that imatinib dosage of 400 mg/day is recommended for a patient with a large BSA (≥1.56 m2) and that of 300 mg/day might be sufficient for patients who have undergone a gastrectomy.

Regulating surgical oncotaxis to improve the outcomes in cancer patients.

Excessive surgical stress and postoperative complications cause a storm of perioperative cytokine release, which has been shown to enhance tumor metastasis in experimental models. We have named this phenomenon "surgical oncotaxis". The mechanisms that underpin this process are thought to be excessive corticosteroid secretion, coagulopathy in the peripheral vasculature, immune suppression and excessive production of reactive oxygen species. Nuclear factor-kappa B (NFkB) activation plays a key role in these mechanisms. Minimally invasive surgical techniques should be used, and postoperative complications should be avoided whenever possible to lessen the impact of surgical oncotaxis. Furthermore, there may be a role for a small preoperative dose of corticosteroid or the use of free radical scavengers in the perioperative period. Recently, there has been a great deal of interest in omega-3 fatty acid, because it regulates NFkB activation. The use of multimodal treatments that regulate surgical oncotaxis may be as important as chemotherapy for determining the outcome of patients with cancer undergoing surgery.

Reconstruction of phase dynamics from macroscopic observations based on linear and nonlinear response theories.

We propose a method to reconstruct the phase dynamics in rhythmical interacting systems from macroscopic responses to weak inputs by developing linear and nonlinear response theories, which predict the responses in a given system. By solving an inverse problem, the method infers an unknown system: the natural frequency distribution, the coupling function, and the time delay which is inevitable in real systems. In contrast to previous methods, our method requires neither strong invasiveness nor microscopic observations. We demonstrate that the method reconstructs two phase systems from observed responses accurately. The qualitative methodological advantages demonstrated by our quantitative numerical examinations suggest its broad applicability in various fields, including brain systems, which are often observed through macroscopic signals such as electroencephalograms and functional magnetic response imaging.

Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma.

BACKGROUND: The system L amino acid transporter (LAT) has an important role in the transport of various amino acids, and there have been reports about the relation of this system to cancer. Although LATs are highly expressed in the kidneys, little is known about their influence on human renal cancer. METHODS: To clarify the role of LATs in human clear cell renal cell carcinoma (RCC), we investigated the expression of mRNAs for LAT1, LAT2, LAT3, LAT4, and 4F2hc in clear cell RCC tissues. The mRNAs of these five genes were analyzed by the real-time reverse transcription polymerase chain reaction in matched sets of tumor and non-tumor tissues obtained at operation from 82 Japanese patients with clear cell RCC. We also measured phosphorylated S6 ribosomal protein (Ser-235/236) proteins levels in 18 paired tumor and non-tumor tissues of the patients by Western blotting. RESULTS: Expression of LAT1 mRNA was significantly increased in tumor tissue compared with non-tumor tissue, while expression of LAT2 and LAT3 mRNAs was reduced. There was no difference in the expression of LAT4 and 4F2hc mRNAs between tumor and non-tumor tissues. Increased expression of LAT1 mRNA was associated with less differentiated tumors, local invasion, microscopic vascular invasion, and metastasis. Kaplan-Meier survival analysis showed that a higher serum LAT1 mRNA level was associated with a shorter overall survival time. Phosphorylated S6 ribosomal protein levels were associated with metastatic potential. LAT1 mRNA levels positively correlated with phosphorylated S6 ribosomal protein proteins levels in primary tumors. CONCLUSIONS: These findings suggest that LAT1 mRNA is related to the invasive and progressive potential of clear cell RCC.

[History of and novel developments in cancer immunotherapy - introduction to the special issue].

Over the last 50 years, development in the field of cancer immunotherapy has been fluctuating, ranging from exciting expectations to disappointing clinical outcomes. Now, the time has come again, for cancer immunotherapy. Since 2010, new immunotherapeutics have been approved one after another in the United States of America and other countries. Thus, immunotherapy has definitely been recognized as the fourth therapy for cancer after surgery, radiotherapy, and chemotherapy. Under this establishment, there has been progress not only in the fundamental understanding of the immune system but also in the design of scientific clinical trials, in which delayed-type tumor responses and survival benefits with less tumor shrinkage are used as indicators. The next 3 papers provide exciting insights on novel cancer immunotherapy as an innovative treatment modality for cancer.

Mode selectivity of dynamically induced conformation in many-body chainlike bead-spring models.

We consider conformation of a chain consisting of beads connected by stiff springs, where the conformation is determined by the bending angles between the consecutive two springs. Stability of a conformation is determined intrinsically by a potential energy function depending on the bending angles. However, effective forces induced by excited springs can change the stability, and a conformation can stay around a local maximum or a saddle of the bending potential. A stabilized conformation was named the dynamically induced conformation in a previous work on a three-body system [Y. Y. Yamaguchi et al., Phys. Rev. E 105, 064201 (2022)2470-004510.1103/PhysRevE.105.064201]. A remarkable fact is that the stabilization by the spring motion depends on the excited normal modes, which depend on a conformation. We extend analyses of the dynamically induced conformation in many-body chainlike bead-spring systems. Simple rules are that the lowest-eigenfrequency mode contributes to the stabilization and that the higher the eigenfrequency is, the more the destabilization emerges. We verify theoretical predictions by performing numerical simulations.