Impact of Hepatitis B Surface and Core Antibody Levels on Hepatitis B Virus Reactivation.

Hepatitis B virus reactivation (HBV-R) is a serious complication that can occur in patients with resolved HBV infection during cancer chemotherapy. We examined the levels of HBV surface antibody (HBsAb) and HBV core antibody (HBcAb) to assess the incidence of HBV-R in cancer patients including hematopoietic stem cell transplantation (HSCT) and rituximab administration. This retrospective cohort study included 590 patients with resolved HBV infection. The incidence of HBV-R was evaluated 761.5 (range, 90-3898) days after the inititiation of chemotherapy. Of the patients, 13 (2.2%) developed HBV-R after the start of chemotherapy. All 13 patients exhibited lower HBsAb (<100 mIU/mL) levels at baseline. A higher level of HBcAb (≥100 cut off index (C.O.I.)) was a possible risk factor for HBV-R as well as HSCT and rituximab administration. The simultaneous presence of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I. increased the risk of HBV-R by 18.5%. Patients treated with rituximab were at a higher risk of HBV-R (18.4%) despite having HBcAb <100 C.O.I. Our results suggest that assessment of HBsAb and HBcAb levels prior to the chemotherapy is important for identifying patients at high risk of HBV-R, especially in solid cancers without HSCT and rituximab administration.

Evaluation of mycophenolic acid exposure in a patient with immune-related hepatotoxicity caused by nivolumab and ipilimumab therapy for malignant melanoma: a case report.

BACKGROUND: Guidelines such as the National Comprehensive Cancer Network recommend mycophenolate mofetil (MMF) for the treatment of severe steroid-refractory immune-related hepatotoxicity. Mycophenolic acid (MPA) is an active form of MMF that suppresses T- and B-lymphocyte proliferation and immune-related adverse events caused by immune checkpoint inhibitors. MPA has a narrow therapeutic range (37-70 µg·h/mL) and overexposure increases the risk of leukopenia in transplantation. However, the optimal use of MMF in oncology has not yet been established; thus, monitoring plasma MPA concentrations is necessary to avoid excessive immunosuppression in oncology practice. CASE PRESENTATION: We evaluated plasma MPA concentration in a 75-year-old man with immune-related hepatotoxicity following nivolumab and ipilimumab combination therapy for malignant melanoma. The patient developed severe hepatotoxicity after immunotherapy, and immunosuppressant therapy with corticosteroids was initiated. The patient then developed steroid-refractory immune-related hepatotoxicity; therefore, MMF (1,000 mg twice daily) was co-administered. Seven days after the administration of MMF, the plasma MPA concentration was measured using an enzyme multiplied immunoassay technique. The area under the plasma concentration-time curve for MPA from 0 to 12 h was 41.0 µg·h/mL, and the same dose of MMF was continued. Grade 2 lymphocytopenia, which could be attributed to MMF, was observed during the administration period. Unfortunately, the patient was infected with SARS-CoV-2 and died from respiratory failure. CONCLUSION: Our patient did not exceed the upper limit of MPA levels as an index of the onset of side effects of kidney transplantation and achieved rapid improvement in liver function. Prompt initiation of MMF after assessment of the steroid effect leads to adequate MPA exposure. Therapeutic drug monitoring should be considered when MMF is administered, to avoid overexposure.

Effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers: a population pharmacokinetic analysis.

PURPOSE: Considerable amounts of injected immunoglobulin G-based therapeutic monoclonal antibodies, such as ramucirumab, are distributed into ascites. This study aimed to examine the effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers. METHODS: Population pharmacokinetic analysis of ramucirumab was performed using data on serum ramucirumab concentrations of 52 patients with gastrointestinal cancers, including 8 patients with massive ascites. The Bayesian method using the final population pharmacokinetic model was utilized to estimate trough ramucirumab concentrations after the first dose and at steady state. RESULTS: Population pharmacokinetic analysis revealed that massive ascites as well as body weight were influencing factors for ramucirumab clearance. The estimated ramucirumab clearance was significantly higher in patients with massive ascites than in those with no/mild ascites (0.020 ± 0.004 versus 0.013 ± 0.004 L/h, P < 0.001). The estimated trough ramucirumab concentrations were significantly lower in patients with massive ascites than in those with no/mild ascites after the first dose (26.4 ± 6.8 versus 36.1 ± 7.1 µg/mL, P < 0.001) and at steady state (41.4 ± 16.3 versus 65.9 ± 18.0 µg/mL, P < 0.001). CONCLUSION: In the present study, the presence of massive ascites affected the pharmacokinetics of ramucirumab in patients with gastrointestinal cancers. Our results suggest that dose optimization of ramucirumab may be necessary in patients with massive ascites due to higher ramucirumab clearance.

Transformation process of ice crystallized from a glassy dilute trehalose aqueous solution.

Metastable forms of ice and their crystal growth play an important role in meteorology, cryobiology, and planetary science. However, it is difficult to investigate the effects of solute on the crystal growth of ice in a dilute aqueous solution due to the segregation. Herein, we made a non-segregated glass of dilute trehalose aqueous solution (0.023 mole fraction) and examined the transformation of crystalline ice in the aqueous solution with increasing temperature using powder X-ray diffraction measurements. The ice formed immediately after the crystallization is nano-sized stacking disordered ice (ice Isd) with few stacking faults and has high cubicity. The crystal growth of ice Isd in the trehalose aqueous solution was remarkably slower than those of ice Isd in a glycerol aqueous solution and pure ice Isd. The ice Isd survived up to ∼230 K which is higher than the transformation temperature from ice Isd to hexagonal ice (ice Ih) of pure water (∼200 K). The existence of trehalose inhibits the crystal growth of ice Isd and, as a result, the ice sublimates easily under vacuum conditions. Moreover, the occurrence of macroscopic segregation at ∼245 K is related to the Isd-to-Ih transformation. These results are important for the improvement of thawing techniques for cryopreserved biological tissues and for the understanding of the mechanism of ice cloud formation in the Earth's atmosphere.

Distribution of therapeutic monoclonal antibodies into ascites in advanced gastric cancer patients with peritoneal metastasis: case reports and literature review.

BACKGROUND: Therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are used to treat advanced gastric cancer (AGC). Malignant ascites is often accompanied by peritoneal metastasis in AGC patients. However, the distribution of therapeutic monoclonal antibodies into ascites has yet to be adequately investigated. METHODS: We determined serum and ascites concentrations of ramucirumab or nivolumab and total IgG in three AGC patients with massive ascites. When serum and ascites samples were obtained on the same day, the ascites-to-serum ratio (A/S ratio) of the concentration of monoclonal antibodies was evaluated. The relationship between time after last infusion and the A/S ratio of therapeutic monoclonal antibodies was examined using 15 datasets from the present study and the literature. RESULTS: Ramucirumab and nivolumab were detected in massive ascites at considerable amounts (A/S ratios of 0.24-0.35 for ramucirumab and 0.17-0.55 for nivolumab). A positive correlation was detected between the A/S ratios of the therapeutic monoclonal antibodies and the time after last infusion (r = 0.747). Removal of ascites using paracentesis eliminated at least 15.3%-30.3% and 5.2-27.4% of the injected ramucirumab and nivolumab, respectively. Endogenous IgG, as well as therapeutic monoclonal antibodies, were distributed into ascites; the A/S ratios for IgG were 0.22-0.45. CONCLUSION: Our results suggest that therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are distributed into massive ascites in AGC patients concomitantly with endogenous IgG. In these patients, retention of ascites and its removal may result in decreased systemic drug exposure to ramucirumab and nivolumab.

Stochastic Resonance in Organic Electronic Devices.

Stochastic Resonance (SR) is a phenomenon in which noise improves the performance of a system. With the addition of noise, a weak input signal to a nonlinear system, which may exceed its threshold, is transformed into an output signal. In the other words, noise-driven signal transfer is achieved. SR has been observed in nonlinear response systems, such as biological and artificial systems, and this review will focus mainly on examples of previous studies of mathematical models and experimental realization of SR using poly(hexylthiophene)-based organic field-effect transistors (OFETs). This phenomenon may contribute to signal processing with low energy consumption. However, the generation of SR requires a noise source. Therefore, the focus is on OFETs using materials such as organic materials with unstable electrical properties and critical elements due to unidirectional signal transmission, such as neural synapses. It has been reported that SR can be observed in OFETs by application of external noise. However, SR does not occur under conditions where the input signal exceeds the OFET threshold without external noise. Here, we present an example of a study that analyzes the behavior of SR in OFET systems and explain how SR can be made observable. At the same time, the role of internal noise in OFETs will be explained.

Direct observation of reversible liquid-liquid transition in a trehalose aqueous solution.

Water forms two glassy waters, low-density and high-density amorphs, which undergo a reversible polyamorphic transition with the change in pressure. The two glassy waters transform into the different liquids, low-density liquid (LDL) and high-density liquid (HDL), at high temperatures. It is predicted that the two liquid waters also undergo a liquid-liquid transition (LLT). However, the reversible LLT, particularly the LDL-to-HDL transition, has not been observed directly due to rapid crystallization. Here, I prepared a glassy dilute trehalose aqueous solution (0.020 molar fraction) without segregation and measured the isothermal volume change at 0.01 to 1.00 GPa below 160 K. The polyamorphic transition and the glass-to-liquid transition for the high-density and low-density solutions were examined, and the liquid region where both LDL and HDL existed was determined. The results show that the reversible polyamorphic transition induced by the pressure change above 140 K is the LLT. That is, the transition from LDL to HDL is observed. Moreover, the pressure hysteresis of LLT suggests strongly that the LLT has a first-order nature. The direct observation of the reversible LLT in the trehalose aqueous solution has implications for understanding not only the liquid-liquid critical point hypothesis of pure water but also the relation between aqueous solution and water polyamorphism.

Drug-Drug Interaction between Tacrolimus and Vonoprazan in Kidney Transplant Recipients.

Kidney transplant recipients with tacrolimus-based immunosuppressive therapy are often treated with proton-pump inhibitors (PPIs) to prevent gastric ulcer complications. Vonoprazan, a potassium-competitive acid blocker, is a novel PPI possessing different metabolic pathways from conventional PPIs (e.g., omeprazole, lansoprazole and rabeprazole). However, no data are available on the change in blood concentration of tacrolimus after switching rabeprazole, a conventional PPI, to vonoprazan coadministration in the initial period of post-transplantation. This is a retrospective study of 18 kidney transplant recipients. The blood concentration and the concentration to dose (C/D) ratio of tacrolimus were compared before and after switching from rabeprazole to vonoprazan. Impacts of CYP2C19 and CYP3A5 genetic polymorphisms on the drug-drug interaction were also examined. The median (range) trough concentration of tacrolimus was significantly increased from 5.2 (3.6-7.4) to 8.1 (6.1-11.7) ng/mL (p < 0.0005) after switching from rabeprazole to vonoprazan. The C/D ratio of tacrolimus was also significantly increased from 38.1 (16.5-138.1) to 48.9 (26.2-207.2) (p < 0.0005). The percent changes of tacrolimus concentrations and C/D were 65.8% and 41.8%, respectively. CYP2C19 and CYP3A5 genetic polymorphisms did not affect the change in concentration and C/D ratio of tacrolimus. The present study indicates that vonoprazan coadministration increases the tacrolimus concentration regardless of CYP2C19 or CYP3A5 genetic polymorphisms. Thus, frequent monitoring of blood tacrolimus concentration is required when vonoprazan is introduced as an intensive gastric acid blocker in the early phase of post-transplantation.

3,5,7,3',4'-Pentamethoxyflavone Enhances the Barrier Function through Transcriptional Regulation of the Tight Junction in Human Intestinal Caco-2 Cells.

The intestinal tight junction (TJ) barrier plays a pivotal role in the regulation of intestinal homeostasis. This study investigated the effects of 3,5,7,3',4'-pentamethoxyflavone (PMF), a major polymethoxyflavone found in black ginger, on TJ barrier regulation using intestinal Caco-2 cells. PMF treatment enhanced the TJ barrier integrity in Caco-2 cells, indicated by increased transepithelial electrical resistance (control, 1261 ± 36 Ω·cm2; 100 µM PMF, 1383 ± 55 Ω·cm2 at 48 h, p < 0.05) and decreased permeability to fluorescein-conjugated dextran (control, 24.2 ± 1.8 pmol/(cm2 × h); 100 µM PMF, 18.6 ± 1.0 pmol/(cm2 × h), p < 0.05). Immunoblot analysis revealed that PMF increased the cytoskeletal association and cellular expression of the TJ proteins, zonula occludens-1, claudin-3, and claudin-4 (e.g., occludin; control, 1.00 ± 0.2; 100 µM PMF, 3.69 ± 0.86 at 48 h, p < 0.05). Quantitative reverse transcriptase-polymerase chain reaction analysis and a luciferase promoter assay showed that PMF enhanced the transcription of occludin, claudin-3, and claudin-4. The promoter assay with site-directed mutagenesis indicated that PMF-induced occludin and claudin-3 transcription was mediated by transcription factors, KLF5 and EGR1, respectively, while PMF activated claudin-4 transcription through GATA1 and AP1. Taken together, the transcriptional regulation of TJ proteins is involved in PMF-mediated promotion of the intestinal barrier in vitro.

Slow Crystal Growth of Cubic Ice with Stacking Faults in a Glassy Dilute Glycerol Aqueous Solution.

Control of ice formation is an important issue as catastrophic ice growth influences our life activities and many industrial systems. We prepared a homogeneous glass of a dilute glycerol aqueous solution by a pressure liquid cooling vitrification method and examined the effect of solute on the ice formation of solvent water using a powder X-ray diffraction method. The solvent water immediately after the crystallization is composed of nanosized pure cubic ice (ice Ic). The crystal growth of ice Ic with stacking faults is much slower than that of pure water. The presence of glycerol molecules dispersing homogeneously may hinder crystal growth. The macroscopic segregation occurs rapidly during the transformation from stacking disordered ice to hexagonal ice. The results suggest that ice formation can be controlled by changing the solute type and concentration. This study has implications for thawing technology in cryobiology and frozen food engineering.

Non-segregated crystalline state of dilute glycerol aqueous solution.

When a dilute aqueous solution freezes at 1 atm, it is segregated into water-rich ice Ih and solute-rich freeze-concentrated glassy solution. A similar segregation is observed at the crystallization of homogeneous glassy aqueous solutions by heating. The influence of solutes on the nucleation of solvent water and the solute discharge process from the crystalline ice are not clear. In this study, I made a homogeneous dilute glassy glycerol aqueous solution (0.07 mol fraction) using pressure liquid cooling vitrification (PLCV), measured the specific volume and the sample temperature during the compression and decompression processes, and examined the polyamorphic and crystallization behaviors. It is found that the sample crystallized slightly above the crystallization temperature is amorphized homogeneously under pressure, and that the amorphized sample is equivalent to the homogeneous glassy sample made by PLCV. This indicates that glycerol solutes in the crystalline sample are dispersed homogeneously and the crystalline sample does not segregate. These experimental results suggest that nucleation does not involve segregation and that crystal growth induces segregation. The discovery of the non-segregated crystalline state has an implication in not only the understanding of crystallization of glassy ice in meteorology and planetary physics but also the application to cell thawing techniques in cryobiology and food engineering.

Effect of OH groups on the polyamorphic transition of polyol aqueous solutions.

Polyamorphic transition in water is expected to occur at low temperatures and high pressures. Recently, the polyamorphic transitions of polyol aqueous solutions were examined under pressure at low temperatures, and the location of their liquid-liquid critical points was estimated experimentally. The addition of polyol solute in water induces the shift of polyamorphic transition pressure toward the lower pressure side. Here, by comparing the polyamorphic transition of various polyol aqueous solutions, especially by comparing those of dilute 1,2-propanediol and dilute 1,3-propanediol aqueous solutions, it is clarified that the OH-groups in the polyol molecule efficiently affect the polyamorphic behavior of solvent water. This suggests that the hydrogen bonding interaction between solvent water and polyol solute relates closely to the polyamorphic behavior of solvent water such as the stabilization of high-density-amorph-like solvent water induced by the presence of polyol solute. In addition, the effect of CH3 groups in the 1,2-propanediol molecule seems to be opposite to the effect of OH groups. These results have important implications for the understandings of low-temperature phenomena of aqueous solutions, for example, hydration, segregation, phase separation, folding/unfolding of macromolecules, glass forming, and nucleation of crystalline ice Ih.

Experimental estimation of the location of liquid-liquid critical point for polyol aqueous solutions.

To solve a mystery of low-temperature liquid water, a liquid-liquid critical point (LLCP) hypothesis that the two kinds of waters, low-density and high-density liquids (LDL and HDL), and a critical point relating to the two waters exist is thought to be the most realistic idea. However, there is no conclusive evidence showing the existence of LLCP. I measured the polyamorphic volume changes of the glassy dilute polyol (ethylene glycol, glycerol, meso-erythritol, xylitol, and D-sorbitol) aqueous solutions during the compression and decompression processes and estimated the location of LLCP for the polyol aqueous solution by a new analysis of the concentration dependence of polyamorphic transition. The LLCP of glycerol aqueous solution around 150 K is estimated to be around 0.045 GPa and around 0.135 molar fraction. This indicates that the solvent water in the glycerol aqueous solution at 1 atm changes continuously from the LDL-like state to the HDL-like state with the increase of solute concentration. The concentration region in which the crossover between LDL-like solvent water and HDL-like solvent water occurs is located near the region that the liquid-liquid transition line is extended to the concentration axis at 1 atm. Moreover, the formation of LDL-like solvent water relates deeply to the homogeneous nucleation of ice Ih in the polyol aqueous solution. This conclusion shows that the LLCP hypothesis of water has an important implication for understanding the dynamics of aqueous solution such as solubility, hydration, segregation, aggregation of solute, nucleation of ice Ih, glass formation, glass transition, and so on.

Robust thresholdlike effect of internal noise on stochastic resonance in an organic field-effect transistor.

The application of noise to a nonlinear system can have the effect of increasing the signal transmission of the system through the phenomenon of stochastic resonance (SR). This paper presents an analytical characterization of the dependence of the signal transmission performance of an organic field-effect transistor (OFET) on external noise. Similarly to the threshold of a nonlinear system, the additive internal noise of the system can be used to control the emergence of SR. Internal noise or the addition of random numbers to the system enables one to observe the SR phenomenon in an OFET under an intrinsically nonresonant condition. Internal noise plays a thresholdlike role, but it functions in a different manner. The fluctuations in performance due to external noise become smaller when the effect of internal noise becomes dominant compared with that of the threshold. In conclusion, it is found that internal noise plays a robust thresholdlike role with respect to variations in external noise intensity.

Effect of solute nature on the polyamorphic transition in glassy polyol aqueous solutions.

I examined the polyamorphic behavior of glassy dilute aqueous solutions of polyols (ethylene glycol, glycerol, meso-erythritol, xylitol, and D-sorbitol) under pressure at low temperatures. Although the volume change of the glassy aqueous solution varied continuously against pressure, the rate of the volume change appeared to vary discontinuously at the onset pressure of the gradual polyamorphic transition. It is thought that low-density liquid-like solvent water and high-density liquid-like solvent water coexist during the transition. Moreover, the existence of a solute induces the shift of polyamorphic transition to the lower-pressure side. The effect of a solute on the polyamorphic transition becomes larger in the order ethylene glycol, glycerol, meso-erythritol, xylitol, and D-sorbitol. Therefore, the solute can become a variable controlling the polyamorphic state of liquid water. This experimental result suggests that the metastable-equilibrium phase boundary between the low-density and the high-density amorphs for pure water is likely to be located at 0.22-0.23 GPa at about 150 K, which is slightly larger than the previously estimated pressure. Moreover, the solute-nature dependence on the polyamorphic transition seems to connect to that on the homogeneous nucleation temperature of polyol aqueous solution at ambient pressure. The region in which a low-density liquid appears coincides with the region in which the nucleus of ice Ih appears, suggesting that the formation of a low-density liquid is a precursory phenomenon of the nucleation of ice Ih.

A Simple High-Performance Liquid Chromatography for Determining Lapatinib and Erlotinib in Human Plasma.

BACKGROUND: Lapatinib and erlotinib are used for cancer treatment, showing large interindividual variability. Therapeutic drug monitoring may be useful for assessing the clinical outcomes and adverse events. A simple high-performance liquid chromatography UV method was developed for the determination of lapatinib and erlotinib in human plasma. METHODS: An aliquot of plasma sample spiked with internal standard was treated with acetonitrile to precipitate the proteins. Lapatinib and erlotinib were separated on an octadecylsilyl silica gel column using a mobile phase consisting of acetonitrile, methanol, water, and trifluoroacetic acid (26:26:48:0.1) pumped at a flow rate of 1.0 mL/min. The detection wavelength was set at 316 nm. RESULTS: The calibration curves for lapatinib and erlotinib were linear (r = 0.9999) in the range of 0.125-8.00 mcg/mL. The extraction recoveries for both lapatinib and erlotinib at the plasma concentration of 0.125-8.00 mcg/mL were higher than 89.9% with coefficients of variation less than 3.5%. The coefficients of variation for intraday and interday assays of lapatinib and erlotinib were less than 5.1% and 6.1%, respectively. CONCLUSIONS: The present method can be used for blood concentration monitoring for lapatinib or erlotinib in exactly the same conditions.

Effect of water polyamorphism on the molecular vibrations of glycerol in its glassy aqueous solutions.

A glassy dilute glycerol-water solution undergoes a mutual polyamorphic transition relating to the transition between high- and low-density amorphous ices of solvent water. The polyamorphic transition behavior depends on the glycerol concentration, indicating that the glycerol affects the water polyamorphism. Here, we used the glassy dilute glycerol-water solution of the solute molar fraction of 0.07 and examined the effect of the polyamorphic change in solvent water on the molecular vibrations of glycerol via Raman spectroscopy. It is found that the molecular vibration of glycerol in high-density liquid like solvent water is different from that in the low-density liquid like solvent water and that the change in the molecular vibration of glycerol is synchronized with the polyamorphic transition of solvent water. The dynamical change of the solute molecule relates to the polyamorphic state of solvent water. This result suggests that the polyamorphic fluctuation of water structure emanated from the presumed liquid-liquid critical point plays an important role for the function of aqueous solution under an ambient condition such as the conformational stability of solute, the functional expression of solute, and so on.

Nuclear DNA damage-triggered NLRP3 inflammasome activation promotes UVB-induced inflammatory responses in human keratinocytes.

Ultraviolet (UV) radiation in sunlight can result in DNA damage and an inflammatory reaction of the skin commonly known as sunburn, which in turn can lead to cutaneous tissue disorders. However, little has been known about how UV-induced DNA damage mediates the release of inflammatory mediators from keratinocytes. Here, we show that UVB radiation intensity-dependently increases NLRP3 gene expression and IL-1ß production in human keratinocytes. Knockdown of NLRP3 with siRNA suppresses UVB-induced production of not only IL-1ß, but also other inflammatory mediators, including IL-1α, IL-6, TNF-α, and PGE2. In addition, inhibition of DNA damage repair by knockdown of XPA, which is a major component of the nucleotide excision repair system, causes accumulation of cyclobutane pyrimidine dimer (CPD) and activation of NLRP3 inflammasome. In vivo immunofluorescence analysis confirmed that NLRP3 expression is also elevated in UV-irradiated human epidermis. Overall, our findings indicate that UVB-induced DNA damage initiates NLRP3 inflammasome activation, leading to release of various inflammatory mediators from human keratinocytes.