Early defibrotide therapy and risk factors for post-transplant veno-occlusive disease/sinusoidal obstruction syndrome in childhood.

BACKGROUND: Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complications of hematopoietic cell transplantation (HCT). METHODS: We studied the impact of early defibrotide (DF) therapy on the outcomes of pediatric patients with VOD/SOS after transplantation, focusing on recent immunotherapies. A total of 111 pediatric patients who underwent HCT for malignant disease between February 2017 and March 2023 at Kyushu University Hospital were included. RESULTS: Among 111 patients of less than 20 years of age who underwent HCT for malignancy at a single institution between 2017 and 2023, VOD/SOS occurred in 25 (23%) patients. VOD/SOS developed more frequently in the post-DF era (2020-2023, n = 58) than in the pre-DF era (31% vs. 13%, p = .04). The proportion of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) was higher in the post-DF era than in the pre-DF era (44% vs. 8%, p = .04). Early DF therapy that was started at two European Society for Blood and Marrow Transplantation diagnostic criteria reduced the severity of VOD/SOS (p < .01) in comparison to non-early therapy started at less than two criteria. A multivariate analysis indicated that a history of cytokine release syndrome (odds ratio [OR] = 10.4, p = .01) and juvenile myelomonocytic leukemia (OR = 8.98, p = .04), but not an endothelial activation and stress index (EASIX) score of greater than 0.85, were independent risk factors for VOD/SOS. CONCLUSIONS: Early DF therapy improves the severity and survival outcomes of post-transplant VOD/SOS in children. However, its incidence is increasing in the era of immunotherapy for progressive diseases.

Acaricide Flupentiofenox Inhibits the Mitochondrial ß-Oxidation Pathway of Fatty Acids.

A newly developed pesticide, flupentiofenox, has a unique trifluoroethyl phenylsulfoxide structure, and it powerfully affects spider mites, including those with resistance to multiple commercial acaricides. To clarify the mode of action of flupentiofenox, we investigated its effect on mitochondrial energy generation. We observed that flupentiofenox decreased adenosine triphosphate (ATP) levels in two-spotted spider mites (Tetranychus urticae) at a practical dose. Flupentiofenox potently inhibited mitochondrial oxygen consumption under conditions of palmitoyl-carnitine or octanoic acid supply, but not under conditions of pyruvate supply. These results show that flupentiofenox inhibits the mitochondrial fatty acid metabolic pathway between the uptake of long-chain acylcarnitine or medium-chain fatty acid and the synthesis of acetyl-CoA by ß-oxidation, resulting in suppressed mitochondrial energy generation. Our investigations have led us to conclude that flupentiofenox is a pesticide with a novel mode of action.

Ultrathin Ionic Diodes with Electrostatically Heterogeneous Hybrid Interfaces of Nanoporous SiO2 Nanofilms and Polymer Layer-by-Layer Multilayers.

Nanofluidic ionic diodes have attracted much attention due to their unique functions as unidirectional ion transportation ability and promising applications from molecular sensing, and energy harvesting to emerging neuromorphic devices. However, it remains a challenge to fabricate diode-like nanofluidic systems with ultrathin film thickness <100 nm. Herein the formation of ultrathin ionic diodes from hybrid nanoassemblies of nanoporous (NP) SiO2 nanofilms and polyelectrolyte layer-by-layer (LbL) multilayers is described. Ultrathin ionic diodes are prepared by integrating polyelectrolyte multilayers onto photo-oxidized NP SiO2 nanofilms obtained from silsesquioxane-containing block copolymer thin films as a template. The obtained ultrathin ionic diodes exhibit ion current rectification (ICR) properties with high ICR factor = ≈20 under low ionic strength and asymmetric pH conditions. It is concluded that this ICR behavior arises from effective ion accumulation and depletion at the interface of NP SiO2 nanofilms and LbL multilayers attributed to high ion selectivity by combining the experimental data and theoretical calculations using finite element methods. These results demonstrate that the hybrid nano assemblies of NP SiO2 nanofilms and polyelectrolyte LbL multilayers have potential applications for (bio)sensing materials and integrated ionic circuits for seamless connection of human-machine interfaces.

Underwater EMR in the reconstructed gastric conduit after esophagectomy.

Video 1Three cases of underwater EMR for small gastric neoplasms in the reconstructed gastric conduit after esophagectomy.

High incidence of lung cancer death after curative endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

BACKGROUND AND AIM: Following treatment of superficial esophageal squamous cell carcinoma (ESCC), surveillance for a second primary malignancy (SPM) is necessary. However, detailed evidence regarding the timing and prognosis of SPMs is insufficient. We aimed to clarify the details of SPMs and their effects on patient outcomes. METHODS: This retrospective, multicenter study involved 11 hospitals. Patients with superficial ESCC curatively resected using endoscopic submucosal dissection between May 2005 and December 2012, were included in this study. RESULTS: The 5-year survival rate of 187 patients was 92.6% during a median follow-up duration of 96.8 months. Thirty-one patients died, 14 of whom died of SPMs. Compared to patients with SPMs detectable by esophagogastroduodenoscopy (EGD), patients with SPMs detectable only by modalities other than EGD had a significantly higher mortality rate (p < 0.001). Patients with second primary lung cancer (LC) had a high mortality rate (56.3%). Univariate and multivariate analyses showed that multiple Lugol-voiding lesions (LVLs) tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91-6.50), and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08-11.41). CONCLUSIONS: SPMs that cannot be detected by EGD, such as LC, must be considered after the curative resection of ESCC. We suggest strict screening by both EGD and computed tomography for patients with multiple LVLs or metachronous ESCC to detect SPMs in their early stages.

A machine learning model for predicting the lymph node metastasis of early gastric cancer not meeting the endoscopic curability criteria.

BACKGROUND: We developed a machine learning (ML) model to predict the risk of lymph node metastasis (LNM) in patients with early gastric cancer (EGC) who did not meet the existing Japanese endoscopic curability criteria and compared its performance with that of the most common clinical risk scoring system, the eCura system. METHODS: We used data from 4,042 consecutive patients with EGC from 21 institutions who underwent endoscopic submucosal dissection (ESD) and/or surgery between 2010 and 2021. All resected EGCs were histologically confirmed not to satisfy the current Japanese endoscopic curability criteria. Of all patients, 3,506 constituted the training cohort to develop the neural network-based ML model, and 536 constituted the validation cohort. The performance of our ML model, as measured by the area under the receiver operating characteristic curve (AUC), was compared with that of the eCura system in the validation cohort. RESULTS: LNM rates were 14% (503/3,506) and 7% (39/536) in the training and validation cohorts, respectively. The ML model identified patients with LNM with an AUC of 0.83 (95% confidence interval, 0.76-0.89) in the validation cohort, while the eCura system identified patients with LNM with an AUC of 0.77 (95% confidence interval, 0.70-0.85) (P = 0.006, DeLong's test). CONCLUSIONS: Our ML model performed better than the eCura system for predicting LNM risk in patients with EGC who did not meet the existing Japanese endoscopic curability criteria. We developed a neural network-based machine learning model that predicts the risk of lymph node metastasis in patients with early gastric cancer who did not meet the endoscopic curability criteria.

Carrier Transport Switching of Ferroelectric BTBT Derivative.

Alkylamide-substituted [1]benzothieno[3,2-b][1]benzothiophene (BTBT) derivative of BTBT-NHCOC14H29 (1), which has ferroelectric N-H···O= hydrogen-bonding network of alkylamide group and two-dimensional (2D) electric structure of BTBT π-cores, was prepared to design the external electric field-responsive organic semiconductors. The short-chain derivative of BTBT-NHCOC3H7 (1') revealed the coexistence of a 2D electronic band structure based on the herringbone BTBT arrangement and the one-dimensional (1D) hydrogen-bonding chain. 1 formed a smectic E (SmE) liquid crystal phase above 412 K and showed ferroelectric hysteresis in the electric field-polarization (P-E) curves at 403-433 K. The remanent polarization (Pr) and coercive electric field (Ec) of 1 at 408 K, 0.1 Hz were 24.0 µC cm-2 and 5.54 V µm-1, respectively. By thermal annealing of thin-film 1 at 443 K, the molecular assembly structure of 1 changed from a monolayer to a bilayer structure with high crystallinity, resulting in conducting layers of BTBT parallel to the substrate surface. The organic field-effect transistor (OFET) device with thermally annealed thin-film 1 showed p-type semiconducting behavior with the hole mobility of 1.0 × 10-3 cm2 V-1 s-1. Furthermore, device 1 showed switching behavior of semiconducting properties by electric field poling and thermal annealing cycle. The electric field response of ferroelectrics modulated the molecular orientation and conduction properties of organic semiconductors, resulting in external electric field control of carrier transport properties.

Comprehensive Epitope Analysis of Monoclonal Antibodies Binding to Hen Egg Ovalbumin Using a Peptide Array.

Food allergies are a significant health issue worldwide. In many countries, labeling of primary allergens in food products has been made mandatory to ensure consumer safety. In food manufacturing settings, the lateral flow immunoassay (LFI)-based on antigen-antibody reactions-is a rapid and accurate method for allergen testing and is widely used. Peptide arrays are tools that enable the synthesis of peptides of any sequence on a substrate and high-throughput analysis of their interactions with chemicals. This study aimed to investigate a new application of peptide arrays in the field of food technology, particularly in the development of antibodies for food allergen testing. First, monoclonal antibodies against hen egg ovalbumin, a major food allergen, were produced. Then, using a peptide array, the epitope and specificity of the antibodies were comprehensively and precisely analyzed. Finally, an LFI kit incorporating the antibodies demonstrated both high specificity and detection sensitivity for food allergen testing. These findings indicate that peptide arrays are valuable tools in the development of antibodies for food allergen testing, ensuring reliability and accuracy at the molecular level.

Multiemission of Ce3+ from a Single Crystallographic Site Induced by Disordering of Ions.

White-light emission with a single activator is an attractive function of phosphors. In this work, we investigated the photoluminescence properties of Ca5.7Y1.3Si7O16.7N3.3, which is a compound denoted as Ca4+xY3-xSi7O15+xN5-x discovered by our group, with Ce-activation using optical measurements and density functional theory (DFT) calculation. Samples showed a tunable emission from purple to white under ultraviolet (UV) light. In this compound, Ca and Y as well as anions are distributed disorderly, and Ca/Y ions occupy two crystallographically distinct sites; those sites are possible sites for Ce substitution. DFT calculation and structural refinement revealed that the tunable emission was generated by Ce at the crystallographically equivalent site but with distinct local structures caused by the disordering of cations and anions. As far as we know, this is the first report about a white-light-emitting phosphor with only Ce activation.

Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drug-induced thromboembolism.

ABSTRACT: Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography-mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

Impact of AI-aided colonoscopy in clinical practice: a prospective randomised controlled trial.

OBJECTIVE: Colorectal cancer (CRC) has a significant role in cancer-related mortality. Colonoscopy, combined with adenoma removal, has proven effective in reducing CRC incidence. However, suboptimal colonoscopy quality often leads to missed polyps. The impact of artificial intelligence (AI) on adenoma and polyp detection rate (ADR, PDR) is yet to be established. DESIGN: We conducted a randomised controlled trial at Sahlgrenska University Hospital in Sweden. Patients underwent colonoscopy with or without the assistance of AI (AI-C or conventional colonoscopy (CC)). Examinations were performed with two different AI systems, that is, Fujifilm CADEye and Medtronic GI Genius. The primary outcome was ADR. RESULTS: Among 286 patients, 240 underwent analysis (average age: 66 years). The ADR was 42% for all patients, and no significant difference emerged between AI-C and CC groups (41% vs 43%). The overall PDR was 61%, with a trend towards higher PDR in the AI-C group. Subgroup analysis revealed higher detection rates for sessile serrated lesions (SSL) with AI assistance (AI-C 22%, CC 11%, p=0.004). No difference was noticed in the detection of polyps or adenomas per colonoscopy. Examinations were most often performed by experienced endoscopists, 78% (n=86 AI-C, 100 CC). CONCLUSION: Amidst the ongoing AI integration, ADR did not improve with AI. Particularly noteworthy is the enhanced detection rates for SSL by AI assistance, especially since they pose a risk for postcolonoscopy CRC. The integration of AI into standard colonoscopy practice warrants further investigation and the development of improved software might be necessary before enforcing its mandatory implementation. TRIAL REGISTRATION NUMBER: NCT05178095.

Pediatric leukemia and maternal occupational exposure to anticancer drugs: the Japan Environment and Children's Study.

ABSTRACT: Occupational exposure to medical agents and ionizing radiation has been suggested as a possible risk factor for childhood cancer. However, the relationship between such exposure and pediatric malignant neoplasms has not yet been comprehensively studied. This cohort study aimed to investigate the association between parental occupational exposure to hazardous medical agents or ionizing radiation and the risk of childhood cancer in offspring. Data from a large birth cohort in Japan, which included 104 062 fetuses, were analyzed. The primary outcome was the development of leukemia or brain tumors diagnosed by community physicians during the first 3 years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for 3 months before conception. The incidence of leukemia, but not of brain tumors, was higher in mothers exposed to anticancer drugs. Multivariable regression analysis showed that maternal exposure to anticancer drugs was associated with an increased risk of leukemia in offspring older than 1 year (adjusted relative risk, 7.99 [95% confidence interval, 1.98-32.3]). Detailed information obtained from medical certificates of patients with identified leukemia revealed no infant leukemia but acute lymphoblastic leukemias in the exposed group. Our findings suggest that maternal occupational exposure to anticancer drugs may be a potential risk factor for acute lymphoblastic leukemia in offspring older than 1 year. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignant neoplasms.

Ferroelectric Organic Semiconductor: [1]Benzothieno[3,2-b][1]benzothiophene-Bearing Hydrogen-Bonding -CONHC14H29 Chain.

An alkylamide-substituted [1]benzothieno[3,2-b][1]benzothiophene (BTBT) derivative of BTBT-CONHC14H29 (1) and C8H17-BTBT-CONHC14H29 (2) were prepared to design the multifunctional organic materials, which can show both ferroelectric and semiconducting properties. Single-crystal X-ray structural analyses of short-chain (-CONHC3H7) derivatives revealed the coexistence of two-dimensional (2D) electronic band structures brought from a herringbone arrangement of the BTBT π core and the one-dimensional (1D) hydrogen-bonding chains of -CONHC3H7 chains. The thin films of 1 and 2 fabricated on the Si/SiO2 substrate surface have monolayer and bilayer structures, respectively, resulting in conducting layers parallel to the substrate surface, which is suitable for a channel layer of organic field-effect transistors (OFETs). The thin film of 1 indicated a hole mobility µFET = 2.4 × 10-5 cm2 V-1 s-1 and threshold voltage VTh = - 29 V, whereas that of 2 showed a µFET = 2.1 × 10-2 cm2 V-1 s-1 and threshold voltage VTh = -9.7 V. Both 1 and 2 formed the smectic E (SmE) phase above 410 and 369 K, respectively, where the existence of a hole transport pathway was confirmed in the SmE phase. The ferroelectric hysteresis behavior was observed in bulk 1 and 2 in the polarization-electric field (P-E) curves at the SmE phase. 1 showed the remanent polarization Pr = 2.3 µC cm-2 and coercive electric field Ec = 5.2 V µm-1, whereas the Pr and Ec of 2 were 3.4 µC cm-2 and 7.0 V µm-1 at the conditions of 453 K and 1 Hz. Introduction of alkylamide units into the BTBT π core has the potential to develop the external stimulus-responsive organic semiconductors brought from both ferroelectricity and semiconducting properties.

Diversity and composition of flower-visiting insects and related factors in three fruit tree species.

Animal-mediated pollination is an essential ecosystem service for the production of many fruit trees. To reveal the community composition of flower-visiting wild insects which potentially contribute to fruit production and to examine the effects of geographic location, local meteorological conditions and locally introduced domesticated pollinators on them, we investigated the community composition of insects visiting the flowers (hereafter, "visitors") of apple, Japanese pear and Oriental persimmon for 1‒3 years at 20 sites around Japan. While most of the variation (82%) of the community composition was explained by tree species with a slight contribution by geographic distance (2%), maximum temperature and tree species contributed 62% and 41% of the variation in total abundance of the visitors, respectively. Though the dominant families of the visitors varied spatiotemporally, the community composition of the visitors of apple and Japanese pear clearly differed from that of Oriental persimmon. While Andrenidae and Syrphidae together accounted for 46%‒64% of the visitors of apple and Japanese pear, Apidae represented 57% of the visitors of Oriental persimmon. The taxonomic richness, diversity and evenness of the visitors were best predicted by locally introduced domesticated pollinators and local meteorological conditions of wind speed and maximum temperature. Amongst these selected factors, locally introduced domesticated pollinators could have the largest impact. It seemed to be strongly related to the reduction of taxonomic richness, diversity and evenness of the visitors, accounting for 41‒89% of the variation. Results suggested that the community composition and total abundance of potential pollinators were predominantly determined by tree species and temperature, but locally introduced domesticated pollinators could have a determinantal pressure on the taxonomic diversity of the community.

[Rectal cancer with multiple metastases complicated by Crohn's disease 5 years after surgery:a case report].

In recent years, with the rising incidence of patients having long-term Crohn's disease, there has been an increase in the number of reports of carcinogenesis from dysplasia with chronic inflammation as the primary pathogenic factor. We hereby report a case of multiple metastases that appeared 5 years after surgery, in a patient with rectal cancer who had Crohn's disease. A man in his 50s was diagnosed with Crohn's disease which affected his small and large intestines 21 years back. The patient was being treated with oral steroids, 5-aminosalicylic acid, and modified nutrition. Infliximab was added to the treatment after it was introduced 11 years ago. He also had a history of rectal cancer and had undergone surgery for the same 5 years back. He was diagnosed with stage II cancer, and had not received any adjuvant chemotherapy. However, 5 years after surgery, multiple metastases recurred, and chemotherapy with mFOLFOX6 was administered. Additionally, for treating his Crohn's disease, which was also active, infliximab was changed to vedolizumab;however, the patient died a year later. Colorectal cancer accompanied with Crohn's disease has a higher risk of developing metastasis and is associated with poorer prognosis as compared to the noncomplicated colorectal cancer. Regarding treatment modalities, while searching for multidisciplinary treatment methods centered on surgical treatment in collaboration with medical oncologists and radiologists, the safety of treatment for Crohn's disease in patients with cancer must be borne in mind. The rising prevalence of cases of colorectal cancer with Crohn's disease is expected to lead to the formulation of specialized diagnostic and treatment strategies for these patients.

Operando NMR electrochemical gating studies of ion dynamics in PEDOT:PSS.

Although organic mixed ionic-electronic conductors are widely proposed for use in bioelectronics, energy generation/storage and neuromorphic computing, our fundamental understanding of the charge-compensating interactions between the ionic and electronic carriers and the dynamics of ions remains poor, particularly for hydrated devices and on electrochemical cycling. Here we show that operando 23Na and 1H nuclear magnetic resonance (NMR) spectroscopy can quantify cation and water movement during the doping/dedoping of films comprising the widely used mixed conductor poly(3,4-ethylene dioxythiophene) poly(styrene sulfonate) (PEDOT:PSS). A distinct 23Na quadrupolar splitting is observed due to the partial ordering of the PSS chains within the PEDOT:PSS-rich domains, with respect to the substrate. Operando 23Na NMR studies reveal a close-to-linear correlation between the quadrupolar splitting and the charge stored, which is quantitatively explained by a model in which the holes on the PEDOT backbone are bound to the PSS SO3- groups; an increase in hole concentration during doping inversely correlates with the number of Na+ ions bound to the PSS chains within the PEDOT-rich ordered domains, leading to a decrease in ions within the ordered regions and a decrease in quadrupolar splitting. The Na+-to-electron coupling efficiency, measured via 23Na NMR intensity changes, is close to 100% when using a 1 M NaCl electrolyte. Operando 1H NMR spectroscopy confirms that the Na+ ions injected into/extracted from the wet films are hydrated. These findings shed light on the working principles of organic mixed conductors and demonstrate the utility of operando NMR spectroscopy in revealing structure-property relationships in electroactive polymers.