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Background Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. Methods We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39–77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. Results We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of ‘Val Leu Ile degradation pathway’. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. Conclusions We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

Stroke-induced cerebral microvascular dysfunction contributes to aggravation of neuronal injury and compromises the efficacy of current reperfusion therapies. Understanding the molecular alterations in cerebral microvessels in stroke will provide original opportunities for scientific investigation of novel therapeutic strategies. Toward this goal, using a recently optimized method which minimizes cell activation and preserves endothelial cell interactions and RNA integrity, we conducted a genome-wide transcriptomic analysis of cerebral microvessels in a mouse model of stroke and compared these transcriptomic alterations with the ones observed in human, nonfatal, brain stroke lesions. Results from these unbiased comparative analyses have revealed the common alterations in mouse stroke microvessels and human stroke lesions and identified shared molecular features associated with vascular disease (e.g., Serpine1/Plasminogen Activator Inhibitor-1, Hemoxygenase-1), endothelial activation (e.g., Angiopoietin-2), and alterations in sphingolipid metabolism and signaling (e.g., Sphigosine-1-Phosphate Receptor 2). Sphingolipid profiling of mouse cerebral microvessels validated the transcript data and revealed the enrichment of sphingomyelin and sphingoid species in the cerebral microvasculature compared to brain and the stroke-induced increase in ceramide species. In summary, our study has identified novel molecular alterations in several microvessel-enriched, translationally relevant, and druggable targets, which are potent modulators of endothelial function. Our comparative analyses have revealed the presence of molecular features associated with cerebral microvascular dysfunction in human chronic stroke lesions. The results shared here provide a detailed resource for therapeutic discovery of candidates for neurovascular protection in stroke and potentially, other pathologies exhibiting cerebral microvascular dysfunction.

Antithrombin deficiency is a high-risk factor for venous thromboembolism during pregnancy, whereas cerebral venous thrombosis is rare. Cerebral venous thrombosis related to coronavirus disease 2019 (COVID-19) vaccines has been reported; however, there are a few reports of cerebral venous thrombosis after a messenger RNA (mRNA) vaccination. A 25-year-old female in her sixth week of pregnancy presented with headache 24 days after BNT162b2 mRNA COVID-19 vaccination. The following day, she presented with altered sensorium and was diagnosed with severe cerebral venous thrombosis. She demonstrated heparin resistance and was found to have an inherited antithrombin deficiency. A heterozygous missense variant in SERPINC1 (c.379TC, p.Cys127Arg, 'AT Morioka') was detected by DNA analysis. Despite intensive care with unfractionated heparin, antithrombin concentrate, and repeated endovascular treatments, she died on the sixth day of hospitalization. Cerebral venous thrombosis in pregnant women with an antithrombin deficiency can follow a rapid and fatal course. Treatment with unfractionated heparin and antithrombin concentrate may be ineffective in severe cerebral venous thrombosis cases with antithrombin deficiency. Early recognition of antithrombin deficiency and an immediate switch to other anticoagulants may be required. Although the association between cerebral venous thrombosis and the vaccine is uncertain, COVID-19 vaccinations may require careful evaluation for patients with prothrombic factors.

In automated laboratories consisting of multiple different types of instruments, scheduling algorithms are useful for determining the optimal allocations of instruments to minimize the time required to complete experimental procedures. However, previous studies on scheduling algorithms for laboratory automation have not emphasized the time constraints by mutual boundaries (TCMBs) among operations, which is important in procedures involving live cells or unstable biomolecules. Here, we define the "scheduling for laboratory automation in biology" (S-LAB) problem as a scheduling problem for automated laboratories in which operations with TCMBs are performed by multiple different instruments. We formulate an S-LAB problem as a mixed-integer programming (MIP) problem and propose a scheduling method using the branch-and-bound algorithm. Simulations show that our method can find the optimal schedules of S-LAB problems that minimize overall execution time while satisfying the TCMBs. Furthermore, we propose the use of our scheduling method for the simulation-based design of job definitions and laboratory configurations.

Carbonate-intercalated Mg–Al layered double hydroxides (CO3·Mg–Al LDHs) are examined as a means of sequestering gaseous pollutants, such as HCl, NOx, and SOx, which are bound to afford X·Mg–Al LDH (X = Cl, SO4, or NO3). In view of the fact that the common regeneration method of CO3·Mg–Al LDH (agitation in aqueous Na2CO3) poses a number of problems, we herein develop a new method of regenerating CO3·Mg–Al LDH by treatment of X·Mg–Al LDH with gaseous CO2 under neutral or alkaline conditions. The desorption of X is shown to follow the intraparticle diffusion model, featuring the diffusion of CO32− in between LDH layers as the rate-determining step. Given the importance of LDHs for wastewater treatment and gaseous pollutant removal, the obtained results pave the way to the efficient utilization of these adsorbents and contribute to the development of next-generation decontamination techniques.

Mg-Al layered double hydroxide intercalated with CO32− (CO3·Mg-Al LDH) is effective for treating HCl exhaust gas. HCl reacts with CO32− in CO3·Mg-Al LDH, resulting in the formation of Cl·Mg-Al LDH. We propose that CO2 can be used for the desorption of Cl− from Cl·Mg-Al LDH to regenerate CO3·Mg-Al LDH. Herein, we studied the desorption of Cl− from Cl·Mg-Al LDH by adding water to Cl·Mg-Al LDH and blowing CO2 into it. We also analyzed the effects of temperature and water addition speed on the desorption of Cl− from Cl·Mg-Al LDH. Our results show that the added water adhered to Cl·Mg-Al LDH and that CO2 in the gaseous phase was dissolved in this adhered water, thus generating CO32−. Therefore, anion exchange occurred between CO32− and Cl− in the Cl·Mg-Al LDH, thus desorbing Cl−.

Background Endoscopic hematoma evacuation is one of the most promising procedures for the treatment of intracerebral hemorrhage (ICH) to avoid severe outcomes, such as death or dependency. However, the effect of the procedure on the functional outcome remains controversial. Thus, standardization and sophistication are required to enhance the surgical results. This study aimed to evaluate the potential efficacy of ultrasonography (US) in endoscopic hematoma evacuation. methods This study included 39 consecutive patients with spontaneous supratentorial ICH who underwent endoscopic hematoma evacuation between April 2019 and July 2021. The patients were divided into two groups, namely, surgery with or without US assistance. Rebleeding and evacuation rate were set as the primary endpoints, and operation time, requirement for repeat puncture, and modified Rankin scale at discharge were set as the secondary endpoints. During surgery, the burr hole was placed, and the dura mater was widely opened. The US probe was applied on the brain surface via the burr hole to detect the depth and direction of the hematoma cavity. With US assistance, the hematoma cavity was punctured with a cannula, and the transparent port was introduced into the hematoma cavity along the tract. The hematoma was gently evacuated with the irrigation–suction instrument. Results Of the 39 cases, 9 underwent endoscopic hematoma evacuation with US assistance. Rebleeding was noted in 0 and 2 (6.7%) patients with and without US assistance, respectively (p = 0.43). The mean hematoma evacuation rates were 78.6 and 80.6% in patients with and without US assistance, respectively (p = 0.80). In all cases with US assistance, the cavity could be reached with a single tap. However, repeat puncture was required in 20 (66.7%) cases without US assistance (p = 0.04). In one case, an unexpected residual hematoma was detected using US, which was applied after hematoma evacuation and before wound closure. The operation time was not extended even if US was used during the surgery. Conclusions US-assisted hematoma evacuation is an effective procedure that can assist in the precise insertion of the puncture cannula and exclusion of the residual hematoma. US might contribute toward improving the accuracy of each step of the procedure, thus leading to better clinical outcomes.

BACKGROUND Basilar artery occlusion (BAO) accounts for 1% of all strokes, and its natural prognosis is extremely poor. There is no consensus on the treatment strategy for mild BAO. OBSERVATIONS Between August 2015 and May 2021, 429 patients received mechanical thrombectomy (MT) in the authors’ hospital. Three patients had a BAO with a National Institutes of Health Stroke Scale (NIHSS) score of ≤6 and showed eye movement disorder as the main symptom. MT immediately improved ocular symptoms in all three cases, and the patients were discharged with a modified Rankin Scale ≤2. LESSONS Lesions responsible for the eye movement disorder are distributed from the midbrain to the pontine tegmentum. These lesions are supplied by the arteries of the interpeduncular fossa, which is impaired by BAO. Symptoms due to problems with the arteries of the interpeduncular fossa can be rapidly improved by MT, and it is useful for preventing neurological deterioration in mild cases. BAO with a low NIHSS score in the presence of eye movement disorder as the main symptom may be a good indication for MT.

Objective The aim of this study was to clarify the genetic and epidemiological properties of multidrug-resistant Acinetobacter baumannii in medical settings in Myanmar. Methods A total of 45 A. baumannii clinical isolates were obtained in medical settings in Myanmar. The whole genomes were sequenced by a next generation sequencer, and the phylogenetic tree was constructed from single nucleotide polymorphism concatemers. Multilocus sequence types were deduced and drug resistance genes were identified. Results Thirty-eight MDR Acinetobacter baumannii isolates were obtained from seven hospitals in Myanmar. The majority of MDR A. baumannii isolates belonged to ST2. Of the 38 isolates, 5 harbored blaNDM-1, and 28 did armA or armA2 Conclusions A. baumannii ST2 producing 16S rRNA methylase ArmA has been spreading in medical settings in Myanmar.

Background/aim Programmed death-ligand 1 (PD-L1/CD274) elicits T-cell anergy, leading to immune suppression. We aimed to determine the prognostic relevance of PD-L1 expression in the blood of breast cancer (BC) patients. Materials and methods We measured PD-L1 mRNA expression in blood and tumor tissues of BC patients using RT-qPCR and a dataset from The Cancer Genome Atlas, and performed a survival analysis of PD-L1 expression in the blood of 330 BC patients. Flow cytometric analysis was performed using blood cells. Results No statistical difference in PD-L1 expression was seen between normal controls and BC in blood or tissues. There was a significant positive correlation between the PD-L1 expression levels in blood and tissues. Decreased PD-L1 expression in blood or tissues was associated with poor recurrence-free survival. PD-L1 is mainly expressed in polymorphonuclear leukocytes. Conclusion Low expression of PD-L1 in the blood could serve as a biomarker of poor prognosis in BC patients.

Morganella morganiican harbour extended-spectrum β-lactamases and carbapenemases, resulting in increased resistance to multiple antibiotics and a high mortality rate. This study describes the emergence of highly multidrug-resistant clinical isolates ofM. morganiifrom Nepal co-producing NDM-type metallo-β-lactamases, including NDM-1 and NDM-5, and the 16S rRNA methylase ArmA. This is the first report ofM. morganiiclinical isolates from Nepal co-producing NDM-1/-5 and ArmA. It is important to establish infection control systems and effective treatments against multidrug-resistantM. morganii.

Objectives: The aim of this study was to describe the emergence in Nepal of clinical isolates of Klebsiella pneumoniae harboring both blaNDM-5 and blaOXA-181/-232. Methods: Six clinical isolates of K. pneumoniae highly resistant to carbapenems and aminoglycosides were obtained from inpatients in Nepal. Their whole genomes were sequenced by a next generation sequencer. Results: The minimum inhibitory concentrations of meropenem, amikacin and ciprofloxacin were ≥128 μg/ml, >1024 μg/ml and ≥256 μg/ml, respectively. All six isolates co-harbored blaNDM-5, blaOXA-181 or -232 and rmtB. Of them, 1 also harbored rmtF. The blaNDM-5, blaOXA-232 and rmtB in all six isolates were located on plasmids. Of the six isolates tested, one isolate harbored two copies of blaOXA-181 and rmtF on the chromosome. Conclusions: This is the first report of clinical isolates of K. pneumoniae co-harboring blaNDM-5, blaOXA-181 or -232 and rmtB in Nepal. These strains were highly carbapenem- and aminoglycoside-resistant, and belonged to ST147 or ST395. Of them, ST147 isolate harbored two copies of blaOXA-181 on the chromosome. Keywords: Klebsiella pneumoniae, Multidrug resistance, Carbapenemase, 16S rRNA methylase

Cancer is a leading cause of death worldwide, and the incidence continues to increase. Despite major research aimed at discovering and developing novel and effective anticancer drugs, oncology drug development is a lengthy and costly process, with high attrition rates. Drug repositioning (DR, also referred to as drug repurposing), the process of finding new uses for approved noncancer drugs, has been gaining popularity in the past decade. DR has become a powerful alternative strategy for discovering and developing novel anticancer drug candidates from the existing approved drug space. Indeed, the availability of several large established libraries of clinical drugs and rapid advances in disease biology, genomics/transcriptomics/proteomics and bioinformatics has accelerated the pace of activity‐based, literature‐based and in silico DR, thereby improving safety and reducing costs. However, DR still faces financial obstacles in clinical trials, which could limit its practical use in the clinic. Here, we provide a brief review of DR in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan., We provide a brief review of drug repositioning (DR) in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, operative procedures have been standardized, and the safety and efficacy of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less invasive type of surgery, the number of endoscopic procedures performed has increased in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. Notably, a technical skills certification system for surgeons was established by the JSES to train instructors on how to teach safe endoscopic surgery. Furthermore, the JSES has conducted a national survey every 2 years. In 2019, 291,792 patients underwent endoscopic surgery in all surgical domains, such as abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The 15th National Survey of Endoscopic Surgery conducted by the JSES demonstrated the status of laparoscopic surgery in Japan in 2018-2019.

With the Augmented Reality mirror display method using a half-mirror, there is a difference in the focal length between the mirror image and the AR image. Therefore, the observer perceives a mismatch in depth perception, which impairs usability. In this study, we developed an optical-reflection AR display, ALiSE (Augment Layer interweaved Semi-reflecting Existence), which enhances the depth perception experience of AR images by adding a gap zone with the same depth as the target depth between the display and the half-mirror. We conducted an experiment to view 3D objects and achieve virtual fitting using the existing AR with video synthesis and the proposed ALiSE method. As a result of the questionnaire survey, although the comfort of wearing virtual objects was below existing methods, we confirmed that the presence and solidity were superior with the proposed method to other approaches. This is an attempt to create a sense of the stereoscopic effect despite the 2D projection, as the object to be projected is simultaneously reflected in the mirror along with the observer themselves.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, operative procedures have been standardized, and the safety and efficacy of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less invasive type of surgery, the number of endoscopic procedures performed has increased in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. Notably, a technical skills certification system for surgeons was established by the JSES to train instructors on how to teach safe endoscopic surgery. Furthermore, the JSES has conducted a national survey every two years to evaluate the status of endoscopic surgery over time. In 2017, 248 743 patients underwent endoscopic surgery in all surgical domains, such as abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The 14th National Survey of Endoscopic Surgery conducted by the JSES demonstrated the status of laparoscopic surgery in Japan in 2016-2017.

Chemotherapy after hepatectomy for colorectal liver metastasis has not been established, due to the toxic side effects, which are likely related to impaired drug clearance during liver regeneration. We investigated the pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil (5-FU) during liver regeneration after major hepatectomy in a rat model. Thirty-six male Wistar rats were divided into control (C), control with chemotherapy (CC), hepatectomy (H), and hepatectomy with chemotherapy (HC) groups. The CC and HC groups were administered 5-FU for 4 days. Plasma 5-FU, liver weight, and liver dihydropyrimidine dehydrogenase (DPD) were measured. The ileal villous height was measured to determine adverse effects. The area under the curve and maximum plasma concentration of 5-FU increased by up to 51% and 32%, respectively, in the HC group compared to the CC group. The liver regeneration rate was significantly lower in the HC group than in the H group (67.3 ± 7.4 vs 33.0 ± 5.7%, p

Intensive membrane cleaning can be used with ceramic membranes since they are physically/chemically robust. It might therefore be possible for membrane bioreactors (MBRs) to be operated under the condition of a high membrane flux when ceramic membranes are used with such intensive membrane cleaning. In this study, bench-scale MBRs equipped with flat-sheet ceramic membranes were operated for long periods. Circulation of granular materials (cylindrical polyurethane) in the tank and frequent chemically enhanced backwash (CEB) were used as intensive physical cleaning and chemical cleaning in this study, respectively. Experiments were carried out with synthetic wastewater. The use of granular materials, which can cause significant damage to polymeric membranes (Kurita et al., 2015), was effective for controlling the formation of cake (deposition of microbial flocs) on the surface of the ceramic membranes. When both mechanical cleaning using the granular materials and CEB with 1000 ppm of sodium hypochlorite (NaClO) were applied, contrary to an expectation, evolution of reversible fouling (formation of a transparent gel layer on the membrane surface) became uncontrollable, whereas irreversible fouling was effectively controlled. The use of NaClO induced release of organic macromolecules via biomass decay, leading to the evolution of reversible fouling. When the intensity of CEB with NaClO was adequately lowered, with the aid of the mechanical cleaning using the granules, the bench-scale MBR could be operated stably under an elevated membrane flux for a long period (>70 days). It was postulated that the adjustment of CEB intensity preferably altered properties of organic macromolecules released from biomass: the structure of the gel layer was porous when the CEB intensity was lowered. When CEB is used in MBRs, it is thus important to balance cleaning efficiency and its harmful effect on biomass. When adequate CEB is used with intensive mechanical cleaning, MBRs with ceramic membranes can be operated under high flux conditions.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, the operative procedure has been standardized, and the safety and usefulness of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less-invasive surgery, the number of endoscopic procedures has been increasing in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. For example, JSES established a technical skills certification system for surgeons to train instructors how to teach safe endoscopic surgery, and the organization performs a national survey every 2 years. In 2015, a total of 211 953 patients underwent endoscopic surgery in all surgical domains, including abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The course of laparoscopic surgery's development and its current status are reported here based on the results of the most recent questionnaire survey conducted by JSES.

Combination therapy of tegafur/uracil (UFT) and leucovorin (LV) is widely used to treat colorectal cancers. Although this therapy has a significant therapeutic effect, severe adverse effects occur frequently. Therapeutic drug monitoring (TDM) may help to prevent adverse effects. A useful assay that can quantitate plasma levels of 5-FU, uracil, and tegafur simultaneously for TDM has been desired, but such a method is not currently available. In this study, we aimed to develop a sensitive method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). After preparing plasma samples by protein precipitation and liquid extraction, 5-FU, uracil, and tegafur were analyzed by UPLC-MS/MS in negative electrospray ionization mode. Validation was performed according to US Food and Drugs Administration guidance. The calibration curves were linear over concentration ranges of 2–500 ng/mL for 5-FU, 20–5000 ng/mL for uracil, and 200–50,000 ng/mL for tegafur. The corresponding average recovery rates were 79.9, 80.9, and 87.8%. The method provides accuracy within 11.6% and precision below 13.3% for all three analytes. Matrix effects of 5-FU, uracil, and tegafur were higher than 43.5, 84.9, and 100.2%, respectively. This assay was successfully applied to assess the time courses of plasma 5-FU, uracil, and tegafur concentrations in two patients with colorectal liver metastasis who received UFT/LV therapy after hepatectomy. In conclusion, we succeeded to develop a sensitive and robust UPLC-MS/MS method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma. This method is potentially useful for TDM in patients receiving UFT/LV combination therapy.

Daptomycin (DAP) is one of the most potent antibiotics used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Due to an increase in its administration for combating MRSA infections, DAP non-susceptible (DAP-NS) MRSA strains have recently been reported in clinical settings. The presence of single nucleotide polymorphisms (SNPs) in the multiple peptide resistance factor (mprF) gene is the most frequently reported cause for the evolution of DAP-NS MRSA strains; however, there are some variations of SNPs that could lead to DAP-NS. In this study, we used two clinical MRSA strains, including DAP susceptible (DAP-S) and DAP-NS, isolated from the same patient at different time points. We introduced T345I SNP to mprF of the DAP-S MRSA strain using the gene exchange method with pIMAY vector. Further, we investigated the phenotype of the mutant strain, including drug susceptibility, cell surface positive charge, and growth speed. The mutant strain exhibited (i) resistance to DAP, (ii) up-regulation of positive surface charge, (iii) slower growth speed, and (iv) thickened cell walls. Hence, the SNP in mprF may have caused an up-regulation in MprF function, with a subsequent increase in positive surface charge. Cumulatively, these results demonstrated that the T345I amino acid substitution in mprF represents one of the primary causes of DAP-NS in MRSA strains.