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Abstract Mast cells (MCs) are tissue-resident cells of hematopoietic origin that play an important role in host’s defense mechanism against nematodes. However, excessive activation of these cells contributes to the development of certain allergic diseases. Immunoglobin E (IgE) is one of the well-known molecules that activate MCs. Even in the absence of specific antigens, the binding of highly cytokinergic IgE to FcεRI on MCs prolongs their survival and induces cytokine production without enhancing their degranulation. In the present study, we examined the effects of the members of the interleukin-10 (IL-10) family of cytokines on IgE-mediated MCs functions. The receptors including Il10r1, Il10r2, and Il20r2, but not Il20r1, Il22r1 or Il28r1, were constitutively expressed in mouse bone marrow cell-derived cultured MCs (BMCMCs), suggesting that IL-10 may influence MCs function. Indeed, we found that only IL-10 could influence upon BMCMCs function; IL-10 enhanced prolongation of survival, promoted IL-6 and/or IL-13 production dependently of STAT1 and STAT3, and suppressed tumor necrosis factor production independently of STAT1 and STAT3 on IgE-stimulated BMCMCs. Moreover, the IL-10-mediated enhancement of IL-6 production by IgE-stimulated BMCMCs promotes Th17 cell expansion. These results suggest that IL-10 has a dual role as an anti-inflammatory and pro-inflammatory cytokine in MCs functions.

Abstract Aim To clarify the usefulness of intraoperative lavage cytology in patients undergoing curative resection for pStage II‐III colorectal cancer in a prospective multicenter study. Methods Patients preoperatively diagnosed with stage II‐III colorectal cancer between 2013 and 2017 from 20 hospitals were enrolled. Lavage cytology was performed twice during the surgery. The primary endpoint was the effect of lavage cytology on the 5‐year relapse‐free survival (RFS) in patients with pStage II‐III colorectal cancer. The secondary endpoint was the effect of lavage cytology on the 5‐year overall survival (OS) and peritoneal recurrence. Results A total of 1378 patients were eligible for analysis. The number of patients with pStage II‐III colorectal cancer was 670 and 708, respectively. Fifty‐four patients (3.9%) had positive cytological results. In pStage II patients, the 5‐year RFS rates with positive and negative cytology were 61.1% and 81.6%, respectively (p = 0.023). The 5‐year OS rates were 67.1% and 91.7%, respectively (p = 0.0083). However, there was no difference in RFS or OS between pStage III patients with positive and negative cytology results. The peritoneal recurrence rates were 11.8% and 1.5% in pStage II patients with positive and negative cytology results, respectively (p = 0.032). These rates were 10.5% and 2.5% in patients with stage III disease, respectively (p = 0.022). Conclusion Stage II colorectal cancer patients with negative cytology had better outcomes than those with positive cytology. Peritoneal lavage cytology is useful for predicting peritoneal recurrence after curative resection of stage II‐III colorectal cancer.

Abstract Background Regulatory T (Treg) cells reportedly play crucial roles in tumor angiogenesis as well as antitumor immunity. In order to explore their therapeutic potential, we investigated the precise prognostic impact of Treg markers in endometrial carcinoma. Methods We performed multiplexed immunofluorescence and quantitative image analyses of CD25, FOXP3, CTLA4, and CD45RA in tumor specimens from 176 consecutive patients treated at our institution for primary endometrial carcinomas. Bioinformatics analyses were further conducted to corroborate the findings. Results High CD25+, FOXP3+, and CD25+FOXP3+CD45RA− stromal cell counts correlated with better overall survival (OS) (p = 0.00019, 0.028 and 0.0012) and MSI-high (p = 0.015, 0.016 and 0.047). High CD45RA+ stromal cell count was associated with superficial myometrial invasion (p = 0.0038). Bioinformatics survival analysis by Kaplan-Meier plotter showed that high CD25, FOXP3, CTLA4, and CD45RA mRNA expressions correlated with better OS (p = 0.046, 0.00042, 0.000044, and 0.0022). Univariate and multivariate analyses with various clinicopathologic prognostic factors indicated that high CD25+ or CD25+FOXP3+CD45RA− stromal cell count was significant and independent for favorable OS (p = 0.0053 and 0.0015). We subsequently analyzed the correlations between the multiplexed immunofluorescence results and treatment-free interval (TFI) after primary chemotherapy in recurrent cases, finding no significant associations. Further analysis revealed that high ratio of CD25+ : CD8+ cell count or CD25+FOXP3+CD45RA− : CD8+ cell count correlated with longer TFI (p = 0.021 and 0.021). Conclusion The current observations suggest that the balance between CD25+ or CD25+FOXP3+CD45RA− cells and CD8+ cells, corresponding to promoting or inhibiting effect on tumor angiogenesis, affect tumor chemosensitivity leading to prognostic significance. CD25+FOXP3+CD45RA− effector Treg tumor infiltration may serve as a useful prognostic biomarker and a potential target for immunotherapeutic manipulation of tumor chemosensitivity by novel management for advanced/recurrent endometrial carcinomas.

Background: Ensitrelvir, a 3C-like protease inhibitor, received emergency approval in Japan in November 2022 for treating non-hospitalized patients with mild-to-moderate COVID-19. However, confirmation of its real-world clinical effectiveness is limited. Methods: This retrospective study evaluated 18 vaccinated outpatients (15 men; median age, 39.5 years; range, 26–56), treated with a 5-day oral ensitrelvir regimen (375 mg loading dose, followed by 125 mg daily) between December 1, 2022, and January 31, 2023. Nasal swabs were collected on days 0, 3, 6, and 9 for RT-qPCR to assess viral load. Variants were identified by Sanger sequencing, and outcomes were compared to historical controls. Patients were followed for 60 days to monitor for post-acute sequelae of COVID-19 (PASC). Results: Symptoms such as mild fever and sore throat improved rapidly after one day of ensitrelvir treatment, with 66 % of patients recovering within six days. All individuals were infected with the BA.5 Omicron variant. Viral loads, as measured by Ct values, increased significantly from 21.82 at symptom onset to 37.65 b y day 6, with SARS-CoV-2 RNA undetectable in most patients by day 9. Those treated within 48 h of symptom onset showed the viral load reduction. Compared to historical controls, where symptom resolution took 8.5 days, ensitrelvir shortened recovery time to as little as 1.4 days for over 66 % of patients. Conclusion: Ensitrelvir treatment resulted in rapid symptom relief and significant viral load reduction, with no adverse events, viral rebound, or PASC symptoms, demonstrating its potential efficacy and safety. Larger studies are needed for further confirmation.

Abstract Background The Greenhouse gas Observations of Biospheric and Local Emissions from the Upper sky (GOBLEU) is a new joint project by Japan Aerospace Exploration Agency (JAXA) and ANA HOLDING INC. (ANAHD), which operates ANA flights. GOBLEU aims to visualizes our climate mitigation effort progress in support of subnational climate mitigation by collecting greenhouse gas (GHG) data as well as relevant data for emissions (nitrous dioxide, NO2) and removals (Solar-Induced Fluorescence, SIF) from regular passenger flights. We developed a luggage-sized instrument based on the space remote-sensing techniques that JAXA has developed for Japan’s Greenhouse gas Observing SATellite (GOSAT). The instrument can be conveniently installed on a coach-class passenger seat without modifying the seat or the aircraft. Results The first GOBLEU observation was made on the flight from the Tokyo Haneda Airport to the Fukuoka Airport, with only the NO2 module activated. The collected high-spatial-resolution NO2 data were compared to that from the TROPOspheric Monitoring Instrument (TROPOMI) satellite and surface NO2 data from ground-based air quality monitoring stations. While GOBLEU and TROPOMI data shared the major concentration patterns largely driven by cities and large point sources, regardless of different observation times, we found fine-scale concentration pattern differences, which might be an indication of potential room for GOBLEU to bring in new emission information and thus is worth further examination. We also characterized the levels of NO2 spatial correlation that change over time. The quickly degrading correlation level of GOBLEU and TROPOMI suggests a potentially significant impact of the time difference between CO2 and NO2 as an emission marker and, thus, the significance of co-located observations planned by future space missions. Conclusions GOBLEU proposes aircraft-based, cost-effective, frequent monitoring of greenhouse emissions by GOBLEU instruments carried on regular passenger aircraft. Theoretically, the GOBLEU instrument can be installed and operated in most commercially used passenger aircraft without modifications. JAXA and ANAHD wish to promote the observation technique by expanding the observation coverage and partnership to other countries by enhancing international cooperation under the Paris Agreement.

Abstract Group 2 innate lymphoid cells (ILC2s) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 is a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains unclear. Herein, we identify ILC2-specific GATA3-related tandem super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 deficiency in the bone marrow, lung, liver, and small intestine with minimal impact on other ILC lineages or Th2 cells. Single-cell RNA-sequencing and subsequent flow cytometry analysis show that GATA3 induction mechanism, which is required for entering the ILC2 stage, is lost in IL-17RB+PD-1− late ILC2-committed precursor stage in G3SE-deficient mice. Cnot6l, part of the CCR4-NOT deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings implicate a stage-specific regulatory mechanism for GATA3 expression during ILC2 development.

Abstract Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd’s response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer.

Background: The survival benefit of adjuvant chemotherapy after surgical resection of oligometastases from colorectal cancer (CRC) remains unclear. The prognostic role of circulating-tumor DNA (ctDNA) was reported recently and a risk stratification strategy based on monitoring minimal/molecular residual disease (MRD) has been proposed, however, which drug regimen is most effective for ctDNA-positive patients is unknown. Methods/Design: Oligometastatic CRC patients planning to undergo surgery were registered in this study. After metastasectomy, the registered patients were enrolled in the treatment arm, in which 8 courses of modified-FOLFOXIRI (mFOLFOXIRI; irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin (l-LV) 200 mg/m2, and 46-h continuous infusion of 5-fluorouracil (5-FU) 2400 mg/m2 every 2 weeks) followed by 4 courses of 5-FU/l-LV are administered. The patients who did not meet the eligibility criteria for the treatment arm or did not consent to mFOLFOXIRI enrolled in the observation arm in which standard of care treatment is provided. Prospective blood collections for retrospective ctDNA analysis are scheduled pre-surgery, and at 28 days, 4 and 7 months after surgery. The primary endpoint is treatment compliance at 8 courses of mFOLFOXIRI and the key secondary endpoints are the ctDNA-positivity rate and survival outcomes in ctDNA-positive and -negative groups. A total of 85 patients will be enrolled from 11 institutions. First patient-in was on July 2020. Accrual completed in February 2024. Discussion: This study will potentially identify a better treatment strategy for patients with resectable oligometastatic CRC having postsurgical ctDNA positivity, compared to the current standard of care approaches.

ABSTRACT Objective: To learn about the structure of nursing students’ social representations about obstetric violence. Method: Qualitative study conducted with 117 nursing students from a state university in Brazil, between July and October 2022. Data were collected in person using the free Word evocation technique and processed using the Evoc software to create a four-box chart, through prototypical analysis. Results: The representational structure was organized on the central elements of disrespect, suffering and violation, which attribute to the representation negative meanings related to the group’s position on the grievance and its repercussions. The similarity analysis showed that the elements with the greatest connection were disrespect and suffering. Final considerations: Social representations of nursing students were organized around an attitudinal dimension through the terms disrespect and violation, and the affective dimension defined by suffering. It is noteworthy that, for students, obstetric violence is centered on disrespectful professional practices that cause suffering to women.

Background: Biomarkers to predict the recurrence risk are required to optimize perioperative treatment. Adjuvant chemotherapy for patients with human epidermal growth factor 2-positive (HER2-positive) early breast cancer is decided by pathological responses of neoadjuvant chemotherapy (NAC). However, whether pathological responses are appropriate biomarkers is unclear. Currently, there are several studies using minimal residual disease (MRD) as a predictor of prognosis in solid tumors. However, there is no standard method for detecting MRD. Objectives: This study aimed at prospectively evaluating the relationship between MRD detection and recurrence in Asian patients with HER2-positive early breast cancer. Design: Prospective, observational, single-group, and exploratory. This study will include 60 patients from 2 institutions in Japan and the Philippines. The invasive disease-free survival (IDFS) rates of the MRD-positive and MRD-negative groups are compared in patients with HER2-positive early breast cancer who undergo surgery after receiving NAC. Methods and analysis: Circulating tumor DNA (ctDNA) levels of patients will be evaluated 6 times: before NAC, after NAC, after surgery, and annually after surgery for 3 years. We will analyze the genetic profile of blood and tissue samples using the Todai OncoPanel (TOP) and the methylation level of DNA. The primary endpoint is IDFS. Secondary endpoints include overall survival (OS) and disease-free survival (DFS). Patient enrollment began in June 2022, and new participants are still being recruited. Ethics: This study has been approved by the National Cancer Center Hospital Certified Review Board in March 2022 and has been approved by the Research Ethics Board of the participating center. Discussion: Our findings will contribute to determining whether MRD detection using TOP is useful for predicting the recurrence of HER2-positive early breast cancer. If this is proven, MRD detected by TOP could be used in the future as a biomarker to assist in the de-/escalation of treatment strategies in the next interventional trial, thereby avoiding overtreatment in patients at low risk, and in the addition of intensive treatment modalities for those in patients at high risk.

Objetivo: analisar as percepções das enfermeiras sobre o serviço de Acolhimento e Classificação de Risco de uma maternidade pública. Método: estudo descritivo, desenvolvido em uma maternidade do Estado da Bahia, onde sete enfermeiras do serviço de acolhimento e classificação de risco foram entrevistadas entre fevereiro e março de 2023. Foi elaborado um corpus textual processado pelo software Iramuteq que possibilitou a de análise da Classificação Hierárquica Descendente associada à Análise Temática na perspectiva de Bardin. Resultados: foram conformadas cinco classes e definidas quatro categorias: As dificuldades em trabalhar com classificação de risco; Principais queixas/sintomas atendidos no serviço; Importância percebida do acolhimento e classificação de risco e a responsabilização da gestão para o bom desempenho do serviço; e, Condutas das enfermeiras centradas em tecnologias leves e na necessidade de (re)avaliação pelo médico. Conclusão: as enfermeiras entendem a importância e a responsabilidade do papel executado dentro do serviço e apontam questões importantes quanto ao modelo de atenção à saúde, como a necessidade de valorização da enfermagem obstétrica. O estudo pode contribuir para a melhoria da assistência à saúde prestada por enfermeiras no acolhimento e classificação de risco e fomentar políticas públicas voltadas para a melhoria da atenção à saúde da mulher grávida.

Abstract Many targeted cancer therapies rely on biomarkers assessed by scoring of immunohistochemically (IHC)-stained tissue, which is subjective, semiquantitative, and does not account for expression heterogeneity. We describe an image analysis-based method for quantitative continuous scoring (QCS) of digital whole-slide images acquired from baseline human epidermal growth factor receptor 2 (HER2) IHC-stained breast cancer tissue. Candidate signatures for patient stratification using QCS of HER2 expression on subcellular compartments were identified, addressing the spatial distribution of tumor cells and tumor-infiltrating lymphocytes. Using data from trastuzumab deruxtecan-treated patients with HER2-positive and HER2-negative breast cancer from a phase 1 study (NCT02564900; DS8201-A-J101; N = 151), QCS-based patient stratification showed longer progression-free survival (14.8 vs 8.6 months) with higher prevalence of patient selection (76.4 vs 56.9%) and a better cross-validated log-rank p value (0.026 vs 0.26) than manual scoring based on the American Society of Clinical Oncology / College of American Pathologists guidelines. QCS-based features enriched the HER2-negative subgroup by correctly predicting 20 of 26 responders.

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

Abstract Background Undernutrition and underweight are osteoporosis risk factors. Therefore, improving the health of underweight young women in Japan is an important medical issue. However, few studies have evaluated the association between being preconception underweight and postnatal osteoporotic fractures in young women. Methods This retrospective cohort study used a Japanese nationwide claims database (JMDC Inc.) to evaluate the effect of preconception underweight on the incidence of osteoporotic fracture within two years after delivery. Data from 16,684 mothers who delivered their first singleton babies between January 2006 and December 2020 were analysed. The combination of disease codes of fractures at sites associated with osteoporosis and medical procedures for fractures was defined as the incidence of osteoporotic fractures, whereas the body mass index (BMI) recorded 12–36 months before delivery was used as the exposure. We estimated the incidence of osteoporotic fractures by BMI category using a Kaplan–Meier curve and examined the fracture risk using Cox hazard regression analyses. Results Fifty-one women (0.31%) were affected by osteoporotic fractures within two years of delivery. More than 80% of these were rib fractures, and approximately 65% of fractures occurred after the first year postpartum. Preconception underweight (BMI

Abstract Aim The aim of this study was to clarify the significance of resection of ovarian metastases from colorectal cancer and to identify the clinicopathologic characteristics. Methods In this multicenter retrospective study, we evaluated data on ovarian metastases from colorectal cancer obtained from patients at 20 centers in Japan between 2000 and 2014. We examined the impact of resection on the prognosis of patients with ovarian metastases and examined prognostic factors. Results The study included 296 patients with ovarian metastasis. The 3‐y overall survival rate was 68.6% for solitary ovarian metastases. In all cases of this cohort, the 3‐y overall survival rates after curative resection, noncurative resection, and nonresection were 65.9%, 31.8%, and 6.1%, respectively (curative resection vs noncurative resection [P

BackgroundBone marrow metastasis (BMM) of gastric cancer (GC), which is the most common cause of disseminated intravascular coagulation (DIC) among solid tumors, has a poor prognosis. Studies on prognostic improvement beyond one year in patients with GC with BMM are limited. This is the first report of a patient who survived over three years after 30 months of S-1 plus oxaliplatin (SOX) therapy for GC with BMM.Case ReportThe patient was a 72-year-old woman who presented with anemia and high levels of alkaline phosphatase (ALP) and carbohydrate antigen 19-9 (CA19-9). Detailed examination led to the diagnosis with BMM of GC uncomplicated by DIC and the SOX regimen was initiated in November 2018. After six cycles, she was switched to S-1 monotherapy, and both ALP and CA19-9 levels reached normal by November 2019. However, computed tomography in April 2021 showed multiple bone metastases. Therefore, she was switched to paclitaxel-based therapy. In November 2021, the patient was further switched to nivolumab monotherapy, but she succumbed due to DIC in March 2022.ConclusionGCs with BMM are prone to DIC, and the SOX regimen, which includes S-1 with efficacy against micrometastases, may constitute a safe and effective treatment modality.

Abstract Self-efficacy is defined as people’s beliefs in their own abilities to achieve something. This study aimed to systematically review the literature on psychological variables associated with self-efficacy in sport. Searches were conducted in six electronic databases: LILACS, PubMed, SciELO, SPORTDiscus, Web of Science, and Scopus, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Content analysis of 29 included articles allowed for the identification of three research groups: psychological variables (n = 31; 72.1%), performance variables (n = 7; 13.3%), and other variables (n = 5; 11, 6%). There was a predominance of cross-sectional quantitative studies (72.4%; n = 21). The most used instrument was the General Self-Efficacy Scale (GSE), with 13 (44.8%) articles. In seven (24.1%) articles, specific questions were developed for the study. It is concluded that self-efficacy is a widely studied variable, but there is a lack of specific instruments in the Brazilian context of high-performance sports.

Information regarding follow-up duration after treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL) is important. However, a clear endpoint has yet to be established. We totally enrolled 2182 patients newly diagnosed with DLBCL between 2008 and 2018. The median age of the patients was 71 years. All patients were treated with rituximab- and anthracycline-based chemotherapies. Each overall survival (OS) was compared with the age- and sex-matched Japanese general population (GP) data. At a median follow-up of 3.4 years, 985 patients experienced an event and 657 patients died. Patients who achieved an event-free survival (EFS) at 36 months (EFS36) had an OS equivalent to that of the matched GP (standard mortality ratio [SMR], 1.17; P=0.1324), whereas those who achieved an EFS24 did not have an OS comparable to that of the matched GP (SMR, 1.26; P=0.0095). Subgroup analysis revealed that relatively old patients (>60 years), male patients, those with limited-stage disease, those with a good performance status, and those with low levels of soluble interleukin 2 receptor already had a comparable life expectancy to the matched GP at an EFS24. In contrast, relatively young patients had a shorter life expectancy than matched GP, even with an EFS36. In conclusion, an EFS36 was shown to be a more suitable endpoint for newly diagnosed DLBCL patients than an EFS24. Of note, younger patients require a longer EFS period than older patients in order to obtain an equivalent life expectancy to the matched GP.

IntroductionThe field of Medicines Development faces a continuous need for educational evolution to match the interdisciplinary and global nature of the pharmaceutical industry. This paper discusses the outcomes of a 7-year collaboration between King’s College London and the Global Medicines Development Professionals (GMDP) Academy, which aimed to address this need through a blended e-learning program.MethodsThe collaboration developed a comprehensive curriculum based on the PharmaTrain syllabus, delivered through a combination of asynchronous and synchronous e-learning methods. The program targeted a diverse range of professionals serving in areas related to Medical Affairs.ResultsOver seven annual cohorts, 682 participants from eighty-six countries were enrolled in the program. The program’s effectiveness was assessed using Kirkpatrick’s model, showing elevated levels of satisfaction (over 4.0 on a five-point scale), suggesting significant gains in competence at the cognitive level and leveraged performance. Notably, 70% of responding alumni reported significant improvement in their functions, corroborated by 30% of their supervisors. The further long-term impact of the program on their respective organization has not been established.DiscussionThe GMDP Academy’s program has significantly contributed to life-long learning in Medicines Development, addressing educational gaps and fostering interdisciplinary collaboration. Its success highlights the importance of continuous education in keeping pace with the industry’s evolving demands and underscores the potential of blended learning in achieving educational objectives in pharmaceutical medicine.

Purpose: To investigate the disease activity in real-world patients with rheumatoid arthritis (RA) who switched from originator etanercept (ETN) to biosimilar YLB113. Methods: Forty one RA patients who switched from ETN to YLB113 were divided into 2 groups based on the Disease Activity Score based on the 28-joint count (DAS28) 12 months after switching (R group: DAS28 < 2.6, N group: DAS28 ≥ 2.6), and the baseline characteristics were statistically examined. A receiver operating characteristics (ROC) analysis was performed to estimate the cut-off value of DAS28 at baseline to achieve remission 12 months after switching. Results: There was no significant difference in the DAS28 at baseline and 12 months after switching ( p = .83). Sixteen out of the 20 patients in remission at baseline achieved remission after switching. A univariate analysis revealed the rheumatoid factor ( p = .04) and DAS28 ( p < .001) at baseline were significantly lower in the R group than in the N group. Furthermore, logistic regression analysis revealed DAS28 was an independent factor ( p = .004) for achieving remission 12 months after switching. An ROC curve analysis showed the optimal cut-off value for DAS28 at baseline to achieve remission at 12 months after switching was 2.5. Conclusions: RA patients who achieved remission using originator ETN, were able to maintain remission even if they switched to YLB113.

Abstract Background This study aimed to investigate the relationship between femoral neck fractures and sarcopenia. Methods This was a retrospective analysis of 92 patients with femoral neck fractures, from September 2017 to March 2020, who were classified into high ambulatory status (HG) and low ambulatory status (LG) groups. Ambulatory status was assessed before surgery, one week after surgery, at discharge, and during the final follow-up. To evaluate sarcopenia, muscle mass and fatty degeneration of the muscles were measured using preoperative CT. An axial slice of the superior end of the L5 vertebra was used to evaluate the paraspinal and psoas muscles, a slice of the superior end of the femoral head for the gluteus maximus muscle, and a slice of the inferior end of the sacroiliac joint for the gluteus medius muscle. The degeneration of the muscles was evaluated according to the Goutallier classification. Results The cross-sectional area of the gluteus medius and paraspinal muscles was significantly correlated with ambulatory status before the injury, at discharge, and during the final follow-up. Conclusions Measurement of the gluteus medius and paraspinal muscles has the potential to evaluate sarcopenia and predict ambulatory status after femoral neck fractures.

Abstract Background The worldwide vaccination response to COVID-19 has been associated with rare thrombotic complications, including the case of postvaccination splanchnic venous thrombosis we report here. Case presentation An 80-year-old Japanese male with abdominal pain presented to our hospital six days after receiving a dose of the COVID-19 messenger ribonucleic acid vaccine. Abdominal computed tomography showed localized edema of the small intestine, increased density of the surrounding adipose tissue, and a thrombus in the superior mesenteric vein. Conservative inpatient treatment with unfractionated heparin relieved the thrombosis, and the patient is currently receiving oral apixaban as an outpatient. Conclusion Reported cases of thrombosis after COVID-19 vaccination typically have been associated with viral vector vaccines, with few reports of thrombosis induced by mRNA vaccines. The potential for venous thrombosis should be explored when patients present with abdominal pain soon after COVID-19 vaccination.

Objetivos: Explorar as representações sociais de estudantes de enfermagem sobre o abortamento provocado e discutir as representações sociais sobre o cuidado de enfermagem à mulheres em processo de abortamento ou pós-aborto com complicações. Método: Trata-se de um estudo qualitativo, fundamentado na Teoria das Representações Sociais, realizado com 16 estudantes de enfermagem do curso de Enfermagem da região do nordeste do Brasil, realizado no período de novembro de 2022. Foi utilizado como critério de inclusão ser estudante de enfermagem devidamente matriculado(a) no semestre 2022.2 da UNEB e de exclusão ser menor de 18 anos. Os dados foram coletados através da entrevista semiestruturada e analisados por meio do software Iramuteq que gerou a Classificação Hierárquica Descendente. Resultados: Após o processamento dos dados e o agrupamento das palavras feito pelo sistema, obteve-se a classificação dos segmentos de texto e a definição dos nomes das classes: Classe 1: Cuidado de enfermagem à mulher em situação de aborto; Classe 2: Representação do abortamento provocado na perspectiva dos direitos sexuais e reprodutivos e sua legalização como forma de reduzir o risco de complicações e morte; Classe 3: Representação do abortamento provocado na perspectiva dos direitos sexuais e reprodutivos e sua legalização como forma de reduzir o risco de complicações e morte. Conclusão: Torna-se necessário que na graduação o tema seja discutido com mais frequência para que se possa ampliar o conhecimento frente aos desafios e complexidades que futuros profissionais irão lidam na prestação de cuidados à mulheres em processo de abortamento ou pós-aborto com complicações.

Abstract A 37‐year‐old man with systemic lupus erythematosus underwent esophagogastroduodenoscopy as a screening examination for anemia and bloody stool. A semi‐pedunculated edematous lobular polyp of 25 mm in size was detected in the greater curvature of the upper gastric body. At that time, a definitive diagnosis of cancer could not be made based on a biopsy specimen from the lesion. Since the patient was on proton pump inhibitor (PPI) for a long time to prevent peptic ulceration due to prolonged prednisolone administration for systemic lupus erythematosus, we diagnosed the lesion as a PPI‐associated hyperplastic polyp and switched lansoprazole to famotidine. Two months later, esophagogastroduodenoscopy revealed that the polyp had decreased in size to 8 mm, whereas the biopsy specimen led to a histological diagnosis of gastric cancer. The polyp was removed by endoscopic submucosal dissection. Immunohistochemistry revealed that the tumor cells were positive for MUC5AC, but negative for MUC2 and MUC6, leading to a final diagnosis of foveolar‐type gastric adenocarcinoma. In conclusion, we may suggest that PPI induces reversible morphological changes in foveolar‐type gastric adenocarcinoma. Furthermore, short‐term follow‐up of polypoid lesions should be prepared, considering tumor comorbidity with morphological changes during long‐term PPI usage.

Abstract Metastasis from small‐cell lung cancer to the colon is very rare. A 74‐year‐old man without respiratory or abdominal symptoms underwent a follow‐up lower gastrointestinal endoscopy after a polypectomy. He was diagnosed with a 5 mm IIa non‐hyperplastic polyp in the cecum and underwent a cold snare polypectomy. The histopathological findings confirmed the diagnosis of small cell carcinoma. The tumor was positive in the deep margins of the submucosal layer. Subsequent systemic examination revealed a mass in the lower lobe of the left lung. Thus, the tumor in the cecum was determined to be a colorectal metastasis from primary small‐cell carcinoma of the lung. Metastasis to the colon was diagnosed as small‐cell lung cancer based on local positivity for thyroid transcription factor‐1 and morphologic and immunochemical features. To our best knowledge, this is the first report of colon metastasis from small cell carcinoma identified by endoscopic treatment.

Traditionally, monitoring insect populations involved the use of externally placed sticky paper traps, which were periodically inspected by a human operator. To automate this process, a specialized sensing device and an accurate model for detecting and counting insect pests are essential. Despite considerable progress in insect pest detector models, their practical application is hindered by the shortage of insect trap images. To attenuate the “lack of data” issue, the literature proposes data augmentation. However, our knowledge about data augmentation is still quite limited, especially in the field of insect pest detection. The aim of this experimental study was to investigate the effect of several widely used augmentation techniques and their combinations on remote-sensed trap images with the YOLOv5 (small) object detector model. This study was carried out systematically on two different datasets starting from the single geometric and photometric transformation toward their combinations. Our results show that the model’s mean average precision value (mAP50) could be increased from 0.844 to 0.992 and from 0.421 to 0.727 on the two datasets using the appropriate augmentation methods combination. In addition, this study also points out that the integration of photometric image transformations into the mosaic augmentation can be more efficient than the native combination of augmentation techniques because this approach further improved the model’s mAP50 values to 0.999 and 0.756 on the two test sets, respectively.

Heavy metals such as lead (Pb) are significantly harmful to human health and may have disastrous effects on the ecosystem. Consequently, Pb-contaminated soil necessitates remediation to bring Pb levels below the standard threshold of 150 mg/kg. This study aimed to devise processes for extracting and enriching Pb using chelation reactions. Pb was effectively extracted from the soil using EDTA as the chelating agent, forming a complex ([Pb-HEDTA]-) that is solubilized in the solution. Extraction efficiency increased with higher EDTA/Pb molar ratios, remaining relatively constant at 100 or above. Elevated temperatures also enhanced Pb extraction; concentrations below 150 mg/kg were achieved at 25 °C or higher. The desorption of Pb followed the Langmuir equation, indicating uniform one-to-one Pb desorption. The addition of the chelating flocculant diethyldithiocarbamic acid (DDTC) concentrated Pb in the solid phase, reducing sludge volume. Pb transfer rate rose with increasing DDTC/[Pb-EDTA]2− ratio, peaking at 90 % with a ratio of 50. The presence and extraction of other elements (Fe, Cu, and Zn) did not impede Pb extraction and enrichment. Therefore, this study and its findings could provide the basis for further development of the Pb extraction process and mitigate the problem of Pb-contaminated soil when designing Pb extraction plants.

AimMetabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH.MethodsChanges in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH.ResultsCDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage.ConclusionS1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.

The Comparative Thyroid Assay (CTA, USEPA) is a screening test for thyroid hormone (TH) disruption in peripheral blood of dams and offspring. Recently, we began investigating feasible improvements to the CTA by adding examination of offspring brain TH concentrations and brain histopathology. In addition, we hypothesize that the number of animals required could be reduced by 50 % while still maintaining sensitivity to characterize treatment related changes in THs. Previously, we showed that the prenatal test cohort of the modified CTA could detect 1000 ppm sodium phenobarbital (NaPB)-induced suppression of brain T3 (by 9 %) and T4 (by 33 %) with no significant changes in serum T3 and T4 (less than 8 %). In the current study we expanded the dose response in a prenatal test cohort. Pregnant SD rats (N = 10/group) were exposed to 0, 1000 or 1500 ppm NaPB in the diet from gestational days (GD) 6 to GD20. Serum THs concentrations in GD20 dams together with serum/brain THs concentrations and brain histopathology in the GD20 fetuses were examined. NaPB dose-dependently suppressed serum T3 (up to −26 %) and T4 (up to −44 %) in dams, with suppression of T3 in serum (up to −26 %) and brain (up to −18 %) and T4 in serum (up to −26 %) and brain (up to −29 %) of fetuses but without clear dose dependency. There were no remarkable findings that deviated significantly from controls in GD20 fetal brain by qualitative histopathology. Overall, the present study suggests that the prenatal test cohort of this modified CTA is able to detect the expected fetal TH disruptions by prenatal exposure to NaPB, while also reducing the number of animals used by 50 %, consistent with the results of our previous study. These findings add to the suggestion that lowering group sizes and adding endpoints may be a useful alternative to the original CTA design.

ABSTRACTWe develop a high-throughput method for measuring the composition dependence of magnetoresistance (MR) and spin-transfer-torque (STT) effects in current-perpendicular-to-plane giant magnetoresistance (CPP-GMR) devices and report its application to the CoFe system. The method is based on the use of composition-gradient films deposited by combinatorial sputtering. This structure allows the fabrication of devices with different compositions on a single substrate, drastically enhancing the throughput in investigating composition dependence. We fabricated CPP-GMR devices on a single GMR film consisting of a CoxFe1-x (0 ≤ x ≤ 1) composition-gradient layer, a Cu spacer layer, and a NiFe layer. The MR ratio obtained from resistance-field measurements exhibited the maximum in the broad Co concentration range of 0.3 ≤ x ≤ 0.65. In addition, the STT efficiency was estimated from the current to induce magnetization reversal of the NiFe layer by spin injection from the CoxFe1-x layer. The STT efficiency was also the highest around the same Co concentration range as for the MR ratio, and this correlation was theoretically explained by the change in the spin polarization of the CoxFe1-x layer. The results revealed the CoxFe1-x composition range suitable for spintronic applications, demonstrating the advantages of the developed method.

Background Sterile inflammation caused by metabolic disorders impairs endothelial function; however, the underlying mechanism by which hyperglycemia induces inflammation remains obscure. Recent studies have suggested that stimulator of interferon genes (STING), a key cytosolic DNA sensor in the innate immune system, contributes to the pathogenesis of inflammatory diseases. This study examines the role of the STING in endothelial dysfunction in streptozotocin‐induced diabetic mice. Methods and Results Injection of streptozotocin promoted the expression of STING and DNA damage markers in the aorta of wild‐type mice. Streptozotocin elevated blood glucose and lipid levels in both wild‐type and STING‐deficient mice, which showed no statistical differences. Genetic deletion of STING ameliorated endothelial dysfunction as determined by the vascular relaxation in response to acetylcholine (P

Interest in psychosocial predictors of doping has been increasing as a way of finding new approaches to reduce the use of performance-enhancing drugs. This investigation aimed to test the psychometric properties of an instrument to assess doping attitudes in Brazilian athletes. The PEAS was validated in Brazilian sports through a process of translation, back-translation and content validity assessment, presenting satisfactory evidence based on its content (CVC > 0.80). Then, 994 athletes from different sexes, types of sports and competitive levels answered the Brazilian version of the PEAS. The results showed satisfactory evidence of validity based on its response process, internal structure (X2/df = 2.04; RMSEA = 0.032 (0.026–0.038); CFI = 0.96; TLI = 0.95) and reliability (Cronbach’s α, McDonald’s ω and CR > 0.70). Network analysis was also used to further explore the PEAS’s internal structure. Overall, the results provide support for the adoption of the PEAS for Brazilian athletes and possibly other Portuguese-speaking countries.

Oral tolerance has been defined as the specific suppression of immune responses to an antigen by prior oral administration of the antigen. It has been thought to serve to suppress food allergy. Previous studies have shown that dendritic cells (DCs) and regulatory T cells (Tregs) are involved in the induction of oral tolerance. However, the detailed mechanisms of Treg induction in oral tolerance remain largely unknown. Eosinophils have been recognized as effector cells in allergic diseases, but in recent years, the diverse functions of tissue-resident eosinophils have been reported. Eosinophils in the intestine have been reported to induce Tregs by releasing TGF-β, but the role of eosinophils in oral tolerance is still controversial. In this study, we analyzed the roles of eosinophils in oral tolerance using eosinophil-deficient ΔdblGATA mice (mice lacking a high-affinity GATA-binding site in the GATA1 promoter). ΔdblGATA mice showed impaired antigen-induced oral tolerance compared to wild-type mice. The induction of RORγt+ Tregs in mesenteric lymph nodes (MLNs) by oral tolerance induction was impaired in ΔdblGATA mice compared to wild-type mice. An increase in RORγt+ antigen-presenting cells (APCs), which are involved in RORγt+ Treg differentiation, in the intestine and MLNs was not seen in ΔdblGATA mice. Notably, the expansion of group 3 innate lymphoid cells (ILC3s), a subset of RORγt+ APCs, by oral tolerance induction was seen in wild-type mice but not ΔdblGATA mice. These results suggest that eosinophils are crucial in the induction of oral tolerance, possibly via the induction of RORγt+ APCs and RORγt+ Tregs.

This study aimed to clarify diseases that occur more frequently by age and identify the peaks and trends of each disease from infancy to adolescence for early detection and treatment. This retrospective observational study was conducted using Japan’s National Database of Health Insurance Claims Specific Health Checkups from January 2012 to December 2016. Using peak ages and trends in the number of patients, we grouped diseases by the International Classification of Diseases chapters. Although diseases that peaked during infancy were the most common (10 disease chapters), other diseases peaked at school-going age and adolescence. Diseases in four chapters peaked during adolescence and continued to increase toward the age of 18. These four chapters included mental, behavioral, and neurodevelopmental disorders; diseases of the nervous system; the genitourinary system; and pregnancy, childbirth, and the puerperium. Childhood-onset diseases can affect long-term health and healthcare needs, and timely screening and guidance based on disease trends can provide an effective intervention. To establish a child healthcare system that provides preventive support for children and adolescents’ physical, psychological, and social health, further research is needed to comprehensively understand the issues per age and developmental stage.

Observed protostellar outflows exhibit a variety of asymmetrical features, including remarkable unipolar outflows and bending outflows. Revealing the formation and early evolution of such asymmetrical protostellar outflows, especially the unipolar outflows, is essential for a better understanding of the star and planet formation because they can dramatically change the mass accretion and angular momentum transport to the protostars and protoplanetary disks. Here we perform three-dimensional nonideal magnetohydrodynamics simulations to investigate the formation and early evolution of the asymmetrical protostellar outflows in magnetized turbulent isolated molecular cloud cores. We find, for the first time to our knowledge, that the unipolar outflow forms even in the single low-mass protostellar system. The results show that the unipolar outflow is driven in the weakly magnetized cloud cores with the dimensionless mass-to-flux ratios of μ = 8 and 16. Furthermore, we find the protostellar rocket effect of the unipolar outflow, which is similar to the launch and propulsion of a rocket. The unipolar outflow ejects the protostellar system from the central dense region to the outer region of the parent cloud core, and the ram pressure caused by its ejection suppresses the driving of additional new outflows. In contrast, the bending bipolar outflow is driven in the moderately magnetized cloud core with μ = 4. The ratio of the magnetic to turbulent energies of a parent cloud core may play a key role in the formation of asymmetrical protostellar outflows.

Riverbed materials serve multiple environmental functions as a habitat for aquatic invertebrates and fish. At the same time, the particle size of the bed material reflects the tractive force of the flow regime in a flood and provides useful information for flood control. The traditional riverbed particle size surveys, such as sieving, require time and labor to investigate riverbed materials. The authors of this study have proposed a method to classify aerial images taken by unmanned aerial vehicles (UAVs) using convolutional neural networks (CNNs). Our previous study showed that terrestrial riverbed materials could be classified with high accuracy. In this study, we attempted to classify riverbed materials of terrestrial and underwater samples including that which is distributed in shallow waters where the bottom can be seen using UAVs over the river segment. It was considered that the surface flow types taken overlapping the riverbed material on images disturb the accuracy of classification. By including photographs of various surface flow conditions in the training data, the classification focusing on the patterns of riverbed materials could be achieved. The total accuracy reached 90.3%. Moreover, the proposed method was applied to the river segments to determine the distribution of the particle size. In parallel, the microtopography was surveyed using a LiDAR UAV, and the relationship between the microtopography and particle size distribution was discussed. In the steep section, coarse particles were distributed and formed riffles. Fine particles were deposited on the upstream side of those riffles, where the slope had become gentler due to the dammed part. The good concordance between the microtopographical trends and the grain size distribution supports the validity of this method.

To test the usefulness of the Cancer and Aging Research Group (CARG) predictive tool, it was used to assess elderly cancer patients with prior anticancer therapy. Among patients with solid malignancies aged ≥ 65 years receiving second-line chemotherapy who were admitted to the Department of Medical Oncology/Hematology at Kakogawa Central City Hospital between April 2016 and September 2019, the risk ≥ grade 3 of developing chemotherapy-related adverse events (CRAEs) (low, intermediate, or high) was calculated using the tool. Correlations between grades 3 and 5 CRAE incidence rates in the first course of each regimen and CARG risk score, age, and Eastern Cooperative Oncology Group performance status (ECOG PS) were assessed. Included patients (n = 62) had a mean age of 71 years (range, 65–82 years). Severe CRAE incidence in patients with low, medium, or high CARG risk was 27%, 54%, and 71%, respectively (p = 0.026). The incidence of severe non-hematological toxicities was 5%, 35%, and 64%, respectively (p < 0.01). There was no association between age or ECOG PS and chemotherapy toxicity. The results suggest the validity of the CARG predictive tool in elderly cancer patients with prior anticancer therapy. Particularly, the tool showed potential for predicting non-hematological toxicity.

Abstract Understanding residual radioactive contamination state and the resulting radiation environment is vital before reconstructing the lives of residents in areas affected by nuclear power plant accidents. In this study, we surveyed the depth profiles of Cs‐137 in three artificially paved ground surfaces: impermeable asphalt, permeable asphalt, and concrete, in areas affected by the Fukushima Daiichi Nuclear Power Plant accident after a period of 10 years and analyzed the gamma‐ray air dose rate distribution in a two‐story wooden house model surrounded by different ground surfaces using the Particle and Heavy Ion Transport code System of the Japan Atomic Energy Agency. The air dose rate distribution tendencies within the building for different surrounding ground surfaces were clarified by analyzing the transport of gamma rays emitted from the Cs‐137 in the ground. Moreover, the shielding effect of an ordinal concrete fence on the indoor air dose rate was analyzed. The analysis showed that the indoor air dose rate was higher in an environment with artificial pavement than in that with a soil surface, and even a simple measure, such as installing an ordinal concrete fence, could significantly reduce indoor radiation dose rates.

In recent years, the achievements of machine learning (ML) have affected all areas of industry and it plays an increasingly important role in agriculture as well [...]

Human epidermal growth factor receptor 2 (HER2) protein, which is characterized by the amplification of ERBB2, is a molecular target for HER2-overexpressing breast cancer. Many targeted HER2 strategies have been well developed thus far. Furthermore, intratumoral heterogeneity in HER2 cases has been observed with immunohistochemical staining and has been considered one of the reasons for drug resistance. Therefore, we conducted an integrated analysis of the breast cancer single-cell gene expression data for HER2-positive breast cancer cases from both scRNA-seq data from public datasets and data from our cohort and compared them with those for luminal breast cancer datasets. In our results, heterogeneous distribution of the expression of breast cancer-related genes (ESR1, PGR, ERBB2, and MKI67) was observed. Various gene expression levels differed at the single-cell level between the ERBB2-high group and ERBB2-low group. Moreover, molecular functions and ERBB2 expression levels differed between estrogen receptor (ER)-positive and ER-negative HER2 cases. Additionally, the gene expression levels of typical breast cancer-, CSC-, EMT-, and metastasis-related markers were also different across each patient. These results suggest that diversity in gene expression could occur not only in the presence of ERBB2 expression and ER status but also in the molecular characteristics of each patient.

Abstract Discriminating between urothelial carcinoma (UC), including bladder cancer (BCa) and upper urinary tract UC (UTUC), is often challenging. Thus, the current study evaluated the diagnostic performance of N‐glycosylation signatures of immunoglobulins (Igs) for detecting UC, including BCa and UTUC. N‐glycosylation signatures of Igs from serum samples of the training cohort, including 104 BCa, 68 UTUC, 10 urinary tract infection, and 5 cystitis cases, as well as 62 healthy volunteers, were measured retrospectively using automated capillary‐electrophoresis‐based N‐glycomics. UTUC or BCa scores were then established through discriminant analysis using N‐glycan signatures of Igs. Diagnostic performance was evaluated using the area under receiver operating characteristics curve (AUC) and decision curve analyses (DCA). Our result showed that BCa and UTUC scores for discriminating BCa (AUC: 0.977) and UTUC (AUC: 0.867), respectively, provided significantly better clinical performance compared to urine cytology, gross hematuria, or clinical T1 cases. DCA revealed that adding BCa and UTUC scores to gross hematuria status was the best combination for detecting UC and avoiding the need for more intervention without overlooking UC (risk threshold: 13%–93%). The UC nomogram based on the combination of gross hematuria, UTUC score, and BCa score could detect UC with an AUC of 0.891, indicating significantly better performance compared to gross hematuria status in the validation cohort (251 patients). The limitations of this study include its small sample size and retrospective nature. The UC nomogram based on gross hematuria and N‐glycosylation signatures of Igs can be a promising approach for the diagnosis of UC.

Abstract Background It remains unclear whether patients’ self‐perceptions of symptoms at baseline clinically impact the prognostic relevance, treatment efficacy, or toxicity profiles in metastatic colorectal cancer (mCRC) patients treated with the first‐line cetuximab and standard chemotherapy. Methods The data were collected from a prospective trial that assessed the relationships between quality of life (QOL), treatment efficacy, and adverse events (AEs). Results The analysis of 137 mCRC patients revealed a significant association between the presence of baseline tumor‐related symptoms and a lower overall survival (OS) compared to the absence of symptoms (HR, 2.49; 95% CI, 1.37‐4.62; P = .003). The asymptomatic responders had favorable outcomes compared to the symptomatic nonresponders (2‐year OS rates: 83.6% and 35.9%, respectively), while the symptomatic responders had similar outcomes to the asymptomatic nonresponders. The median postprogression survival differed significantly: 10.2 months for the symptomatic patients and 15.9 months for the asymptomatic patients (HR, 2.29; 95% CI, 1.25‐4.29, P = .008). The objective response rates and patient toxicity profiles were similar irrespective of the severity of baseline symptoms. Conclusion Baseline symptoms were associated with worse OS but not with impaired treatment efficacy or more frequent AEs in mCRC patients treated with cetuximab in addition to chemotherapy.

The incidence of inflammatory bowel diseases (IBD) is increasing worldwide. Mesenchymal stem/stromal cells (MSCs) have immunomodulatory functions and are a promising source for cell transplantation therapy for IBD. However, owing to their heterogeneous nature, their therapeutic efficacy in colitis is controversial and depends on the delivery route and form of transplanted cells. Cluster of differentiation (CD) 73 is widely expressed in MSCs and used to obtain a homogeneous MSC population. Herein, we determined the optimal method for MSC transplantation using CD73+ cells in a colitis model. mRNA sequencing analysis showed that CD73+ cells exhibited a downregulation of inflammatory gene expression and an upregulation of extracellular matrix-related gene expression. Furthermore, three-dimensional CD73+ cell spheroids showed enhanced engraftment at the injured site through the enteral route, facilitated extracellular matrix remodeling, and downregulated inflammatory gene expression in fibroblasts, leading to the attenuation of colonic atrophy. Therefore, the interaction between intestinal fibroblasts and exogenous MSCs via tissue remodeling is one mechanism that can be exploited for colitis prevention. Our results highlight that the transplantation of homogeneous cell populations with well-characterized properties is beneficial for IBD treatment.

Une exposition peut être considérée comme un dispositif producteur de signes qui encadre le sens des objets qu’elle présente, ceux-ci sont resémantisés à chaque fois qu’ils sont montrés au public, qu’ils sont rendus visibles sous un point de vue particulier. Dans les musées, les vestiges archéologiques préhistoriques se caractérisent par la pluralité des logiques discursives qui peuvent être utilisées pour unifier le caractère profondément fragmentaire de ces objets immémoriaux. Les affiches japonaises d’expositions archéologiques mettent en scène les vestiges et les sémiotisent conformément aux dispositifs muséaux utilisés pour l’occasion. Cet article, à travers l’analyse d’affiches, vise à discerner les caractères généraux concernant la sémiotisation des objets préhistoriques, relevant notamment de la période Jômon et de la période Yayoi, dans des expositions muséales au Japon qui convoquent des discours scientifiques, esthétiques et mémoriels.

Orotate phosphoribosyltransferase (OPRT) exists as a bifunctional enzyme, uridine 5′-monophosphate synthase, in mammalian cells and plays an important role in pyrimidine biosynthesis. Measuring OPRT activity has been considered important for understanding biological events and development of molecular-targeting drugs. In this study, we demonstrate a novel fluorescence method for measuring OPRT activity in living cells. The technique utilizes 4-trifluoromethylbenzamidoxime (4-TFMBAO) as a fluorogenic reagent, which produces selective fluorescence for orotic acid. To perform the OPRT reaction, orotic acid was added to HeLa cell lysate, and a portion of the enzyme reaction mixture was heated at 80 °C for 4 min in the presence of 4-TFMBAO under basic conditions. The resulting fluorescence was measured using a spectrofluorometer, which reflects the consumption of orotic acid by the OPRT. After optimization of the reaction conditions, the OPRT activity was successfully determined in 15 min of enzyme reaction time without further procedures such as purification of OPRT or deproteination for the analysis. The activity obtained was compatible with the value measured by the radiometric method with [3H]-5-FU as the substrate. The present method provides a reliable and facile measurement of OPRT activity and could be useful for a variety of research fields targeting pyrimidine metabolism.

Abstract Background To compare the efficacy of 12-month denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTMs) between treatment-naïve osteoporosis patients with rheumatoid arthritis (RA) and those with previous bisphosphonate (BP) therapy. Methods A total of 36 RA patients with osteoporosis completed 12-month follow-up. Twenty-five patients were osteoporotic treatment-naïve (naïve group), and 11 patients were previously treated with BPs (switch group) (average 7.9 years). BMD and BTMs were measured before and 6 and 12 months after treatment. Results BTM levels were higher in the naïve group at baseline. However, the same level of suppression was achieved at 6 months in both groups. Spine BMD increased significantly in both groups. There was no significant difference in the mean percent changes of BMD of the spine (naïve group: 6.8 ± 0.8, switch group: 5.1 ± 1.5), femoral neck (2.9 ± 1.4, 2.9 ± 1.3), and total hip (1.7 ± 0.9, 1.4 ± 1.1) between these two groups at 12 months. Conclusions The effects of denosumab on BMD and BTMs of the switch group after long-term BP treatment are comparable to those of the naïve group in RA patients. Thus, switching BPs to denosumab is one of the useful options to treat osteoporosis with RA.