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.

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.

Discontinuous codimension-two bifurcation in a Vlasov equation.

In a Vlasov equation, the destabilization of a homogeneous stationary state is typically described by a continuous bifurcation characterized by strong resonances between the unstable mode and the continuous spectrum. However, when the reference stationary state has a flat top, it is known that resonances drastically weaken and the bifurcation becomes discontinuous. In this article we analyze one-dimensional spatially periodic Vlasov systems, using a combination of analytical tools and precise numerical simulations to demonstrate that this behavior is related to a codimension-two bifurcation, which we study in detail.

Neutrophil­to­lymphocyte ratio before each chemotherapy line predicts clinical outcomes in patients with unresectable gastric cancer.

The neutrophil-to-lymphocyte ratio (NLR) is a well-known prognostic biomarker for patients with gastric cancer (GC). However, for patients with GC treated with palliative chemotherapy, the predictive values of NLR remain obscure. Therefore, the present study evaluated the clinical impact of NLR in patients with GC treated with a series of chemotherapies. The present study retrospectively evaluated 83 patients with unresectable GC who received a series of chemotherapies. NLR in the blood was calculated before each chemotherapy initiation (before 1st-, 2nd- and 3rd-line treatment). Of the 83 patients enrolled, 56 patients (67%) received 2nd-line chemotherapy and 34 patients (41%) received 3rd-line chemotherapy. NLR at 1st-line ranged from 0.72 to 48.9 (median NLR, 3.00). Therefore, the median NLR of 3.00 was used as a definite cut-off value throughout the present study. All patients were dichotomized into NLR-high (>3.00) and NLR-low group (<3.00) by NLR evaluated before each line of chemotherapy. The median overall survival (OS) time of the low-NLR group was better than that of the high-NLR group from 1st-line to 3rd-line treatment (1st-line: 18.1 vs. 8.0 months, P=0.06; 2nd-line: 10.7 vs. 4.5 months, P=0.0001; 3rd-line: 8.7 vs. 4.7 months, P=0.003). Of the 24 patients treated with 3rd-line nivolumab, patients with low NLR exhibited better OS than those with high NLR (8.3 months in low-NLR and 6.6 months in high-NLR, P=0.06). In conclusion, NLR should be performed before each chemotherapy line in the clinical setting and may predict outcomes in patients with unresectable GC, including those treated with nivolumab.

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.

Long-term (>5-year) survivors among unresectable or metastatic cancer patients treated with zoledronate-activated killer cells: Seven case reports.

We are conducting an adoptive immunotherapy (AIT) trial using zoledronate-activated killer cells for patients in Japan with incurable cancer. We have encountered seven long-term survivors. Since such long survival may be very rare in cancer treatment, we present the details and a discussion of a possible role of AIT.

Dynamically induced conformation depending on excited normal modes of fast oscillation.

We present dynamical effects on conformation in a simple bead-spring model consisting of three beads connected by two stiff springs. The conformation defined by the bending angle between the two springs is determined not only by a given potential energy function depending on the bending angle, but also by fast motion of the springs which constructs the effective potential. A conformation corresponding with a local minimum of the effective potential is hence called the dynamically induced conformation. We develop a theory to derive the effective potential using multiple-scale analysis and the averaging method. A remarkable consequence is that the effective potential depends on the excited normal modes of the springs and amount of the spring energy. Efficiency of the obtained effective potential is numerically verified.

Phase 3 trial of sequential versus combination treatment in colorectal cancer: The C-cubed study.

BACKGROUND: An optimal treatment strategy using oxaliplatin and bevacizumab for metastatic colorectal cancer has not been defined. We investigated whether the sequential treatment using fluoropyrimidines with bevacizumab followed by the addition of oxaliplatin at first progression was better than a combination treatment using fluoropyrimidines and oxaliplatin with bevacizumab. METHODS: In the sequential treatment, the escalation from fluoropyrimidines plus bevacizumab to fluoropyrimidines plus oxaliplatin with bevacizumab was recommended in case of progressive disease. Time to failure of strategy was the primary end-point, whereas the secondary end-points were overall survival, progression-free survival, overall response rate and safety. RESULTS: Three hundred patients with previously untreated metastatic colorectal cancer were randomised to receive either the sequential treatment (n = 151) or the combination treatment (n = 149). The sequential treatment was superior to the combination treatment about time to failure of strategy (15.2 months; 95% CI, 12.5-17.2 months vs. 7.8 months: 95% CI, 6.3-9.5 months; P < 0.001). However, the median overall survival was 27.5 (95% CI, 24.4 to 32.7) months in the sequential treatment and 27.0 (95% CI, 22.8 to 36.0) months in the combination treatment (hazard ratio, 0.92; 95% CI, 0.66 to 1.28; P = 0.61). The overall response rate was 33.1% in the sequential treatment arm and 51.7% in the combination treatment. CONCLUSIONS: The findings support the extension of the sequential treatment starting from fluoropyrimidine plus bevacizumab to selected patients who do not need an objective response to the threatening disease.

Impacts of SNPs on adverse events and trough concentration of imatinib in patients with gastrointestinal stromal tumors.

Although imatinib has dramatically improved the outcomes of patients with gastrointestinal stromal tumor (GIST), marked inter-individual differences in its efficacy and toxicity have been observed. Extensive pharmacogenetic studies in Caucasian and Asian populations have demonstrated that several genetic polymorphisms are involved in these differences; however, no studies have focused on Japanese patients with GIST. This study aimed to evaluate the impacts of genetic polymorphisms of drug metabolizing enzymes and transporters on the incidence of adverse events and trough plasma concentrations (Ctroughs) of imatinib in Japanese patients with GIST. Of 35 candidate SNPs genotyped from 65 patients, ABCG2 421C>A was significantly associated with increased incidence rates of grade 2 or higher rash. When relationships between the genotypes and Ctroughs were examined in a subgroup of 38 patients from whom plasma was available, 5 SNPs were associated with significant trends toward increased or decreased dose-adjusted Ctroughs. Of them, SLCO1B3 334T>G and SLCO1A2 -1032G>A made significant contributions to the individual variability of Ctrough by multivariate regression analysis. Genetic variations in ABCG2, SLCO1B3, and SLCO1A2 may play important roles in the safety and pharmacokinetics of imatinib in Japanese patients with GIST, although a replication study is necessary for validation.

Republication: A Prospective Observational Study of Adoptive Immunotherapy for Cancer Using Zoledronate-Activated Killer (ZAK) Cells - An Analysis for Patients With Incurable Pancreatic Cancer.

BACKGROUND/AIM: Adoptive immunotherapy (AIT) using autologous zoledronate-activated killer (ZAK) cells has been performed for developing a novel modality of cancer treatment. In this study, data series from incurable pancreatic cancer were analyzed. PATIENTS AND METHODS: Patients were treated with AIT using intravenous administration of ZAK cells every 3 to 4 weeks in combination with standard chemotherapy and possible clinical benefits were examined. RESULTS: Seventy-five patients were treated. A median overall survival (OS) time of 6.7 months was achieved for all patients and 13.1 months for those treated 5 times or more, that increased to 14.6 and 18.3 months, respectively, when the previous treatment period of chemotherapy alone was included in the analysis. The disease control rate was 58.5 %. Multivariate regression analysis showed a significant positive correlation between the survival and baseline value of lymphocyte percentage in white blood cell counts (p=0.031). CONCLUSION: The data suggest that AIT using ZAK cells in combination with chemotherapy is safe and feasible and may be effective in prolonging survival for patients with incurable pancreatic cancer. The lymphocyte percentage at baseline may be a good biomarker for predicting the survival benefit of ZAK cell AIT.

Erratum: Adoptive immunotherapy for gastric cancer using zoledronate-activated killer cells: A prospective observational study.

[This corrects the article DOI: 10.3892/mco.2020.2125.].

Concordance of acquired mutations between metastatic lesions and liquid biopsy in metastatic colorectal cancer.

AIM: To evaluate whether PCR-reverse sequence-specific oligonucleotide can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. MATERIALS & METHODS: We examined acquired mutations in chemoresistant lesions and blood obtained from four patients with RAS wild-type metastatic colorectal cancer who underwent treatment with anti-epidermal growth factor receptor antibodies. RESULTS: In one patient, metastatic lesions harbored diverse acquired mutations in KRAS in all seven metastases; the two acquired mutations were detectable in blood collected after the patient acquired resistance. None of the other patients exhibited liquid biopsy mutations, except one, with a BRAF mutation confirmed in primary tumor and peritoneal dissemination. CONCLUSION: Liquid biopsy based on PCR-reverse sequence-specific oligonucleotide is a successful procedure for capturing acquired mutations with precise information on the RAS mutational spectrum.

Clinical and epigenetic features of colorectal cancer patients with somatic POLE proofreading mutations.

BACKGROUND: Mutations in the POLE gene result in an ultra-hypermutated phenotype in colorectal cancer (CRC); however, the molecular characterisation of epigenetic alterations remains unclear. We examined the genetic and epigenetic profiles of POLE-mutant CRC to elucidate the clinicopathological features of the associated genetic and epigenetic alterations. RESULTS: Tumour tissues (1,013) obtained from a cohort of patients with CRC were analysed to determine associations between the proofreading domain mutations of POLE with various clinicopathological variables, microsatellite instability (MSI) status, BRAF and KRAS mutations, and the methylation status of key regions of MLH1, MGMT, and SFRP2 promoters by calculating the methylation scores (range 0-6). Only four cases (0.4%) exhibited pathogenic POLE hotspot mutations (two p.P286R [c.857C > G], one p.V411L [c.1231G > C], and p.S459F [c.1376C > T] each), which were mutually exclusive to BRAF and KRAS mutations and MSI. CRC patients were divided into four subgroups: patients with POLE mutations (POLE, 0.4%, n = 4), patients with both MSI and extensive methylation in MLH1 (MSI-M, 2.9%, n = 29), patients with MSI but no extensive methylation in MLH1 (MSI-U, 3.6%, n = 36), and patients without MSI (non-MSI, 93.2%, n = 944). The POLE group was younger at diagnosis (median 52 years, P < 0.0001), with frequent right-sided tumour localisation (frequency of tumours located in the right colon was 100%, 93.1%, 36.1%, and 29.9% in POLE, MSI-M, MSI-U, and non-MSI, respectively; P < 0.0001), and was diagnosed at an earlier stage (frequency of stages I-II was 100%, 72.4%, 77.8%, and 46.6% in POLE, MSI-M, MSI-U, and non-MSI, respectively, P < 0.0001). The mean methylation score in POLE was not different from that in MSI-U and non-MSI, but the methylation signature was distinct from that of the other subgroups. Additionally, although the examined number of POLE-mutant tumours was small, the number of CD8-positive cells increased in tumours with partial methylation in the MLH1 gene. CONCLUSIONS: CRC patients with POLE proofreading mutations are rare. Such mutations are observed in younger individuals, and tumours are primarily located in the right colon. Diagnosis occurs at an earlier stage, and distinct epigenetic alterations may be associated with CD8 cell infiltration.

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.

Erratum: Critical exponents in mean-field classical spin systems [Phys. Rev. E 100, 032131 (2019)].

This corrects the article DOI: 10.1103/PhysRevE.100.032131.

Adoptive immunotherapy for gastric cancer using zoledronate-activated killer cells: A prospective observational study.

For several years, adoptive immunotherapy (AIT) has been performed using autologous zoledronate-activated killer (ZAK) cells to develop a novel modality for cancer treatment. In the current study, data from 50 patients with incurable gastric cancer were analyzed. Patients were treated with AIT using intravenous ZAK cells every 3-4 weeks in combination with chemotherapy of the physician's choice. The possible clinical benefits were subsequently examined. The median overall survival (OS) time of all patients was 7.5 months. In patients that received 5 or more rounds of treatment, the OS was 13.5 months. Additionally, the OS times of 1st, 2nd or later line chemotherapy with ZAK cell AIT were 27.3 months and 13.3 months, respectively. No objective response was observed and the disease control rate was 67.9%. No severe adverse event was recorded. Functional Assessment of Cancer Therapy-Biologic Response Modifier analysis revealed possible improvement of quality of life after ZAK cell AIT. Univariate analysis revealed a significant positive association between longer survival times and baseline lymphocyte percentages in white blood cell counts (P<0.001), serum albumin (P=0.001), C-reactive protein (P=0.006), carbohydrate antigen (CA)19-9 (P=0.010), neutrophil-lymphocyte ratio (P<0.001) and Glasgow prognostic score (GPS). Only the GPS value (P=0.024) was a significant survival marker when analyzed using the multivariate Cox proportional hazards model. Although the results cannot provide a definitive conclusion, the current suggested that ZAK cell AIT in combination with chemotherapy is safe, feasible and may be a promising treatment option for patients with incurable gastric cancer. The GPS value at baseline may be a potential biomarker for chemo-immunotherapy.

[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.

Upregulation of microRNA-31 is associated with poor prognosis in patients with advanced colorectal cancer.

Colorectal cancer (CRC) manifests after the accumulation of genetic and epigenetic alterations along with tumor microenvironments. MicroRNA (miRNA/miR) molecules have been revealed to serve in critical roles in the progression various types of cancer, and their expression level is often an important diagnostic, predictive or prognostic biomarker. The aim of the present study was to evaluate the potential of miRNAs as prognostic biomarkers for patients with advanced CRC. miRNA arrays were performed on CRC specimens obtained from tumors with various molecular statuses [e.g. KRAS proto-oncogene, GTPase (KRAS)/B-Raf proto-oncogene, serine/threonine kinase (BRAF)/microsatellite instability (MSI)], and their paired normal mucosal specimens. The miRNA array revealed that miR-31-5p (miR-31) was specifically upregulated in CRCs with the BRAF V600E mutation, the results of which were supported by subsequent analysis of a dataset retrieved from The Cancer Genome Atlas (TCGA) database, which contained information regarding 170 patients with CRC including 51 BRAF-mutant CRCs. Of our cohort of 67 patients with stage IV CRC, 15 (22%) and 4 (6%) showed KRAS and BRAF V600E mutations, respectively. Since the median miR-31 expression was 3.45 (range, 0.004-6330.531), the cut-off value was chosen as 3.5, and all tumors were categorized into two groups accordingly (high-/low-miR-31 expression). The high miR-31 expression group (n=33) was significantly associated with a poorer mortality (univariate hazard ratio=2.12; 95% confidence interval, 0.23-0.95; P=0.03) and exhibited a shorter median survival time (MST; 20.1 months) compared with the low miR-31 expression group (n=34) (MST, 38.3 months; P=0.03), indicating that miR-31 is a promising prognostic biomarker for patients with advanced CRC. Thus, performing a functional analysis of miR-31 expression may lead to the development of new targeted therapies for the various genetic subtypes of CRC.

Critical exponents in coupled phase-oscillator models on small-world networks.

A coupled phase-oscillator model consists of phase oscillators, each of which has the natural frequency obeying a probability distribution and couples with other oscillators through a given periodic coupling function. This type of model is widely studied since it describes the synchronization transition, which emerges between the nonsynchronized state and partially synchronized states. The synchronization transition is characterized by several critical exponents, and we focus on the critical exponent defined by coupling strength dependence of the order parameter for revealing universality classes. In a typical interaction represented by the perfect graph, an infinite number of universality classes is yielded by dependency on the natural frequency distribution and the coupling function. Since the synchronization transition is also observed in a model on a small-world network, whose number of links is proportional to the number of oscillators, a natural question is whether the infinite number of universality classes remains in small-world networks irrespective of the order of links. Our numerical results suggest that the number of universality classes is reduced to one and the critical exponent is shared in the considered models having coupling functions up to second harmonics with unimodal and symmetric natural frequency distributions.

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.