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Lipids interfere with absorbance measurements conducted using colorimetric methods. To monitor lipemia, some systems measure absorbance using an analyzer. This report describes a novel case of interference with the lipemia index without lipemia. A 64-year-old woman with giant basal cell carcinoma underwent resection and sentinel lymph node biopsy. The patient had been subcutaneously injected with patent blue during sentinel lymph node resection. After surgery, her serum and urine were yellow-green, and the lipemia index, calculated by measuring absorbance at 658 nm (main wavelength) and 694 nm (secondary wavelength) using a JCA-BM8040 chemistry analyzer, was high. The absorbance spectrum of the patient's serum and patent blue solution were compared to determine the cause of the high lipemia index. The patient's serum and the patent blue solution showed absorption at wavelengths between 540 and 698 nm. Moreover, the absorbance was concentration-dependent for patent blue. These results thus indicated that the patient's serum contained patent blue. Here, we report a case wherein patent blue affected the lipemia index. Thus, it must be noted that patent blue injection may yield inaccurate results when evaluating lipemia index. [ABSTRACT FROM AUTHOR]

Simple Summary: Regorafenib offers longer survival for patients with refractory metastatic colorectal cancer (mCRC). We aimed to identify biomarkers for regorafenib through preclinical and translational studies. In silico analysis identified matrix metalloproteinase (MMP)-14 and MMP-9 as key biomarkers. Validation in patients receiving regorafenib or FTD/TPI showed that high MMP-14 levels were correlated with a better response to regorafenib. Additionally, lower MMP-9 levels before the second cycle were linked to improved disease control and survival. These findings suggest that MMP-14 and MMP-9 could serve as prognostic markers for regorafenib efficacy. In identifying biomarkers for anticancer drugs, the lack of objectivity in selecting candidate factors makes interpretation difficult. We performed preclinical analysis and a translational validation study to identify candidate biomarkers for regorafenib efficacy in metastatic colorectal cancer (mCRC). Using in silico COMPARE analysis with a human cancer cell line panel, JFCR39, we selected candidate biomarkers whose expression correlates with regorafenib sensitivity. We validated predictive values in mCRC patients receiving regorafenib (discovery, n = 53) and FTD/TPI (control, n = 16). Blood samples were obtained at baseline (BL), before the second cycle (2nd), and at progressive disease (PD), and biomarker levels were measured using ELISA. Our analysis showed that high matrix metalloproteinase (MMP)-14 expression was associated with a high sensitivity to regorafenib. In the discovery cohort, high MMP-14 levels at BL and PD were correlated with tumor shrinkage and longer progression-free survival (PFS). A subsequent analysis of other related factors further indicated that the patients with decreased MMP-9 levels at the 2nd had higher disease control rates, tumor shrinkage, longer PFS, and overall survival than those with increased changes. These findings were not observed in the control cohort. Our study suggests MMP-14 and MMP-9 may serve as prognostic markers for regorafenib and provide insights into novel combination therapies with anti-MMP-9 agents or FTD/TPI. [ABSTRACT FROM AUTHOR]

Both density and surface tension were systematically investigated over a wide temperature and compositional range for the liquid Al–V alloy system. The thermophysical properties were measured in an electromagnetic levitation device. A linear decrease in surface tension and density with increasing temperature was observed for every alloy composition investigated. Additionally, a decrease in density and surface tension was observed for increasing aluminum content among the different probed samples. This decrease is, a strong deviation from an ideal mixing behavior which was experienced for both properties. Different models, including variants of the well-established Butler model, were employed to better describe the compositional dependence of density and surface tension in the liquid Al–V system. The advantages and disadvantages were discussed for each model describing the measured thermophysical property data. Strong similarities were observed when comparing the mixing behavior and segregation effects of the investigated Al–V system with already established works for the liquid Al–Ti system. The results suggest that both vanadium and titanium show similar mixing behavior when alloyed with aluminum. [ABSTRACT FROM AUTHOR]

Background and objective: The disaccharide loading test is a method to assess gastric mucosal damage. Since Trelan-G75, which is used for the sugar tolerance test, contains disaccharide maltose, if maltose is detected at a high sensitivity in the sample blood used in the sugar tolerance test, screening for upper gastrointestinal mucosal damage can be made simultaneously with the sugar tolerance test for the diagnosis of diabetes. Methods: Glucose-6-phosphate is generated by treating maltose with maltose phosphorylase, β-phosphoglucomutase, and glucose-1,6-bisphosphate. Then, change in the absorbance at 405 nm is measured by the enzymatic cycling method using Thio-NADP, β-NADPH, and Glucose-6-phosphate dehydrogenase. After evaluating the optimal condition for this method, it is mounted on an automatic biochemical analyzer, and samples after the sugar tolerance test were assayed. Results: Regarding the performance of this method, the repeatability was 10–50 μmol/L with a CV of ≤1.1%. Concerning the assay range, a curve passing the origin with a range of linearity up to 120 μmol/L was obtained. No effect of dyes or sugars in the blood was noted. As a result of application to patients with gastric mucosal disorders (those who had a health checkup), significant differences were observed depending on the stage of atrophic gastritis. Discussion: This method has a high sensitivity and a high precision and can be used for high-speed analysis on an automatic analyzer. It has the potential to be used as a screening test for gastric mucosal damage. [ABSTRACT FROM AUTHOR]

Cancer cells adopt multiple strategies to escape tumor surveillance by the host immune system and aberrant amino acid metabolism in the tumor microenvironment suppresses the immune system. Among the amino acid‐metabolizing enzymes is an L‐amino‐acid oxidase called interleukin‐4 induced 1 (IL4I1), which depletes essential amino acids in immune cells and is associated with a poor prognosis in various cancer types. Although IL4I1 is involved in immune metabolism abnormalities, its effect on the therapeutic efficacy of immune checkpoint inhibitors is unknown. In this study, we established murine melanoma cells overexpressing IL4I1 and investigated their effects on the intratumor immune microenvironment and the antitumor efficacy of anti‐programmed death‐ligand 1 (PD‐L1) antibodies (Abs) in a syngeneic mouse model. As a result, we found that IL4I1‐overexpressing B16‐F10‐derived tumors showed resistance to anti‐PD‐L1 Ab therapy. Transcriptome analysis revealed that immunosuppressive genes were globally upregulated in the IL4I1‐overexpressing tumors. Consistently, we showed that IL4I1‐overexpressing tumors exhibited an altered subset of lymphoid cells and particularly significant suppression of cytotoxic T cell infiltration compared to mock‐infected B16‐F10‐derived tumors. After treatment with anti‐PD‐L1 Abs, we also found a more prominent elevation of tumor‐associated macrophage (TAM) marker, CD68, in the IL4I1‐overexpressing tumors than in the mock tumors. Consistently, we confirmed an enhanced TAM infiltration in the IL4I1‐overexpressing tumors and a functional involvement of TAMs in the tumor growth. These observations indicate that IL4I1 reprograms the tumor microenvironment into an immunosuppressive state and thereby confers resistance to anti‐PD‐L1 Abs. [ABSTRACT FROM AUTHOR]

Thermal radiation properties of surface micro-Au-line and space structures on direct and indirect electronic transition-type semiconductors of n-type (n-) GaAs and GaP, respectively, are studied. The electron densities range from 0.62 to 1.0 × 1018 cm−3. The emission spectra of samples on n-GaAs wafers show peak energies significantly shifted from the longitudinal optical (LO) phonon energy due to the LO-phonon−plasmon coupling (LOPC) at 630 K, while partial decoupling is observed. The thermal emission from the sample on n-GaP is peaked at 395.9 cm−1, shifted only by 1.5 cm−1 from the LO-phonon energy, with a linewidth of 12.5 cm−1 at 630 K. The effect of LOPC on the emission from the sample on n-GaP is mostly suppressed because of the electron localization in the X-valley, suggesting an advantage of indirect transition-type semiconductors in LO-phonon resonant infrared emitters using the phonons generated via the electron energy relaxation. [ABSTRACT FROM AUTHOR]

The surface tension of liquid zirconium was measured using the oscillating droplet method with electromagnetic levitation while considering the effect of oxygen dissolution from the measurement atmosphere. When liquid zirconium was maintained at approximately 2300 K under the flow of an Ar-He gas at 2 L·min-1 with an oxygen partial pressure (Po2) of 10-2 Pa, the oxygen content (CO) remained stable even after 15 min, resulting in a constant surface tension. However, under the flow of an Ar-He-H2-CO2 gas, CO increased with time even when Po2 was 10-4 and 10-6 Pa. This was attributed to the gasphase equilibrium between H2 and CO2, which facilitated the continuous dissolution of atmospheric oxygen into liquid zirconium. Liquid zirconium was free from any contaminations due to chemical reactions with the supporting material or atmospheric oxygen, and its surface tension was expressed as σ = 1495 - 0.1153 (T - 2128) [10-3 N·m-1]. [ABSTRACT FROM AUTHOR]

Influences of temperature and oxygen adsorption on the surface tension of liquid silicon were investigated by the oscillating droplet method using the electromagnetic levitation technique. Oxygen partial pressure in the vicinity of the liquid surface was controlled by the theoretically derived Ratto, Ricci, and Arato model and the effectiveness of which was experimentally confirmed from the in situ observation of oxidation and reduction behaviors of the droplet surface in this study. The surface tension of liquid silicon was decreased with increasing oxygen partial pressure in the vicinity of the liquid surface due to oxygen adsorption at low temperature, whereas the surface tension converged to a pure state value at high temperature regardless of the oxygen partial pressure due to a decrease in the equilibrium constant of oxygen adsorption reaction. As a result, "boomerang shape" temperature dependence of surface tension was observed; the gradient of the temperature dependence of surface tension was gradually increased with elevating temperature and then became a constant value at high temperature. The influences of oxygen adsorption and temperature on surface tension were successfully derived from the measurement result by using the Szyszkowski equation. Furthermore, the changes in enthalpy and entropy for oxygen adsorption on liquid silicon were also estimated. [ABSTRACT FROM AUTHOR]

The equilibrium crystal structure of LnMnO3 (Ln: lanthanide) is known to be orthorhombic when larger ions from La3+ to Dy3+ are used as Ln3+, and hexagonal when smaller ions from Ho3+ to Lu3+ are used. Research indicates that the hexagonal phase forms when the tolerance factor, expressed as functions of radii of the constituent ions, is less than 0.840. In this study, we attempted to induce oxygen deficiency in DyMnO3 through solidification at low oxygen partial pressure using an aerodynamic levitator. The objective was to decrease the tolerance factor by reducing the valence of manganese ions and thereby increasing their ionic radius. The results showed an increase in oxygen deficiency as the oxygen partial pressure decreased. Based on the assumption that the manganese ions' valence decreased due to an increase in oxygen deficiency, the corresponding tolerance factor evaluated from the average ionic radii of manganese and oxygen also decreased. This decrease promoted the formation of the hexagonal phase, similar to the effect observed when the ionic radius of Ln3+ is reduced. [ABSTRACT FROM AUTHOR]

Senescent cells secrete inflammatory proteins and small extracellular vesicles (sEVs), collectively termed senescence-associated secretory phenotype (SASP), and promote age-related diseases. Epigenetic alteration in senescent cells induces the expression of satellite II (SATII) RNA, non-coding RNA transcribed from pericentromeric repetitive sequences in the genome, leading to the expression of inflammatory SASP genes. SATII RNA is contained in sEVs and functions as an SASP factor in recipient cells. However, the molecular mechanism of SATII RNA loading into sEVs is unclear. In this study, we identified Y-box binding protein 1 (YBX1) as a carrier of SATII RNA via mass spectrometry analysis after RNA pull-down. sEVs containing SATII RNA induced cellular senescence and promoted the expression of inflammatory SASP genes in recipient cells. YBX1 knockdown significantly reduced SATII RNA levels in sEVs and inhibited the propagation of SASP in recipient cells. The analysis of the clinical dataset revealed that YBX1 expression is higher in cancer stroma than in normal stroma of breast and ovarian cancer tissues. Furthermore, high YBX1 expression was correlated with poor prognosis in breast and ovarian cancers. This study demonstrated that SATII RNA loading into sEVs is regulated via YBX1 and that YBX1 is a promising target in novel cancer therapy. [ABSTRACT FROM AUTHOR]

Tumor‐promoting carcinoma‐associated fibroblasts (CAFs), abundant in the mammary tumor microenvironment (TME), maintain transforming growth factor‐β (TGF‐β)‐Smad2/3 signaling activation and the myofibroblastic state, the hallmark of activated fibroblasts. How myofibroblastic CAFs (myCAFs) arise in the TME and which epigenetic and metabolic alterations underlie activated fibroblastic phenotypes remain, however, poorly understood. We herein show global histone deacetylation in myCAFs present in tumors to be significantly associated with poorer outcomes in breast cancer patients. As the TME is subject to glutamine (Gln) deficiency, human mammary fibroblasts (HMFs) were cultured in Gln‐starved medium. Global histone deacetylation and TGF‐β‐Smad2/3 signaling activation are induced in these cells, largely mediated by class I histone deacetylase (HDAC) activity. Additionally, mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signaling is attenuated in Gln‐starved HMFs, and mTORC1 inhibition in Gln‐supplemented HMFs with rapamycin treatment boosts TGF‐β‐Smad2/3 signaling activation. These data indicate that mTORC1 suppression mediates TGF‐β‐Smad2/3 signaling activation in Gln‐starved HMFs. Global histone deacetylation, class I HDAC activation, and mTORC1 suppression are also observed in cultured human breast CAFs. Class I HDAC inhibition or mTORC1 activation by high‐dose Gln supplementation significantly attenuates TGF‐β‐Smad2/3 signaling and the myofibroblastic state in these cells. These data indicate class I HDAC activation and mTORC1 suppression to be required for maintenance of myCAF traits. Taken together, these findings indicate that Gln starvation triggers TGF‐β signaling activation in HMFs through class I HDAC activity and mTORC1 suppression, presumably inducing myCAF conversion. [ABSTRACT FROM AUTHOR]

Flexible sensors that can be attached to the body to collect vital data wirelessly enable real‐time, early‐stage diagnosis for human health management. Wearable sweat sensors have received considerable attention for real‐time physiological monitoring. Unlike conventional methods that require blood‐drawing in a clinic, sweat analyses may enable noninvasive tracking of health conditions for early‐stage diagnosis. Even though a variety of studies to monitor metabolites and other substances have been conducted, automatic, continuous, long‐term, simultaneous monitoring of perspiration rate and electrolytes, which are important parameters in dehydration, has yet to be achieved because of challenges related to sensor design. Here a wireless, wearable, integrated, microfluidic sensor system that can continuously measure these parameters in real‐time for prolonged periods are presented. The proposed sensors are systematically characterized, and machine learning is used to predict device tilt angle to calibrate sensor output signals. Using the sensor design to form a water droplet in a fluidic channel, high‐volume perspiration rate is continuously monitored for more than 7000 s (total sweat volume >170 µL). By testing 10 subjects, physiological responses to ingestion of a sports drink are confirmed by measuring perspiration rhythm changes extracted from real‐time, continuous sweat impedance and rate. [ABSTRACT FROM AUTHOR]

Self-organizing neural organoids grown from pluripotent stem cells1–3 combined with single-cell genomic technologies provide opportunities to examine gene regulatory networks underlying human brain development. Here we acquire single-cell transcriptome and accessible chromatin data over a dense time course in human organoids covering neuroepithelial formation, patterning, brain regionalization and neurogenesis, and identify temporally dynamic and brain-region-specific regulatory regions. We developed Pando—a flexible framework that incorporates multi-omic data and predictions of transcription-factor-binding sites to infer a global gene regulatory network describing organoid development. We use pooled genetic perturbation with single-cell transcriptome readout to assess transcription factor requirement for cell fate and state regulation in organoids. We find that certain factors regulate the abundance of cell fates, whereas other factors affect neuronal cell states after differentiation. We show that the transcription factor GLI3 is required for cortical fate establishment in humans, recapitulating previous research performed in mammalian model systems. We measure transcriptome and chromatin accessibility in normal or GLI3-perturbed cells and identify two distinct GLI3 regulomes that are central to telencephalic fate decisions: one regulating dorsoventral patterning with HES4/5 as direct GLI3 targets, and one controlling ganglionic eminence diversification later in development. Together, we provide a framework for how human model systems and single-cell technologies can be leveraged to reconstruct human developmental biology.A multi-omic atlas of brain organoid development facilitates the inference of an underlying gene regulatory network using the newly developed Pando framework and shows—in conjunction with perturbation experiments—that GLI3 controls forebrain fate establishment through interaction with HES4/5 regulomes. [ABSTRACT FROM AUTHOR]

We previously reported the 95th percentile cutoff value of the serum procalcitonin (PCT) reference curve for diagnosing early-onset bacterial infection. We aimed to verify the effectivity of these novel diagnostic criteria by comparing antibiotic use and incidence of early-onset bacterial infection between pre- and post-introduction periods. We included newborns admitted to our neonatal intensive care unit who underwent blood tests within 72 h after birth between 2018 and 2022. The neonates were divided into the pre-intervention (admitted before the introduction, n = 737) or post-intervention (admitted after the introduction, n = 686) group. The days of antibiotics therapy (DOT) per 1000 patient days up to 6 days after birth, percentage of antibiotic use, and incidence of early-onset bacterial infection were compared between the groups. The post-intervention group had significantly lower DOT per 1000 patient days (82.0 days vs. 211.3 days, p < 0.01) and percentage of newborns receiving antibiotics compared with the pre-intervention group (79 (12%) vs. 280 (38%), respectively, p < 0.01). The incidence of early-onset bacterial infections did not differ between the groups (2% each, p = 0.99). In conclusion, our diagnostic criteria using the 95th percentile cutoff value of the serum PCT reference curve for early-onset bacterial infection were proven safe and effective, promoting appropriate use of antibiotics. [ABSTRACT FROM AUTHOR]

Objective Presence of autoantibodies against troponin I (cTnI) or T (cTnT) has been reported to interfere with troponin assays. However, the extent of the interference with the measurement has not been explored sufficiently. The aims of this study were to examine the frequencies of autoantibodies against troponin I and troponin T and how much these antibodies would affect the measurement. Methods The study comprised 52 subjects who visited Hokkaido University Hospital with suspected ischemic heart diseases. To evaluate the presence of autoantibodies, we calculated the recoveries of cTnI or cTnT after immunoglobulin G depletion, and the distributions of peaks reactive with cTnI or cTnT by high-performance liquid chromatography were examined. Results Autoantibodies against cTnI and cTnT were identified in 8 subjects (15.4%) and 1 subject (1.9%), respectively. Although the greatest difference between cTnI and cTnT was 32-fold, the distributions of cTnI-to-cTnT ratios in groups with and without anti-cTnI were not statistically different. Conclusion Autoantibodies against cTnI were more frequent by several fold than those against cTnT. Their presence did not significantly expand the discrepancy between cTnI and cTnT assays. [ABSTRACT FROM AUTHOR]

The effects of temperature and phosphorus addition on the surface tension of molten CuP alloys were measured by the oscillating droplet method using the electromagnetic levitation technique. We successfully measured the accurate surface tension of molten samples that were sufficiently above the liquidus temperature. The surface tension of liquid copper was determined in its pure state, which is free from any contamination, such as oxygen adsorption and chemical reaction with the supporting material. The surface tension of the molten sample was decreased as phosphorus addition was increased. The surface tension of molten CuP alloys was well expressed as functions of temperature and phosphorus activity from the measurement results using the Szyszkowski model. Furthermore, the enthalpy and entropy changes in phosphorus adsorption on liquid copper were also estimated. [ABSTRACT FROM AUTHOR]

The flow patterns of "pearl string" in draining bubble film as first witnessed by Sir James Dewar some 100 years ago were successfully reproduced by using chemically stable aqueous alkylbenzenesulfonate instead of alkylcarboylate used by Dewar as a soap. The concentration of aqueous surfactant used is as high as 5% by weight. The close-up pictures were taken by both still and video cameras at the magnification of around 10× with time for the draining flat bubble film prepared in vertically held rectangular frame made of a thin glass rod. The flow pattern of "threaded white beads" was found to appear at the shear boundary of black and gray flowing films. The successive and periodical deposition of tiny white particles to form "threaded pearls" is explained as the result of repeated nucleation of liquid crystalline phase as triggered by the stick-slip frictional sliding of black film at the boundary of the isotropic gray film and the subsequent growth of particles by isothermal condensation. The frequency of oscillational shear was found to be around 10 Hz for the shear velocity of 3 cm/s, which was approximated from the increased rate of black film area and the interval of beads in video images. The phenomena were explained as the deposition of liquid crystalline phase in the isotropic gray film the nucleation of which is triggered by the stick-slip frictional sliding motion of black film at the border of gray film. The whole process occurs in the course of gravity-induced syneresis of aqueous soap film. [ABSTRACT FROM AUTHOR]

Here, we report that pancreatic cancer-derived extracellular vesicles (EVs) carry adipocyte-targeting integrins and induce lipolysis, constituting the underlying mechanism of cancer-associated cachexia (CAC). GLO:F2H7/01nov22:ctm21089-fig-0003.jpg PHOTO (COLOR): 3 Panc-1 cell-derived extracellular vesicles (EVs) preferably distribute to adipose and lung tissues via ITGB1 and ITGA6. EVs derived from normal cells induce lipolysis only slightly because these EVs are rarely captured by adipocytes. After 4 h, more Panc-1-derived EVs were taken up by EV-treated adipocytes compared with Capan-2 EVs (Figure S3C). [Extracted from the article]

To accurately measure the surface tension of liquid titanium free of contamination from chemical reaction with the supporting materials and dissolution of atmospheric oxygen, the measurement was performed by using electromagnetic levitation (EML) and electrostatic levitation (ESL) in consideration of the influence of oxygen partial pressure of the measurement atmosphere, P O 2 . When liquid titanium was maintained at 2000 K under Ar–He gas with P O 2 of 10 Pa flowing at 2 L·min−1 using EML, the surface tension decreased with time due to the dissolution of atmospheric oxygen into the sample. When the P O 2 of the gas was decreased to 10−2 Pa, the oxygen content and the surface tension were confirmed to not vary, even after 120 min. Even though P O 2 further decreased to 10−11 Pa under Ar–He–H2 gas, the surface tension slightly increased with time due to gas phase equilibrium between H2 and H2O that allowed for a continuous dissolution of atmospheric oxygen into the liquid titanium. The surface tension of liquid titanium measured by ESL, which prevents contamination of the sample from supporting materials and the high 10−5 Pa vacuum inhibits the dissolution of oxygen, showed almost the same value as that measured under Ar–He gas at P O 2 of 10−2 Pa by EML. From the measurement results of EML and ESL, the surface tension of the 99.98 mass % pure liquid titanium, free from any contaminations from chemical reactions, with the supporting material and dissolved oxygen was expressed as σ 99.98 % = 1613 − 0.2049 T − 1941 (10−3 N·m−1). [ABSTRACT FROM AUTHOR]

Numerous epithelial–mesenchymal transition (EMT) characteristics have now been demonstrated to participate in tumor development. Indeed, EMT is involved in invasion, acquisition of stem cell properties, and therapy‐associated resistance of cancer cells. Together, these mechanisms offer advantages in adapting to changes in the tumor microenvironment. However, recent findings have shown that EMT‐associated transcription factors (EMT‐TFs) may also be involved in DNA repair. A better understanding of the coordination between the DNA repair pathways and the role played by some EMT‐TFs in the DNA damage response (DDR) should pave the way for new treatments targeting tumor‐specific molecular vulnerabilities, which result in selective destruction of cancer cells. Here we review recent advances, providing novel insights into the role of EMT in the DDR and repair pathways, with a particular focus on the influence of EMT on cellular sensitivity to damage, as well as the implications of these relationships for improving the efficacy of cancer treatments. [ABSTRACT FROM AUTHOR]

Erratum: "Influence of oxygen adsorption from atmosphere on surface tension of liquid silicon" [J. Appl. Phys. The surface tension of liquid silicon measured at around 1750 K as a function of oxygen activity, a O 2. 7 and 9, and values related to oxygen activity, HT ht , in Table III. [Extracted from the article]

The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels after ramucirumab administration are associated with a worse prognosis, suggesting that excess VEGF-A induced by ramucirumab negatively affects treatment efficacy and that neutralizing VEGF-A may improve treatment outcomes. Here, we evaluated the effect of combination treatment with an anti-VEGFR2 antibody and anti-VEGF-A antibody on gastric tumor progression and normal tissues using a preclinical BALB/c-nu/nu mouse xenograft model. After anti-VEGFR2 antibody treatment in mice, a significant increase in plasma VEGF-A levels was observed, mirroring the clinical response. The elevated VEGF-A was host-derived. Anti-VEGF-A antibody co-administration enhanced the anti-tumor effect of the anti-VEGFR2-antibody without exacerbating the toxicity. Mechanistically, the combination treatment induced intra-tumor molecular changes closely related to angiogenesis inhibition and abolished the gene expression changes specifically induced by anti-VEGFR2 antibody treatment alone. We particularly identified the dual treatment-selective downregulation of ZEB1 expression, which was critical for gastric cancer cell proliferation. These data indicate that the dual blockade of VEGF-A and VEGFR2 is a rational strategy to ensure the anti-tumor effect of angiogenesis-targeting therapy. [ABSTRACT FROM AUTHOR]

Titanium are often used as dental materials, pure titanium present low strength and titanium alloy is reported poor biocompatibility, respectively. To overcome the problem, we fabricated high-strength multi-directional forged (MDF) titanium with improved mechanical properties without changing the chemical composition and evaluated its applicability in prosthetic crowns. Cutting tests: the average absolute value of the difference before and after cutting was calculated as the uncut amount. Surface evaluations: MDF titanium, pure titanium, and the Ti-6Al-4V alloy were the surface properties (the surface roughness, the contact angles, glossiness) of the samples were evaluated. The fitness test used digital data. These demonstrated that the good workability of high-strength MDF titanium. The surface-roughness and contact-angle properties of MDF titanium and pure titanium were similar. The fitness test showed no significant differences between MDF titanium and pure titanium crowns. These results suggest that MDF titanium is promising for fabricating prosthetic crowns in dental applications. [ABSTRACT FROM AUTHOR]

Urine bags are commonly used to collect urine samples from neonates. However, the sample can be contaminated by stool, or detachment of the bag due to body movement can lead to failure of the collection. A qualitative urine collection kit containing ten filter papers of 3.2 mm diameter was developed and clinically verified among 138 neonates. During a single diaper change (approximately 3 h), the rate of urine collection was calculated. Urine collection was considered to be successful if any filter paper in the urine collection sheet turned from blue to white. Of the 127 neonates who passed urine, 122 had a change in the filter paper. The urine collection rate was 96%, with changes in all 10 filter papers observed in 98 neonates (80%). Urine collection rate was not influenced by sex (p = 1.00), age at collection (p = 0.72), preterm birth (p = 1.00), low birth weight (p = 0.92), or fecal contamination (p = 1.00). The incidence of dermatitis was not higher than in the group in which urine bags were used (urine collection kit: 2/68 [3%]; urine bag: 5/68 [7%]; p = 0.44). Novel urine collection kits using filter paper can collect samples from neonates safely and with a high probability of success. [ABSTRACT FROM AUTHOR]

The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third‐generation EGFR‐tyrosine kinase inhibitor (EGFR‐TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR‐TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor‐like biological activity of lamellarin N into kinase inhibitor‐like activity. Ba/F3 and PC‐9 cells expressing the EGFR in‐frame deletion within exon 19 (del ex19)/T790M/C797S triple‐mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple‐mutant EGFR PC‐9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple‐mutant EGFR PC‐9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR‐TKI that prevents the development of cross‐resistance against known drugs in this class. [ABSTRACT FROM AUTHOR]

Neonatal mitochondrial disease is occasionally observed in patients with intraventricular cysts in the brain. Atypical morphology is rarely seen in these cysts. Here, we report a case of neonatal lethal mitochondrial disease with IBA57 gene mutation. We have, for the first time, described a subependymal pseudocyst (SEPC) with a fluctuating membrane. Our findings suggest that SEPCs with fluctuating membranes can be a potential diagnostic indicator of neonatal mitochondrial disease. [ABSTRACT FROM AUTHOR]

We report the first observation of room temperature spontaneous electric polarization in an electronic ferroelectric material, a YbFe2O4 single crystal. The observation was based on second harmonic generation (SHG), a nonlinear optical process. Tensor analysis of the SHG signal revealed that this material has a polar charge superstructure with Cm symmetry. This result settles the long-term discussion on the uncertainty about electronic ferroelectric properties, including the charge order structure. We present a complete picture of the polar charge ordering of this material via consistent results from two different characterization methods. The SHG signal shows the same temperature dependence as the superlattice signal observed in neutron diffraction experiments. These results prove ferroelectric coupling to electron ordering in YbFe2O4, which results in electronic ferroelectricity which is enabled by the real space ordering of iron cations with different valences. The existence of electronic ferroelectricity holds promise for future electronics technologies where devices run a thousand times faster than frequency of the present CPU (a few gigahertz) embedded in smartphones, etc. [ABSTRACT FROM AUTHOR]

G-quadruplex (G4), a non-canonical higher-order structure formed by guanine-rich nucleic acid sequences, affects various genetic events in cis, including replication, transcription and translation. Whereas up-regulation of innate immune/interferon-stimulated genes (ISGs) is implicated in cancer progression, G4-forming oligonu-cleotides that mimic telomeric repeat-containing RNA suppress ISG induction in three-dimensional (3D) culture of cancer cells. However, it is unclear how G4 suppresses ISG expression in trans. In this study, we found that G4 binding to splicing factor 3B subunit 2 (SF3B2) down-regulated STAT1 phosphorylation and ISG expression in 3D-cultured cancer cells. Liquid chromatography-tandem mass spec-trometry analysis identified SF3B2 as a G4-binding protein. Either G4-forming oli-gonucleotides or SF3B2 knockdown suppressed ISG induction, whereas Phen-DC3, a G4-stabilizing compound, reversed the inhibitory effect of G4-forming oligonucleotides on ISG induction. Phen-DC3 inhibited SF3B2 binding to G4 in vitro. SF3B2-mediated ISG induction appeared to occur independently of RNA splicing because SF3B2 knockdown did not affect pre-mRNA splicing under the experimental conditions, and pharmacological inhibition of splicing by pladienolide B did not repress ISG induction. These observations suggest that G4 disrupts the ability of SF3B2 to induce ISGs in cancer. We propose a new mode for gene regulation, which employs G4 as an inhibitory trans-element. [ABSTRACT FROM AUTHOR]

There is no clinically available biomarker for efficiently indicating the overall survival or therapy response of gastric cancer (GC). The autoantibodies (Abs) in the sera of anti‐far‐upstream element‐binding protein‐interacting repressor‐lacking exon2 (FIRΔexon2), anti‐sorting nexin 15, and anti‐spermatogenesis and oogenesis–specific basic helix–loop–helix 1 were markedly higher in GC patients than in healthy donors (HDs). These Abs were identified by large‐scale serological identification of antigens by recombinant cDNA expression cloning screenings and their expression levels were evaluated by amplified luminescence proximity homogeneous assay. In particular, compared with age‐matched HDs, the level of anti‐FIRΔexon2 Abs in GC patients was significantly higher (P <.001). The Spearman's rank correlation analysis between anti‐FIRΔexon2 Abs and clinically available tumor markers such as carcinoembryonic antigen (CEA) was statistically insignificant, indicating that FIRΔexon2 Abs is an independent biomarker. We performed receiver‐operating curve analysis to evaluate the anti‐FIRΔexon2 Ab as a candidate biomarker with CEA and carbohydrate antigen 19‐9 (CA19‐9). The overall survival of GC patients with high anti‐FIRΔexon2 Abs titer was significantly favorable (P =.04) than that of GC patients who were below detection level of anti‐FIRΔexon2 Abs. However, clinical stages were not apparently correlated with the levels of anti‐FIRΔexon2 Ab, CEA, and CA19‐9. In conclusion, anti‐FIRΔexon2 Abs detected in GC patients is a potential biomarker for monitoring a better prognosis. Hence, anti‐FIRΔexon2 Abs is a promising biomarker for indicating better overall survival of gastric cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: Liver metastasis (LM) is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC). Here, we investigated the prognostic utility of several serum factors in mCRC patients with or without LM who were treated with anti-angiogenic agents in first-line (FL) or salvage-line (SL) settings. Methods: A combined cohort of 125 patients was analyzed in this single institute pooled analysis: FL cohort receiving bevacizumab (n = 71) and SL cohort receiving regorafenib (n = 54). Blood samples were obtained at baseline (BL) and during treatment, and serum factors were measured by ELISA. Overall survival (OS) was analyzed using Kaplan–Meier curves, the log-rank test, and Cox proportional hazard regression methods. Results: In univariate analysis of the combined cohort, right-sided CRC, primary unresected tumor, wild-type KRAS, LM, ≥ 2 metastatic sites, and SL were associated with shorter OS; in multivariable analysis, LM and SL remained significant. Serum angiopoietin-2 (Ang-2) levels ≥ 2190.3 pg/ml and interleukin (IL)-8 levels ≥ 15.1 pg/ml at BL were significantly associated with LM. Using these cut-off values, patients with higher Ang-2 or IL-8 levels at BL had shorter OS than those with lower BL levels (Ang-2: hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.47–4.51, P = 0.001; IL-8: HR 4.31, 95%CI 2.11–8.79, P < 0.001). High serum IL-8 level remained a significant predictor of shorter OS in multivariable analysis (HR 3.24, 95%CI 1.47–7.16, P = 0.004). Conclusion: Circulating IL-8 and Ang-2 levels are associated with LM in mCRC patients. IL-8 may be a prognostic marker of response to anti-angiogenic therapy, regardless of the treatment timing. [ABSTRACT FROM AUTHOR]

Macrocyclic hexaoxazoles (6OTDs) are G-quadruplex (G4) ligands, and some derivatives, such as L2H2-6OTD (1a) bearing two aminobutyl side chains, show cytotoxicity towards cancer cells. To identify the cellular target of 1a, we employed a post-target-binding strategy utilizing click reaction (Huisgen cyclization) between the azide-conjugated ligand L2H2-6OTD-Az (1b) and the cell-permeable dye CO-1 bearing a strained alkyne moiety and the BODIPY fluorophore under Cu-free conditions. We confirmed that introduction of the small azide group did not alter the physical or biological properties, including anti-cancer activity, of 1a, and we also demonstrated bias-free localization of CO-1. The post-binding visualization strategy suggested that L2H2-6OTD (1a) colocalized with RNA G4 in living cells. [ABSTRACT FROM AUTHOR]

The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5′‐TTAGGG‐3′ repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination‐based mechanism to maintain telomeres and exhibit immortality. As the most frequent non‐coding mutations in cancer, gain‐of‐function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere‐directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter‐driven oncolytic adenoviruses. Tankyrase poly(ADP‐ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt‐driven cancer. Meanwhile, telomeric nucleic acids form a higher‐order structure called a G‐quadruplex (G4). G4s are formed genome‐wide and their dynamics affect various events, including replication, transcription, and translation. G4‐stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs. [ABSTRACT FROM AUTHOR]

Background: The objective of the present study was to verify the speed and accuracy of fetal ultrasonic Doppler (fetal Doppler) in measuring heart rate of newborns at rest, including preterm, low‐birthweight infants, and its efficacy during neonatal resuscitation, including cases of neonatal asphyxia. Methods: A three‐lead electrocardiogram and fetal Doppler were used to measure resting heart rates in 100 newborns, including 48 preterm, low‐birthweight infants, at 0 to 72 h after birth. Times to display heart rate were compared between electrocardiogram and fetal Doppler by the Bland–Altman analysis and Wilcoxon signed‐rank test. The time required for the fetal Doppler to measure heart rate during neonatal resuscitation was also assessed. Results: In 100 newborns, the mean error of the resting heart rate in 1,293 measurement points was 0.07 beats/min. To display the heart rate, the fetal Doppler required a median time of 5 s, and electrocardiogram required a median time of 10 s (P < 0.001). During neonatal resuscitation, the heart rate was measured within 10 s in 18 of 21 cases (86%) and displayed with a median time of 5 s; this was measured in all neonatal asphyxia cases (9/9, 100%). Conclusions: Fetal Doppler can measure heart rate in newborns accurately and rapidly and is useful for evaluating heart rate not only at rest but also during neonatal resuscitation, especially in asphyxia. [ABSTRACT FROM AUTHOR]

Tumors consist of heterogeneous cell populations that contain cancer cell subpopulations with anticancer drug‐resistant properties called "persister" cells. While this early‐phase drug tolerance is known to be related to the stem cell‐like characteristic of persister cells, how the stem cell‐related pathways contribute to drug resistance has remained elusive. Here, we conducted a single‐cell analysis based on the stem cell lineage‐related and gastric cell lineage‐related gene expression in patient‐derived gastric cancer cell models. The analyses revealed that 5‐fluorouracil (5‐FU) induces a dynamic change in the cell heterogeneity. In particular, cells highly expressing stem cell‐related genes were enriched in the residual cancer cells after 5‐FU treatment. Subsequent functional screening identified aldehyde dehydrogenase 1A3 (ALDH1A3) as a specific marker and potential therapeutic target of persister cells. ALDH1A3 was selectively overexpressed among the ALDH isozymes after treatment with 5‐FU or SN38, a DNA topoisomerase I inhibitor. Attenuation of ALDH1A3 expression by RNA interference significantly suppressed cell proliferation, reduced the number of persister cells after anticancer drug treatment and interfered with tumor growth in a mouse xenograft model. Mechanistically, ALDH1A3 depletion affected gene expression of the mammalian target of rapamycin (mTOR) cell survival pathway, which coincided with a decrease in the activating phosphorylation of S6 kinase. Temsirolimus, an mTOR inhibitor, reduced the number of 5FU‐tolerant persister cells. High ALDH1A3 expression correlated with worse prognosis of gastric cancer patients. These observations indicate that the ALDH1A3‐mTOR axis could be a novel therapeutic target to eradicate drug‐tolerant gastric cancer cells. [ABSTRACT FROM AUTHOR]

Regorafenib has improved the survival of patients with refractory metastatic colorectal cancer (mCRC), yet the mechanisms of inherited or acquired resistance are not well understood. A total of 50 patients with refractory mCRC were enrolled. Circulating tumor cell (CTC) enumeration was carried out at baseline, day 21 after initiation of regorafenib, and at the time of progression of disease (PD) using the CellSearch System (Veridex LLC, NJ, USA). Poly(A) mRNA was extracted from CTCs, and gene expression of epithelial and epithelial‐mesenchymal transition markers was analyzed by a multiplex‐PCR based DNA Chip. Patients with fewer than 3 CTCs at baseline and day 21 had a longer progression‐free survival than those with 3 or more CTCs (3.3 vs 2.0 months, P =.008 and 3.3 vs 2.0 months, P =.004, respectively). Patients with fewer than 3 CTCs at baseline and day 21 had a longer overall survival (OS) than those with 3 or more CTCs (10.0 vs 4.6 months, P <.001 and 8.7 vs 3.8 months, P =.003, respectively). In multivariable analysis, CTC counts remained significantly associated with OS at baseline and day 21 (P =.019 and P =.028). Circulating tumor cell EGFR gene expression was upregulated at day 21 and/or PD in 64% of patients. Patients had significantly increased EGFR expression at PD compared to baseline (P =.041) and at day 21 and/or PD compared to baseline (P =.004). Our findings suggest that CTC count and EGFR expression could be useful markers of regorafenib efficacy and outcomes. Upregulation of CTC EGFR expression might be a molecular escape mechanism under regorafenib therapy. [ABSTRACT FROM AUTHOR]

Summary: Background The effectiveness of reintroducing oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a phase II study (RE-OPEN). We conducted a phase I study to determine the maximum tolerated dose of oxaliplatin plus trifluridine/tipiracil (FTD/TPI) in patients with refractory mCRC. Patients and Methods Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m2) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m2 twice daily (bid) on days 1–5 and 15–19 every 4 weeks were investigated in patients with refractory mCRC using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study. Results Twelve patients were enrolled in the study. Three of six patients in the oxaliplatin 85 mg/m2 cohort had dose-limiting toxicities (DLTs) with treatment delays during the second cycle at ≥8 days due to grade ≥ 2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. Grade ≥ 3 AEs were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1), and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin or severe peripheral sensory neuropathy. Conclusions A combination of FTD/TPI 35 mg/m2 bid on days 1–5 and 15–19 and oxaliplatin 85 mg/m2 on days 1 and 15 every 4 weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC. [ABSTRACT FROM AUTHOR]

Although the detection of circulating tumor cells (CTCs) should be crucial for future personalized medicine, no efficient and flexible methods have been established. The current study established a polymeric custom-made chip for capturing CTCs with a high efficiency and flexibility. As an example of clinical application, the effects of self-expandable metallic stent (SEMS) placement on the release of cancer cells into the blood of patients with colorectal cancer and bowel obstruction were analyzed. This was assessed as the placement of SEMS may cause mechanical damage and physical force to malignant tissue, increasing the risk of cancer cell release into the bloodstream. The present study examined the number of CTCs using a custom-made chip, before, at 24 h after and at 4 days after SEMS placement in patients with colorectal cancer. The results revealed that, among the 13 patients examined, the number of CTCs was increased in three cases at 24 h after SEMS placement. However, this increase was temporary. The number of CTCs also decreased at 4 days after stent placement in most cases. The CTC chip of the current study detected the number of CD133-positive cancer stem-like cells, which did not change, even in the patient whose total number of CTCs temporarily increased. The results indicated that this custom-made microfluid system can efficiently and flexibly detect CTCs, demonstrating its potential for obtaining information during the management of patients with cancer. [ABSTRACT FROM AUTHOR]

Background: Tumours consist of heterogeneous cancer cells and are likely to contain drug-tolerant cell subpopulations, causing early relapse. However, treatment strategies to eliminate these cells have not been established.Methods: We established gastric cancer patient-derived cells (PDCs) to examine the contribution of CD44 splicing variant 9 (CD44v9)-positive cells in gastric cancer drug tolerance. We performed gene expression signature-based in silico screening using JFCR_LinCAGE, our anticancer compound gene expression database and subsequent validation in BALB/c-nu/nu mouse xenograft to identify agents targeting the drug-tolerant cancer cells.Results: CD44v9-positive cancer cells were enriched among residual cancer cells after treatment with SN-38, an active metabolic of irinotecan. CD44v9 protein was responsible for this drug resistance. We identified epidermal growth factor receptor (EGFR) inhibitors as agents that can target CD44v9-positive cell populations in gastric cancer PDCs. CD44v9 promoted cell proliferation, and EGFR inhibition attenuated CD44v9 protein expression through downregulation of the AKT and the ERK signalling pathways, leading to preferential suppression of CD44v9-positive cells. Importantly, EGFR inhibitors significantly reduced the number of residual cancer cells after cytotoxic anticancer drug treatment and enhanced the antitumor effect of irinotecan in vivo.Conclusions: EGFR inhibitors could be potential agents to eradicate cytotoxic anticancer drug-tolerant gastric cancer cell populations. [ABSTRACT FROM AUTHOR]

Purpose: The 14th Japan–Korea joint symposium on cancer and aging research was held at an auditorium of Saga University, Japan, May 31–Jun 2, 2018. Participants presented 31 oral and 21 poster presentations, two lectures at a luncheon seminar, plus special lectures from two Korean Emeritus Professors and founders of our joint symposia. The essential parts of the lectures are reviewed here. Results: This Symposium was called Japan–Korea, because the host country comes first. Our symposia are organized every 18 months and the program includes keynote and plenary lectures, and oral and poster presentations. (1) Subjects related to cancer development at this symposium were: prostate cancer progression, molecules activating GSK3β, suppressing the activation of cancer stem cells, profiling human B cell receptor repertoires, and hereditary gastrointestinal cancer syndrome. (2) Subjects related to treatment were: G-quadruplex ligands for glioma stem cells, tankyrase inhibitor for colorectal cancer, and eradication of ATL. (3) Cancer prevention subjects were: physical adsorption of EGCG to cell membrane, inhibition of immune evasion of cancer cells with EGCG, and prevention with antidiabetic agents. (4) Aging subjects were life span extension with Toll-like receptor 5 vaccine and reversal of senescence with inhibitors of ATM and ROCK. (5) The results of epidemiology focused on aldehyde dehyrogenase-2 and alcohol consumption. Conclusion: The 14th symposium demonstrated the cutting-edge of presentations with discussion of numerous ideas by the participants. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate cholesterol and triglyceride levels in the chylomicron fraction of preterm infants at birth and during the early postnatal period. Methods: The subjects consisted of 133 infants (81 boys and 52 girls): 74 were term infants born at 37–41 weeks of gestation and 59 were preterm infants born at 29–36 weeks of gestation. Cholesterol and triglyceride in the chylomicron fraction were measured using high‐performance liquid chromatography. Results: Compared with term infants, preterm infants had higher cholesterol and lower triglyceride in the chylomicron fraction, both in cord blood and at 1 month after birth. Thus, the chylomicron triglyceride/cholesterol ratio was significantly lower in preterm infants than in term infants in cord blood and at 1 month of age. On single regression analysis the chylomicron triglyceride/cholesterol ratio correlated positively with gestational age at birth (r = 0.331, P = 0.0003) and at 1 month (r = 0.221, P = 0.0119). Conclusions: Preterm infants have a less‐lipidated chylomicron composition at birth and at 1 month of age. Some prenatal factors may persist to influence chylomicron lipidation during the early postnatal period. [ABSTRACT FROM AUTHOR]

Flexible sensors, ion concentration, perspiration rate, wearable sensors, wireless systems Physiological response and rhythm of sweat electrolyte and sweat rate are successfully monitored under long-time sweating conditions, which can be only realized by continuous monitoring of trend changes of sweat. Keywords: flexible sensors; ion concentration; perspiration rate; wearable sensors; wireless systems EN flexible sensors ion concentration perspiration rate wearable sensors wireless systems 1 1 1 10/30/23 20231025 NES 231025 B Perspiration-Rate Sensor System b In article number 2306516, Kuniharu Takei and co-workers develop a wireless flexible and wearable sweat sensor patch by integrating sweat rate and electrolyte impedance sensors with long-time continuous measurement functions. [Extracted from the article]