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Abstract Background The advantage of intensified myeloablative conditioning (MAC) over standard MAC has not been determined in haematopoietic stem cell transplantation (HSCT) for adult acute lymphoblastic leukemia (ALL) patients. Methods To evaluate heterogeneous effects of intensified MAC among individuals, we analyzed the registry database of adult ALL patients between 2000 and 2021. After propensity score matching, we applied a machine-learning Bayesian causal forest algorithm to develop a prediction model of individualized treatment effect (ITE) of intensified MAC on reduction in overall mortality at 1 year after HSCT. Results Among 2440 propensity score-matched patients, our model shows heterogeneity in the association between intensified MAC and 1-year overall mortality. Individuals in the high-benefit group (n = 1220), defined as those with ITEs greater than the median, are more likely to be younger, male, and to have higher refined Disease Risk Index (rDRI), T-cell phenotype, and grafts from related donors than those in the low-benefit group (n = 1220). The high-benefit approach (applying intensified MAC to individuals in the high-benefit group) shows the largest reduction in overall mortality at 1 year (risk difference [95% confidence interval], +5.94 percentage points [0.88 to 10.51], p = 0.011). In contrast, the high-risk approach (targeting patients with high or very high rDRI) does not achieve statistical significance (risk difference [95% confidence interval], +3.85 percentage points [−1.11 to 7.90], p = 0.063). Conclusions These findings suggest that the high-benefit approach, targeting patients expected to benefit from intensified MAC, has the capacity to maximize HSCT effectiveness using intensified MAC.

Abstract The extent of the stable nitrogen (N) isotope ratio (δ 15N) of mangrove leaves reflects the anthropogenic N accumulation potential of mangroves. Therefore, the present study was designed to investigate the N accumulation potential of Okinawa mangroves in Japan using three ecological indicators from four mangrove watersheds. The dissolved inorganic nitrogen (DIN) concentration in mangrove creeks, the leaf δ 15N and the soil δ 15N are considered immediate indicators, short-term indicators, and long-term indicators, respectively. The four mangrove watersheds are classified into two groups, human-affected and forested mangroves, based on the relative land use ratio (%) of the watersheds. The observed values of the ecological indicators were subsequently compared between two groups of watersheds to determine the relative ecosystem conditions. The results showed that both the leaf δ 15N (0 to 9 ‰) and the soil δ 15N (1.5 to 8.0 ‰) values are significantly greater in human-affected mangroves than in forested mangroves. The DIN of creek water samples does not indicate an immediate risk of excess N input from human perturbation in mangroves. However, the significant relationships among the indicators reflect the anthropogenic N accumulation potential of mangroves in Okinawa, Japan. These findings are highly important, especially for policymakers, environmentalists, and related stakeholders, for initiating conservation and management practices for mangroves. Controlled, limited, and/or restricted human perturbation; proper management of municipal wastes; and planned use of agrochemicals upon necessity may help reduce anthropogenic N inputs in mangrove ecosystems in Okinawa.

Abstract MicroRNAs, including the tumor-suppressor miR-126 and the oncogene miR-221, regulate tumor formation and growth in colitis-associated cancer (CAC) and colorectal cancer (CRC). This study explores the impact of the epithelial cytokine heparin-binding epidermal growth factor (HB-EGF) and its receptor epidermal growth factor receptor (EGFR) on the pathogenesis of CAC and CRC, particularly in the regulation of microRNA-driven tumor growth and protease expression. In murine models of CRC and CAC, lack of miR-126 and elevated miR-221 expression in colonic tissues enhanced tumor formation and growth. MiR-126 downregulation in colon cells established a pro-tumorigenic proteolytic niche by targeting HB-EGF-active metalloproteinase-7, -9 (MMP7/MMP9), disintegrin, and metalloproteinase domain-containing protein 9, and modulating chemokine-mediated recruitment of HB-EGF-loaded inflammatory cells. Mechanistically, downregulation of HB-EGF and EGFR in the colon suppressed miR-221 and enhanced miR-126 expression via activating enhancer-binding protein 2 alpha. Reintroducing miR-126 reduced tumor development and HB-EGF expression. Combining miR-126 reintroduction, which targets specific HB-EGF-active proteases but not ADAM17, with MMP inhibitors like Batimastat or Marimastat effectively suppressed tumor growth. This combination normalized protease expression and balanced miR-126 and miR-221 levels in developing and growing tumors. These findings demonstrate that suppressing HB-EGF and EGFR1 shifts the balance from oncogenic miR-221 to tumor-suppressive miR-126 action. Consequently, normalizing miR-126 expression could open new avenues for treating patients with CAC and CRC, and this normalization is intertwined with the anticancer efficacy of MMP inhibitors.

Abstract Background The cancer genome contains several driver mutations. However, in some cases, no known drivers have been identified; these remaining areas of unmet needs, leading to limited progress in cancer therapy. Whole-genome sequencing (WGS) can identify non-coding alterations associated with the disease. Consequently, exploration of non-coding regions using WGS and other omics data such as ChIP-sequencing (ChIP-seq) to discern novel alterations and mechanisms related to tumorigenesis have been attractive these days. Methods Integrated multi-omics analyses, including WGS, ChIP-seq, DNA methylation, and RNA-sequencing (RNA-seq), were conducted on samples from patients with non-clinically actionable genetic alterations (non-CAGAs) in lung adenocarcinoma (LUAD). Second-level cluster analysis was performed to reinforce the correlations associated with patient survival, as identified by RNA-seq. Subsequent differential gene expression analysis was performed to identify potential druggable targets. Results Differences in H3K27ac marks in non-CAGAs LUAD were found and confirmed by analyzing RNA-seq data, in which mastermind-like transcriptional coactivator 2 (MAML2) was suppressed. The down-regulated genes whose expression was correlated to MAML2 expression were associated with patient prognosis. WGS analysis revealed somatic mutations associated with the H3K27ac marks in the MAML2 region and high levels of DNA methylation in MAML2 were observed in tumor samples. The second-level cluster analysis enabled patient stratification and subsequent analyses identified potential therapeutic target genes and treatment options. Conclusions We overcome the persistent challenges of identifying alterations or driver mutations in coding regions related to tumorigenesis through a novel approach combining multi-omics data with clinical information to reveal the molecular mechanisms underlying non-CAGAs LUAD, stratify patients to improve patient prognosis, and identify potential therapeutic targets. This approach may be applicable to studies of other cancers with unmet needs.

Abstract Human norovirus (HuNoV) is an enteric infectious pathogen belonging to the Caliciviridae family that causes occasional epidemics. Circulating alcohol-tolerant viral particles that are readily transmitted via food-borne routes significantly contribute to the global burden of HuNoV-induced gastroenteritis. Moreover, contact with enzymes secreted by other microorganisms in the environment can impact the infectivity of viruses. Hence, understanding the circulation dynamics of Caliciviridae is critical to mitigating epidemics. Accordingly, in this study, we screened whether environmentally abundant secretase components, particularly proteases, affect Caliciviridae infectivity. Results showed that combining Bacillaceae serine proteases with epsilon-poly-l-lysine (EPL) produced by Streptomyces—a natural antimicrobial—elicited anti-Caliciviridae properties, including against the epidemic HuNoV GII.4_Sydney_2012 strain. In vitro and in vivo biochemical and virological analyses revealed that EPL has two unique synergistic viral inactivation functions. First, it maintains an optimal pH to promote viral surface conformational changes to the protease-sensitive structure. Subsequently, it inhibits viral RNA genome release via partial protease digestion at the P2 and S domains in the VP1 capsid. This study provides new insights regarding the high-dimensional environmental interactions between bacteria and Caliciviridae, while promoting the development of protease-based anti-viral disinfectants.

Introduction: Osimertinib is used as the first-line treatment for EGFR mutation-positive NSCLC. Nevertheless, its efficacy and safety in clinical practice remain to be fully elucidated and the pattern of progression and the optimal subsequent treatment after osimertinib remains unclear. Methods: This was a multicenter prospective observational study. EGFR mutation-positive patients with NSCLC who started first-line osimertinib from September 2018 to August 2020 were enrolled and followed up until August 2022. Results: A total of 583 patients received osimertinib. The median progression-free and overall survival were 20.0 (95% confidence interval [CI]: 17.6–21.7) months and 41.0 (95% CI: 37.1–44.1) months, respectively. Grade 3 or worse adverse events were observed in 136 patients (23.3%). Progression patterns were categorized as central nervous system only, oligo-progression, and multiple organs on the basis of the Response Evaluation Criteria in Solid Tumors—progressive disease and occurred in 37 (10.8%), 156 (45.4%), and 151 patients (43.9%). The patient’s condition on progression was asymptomatic in 195 patients (56.7%). Osimertinib was continued in 163 patients (47.4%) after confirming progression. In clinically stable population with progressive disease (n = 247), survival after progression was 13.3 (95% CI: 10.9–16.4) months for those who continued osimertinib beyond progressive disease (n = 124), and 24.1 (95% CI: 17.7–34.0) months for those who discontinued osimertinib (n = 123) (hazard ratio = 2.01, 95% CI: 1.38–2.91, p = 0.0002). Platinum plus pemetrexed had the best overall survival benefits after osimertinib. Conclusions: First-line osimertinib was found to have good effectiveness comparable to that reported in pivotal studies. Nevertheless, osimertinib should be discontinued among those who develop progression. Trial registration number: UMIN000038683

The study included 12 hemispheres of 9 patients with moyamoya disease who underwent direct-indirect revascularization. The parameters (peak systolic velocity (PSV), mean flow velocity (MV), resistance index (RI), flow volume (FV)) of the superficial temporal artery (STA) on the operated side were measured using a handheld Doppler before and after surgery in all the patients. The examination was conducted in a similar manner on postoperative day (POD)1 on 9 sides of 7 patients except for 3 sides of the first 2 patients. Patency of the superficial temporal artery-middle cerebral artery (STA-MCA) bypass was confirmed by magnetic resonance angiography (MRA) performed on all 12 sides of 9 patients within the first 2 PODs. There was a statistically significant increase in the PSV (p = 0.0201) and the MV (p = 0.0110) and a decrease in the RI (p = 0.0177) in the STA after surgery when compared with those measured before surgery. None of the changes from the immediate postoperative period to POD1 were statistically significant. Postoperative transient neurological events (TNEs) occurred in 3 patients (25 %) in the first 2 weeks, and all of them were attributed to hyperperfusion. The FV of the three sides associated with TNEs was significantly higher than that of the nine sides that were not (p = 0.0273). From the early stage after moyamoya disease bypass surgery, it was clarified that the parameter of the STA changed in which the PSV and the MV increased and the RI decreased. It was clarified that the increase in the FV, which is the blood flow rate that flows through the STA in the immediate postoperative period, may be a predictor of the development of hyperperfusion during the perioperative course.

Abstract Background In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. Methods We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. Results We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. Conclusions Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.

Abstract MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.

IntroductionPlasminogen activator inhibitor-1 (PAI-1) is linked to thrombosis and endothelial dysfunction in severe COVID-19. The +43 G>A PAI-1 and 4G/5G promoter polymorphism can influence PAI-1 expression. The 4G5G PAI-1 promoter gene polymorphism constitutes the 4G4G, 4G5G, and 5G5G genotypes. However, the impact of PAI-1 polymorphisms on disease severity or endothelial dysfunction remains unclear.MethodsClinical data, sera, and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients were studied.ResultsComorbidities and clinical biomarkers did not correlate with genotypes in either polymorphism. However, differences between fibrinolytic factors and interleukin-1β (IL-1β) were identified in genotypes of the 4G/5G but not the 43 G>A PAI polymorphism. Patients with the 4G4G genotype of the 4G/5G polymorphism showed high circulating PAI-1, mainly complexed with plasminogen activators, and low IL-1β and plasmin levels, indicating suppressed fibrinolysis. NFκB was upregulated in PBMCs of COVID-19 patients with the 4G4G genotype.DiscussionMechanistically, IL-1β enhanced PAI-1 expression in 4G4G endothelial cells, preventing the generation of plasmin and cleavage products like angiostatin, soluble uPAR, and VCAM1. We identified inflammation-induced endothelial dysfunction coupled with fibrinolytic system overactivation as a risk factor for patients with the 5G5G genotype.

Abstract Introduction Subjective cognitive decline (SCD) refers to individuals’ perceived decline in memory and/or other cognitive abilities relative to their previous level of performance. Sensory decline is one of the main manifestations of decline in older adults with SCD. The efficient integration of visual and auditory information, known as audiovisual integration, is a crucial perceptual process. This study aims to evaluate audiovisual integration in older adults with SCD. Methods We adopted the audiovisual detection task, the Colavita task, and the Sound‐Induced Flash Illusion (SIFI) task to evaluate the audiovisual integration by examining both redundant and illusory effects. Older adults diagnosed with SCD (N = 50, mean age = 67.8 years) and a control group of non‐SCD older adults (N = 51, mean age = 66.5 years) were recruited. All participants took part in the three aforementioned experiments. Results The outcomes showed that a redundant effect occurred in both SCD and non‐SCD older adults, with SCD older adults gaining more benefits in audiovisual detection task. Moreover, an equivalent amount of the visual dominance effect was observed among both SCD and non‐SCD older adults in Colavita task. In addition, older adults with SCD perceived an equal fission illusion but a bigger fusion illusion compared with non‐SCD older adults in SIFI task. Conclusions Overall, older adults with SCD exhibit increased audiovisual redundant effects and stronger fusion illusion susceptibility compared to non‐SCD older adults. Besides, visual dominance was observed in both groups via the Colavita task, with no significant difference between non‐SCD and SCD older adults. These findings implied that audiovisual integration might offer a potential way for the identification of SCD.

Abstract DNA methylation is an epigenetic modification that results in dynamic changes during ontogenesis and cell differentiation. DNA methylation patterns regulate gene expression and have been widely researched. While tools for DNA methylation analysis have been developed, most of them have focused on intergroup comparative analysis within a dataset; therefore, it is difficult to conduct cross-dataset studies, such as rare disease studies or cross-institutional studies. This study describes a novel method for DNA methylation analysis, namely, methPLIER, which enables interdataset comparative analyses. methPLIER combines Pathway Level Information Extractor (PLIER), which is a non-negative matrix factorization (NMF) method, with regularization by a knowledge matrix and transfer learning. methPLIER can be used to perform intersample and interdataset comparative analysis based on latent feature matrices, which are obtained via matrix factorization of large-scale data, and factor-loading matrices, which are obtained through matrix factorization of the data to be analyzed. We used methPLIER to analyze a lung cancer dataset and confirmed that the data decomposition reflected sample characteristics for recurrence-free survival. Moreover, methPLIER can analyze data obtained via different preprocessing methods, thereby reducing distributional bias among datasets due to preprocessing. Furthermore, methPLIER can be employed for comparative analyses of methylation data obtained from different platforms, thereby reducing bias in data distribution due to platform differences. methPLIER is expected to facilitate cross-sectional DNA methylation data analysis and enhance DNA methylation data resources.

Abstract Although daily higher urinary sodium (Na) and potassium (K) excretion ratio is associated with the risk of cardiovascular disease in the general population, a low Na/K ratio is associated with renal dysfunction in critically ill patients. Thus, we retrospectively analyzed the impact of daily urinary Na and K excretion and their ratio on non-relapse mortality (NRM) and overall mortality in 172 adult single-unit cord blood transplantation (CBT) patients treated at our institution between 2007 and 2020. Multivariate analysis showed that a low urinary Na/K ratio at both 14 days (hazard ratio [HR], 4.82; 95% confidence interval [CI], 1.81–12.83; P = 0.001) and 28 days (HR, 4.47; 95% CI 1.32–15.12; P = 0.015) was significantly associated with higher NRM. Furthermore, a low urinary Na/K ratio at 28 days was significantly associated with higher overall mortality (HR, 2.38; 95% CI 1.15–4.91; P = 0.018). Patients with a low urinary Na/K ratio had decreased urine volume, more weight gain, experienced more grade III–IV acute graft-versus-host disease, and required corticosteroids by 28 days after CBT. These findings indicate that a low urinary Na/K ratio early after single-unit CBT is associated with poor NRM and survival in adults.

Objective physical function assessment is crucial for determining patient eligibility for treatment and adjusting the treatment intensity. Existing assessments, such as performance status, are not well standardized, despite their frequent use in daily clinical practice. This paper explored how artificial intelligence (AI) could predict physical function scores from various patient data sources and reviewed methods to measure objective physical function using this technology. This review included relevant articles published in English that were retrieved from PubMed. These studies utilized AI technology to predict physical function indices from patient data extracted from videos, sensors, or electronic health records, thereby eliminating manual measurements. Studies that used AI technology solely to automate traditional evaluations were excluded. These technologies are recommended for future clinical systems that perform repeated objective physical function assessments in all patients without requiring extra time, personnel, or resources. This enables the detection of minimal changes in a patient’s condition, enabling early intervention and enhanced outcomes.

Abstract Background and Aim Recently, noninvasive fecal markers have been used as indicators of intestinal inflammation in patients with inflammatory bowel disease (IBD). We conducted a clinical validation study to measure fecal calprotectin (Cp), lactoferrin (Lf), and hemoglobin (Hb) levels using an all‐in‐one kit in patients with IBD and colorectal tumors and aimed to clarify the utility of these fecal markers. Methods In this study, 104 patients were analyzed, including 25 patients with ulcerative colitis (UC), 20 with Crohn's disease (CD), 48 with colorectal tumors, and 13 healthy controls (HC). Of the 48 patients with colorectal tumors, 14 had invasive cancer. We validated the utility of fecal Cp, Lf, and Hb levels by simultaneously measuring fecal markers in patients with IBD and colorectal tumors. Results Fecal Cp and Lf had almost equivalent abilities in detecting clinical remission in patients with UC; however, fecal Cp was slightly superior to Lf. Regarding colorectal tumors, fecal Cp and Lf levels tended to be higher in patients with adenomas and colorectal cancer than in HCs. Although fecal Hb alone had the best sensitivity and specificity for detecting colorectal cancer, it had relatively low sensitivity for detecting advanced neoplasms and colorectal cancer. Conclusion Fecal Cp and Lf can be used as almost equivalent biomarkers to assess the clinical activity in patients with UC. Fecal Hb is the most useful marker for screening colorectal cancer; however, adding fecal Cp and Lf may compensate for the low sensitivity of detecting for advanced colorectal tumors based on Hb alone.

Treatment resistance after chemo-/immunotherapy occurs in patients with head and neck squamous cell cancers (HNSCs), including salivary gland cancers (SGCs). Interleukin-10 (IL-10), a cytokine with pro- and anti-cancer effects, has an unclear impact on HNSC/SGC cells. We show that HNSC patients exhibiting high expression of IL-10 and its receptor IL-10Rα experience have prolonged overall survival. Immunoreactive IL-10 was low in ductal cells of human SGC biopsies. Human (A253) and murine WR21-SGC cells expressed IL-10Rβ, but only A253 cells expressed IL-10 and IL-10Rα. The addition of recombinant IL-10 impaired SGC cell proliferation and induced apoptosis in vitro. N-acetylcysteine restored IL-10-induced reactive oxygen species (ROS) production but did not prevent IL-10-mediated viability loss. Mechanistically, recIL-10 delayed cell cycle progression from G0/G1 to the S phase with cyclin D downregulation and upregulation of NF-kB. IL-10 increased tumor necrosis factor-α (TNF-α) in A253 and WR21 and FasL in WR21 cells. Neutralizing antibodies against TNF-α and NF-kB inhibition restored SGC proliferation after IL-10 treatment, emphasizing the critical role of TNF-α and NF-kB in IL-10-mediated anti-tumor effects. These findings underscore the potential of IL-10 to impede SGC cell growth through apoptosis induction, unraveling potential therapeutic targets for intervention in salivary gland carcinomas.

Transmission of antimicrobial-resistant bacteria among humans, animals, and the environment is a growing concern worldwide. The distribution of an international high-risk fluoroquinolone-resistant Escherichia coli clone, ST131, has been documented in clinical settings. However, the transmission of ST131 from humans to surrounding environments remains poorly elucidated. To comprehend the current situation and identify the source of ST131 in nature, we analyzed the genetic features of ST131 isolates from the aquatic environment (lake/river water) and wildlife (fox, raccoon, raccoon dog, and deer) and compared them with the features of isolates from humans in Japan using accessory and core genome single nucleotide polymorphism (SNP) analyses. We identified ST131 isolates belonging to the same phylotype and genome clusters (four of eight clusters were concomitant) with low SNP distance between the human isolates and those from the aquatic environment and wildlife. These findings warn of ST131 transmission between humans and the surrounding environment in Japan.

Introduction: Osimertinib is a standard treatment for patients with EGFR-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance. Methods: We established two osimertinib-resistant cell lines from EGFR mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3. Results: Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA–mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with EGFR-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib. Conclusions: Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.

Temperature seasonality during the middle Cretaceous provides vital information about climate dynamics and ecological traits of organisms under the conditions of the “supergreenhouse” Earth. However, sub-annual scale paleotemperature records in the mid-latitude region remain limited. In this study, sclerochronological and stable oxygen isotope (δ18O) analyses of bivalve fossils from the northwestern Pacific (paleolatitude: 44°N) were used to estimate their life history and sub-annual scale temperature patterns of the middle Cretaceous. The materials studied included Cucullaea (Idonearca) delicatostriata and Aphrodina pseudoplana recovered from middle Turonian (middle Cretaceous) shallow marine deposits in Hokkaido, northern Japan. Growth increment width and shell δ18O of C. (I.) delicatostriata revealed that the growth rate was temporally maximized and then minimized, which can be interpreted as representing spring and winter growth, respectively. Approximately 25 fortnightly growth increments occurred within that cycle, suggesting that shell formation proceeded continuously throughout the year. Based on shell δ18O values, shallow-water temperatures from 28°C to 35°C with 7°C seasonality were estimated, under the assumption that seawater δ18O values were annually invariant at −1‰ relative to VSMOW. This temperature seasonality in the middle Cretaceous is more than 5°C smaller than the seasonality of modern shallow-water environments at the same latitudes. These findings, taken together with previous studies of other oceanic regions, suggest that the Northern Hemisphere had low seasonal shallow-water temperature variation of up to 10°C in the middle Cretaceous.

Abstract Pathway selection principles in reversible reaction networks such as molecular self-assembly have not been established yet, because achieving kinetic control in reversible reaction networks is more complicated than in irreversible ones. In this study, we discovered that coordination squares consisting of cis-protected dinuclear rhodium(II) corner complexes and linear ditopic ligands are assembled under kinetic control, perfectly preventing the corresponding triangles, by modulating their energy landscapes with a weak monotopic carboxylate ligand (2,6-dichlorobenzoate: dcb–) as the leaving ligand. Experimental and numerical approaches revealed the self-assembly pathway where the cyclization step to form the triangular complex is blocked by dcb–. It was also found that one of the molecular squares assembled into a dimeric structure owing to the solvophobic effect, which was characterized by nuclear magnetic resonance spectroscopy and single-crystal X-ray analysis.

Intestinal Behçet disease (BD), associated with myelodysplastic syndrome (MDS), is often refractory to treatment. An 80-year-old man with trisomy 8 MDS (refractory anemia) developed intermittent fever. Despite investigations to exclude infectious disease, autoimmune disease, and malignancy as the cause of the fever, the etiology could not be determined. A colonoscopy revealed several shallow round ulcers in the ileocecal region and ascending colon, and the biopsy specimens showed nonspecific inflammation. Thereafter, the patient experienced abdominal pain and diarrhea. Other than an oral aphthous ulcer, the patient did not show symptoms to meet the diagnostic criteria for BD. The patient was diagnosed with intestinal ulcers (intestinal BD-like disease) with MDS and trisomy 8. After treatment failure with 5-aminosalicylic acid, steroid, colchicine, and azacitidine, cerebral infarction occurred. Eating was difficult because of the patient’s impaired consciousness; hence, total parenteral nutrition (TPN) was commenced. The fever and abdominal symptoms improved with bowel rest over approximately 1 month. Small amounts of food were orally administered to the patient following recovery from the after-effects of the cerebral infarction, but diarrhea and fever repeatedly flared up. Therefore, TPN was continued at home. The patient has not experienced any further intestinal BD symptoms for approximately 1 year with bowel rest. Nutritional therapy, including bowel rest, may be an effective treatment option for intestinal BD with MDS, and might be used as an induction therapy of remission or a supportive therapy for other treatments.

Abstract Background Pulmonary sequestration is a rare pulmonary malformation, with intralobar pulmonary sequestration being the most common subtype. Lobectomy has generally been performed for its treatment, owing to unclear boundaries of the lesion. However, recent reports have introduced lung resection using intravenous indocyanine green (ICG) as a treatment for pulmonary sequestrations. Case description A 34-year-old woman presented with chest pain, and enhanced chest computed tomography (CT) displayed a solid mass of 4.5 × 3.1 cm in the right S10 area. An aberrant artery was found running from the celiac artery through the diaphragm to the thoracic cavity. The patient was diagnosed as having pulmonary sequestration Pryce type III, and surgical resection was performed. Intrathoracic findings demonstrated that the precise area of the pulmonary sequestration could not be clearly identified, and a 5-mm aberrant artery was present in the pulmonary ligament. Following the separation of the aberrant artery, intravenous injection of ICG clearly delineated the border between the normal lung tissue and the pulmonary sequestration. Wedge resection was then performed without any postoperative events, and the pathological diagnosis was also pulmonary sequestration. Conclusions We herein reported a case of a patient who underwent sublobar resection for intrapulmonary sequestration using intravenous ICG injection, together with a literature review. Our case suggests that a comprehensive understanding of abnormal vessels and pulmonary vasculature in pulmonary resection for intrapulmonary sequestrations, complemented with the use of ICG, might potentially avoid unnecessary pulmonary resection and enable sublobar surgical resection.

Abstract Primary tumor cells metastasize to a distant preferred organ. However, the most decisive host factors that determine the precise locations of metastases in cancer patients remain unknown. We have demonstrated that post-translational citrullination of fibrinogen creates a metastatic niche in the vulnerable spots. Pulmonary endothelial cells mediate the citrullination of fibrinogen, changing its conformation, surface charge, and binding properties with serum amyloid A proteins (SAAs), to make it a host tissue-derived metastatic pathogen. The human-specific SAAs-citrullinated fibrinogen (CitFbg) complex recruits cancer cells to form a protein-metastatic cell aggregation in humanized SAA cluster mice. Furthermore, a CitFbg peptide works as a competitive inhibitor to block the homing of metastatic cells into the SAAs-CitFbg sites. The potential metastatic sites in the lungs of patients are clearly visualized by our specific antibody for CitFbg. Thus, CitFbg deposition displays metastatic risks for cancer patients, and the citrullinated peptide is a new type of metastasis inhibitor.

Abstract Background Combination therapy with tazobactam/ceftolozane (TAZ/CTLZ) and high-dose aminoglycosides has been reported to be efficacious in extensively drug-resistant (XDR)-Pseudomonas aeruginosa infection. However, there are no reports of efficacy in XDR-P. aeruginosa infection for combination therapy with low-dose aminoglycosides and TAZ/CTLZ. Herein, we describe a rare case of severe burn injury patients with persistent bacteremia due to XDR-P. aeruginosa, which was successfully treated with TAZ/CTLZ and low-dose tobramycin (TOB). Case presentation A 31-year-old man was admitted to the intensive care unit with severe burn injury involving 52% of the total body surface area and a prognostic burn index of 79.5. The patient had recurrent bacterial infections since admission, and blood cultures collected on the 37th day of admission revealed the presence of P. aeruginosa strains that were resistant to all β-lactams and amikacin (AMK). The results of the antimicrobial synergistic study showed no synergistic effect of low-dose meropenem (MEPM) and AMK combination therapy. The patient had acute renal failure, and it was difficult to increase the dose of MEPM and AMK, respectively. Thus, we initiated TAZ/CTLZ 1.5 g/8 h instead of the AMK and MEPM combination therapy on the 43rd day of hospitalization. Low-dose TAZ/CTLZ was continued because of prolonged renal dysfunction and resulted in a transient clinical improvement. However, the dosage of TAZ/CTLZ could be increased as the renal function improved, but despite an increased TAZ/CTLZ dose, bacteremia persisted, and the blood cultures remained positive. Thus, TOB was added to TAZ/CTLZ at low doses for synergistic effect against Gram-negative bacteria. Blood cultures collected after initiation of combination therapy with TAZ/CTLZ and low-dose TOB were negative on two consecutive follow-up evaluations. Thereafter, although the patient had several episodes of fever and increased inflammatory response, blood cultures consistently tested negative, and all of the wounds healed. On the 93rd day, due to the good healing progress, the patient was transferred to another hospital. Conclusions TAZ/CTLZ and low-dose TOB combination therapy showed the potential for synergistic effects. Our present report suggests a novel synergistic treatment strategy for rare cases that are refractory to the treatment of infections, such as XDR-P. aeruginosa infection.

Abstract Background Rechallenge with platinum‐combination chemotherapy in patients with advanced non‐small cell lung cancer (NSCLC) after disease progression on platinum‐combination chemotherapy occasionally leads to a favorable response. The efficacy and safety of platinum‐combination chemotherapy with or without immune‐checkpoint inhibitor (ICI) for patients with recurrent NSCLC after surgery followed by adjuvant platinum‐doublet chemotherapy remains uncertain. Methods Patients who relapsed after surgery plus adjuvant platinum‐doublet chemotherapy and received platinum‐combination chemotherapy with or without ICI between April 2011 and March 2021 at four Nippon Medical School hospitals were retrospectively analyzed. Results Among 177 patients who received adjuvant platinum‐doublet chemotherapy after surgery, a total of 30 patients who received platinum‐combination rechemotherapy with or without ICI after relapse were included in this study. Seven patients received ICI‐combined chemotherapy. The median disease‐free survival (DFS) after surgery was 13.6 months. The objective response rate and disease‐control rate were 46.7% and 80.0%, respectively. The median progression‐free survival and overall survival were 10.2 and 37.5 months, respectively. Patients with longer DFS (≥12 months) had a better prognosis than others. The most common grade ≥3 toxicity associated with this treatment was neutropenia (33%). Grade ≥3 immune‐related adverse events were pneumonitis (14%) and colitis (14%). Treatment‐related deaths did not occur in this study. Conclusion Platinum‐combination chemotherapy with or without ICI for patients with postoperative recurrent NSCLC who previously received adjuvant platinum‐doublet chemotherapy was effective and safe. In particular, this therapy may be promising for patients with longer DFS.

Abstract Background Colistin (CST) is a last-line drug for multidrug-resistant Gram-negative bacterial infections. CST-heteroresistant Enterobacter cloacae complex (ECC) has been isolated. However, integrated analysis of epidemiology and resistance mechanisms based on the complete ECC species identification has not been performed. Methods Clinical isolates identified as “E. cloacae complex” by MALDI-TOF MS Biotyper Compass in a university hospital in Japan were analyzed. Minimum inhibitory concentrations of CST were determined by the broth microdilution method. The population analysis profiling (PAP) was performed for detecting the heteroresistant phenotype. The heat shock protein 60 (hsp60) cluster was determined from its partial nucleotide sequence. From the data of whole-genome sequencing, average nucleotide identity (ANI) for determining ECC species, multilocus sequence type, core genome single-nucleotide-polymorphism-based phylogenetic analysis were performed. phoPQ-, eptA-, and arnT-deleted mutants were established to evaluate the mechanism underlying colistin heteroresistance. The arnT mRNA expression levels were determined by reverse transcription quantitative PCR. Results Thirty-eight CST-resistant isolates, all of which exhibited the heteroresistant phenotype by PAP, were found from 138 ECC clinical isolates (27.5%). The prevalence of CST-resistant isolates did not significantly differ among the origin of specimens (29.0%, 27.8%, and 20.2% for respiratory, urine, and blood specimens, respectively). hsp60 clusters, core genome phylogeny, and ANI revealed that the CST-heteroresistant isolates were found in all or most of Enterobacter roggenkampii (hsp60 cluster IV), Enterobacter kobei (cluster II), Enterobacter chuandaensis (clusters III and IX), and Enterobacter cloacae subspecies (clusters XI and XII). No heteroresistant isolates were found in Enterobacter hormaechei subspecies (clusters VIII, VI, and III) and Enterobacter ludwigii (cluster V). CST-induced mRNA upregulation of arnT, which encodes 4-amino-4-deoxy-l-arabinose transferase, was observed in the CST-heteroresistant isolates, and it is mediated by phoPQ pathway. Isolates possessing mcr-9 and mcr-10 (3.6% and 5.6% of total ECC isolates, respectively) exhibited similar CST susceptibility and PAP compared with mcr-negative isolates. Conclusions Significant prevalence (approximately 28%) of CST heteroresistance is observed in ECC clinical isolates, and they are accumulated in specific species and lineages. Heteroresistance is occurred by upregulation of arnT mRNA induced by CST. Acquisition of mcr genes contributes less to CST resistance in ECC.

IntroductionPatients with COVID-19 have dysbiosis of the intestinal microbiota with altered metabolites in the stool. However, it remains unclear whether the differences among SARS-CoV-2 variants lead to differences in intestinal microbiota and metabolites. Thus, we compared the microbiome and metabolome changes for each SARS-CoV-2 variant in patients with COVID-19.Materials and methodsWe conducted a multicenter observational study of patients with COVID-19 and performed fecal microbiome, metabolome, and calprotectin analyses and compared the results among the different SARS-CoV-2 variants.ResultsTwenty-one patients with COVID-19 were enrolled and stratified according to the SARS-CoV-2 strain: six with the Alpha, 10 with the Delta, and five with the Omicron variant. Fecal microbiome analysis showed that α-diversity was reduced in the order of the Omicron, Delta, and Alpha variants (p = 0.07). Linear discriminant analysis revealed differences in the abundance of short-chain fatty acid-producing gut microbiota for each SARS-CoV-2 variant. Fecal metabolome analysis showed that the Omicron and Delta variants had markedly reduced propionic and lactic acid levels compared to the Alpha strain (p

Chemical priming has emerged as a promising area in agricultural research. Our previous studies have demonstrated that pretreatment with a low concentration of ethanol enhances abiotic stress tolerance in Arabidopsis and cassava. Here, we show that ethanol treatment induces heat stress tolerance in tomato (Solanum lycopersicon L.) plants. Seedlings of the tomato cultivar ‘Micro-Tom’ were pretreated with ethanol solution and then subjected to heat stress. The survival rates of the ethanol-pretreated plants were significantly higher than those of the water-treated control plants. Similarly, the fruit numbers of the ethanol-pretreated plants were greater than those of the water-treated ones. Transcriptome analysis identified sets of genes that were differentially expressed in shoots and roots of seedlings and in mature green fruits of ethanol-pretreated plants compared with those in water-treated plants. Gene ontology analysis using these genes showed that stress-related gene ontology terms were found in the set of ethanol-induced genes. Metabolome analysis revealed that the contents of a wide range of metabolites differed between water- and ethanol-treated samples. They included sugars such as trehalose, sucrose, glucose, and fructose. From our results, we speculate that ethanol-induced heat stress tolerance in tomato is mainly the result of increased expression of stress-related genes encoding late embryogenesis abundant (LEA) proteins, reactive oxygen species (ROS) elimination enzymes, and activated gluconeogenesis. Our results will be useful for establishing ethanol-based chemical priming technology to reduce heat stress damage in crops, especially in Solanaceae.

Patients with coronavirus disease-2019 (COVID-19) have an increased risk of thrombosis and acute respiratory distress syndrome (ARDS). Thrombosis is often attributed to increases in plasminogen activator inhibitor-1 (PAI-1) and a shut-down of fibrinolysis (blood clot dissolution). Decreased urokinase-type plasminogen activator (uPA), a protease necessary for cell-associated plasmin generation, and increased tissue-type plasminogen activator (tPA) and PAI-1 levels have been reported in COVID-19 patients. Because these factors can occur in free and complexed forms with differences in their biological functions, we examined the predictive impact of uPA, tPA, and PAI-1 in their free forms and complexes as a biomarker for COVID-19 severity and the development of ARDS. In this retrospective study of 69 Japanese adults hospitalized with COVID-19 and 20 healthy donors, we found elevated free, non-complexed PAI-1 antigen, low circulating uPA, and uPA/PAI-1 but not tPA/PAI-1 complex levels to be associated with COVID-19 severity and ARDS development. This biomarker profile was typical for patients in the complicated phase. Lack of PAI-1 activity in circulation despite free, non-complexed PAI-1 protein and plasmin/α2anti-plasmin complex correlated with suPAR and sVCAM levels, markers indicating endothelial dysfunction. Furthermore, uPA/PAI-1 complex levels positively correlated with TNFα, a cytokine reported to trigger inflammatory cell death and tissue damage. Those levels also positively correlated with lymphopenia and the pro-inflammatory factors interleukin1β (IL1β), IL6, and C-reactive protein, markers associated with the anti-viral inflammatory response. These findings argue for using uPA and uPA/PAI-1 as novel biomarkers to detect patients at risk of developing severe COVID-19, including ARDS.

Objectives: Influenza virus infection (IVI) occasionally causes lower respiratory tract infection (LRTI) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Although the progression to LRTI entails a high mortality, the role of early antiviral therapy for its prevention has not been fully elucidated. Methods: This was a multicenter retrospective study using an additional questionnaire. Allo-HSCT recipients who developed IVI between 2012 and 2020 were included. Results: A total of 278 cases of IVI after allo-HSCT were identified from 15 institutions. The median patient age was 49 years, and the median time from allo-HSCT to IVI was 918 days. Neuraminidase inhibitors were administered within 48 hours of symptom onset (early neuraminidase inhibitor [NAI]) in 199 (76.9%) patients. Subsequently, 36 (12.3%) patients developed LRTI. On the multivariate analysis, age ≥50 years (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.02-4.58) and moderate to severe chronic graft-versus-host disease (HR, 2.28; 95% CI, 1.14-4.58) were significantly associated with progression to LRTI, whereas early NAI suppressed the progression (HR, 0.17; 95% CI, 0.06-0.46). The IVI-related mortality rate was 2.2%. Conclusion: To reduce the risk of LRTI development after IVI, early NAI therapy should be considered in allo-HSCT recipients, especially with older patients and those with chronic graft-versus-host disease.

Abstract The exact drivers for the end-Permian mass extinction (EPME) remain controversial. Here we focus on a ~10,000 yr record from the marine type section at Meishan, China, preceding and covering the onset of the EPME. Analyses of polyaromatic hydrocarbons at sampling intervals representing 1.5–6.3 yr reveal recurrent pulses of wildfires in the terrestrial realm. Massive input pulses of soil-derived organic matter and clastic materials into the oceans are indicated by patterns of C2-dibenzofuran, C30 hopane and aluminum. Importantly, in the ~2,000 years preceding the main phase of the EPME, we observe a clearly defined sequence of wildfires, soil weathering, and euxinia provoked by the fertilization of the marine environment with soil-derived nutrients. Euxinia is indicated by sulfur and iron concentrations. Our study suggests that, in South China, centennial scale processes led to a collapse of the terrestrial ecosystem ~300 yr (120–480 yr; ± 2 s.d.) before the onset of the EPME and that this collapse induced euxinic conditions in the ocean, ultimately resulting in the demise of marine ecosystems.

Construction and screening of a library of all stereochemical isomers of coronatine, a mimic of the plant hormone (+)-7-iso-jasmonoyl-L-isoleucine, identify subtype-selective agonists for COI1-JAZ co-receptors in A. thaliana and S. lycopersicum.

Abstract Background Earlier studies have shown male dominance of an early repolarization (ER) pattern and frequent coexistence with high Sokolow‐Lyon voltage. Although possible involvement of androgen is speculated, the underlying mechanism has not been clarified yet. Previous studies were conducted in adult populations or only in children, and there has been no study in which the ER pattern was investigated in a series of individuals ranging from children before puberty to adults. Methods We included 600 individuals comprising six groups according to age: 10–14 years old, 15–19 years old, twenties, thirties, forties, and fifties. Each group had 50 males and 50 females. The distribution of an ER pattern and related ECG parameters were assessed by age and gender. Results In early teenagers, there was no significant gender difference in the prevalence of an ER pattern (24% in men vs. 28% in women, p = .82). The prevalence of an ER pattern increased after puberty and reached a peak in men in their twenties (42%). With further advance of age, the prevalence of an ER pattern decreased. On the other hand, the prevalence of an ER pattern in women peaked at 28% in teenagers, and it decreased through twenties (20%) to thirties (10%). Similar male dominance after puberty was observed in Sokolow‐Lyon voltage and J‐point elevation but not in P‐wave amplitude. Conclusion The prevalence of an ER pattern, Sokolow‐Lyon voltage, and J‐point elevation are all augmented after puberty and decrease with aging, leading to frequent coexistence of these ECG findings in young men.

Candidates and other stakeholders often wish to know the difficulty level of exams, particularly compared with other exams in the same domain. Peak Shift Estimation (PSE) is a method for estimating the comparative difficulty of exams. However, this method requires users to correctly identify the most difficult exam in advance, which is not always possible. Therefore, we aimed to develop an improved version of PSE to overcome this limitation. Our new algorithm involves two key improvements. First, our method overcomes the issue described above using each exam as the most difficult in turn, and comparing the results. The second improvement addresses a potential problem which the first improvement, caused by the large number of exams of moderate difficulty. Instead of using all exams, our method randomly selects a subset of exams to remove this potential problem. We validated our new algorithm using data for the number of successful applicants at different universities from high schools in the Tokyo metropolitan area. The Improved PSE method correctly estimated the comparative difficulty of university entrance exams without prior knowledge of the most difficult exam. Few previous studies have considered selectively omitted exam data. The current findings should encourage other researchers to use these data in future studies.

MraY is a membrane enzyme required for bacterial cell wall synthesis. Here, the authors modify sphaerimicins as antibacterials targeting it via structure-based design and synthesis through two key reactions, showing a platform for further development of MraY inhibitors as antibacterials.

Abstract Background Subarachnoid hemorrhage (SAH) is a fatal disease, with early brain injury (EBI) occurring within 72 h of SAH injury contributes to its poor prognosis. EBI is a complicated phenomenon involving multiple mechanisms. Although neuroinflammation has been shown to be important prognosis factor of EBI, whether neuroinflammation spreads throughout the cerebrum and the extent of its depth in the cerebral cortex remain unknown. Knowing how inflammation spreads throughout the cerebrum is also important to determine if anti-inflammatory agents are a future therapeutic strategy for EBI. Methods In this study, we induced SAH in mice by injecting hematoma into prechiasmatic cistern and created models of mild to severe SAH. In sections of the mouse cerebrum, we investigated neuroinflammation and neuronal cell death in the cortex distal to the hematoma injection site, from anterior to posterior region 24 h after SAH injury. Results Neuroinflammation caused by SAH spread to all layers of the cerebral cortex from the anterior to the posterior part of the cerebrum via the invasion of activated microglia, and neuronal cell death increased in correlation with neuroinflammation. This trend increased with the severity of the disease. Conclusions Neuroinflammation caused by SAH had spread throughout the cerebrum, causing neuronal cell death. Considering that the cerebral cortex is responsible for long-term memory and movement, suppressing neuroinflammation in all layers of the cerebral cortex may improve the prognosis of patients with SAH.

The establishment of a mouse model of MLL-AF4-induced leukaemia is a challenge as the introduction of fusion gene of human MLL-AF4 does not cause leukaemia in mice. Here the authors reveal that MLL-AF4 is post-transcriptionally regulated by RNA-binding proteins that inhibits MLL-AF4 translation, thus, hampering MLL-AF4-mediated leukemic transformation.

Japan has reported a relatively small number of COVID-19 cases. Because not all infected persons receive diagnostic tests for COVID-19, the reported number must be lower than the actual number of infections. We assessed SARS-CoV-2 seroprevalence by analyzing >60,000 samples collected in Japan (Tokyo Metropolitan Area and Hokkaido Prefecture) during February 2020–March 2022. The results showed that ≈3.8% of the population had become seropositive by January 2021. The seroprevalence increased with the administration of vaccinations; however, among the elderly, seroprevalence was not as high as the vaccination rate. Among children, who were not eligible for vaccination, infection was spread during the epidemic waves caused by the SARS-CoV-2 Delta and Omicron variants. Nevertheless, seroprevalence for unvaccinated children

Abstract Since U.S. President Barack Obama announced the Precision Medicine Initiative in his New Year’s State of the Union address in 2015, the establishment of a precision medicine system has been emphasized worldwide, particularly in the field of oncology. With the advent of next-generation sequencers specifically, genome analysis technology has made remarkable progress, and there are active efforts to apply genome information to diagnosis and treatment. Generally, in the process of feeding back the results of next-generation sequencing analysis to patients, a molecular tumor board (MTB), consisting of experts in clinical oncology, genetic medicine, etc., is established to discuss the results. On the other hand, an MTB currently involves a large amount of work, with humans searching through vast databases and literature, selecting the best drug candidates, and manually confirming the status of available clinical trials. In addition, as personalized medicine advances, the burden on MTB members is expected to increase in the future. Under these circumstances, introducing cutting-edge artificial intelligence (AI) technology and information and communication technology to MTBs while reducing the burden on MTB members and building a platform that enables more accurate and personalized medical care would be of great benefit to patients. In this review, we introduced the latest status of elemental technologies that have potential for AI utilization in MTB, and discussed issues that may arise in the future as we progress with AI implementation.

Abstract Acute graft‐versus‐host disease (aGvHD) remains a major threat to a successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Although antibody‐based targeting of the CD40/CD40 ligand costimulatory pathway can prevent aGvHD, side effects hampered their clinical application, prompting a need for other ways to interfere with this important dendritic T‐cell costimulatory pathway. Here, we used small interfering RNA (siRNA) complexed with β‐glucan allowing the binding and uptake of the siRNA/β‐glucan complex (siCD40/schizophyllan [SPG]; chemical modifications called NJA‐312, NJA‐302, and NJA‐515) into Dectin1+ cells, which recognize this pathogen‐associated molecular pattern receptor. aGvHD was induced by the transplantation of splenocytes and bone marrow cells from C57BL/6J into CBF1 mice. Splenic dendritic cells retained Dectin1 expression after HSCT but showed lower expression after irradiation. The administration of siCD40/SPG, NJA‐312, and NJA‐302 ameliorated aGvHD‐mediated lethality and tissue damage of spleen and liver, but not skin. Multiple NJA‐312high injections prevented aGvHD but resulted in early weight loss in allogeneic HSCT mice. In addition, NJA‐312 treatment caused delayed initial donor T and B‐cell recovery but resulted in stable chimerism in surviving mice. Mechanistically, NJA‐312 reduced organ damage by suppressing CCR2+, F4/80+, and IL17A‐expressing cell accumulation in spleen, liver, and thymus but not the skin of mice with aGvHD. Our work demonstrates that siRNA targeting of CD40 delivered via the PAMP‐recognizing lectin Dectin1 changes the immunological niche, suppresses organ‐specific murine aGvHD, and induces immune tolerance after organ transplantation. Our work charts future directions for therapeutic interventions to modulate tissue‐specific immune reactions using Pathogen‐associated molecular pattern (PAMP) molecules like 1,3‐β‐glucan for cell delivery of siRNA.

Pelagic deep-sea siliceous successions in accretionary complexes preserve precious records of a vast deep seafloor that is now lost due to plate subduction. Microfossils are the key means of age assignment of these successions, but poor preservation due to tectonic deformation and metamorphism at the subduction zone hamper biostratigraphic records. X-ray computed microtomography, while not widely used in biostratigraphic studies until now, allows us to visualize fossils that are impossible or difficult to extract from host rocks due to poor preservation. In this study, we applied this method on conodonts from a pelagic chert–claystone succession in Okoshizawa, Iwaizumi Town, Northeast Japan, using a laboratory-based X-ray microscope. This work is a first close look at conodont biostratigraphy across the Carboniferous–Permian boundary in pelagic deep Panthalassa. We identified conodonts including ten species that are used as zonal markers in intensely studied areas such as around the East European Platform and Midcontinent United States. Based on the occurrence of conodonts, the studied section in Okoshizawa was correlated to the lower Moscovian to middle Artinskian. Confirmation of Moscovian to Artinskian age diagnostic conodonts from pelagic Panthalassa strengthens their role as global biostratigraphic indicators. By identifying more numerous specimens compared to the conventional hydrofluoric acid dissolution method, we were able to obtain information about conodont faunal characteristics around the Carboniferous–Permian boundary in pelagic deep areas of Panthalassa. The dominant taxa changed from Streptognathodus to Mesogondolella in the middle Asselian, probably reflecting an ecological takeover by the latter in the deep waters.

Two mechanisms of drug-induced interstitial lung disease (DILD) have been reported: 1) direct injury of lung epithelial cells and/or endothelial cells in lung capillaries by the drug and/or its metabolites and 2) hypersensitivity reactions. In both mechanisms, immune reactions such as cytokine and T cell activation are involved in DILD. While past and present lung diseases and accumulative lung damage due to smoking and radiation are risk factors for DILD, the association between the immune status of the host and DILD is not well known. Herein, we report a case of advanced colorectal cancer with a history of allogeneic bone marrow transplantation for aplastic anemia more than 30 years prior, in which DILD occurred early after irinotecan-containing chemotherapy. Bone marrow transplantation might be a potential risk factor for DILD.

ABSTRACT: Objectives: The dissemination of difficult-to-treat carbapenem-resistant Enterobacterales (CRE) is of great concern. We clarified the risk factors underlying CRE infection mortality in Japan. Methods: We conducted a retrospective, multicentre, observational cohort study of patients with CRE infections at 28 university hospitals from September 2014 to December 2016, using the Japanese National Surveillance criteria. Clinical information, including patient background, type of infection, antibiotic treatment, and treatment outcome, was collected. The carbapenemase genotype was determined using PCR sequencing. Multivariate analysis was performed to identify the risk factors for 28-day mortality. Results: Among the 179 patients enrolled, 65 patients (36.3%) had bloodstream infections, with 37 (20.7%) infections occurring due to carbapenemase-producing Enterobacterales (CPE); all carbapenemases were of IMP-type (IMP-1: 32, IMP-6: 5). Two-thirds of CPE were identified as Enterobacter cloacae complex. Combination therapy was administered only in 46 patients (25.7%), and the 28-day mortality rate was 14.3%. Univariate analysis showed that solid metastatic cancer, Charlson Comorbidity Index ≥3, bloodstream infection, pneumonia, or empyema, central venous catheters, mechanical ventilation, and prior use of quinolones were significant risk factors for mortality. Multivariate analysis revealed that mechanical ventilation (OR: 6.71 [1.42–31.6], P = 0.016), solid metastatic cancers (OR: 5.63 [1.38–23.0], P = 0.016), and bloodstream infections (OR: 3.49 [1.02–12.0], P = 0.046) were independent risk factors for 28-day mortality. Conclusion: The significant risk factors for 28-day mortality in patients with CRE infections in Japan are mechanical ventilation, solid metastatic cancers, and bloodstream infections.

Abstract Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998–2007 vs 2008–2013 vs 2014–2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years.

Abstract Background Early type IIIb endoleak is a very rare complication of endovascular aneurysm repair (EVAR). Case presentation An 87-year-old man was diagnosed with infrarenal abdominal aortic aneurysm. The patient underwent EVAR using the Endurant stent graft. Postoperative color duplex ultrasound revealed a regular row of pulsatile blood flow from the main body and left leg. The blood flow appeared to be bleeding from the stent suture lines because of its regularity. Type IIIb endoleak was suspected due to stent suture line fabric breakage but was not treated surgically or endovascularly because of the patient’s poor general health status. Six months later, contrast-enhanced CT demonstrated a deformation and enlargement of the aneurysm sac as well as an oozing of the contrast medium on the main body and left limb. Thereafter, he died of a subdural hematoma due to a fall. Autopsy showed no visible abnormal erosion or holes on the graft fabric, suggesting that suture line fabric breakage may have existed during the manufacturing process. Conclusions Although rare, type IIIb endoleaks can occur even in the perioperative period after EVAR. Early type IIIb endoleaks may not resolve spontaneously and should be treated promptly, if possible.

Abstract We retrospectively evaluated the optimal time and threshold of absolute lymphocyte count (ALC) recovery as a prognostic factor in 174 adult patients who received single‐unit cord blood transplantation (CBT) at our institute. We analyzed the impact of ALC ≥300, ≥600, and ≥900/μl by 30 and 60 days on transplant outcomes. Multivariate analysis showed that only ALC ≥300/μl at 60 days was significantly associated with overall mortality (hazard ratio, 0.24; p = 0.001) following CBT. The optimal time point to use ALC recovery as a prognostic tool following CBT could be later than those following adult donor transplantation.

We report a patient with a symptomatic intraluminal internal carotid artery thrombus clinically revealed by cerebral infarction. In the preoperative evaluation, it was revealed that essential thrombocythemia existed in the background. Therefore, medical treatment with antithrombotic agents in conjunction with hydroxycarbamide for essential thrombocythemia was initiated, but the thrombus was not dissolved by three weeks. At this time, the patient underwent carotid endarterectomy, which removed the thrombus completely with its adjacent plaque without any perioperative stroke. The possibility of essential thrombocythemia may also be kept in mind when an increased platelet count is observed in patients with internal carotid artery thrombus. It is a reasonable option to precede medical treatment, including anticoagulant therapy, by setting the time limit for surgical intervention in such a disease state.

BackgroundInflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by recurrent flare-ups and remission. Leucine-rich α2-glycoprotein (LRG) has been developed as a new serum biomarker of disease activity in patients with IBD. However, there have been no reports on whether plasma LRG can be used as an alternative to serum LRG. Therefore, in this retrospective study, we evaluated the usefulness of plasma LRG compared to serum LRG.MethodsWe conducted a single-center retrospective observational study. A total of 108 IBD patients (ulcerative colitis [UC], 56; Crohn's disease [CD], 52) who received treatment at Sapporo Medical University Hospital between August 2020 and September 2021 were enrolled. Serum and plasma LRG levels were measured using the NANOPIA LRG kit. Disease activity was assessed using the Crohn's Disease Activity Index (CDAI) for CD and partial Mayo (pMayo) score for UC. Endoscopic activity was evaluated using the Mayo Endoscopic Subscore (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) in patients with UC and the Simple Endoscopic Score for Crohn's Disease (SES-CD) score in patients with CD.ResultsSerum LRG levels significantly correlated with plasma LRG levels (r = 0.990, pConclusionThe present study showed that plasma LRG levels correlate well with serum LRG levels. Therefore, plasma LRG can be clinically applied as a biomarker for assessing endoscopic disease activity in patients with IBD.