Non-improvement of atrophic gastritis in cases of gastric cancer after successful Helicobacter pylori eradication therapy.

BACKGROUND: Helicobacter pylori (H. pylori) infection is closely related to the development of gastric cancer (GC). However, GC can develop even after H. pylori eradication. Therefore, it would be extremely useful if GC could be predicted after eradication. The Kyoto classification score for gastritis (GA) is closely related to cancer risk. However, how the score for GC changes after eradication before onset is not well understood. AIM: To investigate the characteristics of the progression of Kyoto classification scores for GC after H. pylori eradication. METHODS: Eradication of H. pylori was confirmed in all patients using either the urea breath test or the stool antigen test. The Kyoto classification score of GC patients was evaluated by endoscopy at the time of event onset and three years earlier. In addition, the modified atrophy score was evaluated and compared between the GC group and the control GA group. RESULTS: In total, 30 cases of early GC and 30 cases of chronic GA were evaluated. The pathology of the cancer cases was differentiated adenocarcinoma, except for one case of undifferentiated adenocarcinoma. The total score of the Kyoto classification was significantly higher in the GC group both at the time of cancer onset and three years earlier (4.97 vs 3.73, P = 0.0034; 4.2 vs 3.1, P = 0.0035, respectively). The modified atrophy score was significantly higher in the GC group both at the time of cancer onset and three years earlier and was significantly improved only in the GA group (5.3 vs 5.3, P = 0.5; 3.73 vs 3.1, P = 0.0475, respectively). CONCLUSION: The course of the modified atrophy score is useful for predicting the onset of GC after eradication. Patients with severe atrophy after H. pylori eradication require careful monitoring.

Anserine, a Histidine-Containing Dipeptide, Suppresses Pressure Overload-Induced Systolic Dysfunction by Inhibiting Histone Acetyltransferase Activity of p300 in Mice.

Anserine, an imidazole dipeptide, is present in the muscles of birds and fish and has various bioactivities, such as anti-inflammatory and anti-fatigue effects. However, the effect of anserine on the development of heart failure remains unknown. We cultured primary cardiomyocytes with 0.03 mM to 10 mM anserine and stimulated them with phenylephrine for 48 h. Anserine significantly suppressed the phenylephrine-induced increases in cardiomyocyte hypertrophy, ANF and BNP mRNA levels, and histone H3K9 acetylation. An in vitro histone acetyltransferase (HAT) assay showed that anserine directly suppressed p300-HAT activity with an IC50 of 1.87 mM. Subsequently, 8-week-old male C57BL/6J mice were subjected to transverse aortic constriction (TAC) and were randomly assigned to receive daily oral treatment with anserine-containing material, Marine Active® (60 or 200 mg/kg anserine) or vehicle for 8 weeks. Echocardiography revealed that anserine 200 mg/kg significantly prevented the TAC-induced increase in left ventricular posterior wall thickness and the decrease in left ventricular fractional shortening. Moreover, anserine significantly suppressed the TAC-induced acetylation of histone H3K9. These results indicate that anserine suppresses TAC-induced systolic dysfunction, at least in part, by inhibiting p300-HAT activity. Anserine may be used as a pharmacological agent for human heart failure therapy.

Elucidating the binding properties of methemoglobin in red blood cell to cyanide, hydrosulfide, and azide ions using artificial red blood cell.

Methemoglobin (metHb), the oxidized form of hemoglobin, lacks the ability of reversible oxygen binding; however, it has a high binding affinity to toxic substances such as cyanide, hydrosulfide, and azide. This innate property of metHb offers the clinical option to treat patients poisoned with these toxins, by oxidizing the endogenous hemoglobin in the red blood cells (RBCs). The binding properties of naked metHb (isolated from RBC) with these toxins has been studied; however, the binding behaviors of metHb under the intracellular conditions of RBC are unclear because of the difficulty in detecting metHb status changes in RBC. This study aimed to elucidate the binding properties of metHb in RBC under physiological and poisoned conditions using artificial RBC, which was hemoglobin encapsulated in a liposome. The mimic-circumstances of metHb in RBC (metHb-V) was prepared by oxidizing the hemoglobin in artificial RBC. Spectroscopic analysis indicated that the metHb in metHb-V exhibited a binding behavior different from that of naked metHb, depending on the toxic substance: When the pH decreased, (i) the cyanide binding affinity of metHb-V remained unchanged, but that of naked metHb decreased (ii) the hydrosulfide binding affinity was increased in metHb-V but was decreased in naked metHb. (iii) Azide binding was increased in metHb-V, which was similar to that in naked metHb, irrespective of the pH change. Thus, the binding behavior of intracellular metHb in the RBC with cyanide, hydrosulfide, and azide under physiological and pathological conditions were partly elucidated using the oxidized artificial RBC.

Pharmaceutical stability of methemoglobin-albumin cluster as an antidote for hydrogen sulfide poisoning after one-year storage in freeze-dried form.

Long-term stability during storage is an important requirement for pharmaceutical preparations. The methemoglobin (metHb)-albumin cluster, in which bovine metHb is covalently enveloped with an average of three human albumin molecules, is a promising antidote for hydrogen sulfide (H2S) poisoning. In this study, we investigated the pharmaceutical stability of metHb-albumin cluster after storage for one year in solution and as freeze-dried powder. The lyophilized powder of metHb-albumin cluster stored for one year was readily reconstituted in sterile water for injection, yielding a homogeneous brown solution. Physicochemical measurements revealed that the overall structure of the metHb-albumin cluster was still maintained after preservation. Results of the pharmacological study showed that 100 % of the H2S-poisoned mice survived after treatment with the reconstituted solution of metHb-albumin cluster powder. Furthermore, the solution did not cause any toxic reactions. The antidotal efficacy of metHb-albumin cluster for H2S poisoning was preserved in freeze-dried powder form for at least one year.

Significance of the connecting position between Zn(ii) porphyrin and Re(i) bipyridine tricarbonyl complex units in dyads for room-temperature phosphorescence and photocatalytic CO2 reduction: unexpected enhancement by triethanolamine in catalytic activity.

We synthesized three new dyads composed of a Zn porphyrin and fac-Re(bpy)(CO)3Br (bpy = 2,2'-bipyridine) units, ZnP-nBpy[double bond, length as m-dash]ReBr (n = 4, 5, and 6), in which the porphyrin is directly connected at the meso-position through the 4-, 5-, or 6-position of the bpy. We investigated the relationships between the connecting positions and the photophysical properties as well as catalytic activity in the CO2 reduction reaction. The dyad connected through the 6-position, ZnP-6Bpy[double bond, length as m-dash]ReBr, showed obvious phosphorescence with a lifetime of 280 µs at room temperature, in N,N-dimethylacetamide (DMA), whereas the other two dyads showed almost no phosphorescence under the same conditions. The photocatalytic CO2 reduction reactions in DMA using 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole as the electron donor and the three dyads ZnP-nBpy[double bond, length as m-dash]ReBr selectively produced CO with similar initial rates, but the durabilities were low. The addition of triethanolamine (TEOA) suppressed the decomposition of dyads, improving their durabilities and reaction efficiencies. In particular, ZnP-5Bpy[double bond, length as m-dash]ReBr was remarkably improved-it gave the highest durability and reaction efficiency among the three dyads; the reaction quantum yield reached 24%. The reason for this significant activity is no accumulation of electrons on the Zn porphyrin in ZnP-5Bpy[double bond, length as m-dash]ReBr, which would be caused by dual interactions of TEOA with the Re and Zn ions in the dyad. As the highest catalytic activity was observed in ZnP-5Bpy[double bond, length as m-dash]ReBr among the three dyads, which had no room-temperature phosphorescence (RTP), the catalytic activities and RTP properties are considered independent, but they are greatly influenced by the connecting positions on the bpy ligand in ZnP-nBpy[double bond, length as m-dash]ReBr.

Pharmaceutical Integrity of Lyophilized Methemoglobin-Albumin Clusters after Reconstitution.

Covalent attachment of a ferric hemoglobin (metHb) core to three human serum albumin molecules to form metHb-albumin clusters has previously been used to develop an antidote for hydrogen sulfide poisoning. Lyophilization is one of the most effective approaches to preserve protein pharmaceuticals with minimum contamination and decomposition. However, there is concern that lyophilized proteins may undergo pharmaceutical alteration on reconstitution. This study investigated the pharmaceutical integrity of metHb-albumin clusters on lyophilization and reconstitution with three clinically available reconstitution fluids, (i) sterile water for injection, (ii) 0.9% sodium chloride injection, and (iii) 5% dextrose injection. The metHb-albumin clusters retained their physicochemical properties and structural integrity on lyophilization and reconstitution with sterile water for injection or 0.9% sodium chloride injection, along with comparable hydrogen sulfide scavenging ability compared to non-lyophilized metHb-albumin clusters. The reconstituted protein completely rescued lethal hydrogen sulfide poisoning in mice. On the other hand, lyophilized metHb-albumin clusters reconstituted with 5% dextrose injection showed physicochemical changes and a higher mortality rate in mice subjected to lethal hydrogen sulfide poisoning. In conclusion, lyophilization represents a potent preservation method for metHb-albumin clusters if either sterile water for injection or 0.9% sodium chloride injection is used for reconstitution.

COVID-19 mRNA vaccination status and concerns among pregnant women in Japan: a multicenter questionnaire survey.

BACKGROUND: mRNA vaccination is an effective, safe, and widespread strategy for protecting pregnant women against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, information on factors such as perinatal outcomes, safety, and coverage of mRNA vaccinations among pregnant women is limited in Japan. Therefore, this study aimed to investigate the perinatal outcomes, coverage, adverse effects, and short-term safety of mRNA vaccination as well as vaccine hesitancy among pregnant women. METHODS: We conducted a multicenter online survey of postpartum women who delivered their offspring at 15 institutions around Tokyo from October 2021 to March 2022. Postpartum women were divided into vaccinated and unvaccinated groups. Perinatal outcomes, COVID-19 prevalence, and disease severity were compared between the two groups. Adverse reactions in the vaccinated group and the reasons for being unvaccinated were also investigated retrospectively. RESULTS: A total of 1,051 eligible postpartum women were included. Of these, 834 (79.4%) had received an mRNA vaccine, while 217 (20.6%) had not, mainly due to concerns about the effect of vaccination on the fetus. Vaccination did not increase the incidence of adverse perinatal outcomes, including fetal morphological abnormalities. The vaccinated group demonstrated low COVID-19 morbidity and severity. In the vaccinated group, the preterm birth rate, cesarean section rate, and COVID-19 incidence were 7.2%, 33.2%, and 3.3%, respectively, compared with the 13.7%, 42.2%, and 7.8% in the unvaccinated group, respectively. Almost no serious adverse reactions were associated with vaccination. CONCLUSIONS: mRNA vaccines did not demonstrate any adverse effects pertaining to short-term perinatal outcomes and might have prevented SARS-CoV-2 infection or reduced COVID-19 severity. Concerns regarding the safety of the vaccine in relation to the fetus and the mother were the main reasons that prevented pregnant women from being vaccinated. To resolve concerns, it is necessary to conduct further research to confirm not only the short-term safety but also the long-term safety of mRNA vaccines.

The efficacy of a novel integrated outside biliary stent and nasobiliary drainage catheter system for acute cholangitis: a single center pilot study.

BACKGROUND/AIMS: Endoscopic biliary drainage is the gold standard treatment for cholangitis. The two methods of biliary drainage are endoscopic biliary stenting and nasobiliary drainage. A novel integrated outside biliary stent and nasobiliary drainage catheter system (UMIDAS NB stent; Olympus Medical Systems) was recently developed. In this study, we evaluated the efficacy of this stent in the treatment of cholangitis caused by common bile duct stones or distal bile duct strictures. METHODS: We conducted a retrospective pilot study by examining the medical records of patients who required endoscopic biliary drainage for cholangitis due to common bile duct stones or distal bile duct strictures, and who were treated with a UMIDAS NB stent, between December 2021 and July 2022. RESULTS: Records of 54 consecutive patients were reviewed. Technical and clinical success rates were 47/54 (87.0%) and 52/54 (96.3%), respectively. Adverse events were observed in 12 patients, with six patients experiencing pancreatitis as an adverse event, following endoscopic retrograde cholangiopancreatography (ERCP). Regarding late adverse events, five cases of biliary stent migration into the bile duct were observed. Disease-related death occurred in one patient. CONCLUSION: The outside-type UMIDAS NB stent is an efficacious new method for biliary drainage and can be applied to many indications.

Evaluation of Quantitative Decision-Making for Rhythm Management of Atrial Fibrillation Using Tabular Q-Learning.

Background Rhythm management is a complex decision for patients with atrial fibrillation (AF). Although clinical trials have identified subsets of patients who might benefit from a given rhythm-management strategy, for individual patients it is not always clear which strategy is expected to have the greatest mortality benefit or durability. Methods and Results In this investigation 52 547 patients with a new atrial fibrillation diagnosis between 2010 and 2020 were retrospectively identified. We applied a type of artificial intelligence called tabular Q-learning to identify the optimal initial rhythm-management strategy, based on a composite outcome of mortality, change in treatment, and sustainability of the given treatment, termed the reward function. We first applied an unsupervised learning algorithm using a variational autoencoder with K-means clustering to cluster atrial fibrillation patients into 8 distinct phenotypes. We then fit a Q-learning algorithm to predict the best outcome for each cluster. Although rate-control strategy was most frequently selected by treating providers, the outcome was superior for rhythm-control strategies across all clusters. Subjects in whom provider-selected treatment matched the Q-table recommendation had fewer total deaths (4 [8.5%] versus 473 [22.4%], odds ratio=0.32, P=0.02) and a greater reward (P=4.8×10-6). We then demonstrated application of dynamic learning by updating the Q-table prospectively using batch gradient descent, in which the optimal strategy in some clusters changed from cardioversion to ablation. Conclusions Tabular Q-learning provides a dynamic and interpretable approach to apply artificial intelligence to clinical decision-making for atrial fibrillation. Further work is needed to examine application of Q-learning prospectively in clinical patients.

Methemoglobin-albumin clusters for cyanide detoxification.

Sodium nitrite (NaNO2) is a universal antidote for patients with cyanide poisoning. However, its use has serious drawbacks in terms of efficacy and safety. Herein, we present a promising antidote: methemoglobin (metHb)-albumin clusters. The metHb-albumin cluster is made by a metHb core wrapped by covalently bound human serum albumin. Spectral analyses proved that the metHb-albumin clusters possessed cyanide-binding properties similar to those of naked metHb. In vitro cell experiments showed that metHb-albumin clusters prevented the cyanide-induced inhibition of cytochrome c oxidase activity, resulting in a strong cytoprotective effect. In mice subjected to cyanide poisoning, metHb-albumin clusters reduced mortality and alleviated metabolic acidosis, while maintaining the activity of cytochrome c oxidase in organs; their efficacy was better than that of NaNO2. Furthermore, the oxygen carrying capacity was maintained in poisoned mice treated with metHb-albumin clusters and was low in those treated with NaNO2. These results indicate that metHb-albumin clusters could be a more effective and safer antidote against cyanide poisoning than NaNO2.

Correction: Construction of isostructural hydrogen-bonded organic frameworks: limitations and possibilities of pore expansion.

[This corrects the article DOI: 10.1039/D1SC02690A.].

Liposomal methemoglobin as a potent antidote for hydrogen sulfide poisoning.

Hydrogen sulfide (H2S) induces acute and lethal toxicity at high concentrations. However, no specific antidotes for H2S poisoning have been approved. Liposomal methemoglobin (metHb@Lipo) was developed as an antidote for cyanide poisoning. As the toxic mechanism of H2S poisoning is the same as that of cyanide poisoning, metHb@Lipo could potentially be used as an antidote for H2S poisoning. In this study, we evaluated the antidotal efficacy of metHb@Lipo against H2S poisoning. Stopped-flow rapid-scan spectrophotometry clearly showed that metHb@Lipo scavenged H2S rapidly. Additionally, metHb@Lipo showed cytoprotective effects against H2S exposure in H9c2 cells by maintaining mitochondrial function. MetHb@Lipo treatment also improved the survival rate after H2S exposure in vivo, with the maintenance of cytochrome c oxidase activity and suppression of metabolic acidosis. Moreover, metHb@Lipo therapy maintained significant antidotal efficacy even after 1-year-storage at 4-37 °C. In conclusion, metHb@Lipo is a candidate antidote for H2S poisoning.

Methemoglobin-albumin clusters for the treatment of hydrogen sulfide intoxication.

Hydrogen sulfide (H2S) has attracted significant attention as a seed in drug development. However, H2S is toxic and induces lethal acute intoxication. Here, we developed methemoglobin (metHb)-albumin clusters as detoxifying agents for H2S intoxication, which were designed based on the inherent binding property of metHb with H2S. The metHb-albumin clusters comprising an autoxidized ferric Hb center wrapped covalently with an average of three human serum albumins showed a similar H2S binding affinity to that of naked metHb. Owing to the H2S binding capability, metHb-albumin clusters suppressed cell death induced by H2S exposure while maintaining mitochondrial function in H9c2 cells. In addition, lethal H2S intoxication model mice were rescued by a single administration of metHb-albumin clusters, resulting from the recovery of cytochrome c oxidase activity. Furthermore, the metHb-albumin clusters possessed essential characteristics, such as adequate pharmacokinetic properties and biocompatibility, for their use as detoxifying agents against H2S intoxication. In conclusion, the results obtained in this study suggest that metHb-albumin clusters are promising detoxifying agents for H2S intoxication and that harnessing the inherent H2S binding properties of metHb is an innovative approach to develop detoxifying agents for H2S intoxication.

Genetic variations in the ATP-binding cassette transporter ABCC10 are associated with neutropenia in Japanese patients with lung cancer treated with nanoparticle albumin-bound paclitaxel.

ABCC10/MRP7, an ATP-binding cassette (ABC) transporter, has been implicated in the extracellular transport of taxanes. Our group reported that the ABCC10 single nucleotide polymorphism (SNPs), rs2125739, influences docetaxel cytotoxicity in lung cancer cell lines as well as its side effects in clinical practice. In this study, we investigated whether the rs2125739 variant could affect paclitaxel (PTX) cytotoxicity in lung cancer cell lines. We also investigated the effect of rs2125739 on the efficacy and safety of nanoparticle albumin-bound PTX (nab-PTX) in clinical practice. The association between rs2125739 genotypes and the 50% inhibitory concentration (IC50) of PTX was investigated in 18 non-small cell lung cancer (NSCLC) cell lines, HeLa cells, and genome-edited HeLa cells. Next, blood samples from 77 patients with NSCLC treated with carboplatin plus nab-PTX were collected and analyzed for six SNPs, including rs2125739. The clinical outcomes among the different genotype groups were evaluated. In NSCLC cell lines, HeLa cells, and genome-edited HeLa cells, the IC50 was significantly higher in the ABCC10 rs2125739 T/T group than in the T/C and C/C groups. In 77 patients with NSCLC, there were no significant differences in clinical outcomes between the T/T and T/C groups. However, the rs2125739 T/T genotype was associated with a higher frequency of Grades 3/4 neutropenia. In contrast, there was no association between other SNPs and clinical efficacy or neutropenia. Our results indicate that the ABCC10 rs2125739 variant is associated with neutropenia in response to nab-PTX treatment.

HOFs Built from Hexatopic Carboxylic Acids: Structure, Porosity, Stability, and Photophysics.

Hydrogen-bonded organic frameworks (HOFs) have attracted renewed attention as another type of promising candidates for functional porous materials. In most cases of HOF preparation, the applied molecular design principle is based on molecules with rigid π-conjugated skeleton together with more than three H-bonding groups to achieve 2D- or 3D-networked structures. However, the design principle does not always work, but results in formation of unexpected structures, where subtle structural factors of which we are not aware dictate the entire structure of HOFs. In this contribution, we assess recent advances in HOFs, focusing on those composed of hexatopic building block molecules, which can provide robust frameworks with a wide range of topologies and properties. The HOFs described in this work are classified into three types, depending on their H-bonded structural motifs. Here in, we focus on: (1) the chemical aspects that govern their unique fundamental chemistry and structures; and (2) their photophysics at the ensemble and single-crystal levels. The work addresses and discusses how these aspects affect and orient their photonic applicability. We trust that this contribution will provide a deep awareness and will help scientists to build up a systematic series of porous materials with the aim to control both their structural and photodynamical assets.

Long-term pharmaceutical stability of liposome-encapsulated methemoglobin as an antidote for cyanide poisoning.

Liposome-encapsulated methemoglobin (metHb@Lipo) has been developed as a novel antidote for cyanide poisoning. Antidotes for lethal acute poisoning should be capable of being easily stored as ready-to-use formulations without temperature restrictions. Here, we investigated the pharmaceutical stability of the metHb@Lipo suspension after one-year storage as a ready-to-use formulation at 4 °C, room temperature (23-28 °C) and 37 °C. The liposomal integrity of metHb@Lipo was observed after one year of storage at all storage temperatures with no physicochemical change or methemoglobin leakage outside the liposome. Furthermore, the encapsulated methemoglobin remained intact without aggregation, fragmentation, denaturation, or dissociation of heme. Fresh and stored metHb@Lipo were equivalent in their binding affinity against cyanide. Moreover, all one-year stored metHb@Lipo suspensions improved the mortality rates of lethal cyanide poisoning mice comparable to fresh metHb@Lipo suspension. Additionally, all stored metHb@Lipo suspensions preserved high biocompatibility, including blood compatibility and the lack of organ toxicity. In conclusion, the metHb@Lipo suspension was a pharmaceutically stable antidote for cyanide poisoning for at least one year without any temperature restrictions.

Synthesis of N-Boc-α-amino Acids from Carbon Dioxide by Electrochemical Carboxylation of N-Boc-α-aminosulfones.

Electrochemical reduction of N-Boc-α-aminosulfones in DMF using an undivided cell equipped with a Pt plate cathode and an Mg rod anode under atmospheric pressure of bubbling carbon dioxide through the solution under constant current conditions resulted in a reductive C-S bond cleavage with elimination of benzenesulfinate ion generating the corresponding anion species followed by fixation of carbon dioxide to give the corresponding N-Boc-α-amino acids in moderate to good yields.

Construction of isostructural hydrogen-bonded organic frameworks: limitations and possibilities of pore expansion.

The library of isostructural porous frameworks enables a systematic survey to optimize the structure and functionality of porous materials. In contrary to metal-organic frameworks (MOFs) and covalent organic frameworks (COFs), a handful of isostructural frameworks have been reported for hydrogen-bonded organic frameworks (HOFs) due to the weakness of the bonds. Herein, we provide a rule-of-thumb to develop isostructural HOFs, where we demonstrate the construction of the third and fourth generation of isostructural HAT-based HOFs (TolHAT-1 and ThiaHAT-1) by considering three important structural factors, that are (1) directional H-bonding, (2) shape-fitted docking of the HAT core, and (3) modulation of peripheral moieties. Their structural and photo-physical properties including HCl vapor detection are presented. Moreover, TolHAT-1, ThiaHAT-1, and other isostructural HOFs (CPHAT-1 and CBPHAT-1) were thoroughly compared from the viewpoints of structures and properties. Importantly, molecular dynamics (MD) simulation proves to be rationally capable of evaluating the stability of isostructural HOFs. These results can accelerate the development of various isostructural molecular porous materials.