bluuebunny/crossref_metadata_2025 huggingface dataset:
SIRT1-mediated deacetylation of FOXO3 enhances mitophagy and drives hormone resistance in endometrial cancer
Authors: Wei Xuehua , Xiong Xiangpeng , Wang Pingping , Zhang Shufang , Peng Dongxian
Published: September 2024

Background

The complex interplay between Sirtuin 1 (SIRT1) and FOXO3 in endometrial cancer (EC) remains understudied. This research aims to unravel the interactions of deacetylase SIRT1 and transcription factor FOXO3 in EC, focusing on their impact on mitophagy and hormone resistance.

Methods

High-throughput sequencing, cell experiments, and bioinformatics tools were employed to investigate the roles and interactions of SIRT1 and FOXO3 in EC. Co-immunoprecipitation (Co-IP) assay was used to assess the interaction between SIRT1 and FOXO3 in RL95-2 cells. Functional assays were used to assess cell viability, proliferation, migration, invasion, apoptosis, and the expression of related genes and proteins. A mouse model of EC was established to evaluate tumor growth and hormone resistance under different interventions. Immunohistochemistry and TUNEL assays were used to assess protein expression and apoptosis in tumor tissues.

Results

High-throughput transcriptome sequencing revealed a close association between SIRT1, FOXO3, and EC development. Co-IP showed a protein–protein interaction between SIRT1 and FOXO3. Overexpression of SIRT1 enhanced FOXO3 deacetylation and activity, promoting BNIP3 transcription and PINK1/Parkin-mediated mitophagy, which in turn promoted cell proliferation, migration, invasion, and inhibited apoptosis in vitro, as well as increased tumor growth and hormone resistance in vivo. These findings highlighted SIRT1 as an upstream regulator and potential therapeutic target in EC.

Conclusion

This study reveals a novel molecular mechanism underlying the functional relevance of SIRT1 in regulating mitophagy and hormone resistance through the deacetylation of FOXO3 in EC, thereby providing valuable insights for new therapeutic strategies.
Identification of zinc finger MIZ-type containing 2 as an oncoprotein enhancing NAD-dependent protein deacetylase sirtuin-1 deacetylase activity to regulate Wnt and Hippo pathways in non-small-cell lung cancer
Authors: Gan Xueting , Feng Yuheng , Liu Yang , Lin Xuyong , Yu Xinmiao , Rong Xuezhu , Han Qiang
Published: September 2024

Background

Zinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors.

Methods

ZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT–qPCR) were conducted to verify the impact of ZMIZ2–SIRT1 combination on Hippo/Wnt pathways.

Results

ZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells—establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2–SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear β-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of β-catenin-transcription factor 4 (TCF4) and YAP–TEA domain family transcription factors (TEADs) were amplified.

Conclusions

ZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs.

Graphical Abstract
altAFplotter: a web app for reliable UPD detection in NGS diagnostics
Authors: Radtke Maximilian , Moch Johanna , Hentschel Julia , Schumann Isabell
Published: September 2024

Background

The detection of uniparental disomies (the inheritance of both chromosome homologues from a single parent, UPDs) is not part of most standard or commercial NGS-pipelines in human genetics and thus a common gap in NGS diagnostics. To address this we developed a tool for UPD-detection based on panel or exome data which is easy to use and publicly available.

Results

The app is freely available at https://altafplotter.uni-leipzig.de/ and implemented in Python, using the Streamlit framework for data science web apps. It utilizes bcftools and tabix for processing vcf files. The source code is available at https://github.com/HUGLeipzig/altafplotter and can be used to host your own instance of the tool.

Conclusion

We believe the app to be a great benefit for research and diagnostic labs, which struggle identifying and interpreting UPDs in their NGS diagnostic setup. The information provided allows a quick interpretation of the results and thus is suitable for usage in a high throughput manner by clinicians and biologists.
Recruiting people with selected citizenships for the health interview survey GEDA Fokus throughout Germany: evaluation of recruitment efforts and recommendations for future research
Authors: Koschollek Carmen , Gaertner Beate , Geerlings Julia , Kuhnert Ronny , Mauz Elvira , Hövener Claudia
Published: September 2024

Background

Germany is the second most common country of immigration after the US. However, people with own or familial history of migration are not represented proportionately to the population within public health monitoring and reporting. To bridge this data gap and enable differentiated analyses on migration and health, we conducted the health interview survey GEDA Fokus among adults with Croatian, Italian, Polish, Syrian, or Turkish citizenship living throughout Germany. The aim of this paper is to evaluate the effects of recruitment efforts regarding participation and sample composition.

Methods

Data collection for this cross-sectional and multilingual survey took place between 11/2021 and 5/2022 utilizing a sequential mixed-mode design, including self-administered web- and paper-based questionnaires as well as face-to-face and telephone interviews. The gross sample (n = 33436; age range 18–79 years) was randomly drawn from the residents’ registers in 120 primary sampling units based on citizenship. Outcome rates according to the American Association for Public Opinion Research, the sample composition throughout the multistage recruitment process, utilization of survey modes, and questionnaire languages are presented.

Results

Overall, 6038 persons participated, which corresponded to a response rate of 18.4% (range: 13.8% for Turkish citizenship to 23.9% for Syrian citizenship). Home visits accounted for the largest single increase in response. During recruitment, more female, older, as well as participants with lower levels of education and income took part in the survey. People with physical health problems and less favourable health behaviour more often took part in the survey at a later stage, while participants with symptoms of depression or anxiety more often participated early. Utilization of survey modes and questionnaire languages differed by sociodemographic and migration-related characteristics, e.g. participants aged 50 years and above more often used paper- than web-based questionnaires and those with a shorter duration of residence more often used a translated questionnaire.

Conclusion

Multiple contact attempts, including home visits and different survey languages, as well as offering different modes of survey administration, increased response rates and most likely reduced non-response bias. In order to adequately represent and include the diversifying population in public health monitoring, national public health institutes should tailor survey designs to meet the needs of different population groups considered hard to survey to enable their survey participation.
Comparison of a new MR rapid wash-out map with MR perfusion in brain tumors
Authors: Khadhraoui Eya , Schmidt Leon , Klebingat Stefan , Schwab Roland , Hernández-Durán Silvia , Gihr Georg , Paukisch Harald , Stein Klaus-Peter , Behme Daniel , Müller Sebastian Johannes
Published: September 2024

Background

MR perfusion is a standard marker to distinguish progression and therapy-associated changes after surgery and radiochemotherapy for glioblastoma. TRAMs (Treatment Response Assessment Maps) were introduced, which are intended to facilitate the differentiation of vital tumor cells and radiation necrosis by means of late (20–90 min) contrast clearance and enhancement. The differences of MR perfusion and late-enhancement are not fully understood yet.

Methods

We have implemented and established a fully automated creation of rapid wash-out (15–20 min interval) maps in our clinic. We included patients with glioblastoma, CNS lymphoma or brain metastases who underwent our MR protocol with MR perfusion and rapid wash-out between 01/01/2024 and 30/06/2024. Since both wash-out and hyperperfusion are intended to depict the active tumor area, this study involves a quantitative and qualitative comparison of both methods. For this purpose, we volumetrically measured rCBV (relative cerebral blood volume) maps and rapid wash-out maps separately (two raters). Additionally, we rated the agreement between both maps on a Likert scale (0–10).

Results

Thirty-two patients were included in the study: 15 with glioblastoma, 7 with CNS lymphomas and 10 with brain metastasis. We calculated 36 rapid wash-out maps (9 initial diagnosis, 27 follow-up).

Visual agreement of MR perfusion with rapid wash-out by rating were found in 44 ± 40% for initial diagnosis, and 75 ± 31% for follow-up. We found a strong correlation (Pearson coefficient 0.92, p < 0.001) between the measured volumes of MR perfusion and rapid wash-out. The measured volumes of MR perfusion and rapid wash-out did not differ significantly. Small lesions were often not detected by MR perfusion. Nevertheless, the measured volumes showed no significant differences in this small cohort.

Conclusions

Rapid wash-out calculation is a simple tool that provides new information and, when used in conjunction with MR perfusion, may increase diagnostic accuracy. The method shows promising results, particularly in the evaluation of small lesions.
RAS mutation associated with short surgically controllable period in colorectal liver metastases: a retrospective study
Authors: Ito Sono , Takamoto Takeshi , Nara Satoshi , Ban Daisuke , Mizui Takahiro , Nagata Hiroshi , Takamizawa Yasuyuki , Moritani Konosuke , Tsukamoto Shunsuke , Kanemitsu Yukihide , Kinugasa Yusuke , Esaki Minoru
Published: September 2024

Background

The prognostic implications of the RAS status in colorectal cancer liver metastasis (CRLM) remain unclear. This study investigated the prognostic significance of RAS status after curative hepatectomy, focusing on surgical controllability.

Methods

This retrospective study included liver-only CRLM patients who underwent the first hepatectomy between 2015 and 2022 at the National Cancer Center Hospital. Recurrence-free survival (RFS), surgically controllable period (SCP), and overall survival (OS) were compared between RAS wild-type (RAS-wt) and mutant (RAS-mt) patients. Multivariate analyses were conducted to identify independent prognostic factors for each outcome and independent risk factors for less than 1 year SCP.

Results

A total of 150 patients were evaluated, comprising 63 patients with RAS-mt status. There was no significant difference in RFS between RAS-mt and RAS-wt (7.00 vs. 8.03 months, p = 0.48). RAS-mt patients exhibited worse SCP (11.80 vs.21.13 months, p < 0.001) and OS (44.03 vs. 70.03 months, p < 0.001) compared to RAS-wt. Multivariate analysis identified RAS-mt as an independent prognostic factor for both OS (hazard ratio [HR]: 3.37, p < 0.001) and SCP (HR: 2.20, p < 0.001), and as an independent risk factor for less than 1 year of SCP (odds ratio, 2.31; p = 0.03).

Conclusions

CRLM with RAS mutations should be considered for strict surgical indications with preoperative chemotherapy and thorough examination, considering the possibility of short SCP.
Interactions of depression, anxiety, and sleep quality with menopausal symptoms on job satisfaction among middle-aged health workers in England: a STROBE-based analysis
Authors: Asiamah Nestor , Cronin Camille , Abbott Joanne E. , Smith Susan
Published: September 2024

Background

This study examined the association between menopausal symptoms and job satisfaction, and ascertained whether three psychosomatic factors (e.g., anxiety, depression, and sleep quality) interact with menopausal symptoms on job satisfaction.

Methods

A cross-sectional design with sensitivity analysis was adopted. The participants of the study were clinical health workers in England. Data from 154 health workers were analyzed with the hierarchical linear regression (HLR) analysis.

Results

There was a negative association between menopausal symptoms and job satisfaction (β = −0.38; t = −4.81, p < 0.001), but this relationship became non-significant after adjusting for work stress, self-reported health, job tenure, and resilience at work. An interaction between menopausal symptoms and the psychosomatic factors was found. The strength of the negative association between menopausal symptoms and job satisfaction was weakened by sleep quality (β = 0.05; t = 0.48; p > 0.05) but was strengthened by anxiety (β = −0.22; t = −2.28; p < 0.05) and depression (β = −0.24; t = −2.16; p < 0.05).

Conclusion

Menopausal symptoms can be directly associated with lower job satisfaction and indirectly associated with lower job satisfaction through its interaction with depression and anxiety. Menopausal symptoms can weaken the positive association between sleep quality and job satisfaction.
Sex-specific chrono-nutritional patterns and association with body weight in a general population in Spain (GCAT study)
Authors: Pons-Muzzo Luciana , de Cid Rafael , Obón-Santacana Mireia , Straif Kurt , Papantoniou Kyriaki , Santonja Isabel , Kogevinas Manolis , Palomar-Cros Anna , Lassale Camille
Published: September 2024

Background

Altered meal timing patterns can disrupt the circadian system and affect metabolism. Our aim was to describe sex-specific chrono-nutritional patterns, assess their association with body mass index (BMI) and investigate the role of sleep in this relationship.

Methods

We used the 2018 questionnaire data from the population-based Genomes for Life (GCAT) (n = 7074) cohort of adults aged 40–65 in Catalonia, Spain, for cross-sectional analysis and its follow-up questionnaire data in 2023 (n = 3128) for longitudinal analysis. We conducted multivariate linear regressions to explore the association between mutually adjusted meal-timing variables (time of first meal, number of eating occasions, nighttime fasting duration) and BMI, accounting for sleep duration and quality, and additional relevant confounders including adherence to a Mediterranean diet. Finally, cluster analysis was performed to identify chrono-nutritional patterns, separately for men and women, and sociodemographic and lifestyle characteristics were compared across clusters and analyzed for associations with BMI.

Results

In the cross-sectional analysis, a later time of first meal (β 1 h increase = 0.32, 95% CI 0.18, 0.47) and more eating occasions (only in women, β 1 more eating occasion = 0.25, 95% CI 0.00, 0.51) were associated with a higher BMI, while longer nighttime fasting duration with a lower BMI (β 1 h increase=-0.27, 95% CI -0.41, -0.13). These associations were particularly evident in premenopausal women. Longitudinal analyses corroborated the associations with time of first meal and nighttime fasting duration, particularly in men. Finally, we obtained 3 sex-specific clusters, that mostly differed in number of eating occasions and time of first meal. Clusters defined by a late first meal displayed lower education and higher unemployment in men, as well as higher BMI for both sexes. A clear “breakfast skipping” pattern was identified only in the smallest cluster in men.

Conclusions

In a population-based cohort of adults in Catalonia, we found that a later time of first meal was associated with higher BMI, while longer nighttime fasting duration associated with a lower BMI, both in cross-sectional and longitudinal analyses.
Pareto-principle in rare disease education: assessing the representation of common rare diseases in medical education and coding systems
Authors: Berger Alexandra , Grimm Kai Lars , Noll Richard , Wagner Thomas OF
Published: September 2024

Background

The Pareto Principle asserts that a large portion of results can be achieved with a small amount of effort. Wakap et al. found that around 80% of individuals with rare diseases (RD) suffer from one of 149 specific rare diseases. A significant challenge in the RD domain is the lack of information, compounded by the fact that most RD are not specifically codifiable in the ICD-10, leading to a deficit in reliable epidemiological data. Additionally, time constraints in medical education hinder the comprehensive teaching of all RD, contributing to the diagnostic odyssey problem through failure of recognizing diseases. We identified the most and second most prevalent RD (prevalences of 1–5/10,000 and 1–9/100,000, respectively) from the Orphanet Epidemiology File, totaling 454 diseases. We investigated the feasibility of specific coding using ICD-10-GM and whether these diseases were explicitly listed in the subject catalog (GK) of the second state examination in human medicine in Germany. A two-sided chi-square test was employed to identify statistically significant differences between prevalence groups.

Results

Out of 454 diseases, a total of 34% could be specifically coded in ICD-10-GM, with 49% of diseases in the 1–5/10,000 prevalence range (153 RD) and 26% in the 1–9/100,000 range (301 RD) having specific codes. Approximately 15% of all investigated diseases were part of the GK, with 25% of the most prevalent and 10% of the second most prevalent RD group, respectively. Statistically significant differences were observed between prevalence groups concerning the presence of a specific ICD-10-GM code and inclusion in the GK.

Conclusion

Only 49% of the most prevalent RD can be specifically coded, highlighting the challenge of limited epidemiological data on RD. In Germany, the Alpha-ID was introduced in addition to ICD-10 in the inpatient setting to obtain more valid epidemiological data on RD. Recognizing the Pareto Principle’s applicability, the study emphasizes the importance of including the most common rare diseases in medical education. While recognizing the limitations, especially in covering ultra-rare diseases, the study underscores the potential benefits of enhancing medical curricula to improve rare disease awareness and diagnostic accuracy.
Owner satisfaction and prognosis for return to work after pancarpal arthrodesis in working dogs in the United Kingdom: a retrospective study (2011–2020)
Authors: Higgins Joseph , Hayes Graham
Published: September 2024

Background

Pancarpal arthrodesis (PCA) is a commonly performed procedure in the UK. However, it is not known whether working dogs in the UK and other European countries with carpal injuries that have undergone unilateral PCA are able to return to working ability as determined by the owner. Medical records from a referral hospital in the UK were reviewed retrospectively for cases of working dogs treated using unilateral PCA. Case files and radiographs were retrospectively analysed for cause of injury, diagnosis, and complications. The ability of the dog to work after surgery and owner satisfaction with the outcome were assessed using telephone questionnaire.

Results

50% (5/10, 50%) owners stated their dog could perform normal duties, 4/10 (40%) could perform most duties with some allowances. Outcome was not as good for dogs working on steep, uneven fell terrain. 80% (8/10, 80%) owners rated the level of post-operative lameness as unaffected with a normal gait. 90% (9/10, 90%) owners were either very satisfied or satisfied with the outcome of the procedure, and 90% owners stated the financial investment was worthwhile.

Conclusions

Unilateral PCA carries a good prognosis for working dogs with high owner satisfaction. Caution should be advised for dogs expected to work on steep, uneven fell terrain.
Should AI models be explainable to clinicians?
Authors: Abgrall Gwénolé , Holder Andre L. , Chelly Dagdia Zaineb , Zeitouni Karine , Monnet Xavier
Published: September 2024

In the high-stakes realm of critical care, where daily decisions are crucial and clear communication is paramount, comprehending the rationale behind Artificial Intelligence (AI)-driven decisions appears essential. While AI has the potential to improve decision-making, its complexity can hinder comprehension and adherence to its recommendations. “Explainable AI” (XAI) aims to bridge this gap, enhancing confidence among patients and doctors. It also helps to meet regulatory transparency requirements, offers actionable insights, and promotes fairness and safety. Yet, defining explainability and standardising assessments are ongoing challenges and balancing performance and explainability can be needed, even if XAI is a growing field.
Insights from multigene analysis: first report of a Southeast Asian Mosquito, Aedes (Mucidus) laniger (Diptera: Culicidae) on Jeju Island from Korea
Authors: Bang Woo Jun , Seol Ara , Shin Seunggwan
Published: September 2024

Background

Certain mosquitoes are known as dominant vectors worldwide, and transmit infectious diseases. The expansion of mosquito habitats due to climate change and increased human activities poses a significant health threat by facilitating the spread of various non-native infectious diseases. This study focused on the detection of the Southeast Asian mosquito species, Aedes (Mucidus) laniger (Wiedemann, 1820) on Jeju Island, the southernmost region of the Republic of Korea (ROK), highlighting the potential risks associated with the spread of vector-borne diseases, particularly emphasizing the elevated likelihood of invasion by Southeast Asian mosquitoes.

Methods

Field surveys were conducted in August 2023 on Jeju Island. Adult mosquitoes were collected using BG-sentinel traps and identified to the species level using taxonomic keys. Morphological and molecular analyses were employed to confirm species designations. Molecular data, including mitochondrial and nuclear genes, were used for phylogenetic analysis, which was performed to compare and identify among recorded subgenera in ROK. Species distribution modeling for Ae. laniger was performed to predict potential habitats using R package ‘BIOMOD2’.

Results

The two specimens of Ae. laniger were collected for the first time on Jeju Island. Morphological and molecular analyses confirmed the identity of this species within the subgenus Mucidus and validated the first record of this species in the ROK. We employed a simple multigene phylogenetic analysis to confirm a new mosquito record at the genus and subgenus levels, finally validating the consistency between morphological identification and molecular phylogenetic outcomes. Furthermore, we have updated the taxonomic keys for the genus Aedes in the ROK, and revised mosquito lists for Jeju Island, incorporating the inclusion of Ae. laniger. On the basis of species distribution modeling, the area of suitable habitat for Ae. laniger is expected to expand due to climate change, but this change did not appear to be meaningful in East Asia.

Conclusions

This case offers the first report of the Southeast Asian mosquito, Ae. laniger, in the ROK. The detection of this species on Jeju Island suggests the potential establishment of a breeding population their habitat and raises concerns about further expansion into the Korean Peninsula. Considering the annual occurrence of mosquito-borne disease cases in the Southeast Asia, it is essential to conduct monitoring not only in Jeju Island, where Ae. laniger has been identified, but also across the entire Korean Peninsula.

Graphical Abstract
Baseline gut microbiota diversity and composition and albendazole efficacy in hookworm-infected individuals
Authors: Gandasegui Javier , Fleitas Pedro E. , Petrone Paula , Grau-Pujol Berta , Novela Valdemiro , Rubio Elisa , Muchisse Osvaldo , Cossa Anélsio , Jamine José Carlos , Sacoor Charfudin , Brienen Eric A. T. , van Lieshout Lisette , Muñoz José , Casals-Pascual Climent
Published: September 2024

Soil-transmitted helminth (STH) infections account for a significant global health burden, necessitating mass drug administration with benzimidazole-class anthelmintics, such as albendazole (ALB), for morbidity control. However, ALB efficacy shows substantial variability, presenting challenges for achieving consistent treatment outcomes. We have explored the potential impact of the baseline gut microbiota on ALB efficacy in hookworm-infected individuals through microbiota profiling and machine learning (ML) techniques. Our investigation included 89 stool samples collected from hookworm-infected individuals that were analyzed by microscopy and quantitative PCR (qPCR). Of these, 44 were negative by microscopy for STH infection using the Kato-Katz method and qPCR 21 days after treatment, which entails a cure rate of 49.4%. Microbiota characterization was based on amplicon sequencing of the V3–V4 16S ribosomal RNA gene region. Alpha and beta diversity analyses revealed no significant differences between participants who were cured and those who were not cured, suggesting that baseline microbiota diversity does not influence ALB treatment outcomes. Furthermore, differential abundance analysis at the phylum, family and genus levels yielded no statistically significant associations between bacterial communities and ALB efficacy. Utilizing supervised ML models failed to predict treatment response accurately. Our investigation did not provide conclusive insights into the relationship between gut microbiota and ALB efficacy. However, the results highlight the need for future research to incorporate longitudinal studies that monitor changes in the gut microbiota related to the infection and the cure with ALB, as well as functional metagenomics to better understand the interaction of the microbiome with the drug, and its role, if there is any, in modulating anthelmintic treatment outcomes in STH infections. Interdisciplinary approaches integrating microbiology, pharmacology, genetics and data science will be pivotal in advancing our understanding of STH infections and optimizing treatment strategies globally.

Graphical Abstract
Single‑cell RNA sequencing analysis of human embryos from the late Carnegie to fetal development
Authors: Wang Chengniu , Wang Xiaorong , Wang Wenran , Chen Yufei , Chen Hanqing , Wang Weizhen , Ye Taowen , Dong Jin , Sun Chenliang , Li Xiaoran , Li Chunhong , Li Jiaying , Wang Yong , Feng Xingmei , Ding Hongping , Xu Dawei , Shi Jianwu
Published: September 2024

Background

The cell development atlas of transition stage from late Carnegie to fetal development (7–9 weeks) remain unclear. It can be seen that the early period of human embryos (7–9 weeks) is a critical research gap. Therefore, we employed single‑cell RNA sequencing to identify cell types and elucidate differentiation relationships.

Results

The single‑cell RNA sequencing analysis determines eighteen cell clusters in human embryos during the 7–9 weeks period. We uncover two distinct pathways of cellular development and differentiation. Initially, mesenchymal progenitor cells differentiated into osteoblast progenitor cells and neural stem cells, respectively. Neural stem cells further differentiated into neurons. Alternatively, multipotential stem cells differentiated into adipocyte, hematopoietic stem cells and neutrophil, respectively. Additionally, COL1A2-(ITGA1 + ITGB1) mediated the cell communication between mesenchymal progenitor cells and osteoblast progenitor cells. NCAM1-FGFR1 facilitated the cell communication between mesenchymal progenitor cells and neural stem cells. Notably, NCAM1-NCAM1 as a major contributor mediated the cell communication between neural stem cells and neurons. Moreover, CGA-FSHR simultaneously mediated the communication between multipotential stem cells, adipocyte, hematopoietic stem cells and neutrophil. Distinct cell clusters activated specific transcription factors such as HIC1, LMX1B, TWIST1, and et al., which were responsible for their specific functions. These coregulators, such as HOXB13, VSX2, PAX5, and et al., may mediate cell development and differentiation in human embryos.

Conclusions

We provide the cell development atlas for human embryos (7–9 weeks). Two distinct cell development and differentiation pathways are revealed.
Updates on CAR T cell therapy in multiple myeloma
Authors: Nasiri Fatemeh , Asaadi Yasaman , Mirzadeh Farzaneh , Abdolahi Shahrokh , Molaei Sedigheh , Gavgani Somayeh Piri , Rahbarizadeh Fatemeh
Published: September 2024

Multiple myeloma (MM) is a hematological cancer characterized by the abnormal proliferation of plasma cells. Initial treatments often include immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs). Despite salient progress in diagnosis and treatment, most MM patients typically have a median life expectancy of only four to five years after starting treatment. In recent developments, the success of chimeric antigen receptor (CAR) T-cells in treating B-cell malignancies exemplifies a new paradigm shift in advanced immunotherapy techniques with promising therapeutic outcomes. Ide-cel and cilta-cel stand as the only two FDA-approved BCMA-targeted CAR T-cells for MM patients, a recognition achieved despite extensive preclinical and clinical research efforts in this domain. Challenges remain regarding certain aspects of CAR T-cell manufacturing and administration processes, including the lack of accessibility and durability due to T-cell characteristics, along with expensive and time-consuming processes limiting health plan coverage. Moreover, MM features, such as tumor antigen heterogeneity, antigen presentation alterations, complex tumor microenvironments, and challenges in CAR-T trafficking, contribute to CAR T-cell exhaustion and subsequent therapy relapse or refractory status. Additionally, the occurrence of adverse events such as cytokine release syndrome, neurotoxicity, and on-target, off-tumor toxicities present obstacles to CAR T-cell therapies. Consequently, ongoing CAR T-cell trials are diligently addressing these challenges and barriers. In this review, we provide an overview of the effectiveness of currently available CAR T-cell treatments for MM, explore the primary resistance mechanisms to these treatments, suggest strategies for improving long-lasting remissions, and investigate the potential for combination therapies involving CAR T-cells.
Training and validation of a deep learning U-net architecture general model for automated segmentation of inner ear from CT
Authors: Lim Jonathan , Abily Aurore , Ben Salem Douraïed , Gaillandre Loïc , Attye Arnaud , Ognard Julien
Published: September 2024

Background

The intricate three-dimensional anatomy of the inner ear presents significant challenges in diagnostic procedures and critical surgical interventions. Recent advancements in deep learning (DL), particularly convolutional neural networks (CNN), have shown promise for segmenting specific structures in medical imaging. This study aimed to train and externally validate an open-source U-net DL general model for automated segmentation of the inner ear from computed tomography (CT) scans, using quantitative and qualitative assessments.

Methods

In this multicenter study, we retrospectively collected a dataset of 271 CT scans to train an open-source U-net CNN model. An external set of 70 CT scans was used to evaluate the performance of the trained model. The model’s efficacy was quantitatively assessed using the Dice similarity coefficient (DSC) and qualitatively assessed using a 4-level Likert score. For comparative analysis, manual segmentation served as the reference standard, with assessments made on both training and validation datasets, as well as stratified analysis of normal and pathological subgroups.

Results

The optimized model yielded a mean DSC of 0.83 and achieved a Likert score of 1 in 42% of the cases, in conjunction with a significantly reduced processing time. Nevertheless, 27% of the patients received an indeterminate Likert score of 4. Overall, the mean DSCs were notably higher in the validation dataset than in the training dataset.

Conclusion

This study supports the external validation of an open-source U-net model for the automated segmentation of the inner ear from CT scans.

Relevance statement

This study optimized and assessed an open-source general deep learning model for automated segmentation of the inner ear using temporal CT scans, offering perspectives for application in clinical routine. The model weights, study datasets, and baseline model are worldwide accessible.

Key Points

A general open-source deep learning model was trained for CT automated inner ear segmentation.

The Dice similarity coefficient was 0.83 and a Likert score of 1 was attributed to 42% of automated segmentations.

The influence of scanning protocols on the model performances remains to be assessed.

Graphical Abstract
Clinical and laboratory manifestations, ECG findings, and outcomes of right atrial myxoma: a systematic review of cases reported worldwide
Authors: Rabiee Rad Mehrdad , Ghasempour Dabaghi Ghazal , Darouei Bahar , Amani-Beni Reza , Zare Mohammad Mehdi , Shirin Fatemeh , Jamalian Marjan
Published: September 2024

Background

The presence of cardiac myxoma in the right atrium (RA) is rare. There is limited knowledge regarding the clinical symptoms and diagnosis of RA myxoma. This systematic review aimed to provide a summary of the clinical and laboratory characteristics, electrocardiogram (ECG) findings, and outcome previous cases with RA myxoma.

Methods

A comprehensive search was conducted in PubMed, Web of Science, and Scopus to identify relevant studies. Inclusion criteria were case reports and case series written in English that provided sufficient data on the manifestation of RA myxoma. Descriptive statistics were used for quantitative analysis.

Results

The search identified 619 patients from 480 eligible studies. The patient’s mean age was 45.7 ± 17.6 years, and 55.4% of cases were female. The most common clinical manifestations of RA myxoma were cardiac, systemic, and neurologic manifestations which reported in 77.0%, 34.8%, and 21.1% of cases, respectively. Besides, 11.7% of RA myxoma were asymptomatic. ECG findings revealed normal in 39.4% reported cases. The ECG abnormalities included tall or peaked P-wave, RA and LA enlargement (19.2%), abnormal T-wave (14.0%), sinus tachycardia (11.8%), and incomplete or complete RBBB (11.2%). Echocardiography remained the diagnostic method in a majority of the cases. The mortality rate of RA myxoma was low (9.2%) during the follow-up.

Conclusions

This systematic review provides a comprehensive summary of the clinical and laboratory manifestations and outcomes of RA myxoma, contributing to the existing knowledge on this rare cardiac tumor.
Effect of gender on spect myocardial perfusion imaging results in Egypt
Authors: Ahmed Taghreed Abdel-Rahman , Al-Habbaa Ahmed , Naiem Mona , Mokhtar Naglaa , Elhady Fatma
Published: September 2024

Background

Globally, Ischemic heart disease (IHD) is considered a leading cause of mortality and morbidity affecting men than women. The more the population ages, the more the prevalence. There was a concern about improper referral of women to MPI testing. We aimed to study if there a gender effect on the results of MPI studies and if this could have an impact on future referral or investigation selection for diagnosis of IHD as a general or specially in women.

Results

Female gender represented 266 (60%) while male represented in 177 (40%). Males demonstrated significantly higher age (55 ± 10 vs. 49 ± 9, P < .0001), weight (85 ± 11 vs. 83 ± 13, P = 0.006), height (166 ± 4 vs. 165 ± 4, P = 0.02), and smoking (35% vs. 0%, P < 0.001) than females. Male gender was associated with ten times increased risk of positive MPI (OR = 10, 95% CI = 5.348–18.868, P < 0.001). Diabetes was associated with an increased risk of positive MPI (OR = 1.82, 95% CI = 1.052–3.148, P = 0.032).

Conclusions

Positive MPI test are more common in males. Female patients with positive MPI were younger in age than male patients. Diabetes mellitus and age are traditional strong predictors for the presence of positive MPI test.
Full-parametric and joint inversion of multimode surface wave data for identifying glacial ice thickness and freezing extent in subglacial sediments via the hunger games search algorithm
Authors: Ai Hanbing , Song Xianhai , Zhang Xueqiang , Ekinci Yunus Levent , Balkaya Çağlayan , Shekar Bharath , Le Zhao , Yan Yingwei
Published: September 2024

Determining glacier ice thickness and the extent of freezing in subglacial sediments are crucial in glaciological studies. Noninvasive geophysical methods, such as multichannel analysis of surface waves, are typically used for these tasks. In this study, we introduce a novel metaheuristic called hunger games search (HGS), which simulates the hunger-driven instincts and behavioral decisions of animals for the full-parametric inversion of seismic surface waves. We apply HGS to determine layer thicknesses, densities, S-wave velocities, and primary wave velocities of different layers through the joint inversion of multimode Rayleigh wave dispersion curves (RWDCs). This marks the first study using HGS for the inversion of dispersion data. Sensitivity studies of model parameters prior to the inversion indicate the necessity of postinversion uncertainty evaluations to mitigate the effects of varying sensitivity levels. In addition, a parameter tuning study is carried out to maximize the performance of HGS. Compared with some swarm intelligence-based optimizers (particle swarm optimization, cuckoo search, gray wolf optimization, sparrow search optimization, and whale optimization algorithm), HGS outperforms in the inversion of synthetic multimode RWDCs with 10% uncertainties with respect to a simulated glacier structure. In real data applications, a data set acquired at Midtdalsbreen, an outlet of the Norwegian Hardangerjøkulen ice cap, is inverted using the tailored HGS metaheuristic. The results obtained are consistent with previous geophysical studies. Furthermore, our analysis reveals that the performance of HGS when dealing with real applications is not highly sensitive to the selection of layers within the range of five to eight. The accuracy of HGS is undoubtedly contaminated by a larger model space; however, additional depth information derived from colocated ground-penetrating radar data can be directly integrated into HGS to obtain satisfactory results again.
Inversion of induced polarization-affected electrical-source transient electromagnetic data observed in the groundwater survey from eastern Tibet, China
Authors: Wang Xuben , Lu Juntao , Guo Ming , Zhang Saimin , Hu Qinglong , El-Kaliouby Hesham
Published: September 2024

Recent advancements in the signal-to-noise ratio of transient electromagnetic (TEM) devices have highlighted the significance of induced polarization (IP) effects in areas containing polarizable materials such as clays or sulfide minerals. These effects are characterized by an abnormally rapid decay followed by late-time negative values in the voltage response, which often lead to unsatisfactory outcomes in conventional resistivity-only inversion workflows. Previous research demonstrates that incorporating the Cole-Cole complex resistivity model into an inversion workflow enhances the characterization of this phenomenon. In a recent hydrologic survey in eastern Tibet, China, significant TEM-IP-affected phenomena are observed during the implementation of an electrical-source TEM system to map the distribution of groundwater. In this instance, data from two representative survey lines are inverted using a modified quasi-2D regularized Newton inversion scheme that simultaneously extracted the direct current resistivity and three IP parameters: chargeability, time constant, and frequency dependence. The results reveal clear conductive polarization distributions against the resistive host, correlating well with groundwater-enriched weathered layers, as confirmed by borehole lithologic logs. Consequently, conductive polarization signatures are identified as potential key indicators of groundwater presence considering potential associations with clay and shale. This case study emphasizes the significance of accounting for potential IP effects in TEM surveys and highlights the advantages of multiparametric inversion for achieving more accurate results and enhancing the interpretation of subsurface properties.
Integrating Novel Agents Into the Clinical Management of Classic Hodgkin Lymphoma
Authors: Schroers-Martin Joseph G. , Advani Ranjana
Published: September 2024

Classic Hodgkin lymphoma (cHL) is highly curable at all stages. Research efforts over the past few decades have largely focused on interim PET-adapted strategies for therapy de-escalation or intensification. The overarching goals have been to increase cure rates, minimize potential therapy-related effects, and optimize survivorship. Better understanding of the biology of cHL has led to the development and approval of effective novel agents including the antibody-drug conjugate brentuximab vedotin and the checkpoint inhibitor immunotherapies. In this review, we discuss recent trial results and how these agents are integrated into clinical practice with the goal of further optimizing outcomes.
ICH M10 Bioanalytical Method Validation Guideline-1 year Later
Authors: Vazvaei-Smith Faye , Wickremsinhe Enaksha , Woolf Eric , Yu Chongwoo
Published: September 2024

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) adopted Guideline M10 entitled "Bioanalytical Method Validation and Study Sample Analysis" in May 2022. In October 2023, approximately one year after the adoption of the ICH M10 guideline, a "Hot Topic" session was held during the AAPS PharmSci 360 meeting to discuss the implementation of the guideline. The session focused on items the bioanalytical community felt were challenging to implement or ambiguous within the guideline. These topics included cross-validation, parallelism, comparative bioavailability studies, combination drug stability, endogenous analyte bioanalysis, and dilution QCs. In addition, the regulatory perspective on the guideline was presented. This report provides a summary of the Hot Topic session.

Graphical Abstract
Auto Friction: Douglas Fraser's 1980 Trip to Japan and the Roots of the Foreign-Owned Auto Industry in the United States
Authors: Minchin Timothy J.
Published: September 2024

This article explores a February 1980 trip to Japan by Douglas Fraser, the president of the United Automobile Workers. On the trip, Fraser met with the heads of Japan's biggest automakers, along with the prime minister and foreign affairs minister, pressing them to establish auto plants in the United States. Offering the first detailed examination of the trip — and the broader “build it here” campaign — this article argues that the visit was a crucial moment in the industry's history. Using rich and little-known primary records — including Fraser's personal notes and firsthand accounts from Japanese executives — this article shows that Fraser, along with supporters in the industry and federal government, influenced the Japanese to invest in the United States at a time when domestic manufacturers were in crisis. The article also reveals that the Japanese had fears about the move, especially about the quality of labor. Although they established plants, they placed them in the Lower Midwest or South, away from the UAW. The union's campaign had unintended consequences, helping the industry to survive — the foreign-owned sector grew to make half of all cars manufactured in North America — but not creating the union jobs that Fraser anticipated.
A larval zebrafish model of cardiac physiological recovery following cardiac arrest and myocardial hypoxic damage
Authors: Burggren Warren , Abramova Regina , Bautista Naim M. , Fritsche Danielson Regina , Dubansky Ben , Gupta Avi , Hansson Kenny , Iyer Neha , Jagadeeswaran Pudur , Jennbacken Karin , Rydén-Markinhutha Katarina , Patel Vishal , Raman Revathi , Trivedi Hersh , Vazquez Roman Karem , Williams Steven , Wang Qing-Dong
Published: September 2024

Contemporary cardiac injury models in zebrafish larvae include cryoinjury, laser ablation, pharmacological treatment and cardiac dysfunction mutations. Although effective in damaging cardiomyocytes, these models lack the important element of myocardial hypoxia, which induces critical molecular cascades within cardiac muscle. We have developed a novel, tractable, high throughput in vivo model of hypoxia-induced cardiac damage that can subsequently be used in screening cardioactive drugs and testing recovery therapies. Our potentially more realistic model for studying cardiac arrest and recovery involves larval zebrafish (Danio rerio) acutely exposed to severe hypoxia (PO2=5-7 mmHg). Such exposure induces loss of mobility quickly followed by cardiac arrest occurring within 120 min in 5 days post fertilization (dpf) and within 40 min at 10 dpf. Approximately 90% of 5 dpf larvae survive acute hypoxic exposure, but survival fell to 30% by 10 dpf. Upon return to air-saturated water, only a subset of larvae resumed heartbeat, occurring within 4 min (5 dpf) and 6-8 min (8-10 dpf). Heart rate, stroke volume and cardiac output in control larvae before hypoxic exposure were 188±5 bpm, 0.20±0.001 nL and 35.5±2.2 nL/min (n=35), respectively. After briefly falling to zero upon severe hypoxic exposure, heart rate returned to control values by 24 h of recovery. However, reflecting the severe cardiac damage induced by the hypoxic episode, stroke volume and cardiac output remained depressed by ∼50% from control values at 24 h of recovery, and full restoration of cardiac function ultimately required 72 h post-cardiac arrest. Immunohistological staining showed co-localization of Troponin C (identifying cardiomyocytes) and Capase-3 (identifying cellular apoptosis). As an alternative to models employing mechanical or pharmacological damage to the developing myocardium, the highly reproducible cardiac effects of acute hypoxia-induced cardiac arrest in the larval zebrafish represent an alternative, potentially more realistic model that mimics the cellular and molecular consequences of an infarction for studying cardiac tissue hypoxia injury and recovery of function.