Oral Administration of PLGA Nanoparticles to Deliver Antisense Oligonucleotides to Inflammatory Lesions in the Gastrointestinal Tract.

In this study, we prepared antisense oligonucleotide (ASO)-encapsulated nanoparticles (NPs) with a suitable profile for oral administration for the treatment of inflammatory bowel disease (IBD). We chose a water-in-oil-in-water (w/o/w) method to prepare the NPs using poly(lactide-co-glycolide) as a matrix and Pluronic as a stabilizer. The obtained NPs had a suitable diameter (158 nm) for the penetration of the mucus layer, endocytic uptake by enterocytes, and accumulation in inflammatory lesions in the intestine. The amount of ASOs in the NPs was relatively large (6.41% (w/w)). When the NPs were stably dispersed in solutions that mimicked gastrointestinal (GI) juice, minimal leakage of ASOs was demonstrated over the required period. The NPs were administered orally to mice with colitis induced by dextran sodium sulfate, which reduced target gene expression in the colons and rectums of the mice, whereas naked ASO administration caused no reduction in gene expression. Thus, the NPs have the potential of promising oral carriers of ASOs for the treatment of IBD that specifically target inflammatory lesions in the GI tract, thereby reducing the non-specific toxic effects of ASOs.

Impact of prophylactic echinocandin on the development of neurological complications in patients receiving busulfan-containing conditioning regimens for stem cell transplantation: A single-center retrospective study.

BACKGROUND: Although neurotoxicity is a major adverse event associated with busulfan, little information is available regarding the association between drug interactions and neurological symptoms during busulfan-based regimens. This study evaluated the association between prophylactic echinocandins and neurological complications in patients receiving busulfan-containing conditioning regimens for stem cell transplantation. METHODS: We retrospectively included consecutive patients who administered intravenous busulfan as a conditioning regimen at our facility between 2007 and 2022. Prophylactic echinocandin use was defined as the use of an echinocandin antifungal drug to prevent invasive fungal disease in SCT recipients. The primary outcome was the incidence of neurological complications within 7 days of busulfan initiation and was compared between the echinocandin group (patients received prophylactic echinocandin) and nonechinocandin group (patients received prophylactic antifungal drugs other than echinocandin and those without antifungal prophylaxis). RESULTS: Among the 59 patients included in this study, the incidence of neurological complications in the echinocandin (n = 26) and nonechinocandin groups (n = 33) was 30.8% and 63.6%, respectively. We observed a negative association between prophylactic echinocandin use and the development of neurological complications after adjusting for the propensity score for receiving prophylactic echinocandins (adjusted odds ratio 0.294, 95% confidence interval 0.090 to 0.959). We observed a lower incidence of neurological complications in the echinocandin group than in the nonechinocandin group. CONCLUSION: Our results suggested that the choice of antifungal prophylaxis is associated with busulfan neurotoxicity.

Clinical outcomes of left upper segmentectomy vs. lobectomy for early non-small-cell lung cancer: a nationwide database study in Japan.

PURPOSE: Given that left upper lobe and right upper and middle lobes share a similar anatomy, segmentectomy, such as upper division and lingulectomy, should yield identical oncological clearance to left upper lobectomy. We compared the prognosis of segmentectomy with that of lobectomy for early stage non-small-cell lung cancer (NSCLC) in the left upper lobe. METHODS: We retrospectively examined 2115 patients who underwent segmentectomy or lobectomy for c-stage I (TNM 8th edition) NSCLC in the left upper lobe in 2010. We compared the oncological outcomes of segmentectomy (n = 483) and lobectomy (n = 483) using a propensity score matching analysis. RESULTS: The 5-year recurrence-free and overall survival rates in the segmentectomy and lobectomy groups were comparable, irrespective of c-stage IA or IB. Subset analyses according to radiological tumor findings showed that segmentectomy yielded oncological outcomes comparable to those of lobectomy for non-pure solid tumors. In cases where the solid tumor exceeded 20 mm, segmentectomy showed a recurrence-free survival inferior to that of lobectomy (p = 0.028), despite an equivalent overall survival (p = 0.38). CONCLUSION: Segmentectomy may be an acceptable alternative to lobectomy with regard to the overall survival of patients with c-stage I NSCLC in the left upper lobe.

Rituximab-combined anthracycline-free chemotherapy in newly diagnosed paediatric and adolescent patients with non-high-risk aggressive mature B cell lymphoma: protocol for a single-arm, open-label, multicentre, phase II study (the Japan Children's Cancer Group Multicentre Trial, JPLSG B-NHL-20).

INTRODUCTION: Children and adolescents with mature B cell non-Hodgkin lymphoma (B-NHL) are treated with short-intensive chemotherapy. The burden of short-term and long-term toxicity is highly relative to its high cure rate in good-risk patients. Although the addition of rituximab to standard lymphome Malin B (LMB) chemotherapy markedly prolongs event-free survival and overall survival in high-risk patients, the benefit of rituximab in good-risk patients remains to be elucidated. This clinical trial will examine whether the addition of rituximab eliminates anthracyclines in good-risk patients without compromising treatment outcomes. METHODS AND ANALYSIS: We will perform a single-arm, open-label, multicentre phase II study. Low-risk (stage I - completely resected, stage II abdominal) and intermediate-risk (stages I and II - incompletely resected; stage II - resected, other than abdominal; stage III with LDH <2× upper limit of normal) patients with newly diagnosed B-NHL are eligible. Low-risk patients receive two courses of R-COM1P (rituximab, cyclophosphamide, vincristine, methotrexate, prednisolone and intrathecal methotrexate with hydrocortisone), and intermediate-risk patients receive COP (cyclophosphamide, vincristine, prednisolone and intrathecal methotrexate with hydrocortisone) followed by two courses each of R-COM3P and R-CYM (rituximab, cytarabine, methotrexate and intrathecal methotrexate with hydrocortisone). The primary endpoint is a 3-year event-free survival rate in paediatric patients (<18 years) with intermediate-risk disease. 100 patients (10 low-risk and 90 intermediate-risk) will enrol within a 4-year enrolment period and the follow-up period will be 3 years. 108 institutions are participating as of 1 January 2024 (64 university hospitals, 29 general hospitals, 12 children's hospitals and three cancer centres). ETHICS AND DISSEMINATION: This research was approved by the Certified Review Board at NHO Nagoya Medical Center (Nagoya, Japan) on 21 September 2021. Written informed consent is obtained from all patients and/or their guardians. The results of this study will be disseminated through peer-reviewed publications and conference presentations. STUDY REGISTRATION: Japan Registry of Clinical Trials, jRCTs041210104.

Oral Clostridium butyricum on mice endometritis through uterine microbiome and metabolic alternations.

Endometritis occurs frequently in humans and animals, which can negatively affect fertility and cause preterm parturition syndrome. Orally administered Clostridium butyricum, a butyrate-producing gram-positive anaerobe, exhibits anti-inflammatory effects. However, the precise mechanism by which Clostridium butyricum attenuates endometritis remains unclear. This in vivo study evaluated the anti-inflammatory effects of orally administered Clostridium butyricum on uterine tissues. In addition, we conducted uterine microbiome and lipid metabolome analyses to determine the underlying mechanisms. Female Balb/c mice were divided into the following four groups (n = 5-20): (1) mock group, (2) only operation group (mice only underwent operation to exposed uterine horns from the side), (3) control group (mice underwent the same operation with the operation group + perfusion of lipopolysaccharide solution from uterine horns), and (4) Clostridium butyricum administration group (mice underwent the same operation with the control group + oral Clostridium butyricum administration from days 0 to 9). Clostridium butyricum was administered via oral gavage. On day 10, we investigated protein expression, uterine microbiome, and lipid metabolism in uterine tissues. Consequently, orally administered Clostridium butyricum altered the uterine microbiome and induced proliferation of Lactobacillus and Limosilactobacillus species. The effects can contribute to show the anti-inflammatory effect through the interferon-ß upregulation in uterine tissues. Additionally, oral Clostridium butyricum administration resulted in the upregulations of some lipid metabolites, such as ω-3 polyunsaturated fatty acid resolvin D5, in uterine tissues, and resolvin D5 showed anti-inflammatory effects. However, the orally administered Clostridium butyricum induced anti-inflammatory effect was attenuated with the deletion of G protein-coupled receptor 120 and 15-lipooxgenase inhibition. In conclusion, Clostridium butyricum in the gut has anti-inflammatory effects on uterine tissues through alterations in the uterine microbiome and lipid metabolism. This study revealed a gut-uterus axis mechanism and provided insights into the treatment and prophylaxis of endometritis.

Effective design of PEGylated polyion complex (PIC) nanoparticles for enhancing PIC internalisation in cells utilising block copolymer combinations with mismatched ionic chain lengths.

In nanomedicine, PEGylation of nanomaterials poses a dilemma since it inhibits their interaction with target cells and enables their retention in target tissues despite its biocompatibility and nonspecific internalisation suppression. PEGylated polypeptide-based polyion complexes (PICs) are fabricated via the self-assembly of PEGylated aniomers and homocatiomers based on electrostatic interactions. We propose that various parameters like block copolymer design and PIC domain characteristics can enhance the cell-PEGylated PIC interactions. Remarkably, the properties of the PIC domain were tuned by the matched/mismatched ionomer chain lengths, PIC domain crosslinking degree, chemical modification of cationic species after crosslinking, PIC morphologies (vesicles/micelles) and polyethylene glycol (PEG) chain lengths. Cellular internalisation of the prepared PICs was evaluated using HeLa cells. Consequently, mismatched ionomer chain lengths and vesicle morphology enhanced cell-PIC interactions, and the states of ion pairing, particularly cationic residues, affected the internalisation behaviours of PICs via acetylation or guanidinylation of amino groups on catiomers. This treatment attenuated the cell-PIC interactions, possibly because of reduced interaction of PICs with negatively charged species on the cell-surface, glycosaminoglycans. Moreover, morphology and PEG length were correlated with PIC internalisation, in which PICs with longer and denser PEG were internalised less effectively. Cell line dependency was tested using RAW 264.7 macrophage cells; PIC recognition could be maintained after capping amino groups on catiomers, indicating that the remaining anionic groups were still effectively recognised by the scavenger receptors of macrophages. Our strategy for tuning the physicochemical properties of the PEGylated PIC nanocarriers is promising for overcoming the PEG issue.

Lung cancer progression alters lung and gut microbiomes and lipid metabolism.

Despite advances in medical technology, lung cancer still has one of the highest mortality rates among all malignancies. Therefore, efforts must be made to understand the precise mechanisms underlying lung cancer development. In this study, we conducted lung and gut microbiome analyses and a comprehensive lipid metabolome analysis of host tissues to assess their correlation. Alternations in the lung microbiome due to lung cancer, such as a significantly decreased abundance of Firmicutes and Deferribacterota, were observed compared to a mock group. However, mice with lung cancer had significantly lower relative abundances of Actinobacteria and Proteobacteria and higher relative abundances of Cyanobacteria and Patescibacteria in the gut microbiome. The activations of retinol, fatty acid metabolism, and linoleic acid metabolism metabolic pathways in the lung and gut microbiomes was inversely correlated. Additionally, changes occurred in lipid metabolites not only in the lungs but also in the blood, small intestine, and colon. Compared to the mock group, mice with lung cancer showed that the levels of adrenic, palmitic, stearic, and oleic (a ω-9 polyunsaturated fatty acid) acids increased in the lungs. Conversely, these metabolites consistently decreased in the blood (serum) and colon. Leukotriene B4 and prostaglandin E2 exacerbate lung cancer, and were upregulated in the lungs of the mice with lung cancer. However, isohumulone, a peroxisome proliferator-activated receptor gamma activator, and resolvin (an ω-3 polyunsaturated fatty acid) both have anti-cancer effects, and were upregulated in the small intestine and colon. Our multi-omics data revealed that shifts in the microbiome and metabolome occur during the development of lung cancer and are of possible clinical importance. These results reveal one of the gut-lung axis mechanisms related to lung cancer and provide insights into potential new targets for lung cancer treatment and prophylaxis.

Benefit of Adjuvant Chemotherapy for Patients Older Than 75 Years With Completely Resected p-Stage II-IIIA Non-Small-Cell Lung Cancer: A Retrospective Cohort Study Using Japanese Nationwide Real-World Data.

BACKGROUND: The efficacy of adjuvant chemotherapy (ACT) in elderly patients with completely resected p-stage II-IIIA non-small-cell lung cancer (NSCLC) remains unclear because all previous randomized controlled trials on ACT have been conducted among patients aged <75 years. Thus, this study aimed to evaluate the effectiveness of ACT in elderly patients with completely resected NSCLC. PATIENTS: We extracted the nationwide data of 812 patients aged ≥75 years who underwent lobectomy with mediastinal nodal dissection in 2010 and were diagnosed with p-stage II-IIIA NSCLC, from nationwide registry data accumulated in 2016. METHODS: We classified the 812 patients into 2 groups based on the ACT administration status and analyzed the differences in their postoperative overall survival (OS). RESULTS: Overall, 295 patients received ACT (36.3%; group A), whereas 517 patients did not (63.70%; group N). Group A showed significantly better OS as a whole (hazard ratio [HR]: 0.650 [95% confidence interval {CI}: 0.526-0.804]), in the p-stage II subset (HR: 0.688 [95% CI: 0.513-0.925]), and p-stage IIIA subset (HR: 0.547 [95% CI: 0.402-0.743]) than group N. Even after propensity score matching, group A showed significantly better OS as a whole (HR: 0.626 [95% CI: 0.495-0.792]), in the p-stage II subset (HR: 0.690 [95% CI: 0.493-0.964]), and p-stage IIIA subset (HR: 0.554 [95% CI: 0.398-0.772]) than group N. CONCLUSION: ACT is recommended even in elderly patients with completely resected p-stage II-IIIA NSCLC. Hence, physicians should not avoid ACT in patients with completely resected NSCLC based solely on age.

Rituximab with standard LMB chemotherapy in pediatric high-risk mature B-cell non-Hodgkin lymphoma: A report from the JPLSG B-NHL14 trial.

BACKGROUND: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. METHODS: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single-arm multicenter trial. RESULTS: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma, and aggressive mature B-NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow-up period was 47.5 months. Three-year event-free survival and overall survival were 97.7% (95% confidence interval, 84.9-99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B-cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non-hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre-phase treatment, with a frequency of 54.5%. CONCLUSION: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high-risk mature B-NHL was observed in Japan.

Growth Suppression of a Robust Bacterium Methylobacterium extorquens by Porous Materials with Oxygen Functional Groups.

Suppressing the growth of Methylobacterium species without the use of toxic chemicals has been a challenging task owing to their robustness against previous antimicrobial techniques. In this work, we prepared porous materials with various numbers and types of oxygen functional groups and investigated their ability to suppress the growth of Methylobacterium extorquens. It turned out that the number and type of oxygen functional groups in the porous materials greatly affected the growth of the bacterium. Three porous materials (resorcinol-formaldehyde gel (RF), hydrothermally treated RF (RFH), and Wakkanai siliceous shale (WS)) were tested, and RF exhibited the best performance in suppressing the growth of the bacterium. This performance is possibly due to abundant phenolic groups in the porous material.

Safe and efficient oral allergy immunotherapy using one-pot-prepared mannan-coated allergen nanoparticles.

Allergen immunotherapy (AIT) is the only curative treatment for allergic diseases. However, AIT has many disadvantages related to efficiency, safety, long-term duration, and patient compliance. Dendritic cells (DCs) have an important role in antigen-specific tolerance induction; thus, DC-targeting strategies to treat allergies such as glutaraldehyde crosslinked antigen to mannoprotein (MAN) have been established. However, glutaraldehyde crosslinking may reduce the antigen presentation efficiency of DCs. To overcome this, we developed a MAN-coated ovalbumin (OVA) nanoparticle (MDO), which uses intermolecular disulfide bond to crosslink OVA and MAN. MDO effectively targeted DCs resulting in tolerogenic DCs, and promoted higher antigen presentation efficiency by DCs compared with OVA or glutaraldehyde crosslinked nanoparticles. In vitro and in vivo experiments showed that DCs exposed to MDO induced Treg cells. Moreover, MDO had low reactivity with anti-OVA antibodies and did not induce anaphylaxis in allergic mice, demonstrating its high safety profile. In a mouse model of allergic asthma, MDO had significant preventative and therapeutic effects when administered orally or subcutaneously. Therefore, MDO represents a promising new approach for the efficient and safe treatment of allergies.

First GC/MS identification of aqueous ammonia: utilization of ethenesulfonyl fluoride as a selective and rapid derivatization reagent of ammonia in aqueous media.

Identification as well as quantification of ammonia are required in some analytical fields including forensic science. For this purpose, gas chromatography/mass spectrometry (GC/MS) analysis is one of the most suitable techniques. Although ammonia needs to be derivatized for GC/MS analysis, conventional derivatization reagents require anhydrous conditions because they are highly reactive with water. Here, we investigated ethenesulfonyl fluoride (ESF) as a selective reagent for ammonia derivatization in aqueous media to develop a rapid identification method for ammonia in aqueous media. The Michael addition reaction of ammonia with ESF rapidly produced a tri-ESF derivative suitable for GC/MS analysis. We optimized the derivatization reaction conditions and extraction solvent. With the optimized protocol, the detection limit for aqueous ammonia was 0.05 µg mL-1. The calibration curve showed good linearity (R2 = 0.9998) in the range of 0.10-100.0 µg mL-1, and the accuracy (% bias) and the precision (% relative standard deviation) for concentrations of 0.10, 0.25, 10.0, and 75.0 µg mL-1 were within ± 10% (intra- and inter-day). The proposed ESF-based method could quantify ammonia in samples containing interfering nucleophilic substances. This method was successfully applied to ammonia-containing commercial products.

Pick and place process for uniform shrinking of 3D printed micro- and nano-architected materials.

Two-photon polymerization lithography is promising for producing three-dimensional structures with user-defined micro- and nanoscale features. Additionally, shrinkage by thermolysis can readily shorten the lattice constant of three-dimensional photonic crystals and enhance their resolution and mechanical properties; however, this technique suffers from non-uniform shrinkage owing to substrate pinning during heating. Here, we develop a simple method using poly(vinyl alcohol)-assisted uniform shrinking of three-dimensional printed structures. Microscopic three-dimensional printed objects are picked and placed onto a receiving substrate, followed by heating to induce shrinkage. We show the successful uniform heat-shrinking of three-dimensional prints with various shapes and sizes, without sacrificial support structures, and observe that the surface properties of the receiving substrate are important factors for uniform shrinking. Moreover, we print a three-dimensional mascot model that is then uniformly shrunk, producing vivid colors from colorless woodpile photonic crystals. The proposed method has significant potential for application in mechanics, optics, and photonics.

Is adjuvant chemotherapy for completely resected p-stage IA (>2 cm) and stage IB non-small-cell lung cancer beneficial for elderly patients? A large, retrospective cohort study based on real-world data from Japan.

OBJECTIVE: The efficacy of tegafur-uracil as adjuvant chemotherapy for patients with completely resected stage I non-small-cell lung cancer is proven; however, its efficacy for elderly patients remains unclear. Herein, we evaluated the effectiveness of adjuvant chemotherapy for elderly patients with completely resected stage I non-small-cell lung cancer based on real-world Japanese data using propensity score matching. METHODS: This retrospective study extracted data from a nationwide registry study, performed in 2016, on patients ≥75 years who underwent lobectomy with mediastinal nodal dissection for non-small-cell lung cancer in 2010 and were diagnosed with p-stage IA (>2 cm) or stage IB non-small-cell lung cancer. We classified the 1294 patients into two groups-Group A, postoperative adjuvant chemotherapy (n = 295, 22.8%) and Group N, no adjuvant chemotherapy (n = 999, 77.2%)-and analyzed differences in postoperative overall survival between groups. RESULTS: Group A showed no advantage in overall survival over Group N as a whole (hazard ratio: 0.824 [95% confidence interval: 0.631-1.076]), in p-stage IA (hazard ratio: 0.617 [95% confidence interval: 0.330-1.156]) and in p-stage IB (hazard ratio: 0.806 [95% confidence interval: 0.597-1.088]) subsets. Even after propensity score matching, Group A showed no significant advantage in overall survival over Group N as a whole (hazard ratio: 0.975 [95% confidence interval: 0.688-1.381]), in p-stage IA (hazard ratio: 1.390 [95% confidence interval: 0.539-3.586]) and in p-stage IB (hazard ratio: 0.922 [95% confidence interval: 0.633-1.343]). CONCLUSIONS: adjuvant chemotherapy for completely resected p-stage IA (>2 cm) and stage IB non-small-cell lung cancer showed no benefit for recommendation for elderly patients; considering the risk of adverse events, we do not recommend adjuvant chemotherapy for elderly patients.

Development of novel tracers for sentinel node identification in cervical cancer.

Indocyanine green (ICG) with near-infrared (NIR) fluorescence imaging is used for lymphatic mapping. However, binding of ICG to blood proteins like serum albumin can shorten its retention time in sentinel lymph nodes (SLNs). Here, we investigated the efficacy and safety of a new fluorescence tracer comprising phytate and liposome (LP)-encapsulated ICG. Coadministration of phytate with LP containing phosphatidic acid promotes chelation mediated by Ca2+ in bodily fluids to enhance SLN retention. Uniformly sized LPs (100 nm) encapsulating ICG under conditions that minimized fluorescence self-quenching during storage were produced. We analyzed the behavior of the new tracer (ICG-phytate-LP) and control tracers (ICG and ICG-LP) in the lymphatic flow of mice in terms of lymph node retention time. We also tested lymphatic flow and safety in pigs that have a more human-like lymphatic system. LPs encapsulating stabilized ICG were successfully prepared. Mixing LP with phytate in the presence of Ca2+ increased both the particle size and negative surface charge. In mice, ICG-phytate-LP had the best lymph node retention, with a fluorescence intensity ratio that increased over 6 h and then decreased slowly over the next 24 h. In pigs, administration of ICG and ICG-phytate-LP resulted in no death or weight loss. There were no obvious differences between blood test results for the ICG and ICG-phytate-LP groups, and the overall safety was good. ICG-phytate-LP may be a useful new tracer for gynecological cancers that require time for lymph node identification due to a retroperitoneal approach.

Higher levels of minimal residual disease in peripheral blood than bone marrow before 1st and 2nd relapse/regrowth in a patient with high­risk neuroblastoma: A case report.

More than half of patients with high-risk neuroblastoma (HR-NB) experience relapse/regrowth due to the activation of chemoresistant minimal residual disease (MRD). MRD in patients with HR-NB can be evaluated by quantitating neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow (BM) and peripheral blood (PB) samples. Although several sets of NB-mRNAs have been shown to possess a prognostic value for MRD in BM samples (BM-MRD), MRD in PB samples (PB-MRD) is considered to be low and difficult to evaluate. The present report describes an HR-NB case presenting higher PB-MRD than BM-MRD before 1st and 2nd relapse/regrowth. A 3-year-old female presented with an abdominal mass, was diagnosed with HR-NB, and treated according to the nationwide standard protocol for HR-NB. Following systemic induction and consolidation therapy with local therapy, the patient achieved complete remission but experienced a 1st relapse/regrowth 6 months after maintenance therapy. The patient partially responded to salvage chemotherapy and anti-GD2 immunotherapy but had a 2nd relapse/regrowth 14 months after the 1st relapse/regrowth. Consecutive PB-MRD and BM-MRD monitoring revealed that PB-MRD was lower than BM-MRD at diagnosis (100 times) and 1st and 2nd relapse/regrowth (1,000 and 3 times) but became higher than BM-MRD before 1st and 2nd relapse/regrowth. The present case highlights that PB-MRD can become higher than BM-MRD before relapse/regrowth of patients with HR-NB.

One-pot preparation of mannan-coated antigen nanoparticles using human serum albumin as a matrix for tolerance induction.

Nanoparticles (NPs) for allergen immunotherapy have garnered attention for their high efficiency and safety compared with naked antigen proteins. In this work, we present mannan-coated protein NPs, incorporating antigen proteins for antigen-specific tolerance induction. The heat-induced formation of protein NPs is a one-pot preparation method and can be applied to various proteins. Here, the NPs were formed spontaneously via heat denaturation of three component proteins: an antigen protein, human serum albumin (HSA) as a matrix protein, and mannoprotein (MAN) as a targeting ligand for dendritic cells (DCs). HSA is non-immunogenic, therefore suitable as a matrix protein, while MAN coats the surface of the NP. We applied this method to various antigen proteins and found that the self-disperse after heat denaturation was a requirement for incorporation into the NPs. We also established that the NPs could target DCs, and the incorporation of rapamycin into the NPs enhanced the induction of a tolerogenic phenotype of DC. The MAN coating provided steric hindrance and heat denaturation destroyed recognition structures, successfully preventing anti-antigen antibody binding, indicating the NPs may avoid anaphylaxis induction. The MAN-coated NPs proposed here, prepared by a simple method, have the potential for effective and safe allergies treatment for various antigens.

Association between conditioning intensity and height growth after allogeneic hematopoietic stem cell transplantation in children.

BACKGROUND: The present study aimed to examine the association between the conditioning intensity and height growth in pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: We reviewed the clinical records of 89 children with malignant diseases who underwent initial allo-HSCT between 2003 and 2021. Height measurements were standardized using standard height charts prepared by the Japanese Society for Pediatric Endocrinology to calculate standard deviation score (SDS). We defined short stature as a height SDS less than -2.0 in that reference. Myeloablative conditioning (MAC) comprised total-body irradiation at more than 8 Gy and busulfan administration at more than 8 mg/kg (more than 280 mg/m2 ). Other conditioning regimens were defined as reduced intensity conditioning (RIC). RESULTS: A total of 58 patients underwent allo-HSCT with MAC, and 31 patients received allo-HSCT with RIC. There were significant differences in the height SDS at 2 and 3 years after allo-HSCT between MAC and RIC group (-1.33 ± 1.20 vs. -0.76 ± 1.12, p = 0.047, -1.55 ± 1.28 vs. -0.75 ± 1.11, p = 0.022, respectively). Multivariate logistic regression analysis with the adjustments for potential confounding factors of patients less than 10 years of age at allo-HSCT and chronic graft-versus host disease demonstrated that MAC regimen was associated with a markedly increased risk of a short stature at 3 years after allo-HSCT (adjusted odds ratio, 5.61; 95% confidence interval, 1.07-29.4; p = 0.041). CONCLUSION: The intensity of conditioning regimen may be associated with short statures after allo-HSCT.

Features of anaplastic lymphoma kinase rearrangement in early-stage lung cancer: Analysis of a nationwide Japanese database.

BACKGROUND AND OBJECTIVES: Anaplastic lymphoma kinase (ALK) rearrangement is a representative driver mutation in lung cancer. However, the biology of early-stage ALK-rearranged lung cancer remains unclear. We aimed to assess the clinicopathological features, prognostic implications, and influence of ALK rearrangement on the postoperative course in surgically resected lung cancer. METHODS: We retrospectively analyzed data from the Japanese Joint Committee of Lung Cancer Registry database. Of the 12 730 patients with lung adenocarcinoma, 794 (6.2%) were tested for ALK rearrangement and were included. RESULTS: ALK rearrangements were detected in 76 patients (10%). The 5-year overall survival (OS) rate was significantly higher in the ALK rearrangement-positive group than in the ALK rearrangement-negative group (p = 0.030). Multivariable analysis revealed that ALK rearrangement was an independent prognostic factor for improved OS (hazard ratio, 0.521; 95% confidence interval, 0.298-0.911; p = 0.022). Regarding the postrecurrence state, there was no difference in the initial recurrence sites between both groups. Administration of ALK-tyrosine kinase inhibitors (TKIs) improved postrecurrence survival in any treatment lines. CONCLUSION: In one of the largest national surveys, ALK rearrangement was associated with improved long-term outcomes in surgically resected patients. ALK-TKIs may be an important treatment strategy for ALK rearrangement-positive lung adenocarcinoma in the postrecurrence state.