bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: Craniofacial deafness hand syndrome with unusual cardiovascular symptoms and lack of holistic care
Authors: Saenz Hinojosa Samantha , Reyes-Silva Carlos , Hosomichi Kazuyoshi , Romero Vanessa I.
Published: January 2025

Background

Delays in diagnosing rare genetic disorders often arise due to limited awareness and systemic challenges in primary care. This case highlights the importance of a holistic approach to patient care, encompassing timely detection and comprehensive evaluation of clinical features.

Methods

We report the case of a 21-year-old Ecuadorian male with facial and hand dysmorphias, cardiomegaly, pulmonary hypertension, and patent ductus arteriosus (PDA). Whole-exome sequencing, performed using the Illumina NextSeq platform. We extensively analyzed over 100 genes linked to congenital structural heart diseases.

Results

The genetic findings provided a definitive diagnosis of Craniofacial-Deafness-Hand Syndrome, an extremely rare autosomal dominant condition, but found no variants that explain the patient’s cardiac phenotype. We identified a novel pathogenic missense variant in the PAX3 gene (c.A91C, p. T31P).

Discussion and conclusions

This case underscores the necessity of integrating genetic testing into routine clinical practice to enhance diagnostic precision for rare diseases. It also highlights the need for multidisciplinary collaboration and a holistic care model to improve patient outcomes. The unique association of Craniofacial-Deafness-Hand Syndrome with cardiovascular anomalies due to a PAX3 variation provides valuable insights into the genetic underpinnings of this rare condition.
Mapping the use of cardiovascular genetic services in pediatric clinical care: challenges and opportunities for improvement
Authors: Hundal Kerstin , Scherr Courtney L. , Fakhari Hoda , Ramesh Sanjana , Dellefave-Castillo Lisa , Duquette Deb , Cherny Sara , McNally Elizabeth M. , Webster Gregory , Rasmussen-Torvik Laura J.
Published: January 2025

Purpose

Clinical genetic testing is increasingly integrated in managing and diagnosing cardiac conditions and disease. It is important to identify ongoing challenges. This study aimed to better understand how genetic testing is integrated into pediatric cardiac care and identify barriers and opportunities for improvement.

Methods

We conducted qualitative interviews with pediatric cardiology clinicians (N = 12). Following a journey mapping approach to data analysis, we described genetic testing workflow phases, participants’ thoughts and behaviors within each phase, and barriers and opportunities for improvement.

Results

Participants described several challenges across the genetic testing workflow, from identifying patients for testing to disclosing results to the patients. Testing logistics, decision-making, and collaboration emerged as the most prominent challenges. Variation remains in the utilization of genetic testing, partially driven by case complexity and type of testing and attributable to other factors, like the level of interaction with genetics experts and inconsistent processes within the electronic medical record.

Conclusion

Clinical genetic pediatric cardiology requires more systematic integration of genetic testing and transparent processes. Major opportunities include the interplay between clinicians, genetic experts, and the EMR. Incorporating process mapping results into clinical logistics may eradicate some barriers experienced by pediatric cardiologists and increase clinical efficiency.
Dual disease co-expression analysis reveals potential roles of estrogen-related genes in postmenopausal osteoporosis and Parkinson’s disease
Authors: Yu Dongdong , Kang Jian , Ju Chengguo , Wang Qingyan , Qiao Ye , Qiao Long , Yang Dongxiang
Published: January 2025

Introduction

The deficiency of estrogen correlates with a range of diseases, notably Postmenopausal osteoporosis (PMO) and Parkinson’s disease (PD). There is a possibility that PMO and PD may share underlying molecular mechanisms that are pivotal in their development and progression. The objective of this study was to identify critical genes and potential mechanisms associated with PMO by examining co-expressed genes linked to PD.

Methods

Initially, pertinent data concerning PMO and PD were obtained from the GWAS database, followed by conducting a Bayesian colocalization analysis. Subsequently, co-expressed genes from the PMO dataset (GSE35956) and the PD dataset (GSE20164) were identified and cross-referenced with estrogen-related genes (ERGs). Differentially expressed genes (DEGs) among PMO, PD, and ERGs were subjected to an array of bioinformatics analyses, including Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses, in addition to protein-protein interaction (PPI) network analysis. The study also involved constructing TF-gene interactions, TF-microRNA coregulatory networks, interactions of hub genes with diseases, and validation through quantitative reverse transcription polymerase chain reaction (qRT-PCR).

Results

The colocalization analysis uncovered shared genetic variants between PD and osteoporosis, with a posterior probability of colocalization (PPH4) measured at 0.967. Notably, rs3796661 was recognized as a shared genetic variant. A total of 11 genes were classified as DEGs across PMO, PD, and ERGs. Five principal KEGG pathways were identified, which include the p53 signaling pathway, TGF-beta signaling pathway, cell cycle, FoxO signaling pathway, and cellular senescence. Additionally, three hub genes—WT1, CCNB1, and SMAD7—were selected from the PPI network utilizing Cytoscape software. These three hub genes, which possess significant diagnostic value for PMO and PD, were further validated using GEO datasets. Interactions between transcription factors and genes, as well as between microRNAs and hub genes, were established. Ultimately, the expression trends of the identified hub genes were confirmed through qRT-PCR validation.

Conclusions

This study is anticipated to offer innovative approaches for identifying potential biomarkers and important therapeutic targets for both PMO and PD.
Disclosure of oral pre-exposure prophylaxis use for HIV prevention among women enrolled in a contraceptive study: qualitative findings from Durban, South Africa
Authors: Beesham Ivana , Beksinska Mags , Milford Cecilia , Mansoor Leila E.
Published: January 2025

Background

Disclosure of oral pre-exposure prophylaxis (PrEP) use for HIV prevention may improve adherence to PrEP; however, disclosure can be challenging and may result in stigma. Here, we describe disclosure of PrEP use among young women enrolled in a contraceptive study.

Methods

In this qualitative study, we conducted semi-structured, in-depth, face-to-face interviews with 13 women aged 18–25 years who initiated oral PrEP for HIV prevention during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. Interviews were conducted in 2021 with women from Durban, South Africa. In this analysis, we explore women's experiences of PrEP disclosure including whether they disclosed PrEP use, who they disclosed to and the reaction to disclosure, and the impact of disclosure on PrEP use. Interviews were conducted in English, audio-recorded and transcribed. Data were analysed thematically.

Results

All women disclosed oral PrEP use to at least one individual, with some women disclosing to multiple individuals including family, friends, partners and community members. Few women did not disclose oral PrEP use to their partner due to anticipating a negative reaction from the partner, feeling that the partner would assume the woman has HIV and is taking antiretroviral therapy and fear that the partner would associate PrEP use with the woman having other partners. Reactions to oral PrEP disclosure were generally supportive or neutral, however, few women reported negative reactions that included distrust in the efficacy of PrEP to prevent HIV, discouraging the woman from using oral PrEP because of the assumption that PrEP is HIV treatment, and concern about the woman having oral PrEP side effects. Negative reactions to disclosure generally did not impact on oral PrEP use. Supportive disclosures sometimes resulted in reminders for oral PrEP dosing.

Conclusion

Our findings indicate that women are willing to disclose their PrEP use to at least one other person when supported. These study findings may contribute to future PrEP counselling guidelines and strategies.
Protective or limited? Maternal antibodies and RSV-associated lower respiratory tract infection in hospitalized infants aged 28-90 days
Authors: Li Shuanglian , Mei Chenghao , Chen Sainan , Wang Chenglin , Gao Yelei , Ma Jinhua , Zhong Li , Luo Tingting , Zhao Xin , Bu Huaqin , Lyu Ying , Kuang Xiaohu , Jia Zhenxing , Wang Xiaoli , Wang Yuqing , Tian Daiyin
Published: January 2025

Background

Respiratory syncytial virus (RSV) is a major cause of severe health problems in newborns and young children. The protective role and limitations of serum maternal RSV antibodies in infants under 3 months remain controversial.

Methods

A two-center prospective study from 2020 to 2023 recruited infants (n=286) admitted to the respiratory departments of two children’s hospitals in southwestern and southeastern China during RSV epidemic. These infants were hospitalized with lower respiratory tract infections (LRTI). We evaluated the relationship between serum RSV Prefusion (Pre-F), postfusion (Post-F) IgG levels, subtype neutralizing antibodies, and the incidence of RSV infection, as well as the relationship between these maternal antibodies and severity of disease. Since this prospective study only included data from RSV epidemic, we retrospectively reviewed medical records from the Children’s Hospital of Chongqing Medical University for the years 2019 to 2023 (n=3467) to analyze population characteristics during both RSV epidemic and non-epidemic periods, using the same inclusion and exclusion criteria.

Result

There were no significant differences in RSV Pre-F IgG, Post-F IgG, or RSV A or B neutralizing antibody levels between the RSV infected and non-infected groups during the epidemic. While RSV Pre-F IgG antibody was inversely correlated with disease severity, RSV Post-F IgG, and RSV A and B neutralizing antibodies did not show a similar correlation across the three illness severity categories. Additionally, there were no differences in age, gender, or illness severity distribution among hospitalized patients during epidemic and non-epidemic periods.

Conclusion

Serum maternal antibody levels offer insufficient protection against RSV-associated LRTI in hospitalized infants aged 28 to 90 days.
Synergetic role of TRPV4 inhibitor and mechanical loading on reducing inflammation
Authors: Babaniamansour Parto , Jacho Diego , Rabino Agustin , Garcia-Mata Rafael , Yildirim-Ayan Eda
Published: January 2025

Resolution of inflammation is essential for normal tissue healing and regeneration, with macrophages playing a key role in regulating this process through phenotypic changes from a pro-inflammatory to an anti-inflammatory state. Pharmacological and mechanical (mechanotherapy) techniques can be employed to polarize macrophages toward an anti-inflammatory phenotype, thereby diminishing inflammation. One clinically relevant pharmacological approach is the inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4). This study investigates the effects of various mechanical loading amplitudes (0%, 3%, and 6%) and TRPV4 inhibition (10 µM RN-1734) on the phenotypic commitments of pro-inflammatory (M1) macrophages within three-dimensional (3D) collagen matrices. M1 macrophages exposed to 3% mechanical strain exhibited upregulated pro-inflammatory responses, including increased pro-inflammatory gene expression and enhanced proteolytic activity within the extracellular matrix. TRPV4 inhibition partially mitigated this inflammation. Notably, 6% mechanical strain combined with TRPV4 inhibition suppressed Mitogen-Activated Protein Kinase (MAPK) expression, leading to reduced pro-inflammatory gene expression and increased anti-inflammatory markers such as CD206. Gene expression analysis further demonstrated significant reductions in pro-inflammatory gene expression and a synergistic promotion of anti-inflammatory phenotypes under TRPV4 inhibition at 6% mechanical strain. Surface protein analysis via immunohistochemistry confirmed these phenotypic shifts, highlighting changes in the expression of CD80 (pro-inflammatory) and CD206 (anti-inflammatory) markers, alongside F-actin and nuclear staining. This research suggests that TRPV4 inhibition, combined with specific mechanical loading (6%), can drive macrophages toward an anti-inflammatory state, thereby may promote inflammation resolution and tissue repair.
Active withdrawal of corticosteroids using tocilizumab and its association with autoantibody profiles in relapsed Takayasu arteritis: a multicentre, single-arm, prospective study (the Ab-TAK study)
Authors: Shirai Tsuyoshi , Ishii Tomonori , Okazaki Soshi , Shirota Yuko , Ishii Yusho , Sato Hiroko , Fujii Hiroshi
Published: January 2025

Objectives

The feasibility of corticosteroid withdrawal (CW) for Takayasu arteritis (TAK) remains uncertain. Two autoantibodies (Abs) are identified against endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) in TAK, determining its three subgroups. This study aimed to evaluate CW using tocilizumab (TCZ) and its association with the Ab profile.

Methods

This prospective study, lasted for 24 weeks, included patients with relapsed but stable TAK. Scheduled tapering of prednisolone (PSL) was performed with subcutaneous TCZ (CW at week 20). The primary endpoint was the difference in type A remission, defined by CW and the absence of inflammatory signs, according to the Ab profile at week 24.

Results

Twenty patients were included and 18 patients with a mean PSL dose of 4.9 ± 2.8 mg/day were analysed. Anti-EPCR Ab-positive (E+), anti-SR-BI Ab-positive (S+), and double-negative (DN) groups included four (22.2%), eight (44.4%), and six (33.3%) patients, respectively. At week 24, the mean PSL dose was 2.0 ± 2.7 mg/day. Type A remission was observed in eight patients (44.4%), with significant differences based on the Ab profile: E+ (three patients, 75%), S+ (five patients, 62.5%), and DN (zero patients, 0%) (P=0.018). Besides, age, disease duration, PSL dose, type V arterial lesion, arterial dilation, and C-reactive protein >0.01 mg/dL were identified as risks for CW failure.

Conclusion

CW using TCZ was achieved in 44.4% of patients with TAK relapse and was significantly higher in E+ and S+ patients. CW can be a feasible target, and the precise selection of patients is critical.
Magnitude and dynamics of the T-cell response to SARS-CoV-2 infection at both individual and population levels
Authors: Snyder Thomas M. , Gittelman Rachel M. , Klinger Mark , May Damon H. , Osborne Edward J. , Taniguchi Ruth , Jabran Zahid H. , Kaplan Ian M. , Dines Jennifer N. , Noakes Matthew T. , Pandya Ravi , Chen Xiaoyu , Elasady Summer , Svejnoha Emily , Ebert Peter , Pesesky Mitchell W. , De Almeida Patricia , O’Donnell Hope , DeGottardi Quinn , Keitany Gladys , Lu Jennifer , Vong Allen , Elyanow Rebecca , Fields Paul , Al-Asadi Hussein , Greissl Julia , Baldo Lance , Semprini Simona , Cerchione Claudio , Nicolini Fabio , Mazza Massimiliano , Delmonte Ottavia M. , Dobbs Kerry , Laguna-Goya Rocio , Carreño-Tarragona Gonzalo , Barrio Santiago , Imberti Luisa , Sottini Alessandra , Quiros-Roldan Eugenia , Rossi Camillo , Biondi Andrea , Bettini Laura Rachele , D’Angio Mariella , Bonfanti Paolo , Tompkins Miranda F. , Alba Camille , Dalgard Clifton , Sambri Vittorio , Martinelli Giovanni , Goldman Jason D. , Heath James R. , Su Helen C. , Notarangelo Luigi D. , Paz-Artal Estela , Martinez-Lopez Joaquin , Howie Bryan , Carlson Jonathan M. , Robins Harlan S.
Published: January 2025

Introduction

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection.

Methods

Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides. Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared “public” T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells.

Results

Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3–7 = 85.1% [95% CI = 79.9–89.7]; Day 8–14 = 94.8% [90.7–98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1–98.3]).

Discussion

The approaches described in this work provide detailed insights into the adaptive immune response to SARS-CoV-2 infection, and they have potential applications in clinical diagnostics, vaccine development, and monitoring.
Case report: A novel de novo germline loss-of-function mutation in the STAT1 transactivation domain in two Chinese siblings, with the elder sibling presenting with multifocal Bacillus Calmette–Guerin osteomyelitis
Authors: Lim Qin Ying , Leung Daniel , Lam Crystal K. , Yang Xingtian , Cheong Kai N. , Yik Andrew K. H. , Yang Jing , Chan Koon-Wing , Lee Pamela P. W. , Tsumura Miyuki , Au Elaine Y. L. , Rosa Duque Jaime S. , Okada Satoshi , Lau Yu Lung
Published: January 2025

Signal transducer and activator of transcription 1 (STAT1) gene mutations have broad clinical phenotypes, classified by the inheritance pattern and functional state. Individuals with autosomal dominant STAT1 deficiency are more susceptible to intracellular bacteria, the hallmark of which is Mendelian susceptibility to mycobacterial diseases (MSMDs) that are associated with increased risks of invasive disease by weakly virulent mycobacteria. We report a novel de novo heterozygous missense mutation in exon 23 of the STAT1 gene (NM_007315.4):c.2129C>T(p.Ser710Phe) (S710F), located in the transactivation domain (TAD) for two Chinese siblings, whereby the index patient presented with multifocal osteomyelitis after Bacillus Calmette–Guerin (BCG) vaccine, while the younger sibling was spared the infection, as BCG vaccination was withheld at birth. STAT1 loss-of-function was confirmed by the gamma-activated sequence reporter assay, representing the first loss-of-function mutation in the TAD of the STAT1 gene. Both parents did not have the same mutation, and this finding is suggestive of gonadal mosaicism.
Evaluation of deceased-donor kidney offers: development and validation of novel data driven and expert based prediction models for early transplant outcomes
Authors: Mahler Christoph F. , Friedl Felix , Nusshag Christian , Speer Claudius , Benning Louise , Göth Daniel , Schaier Matthias , Sommerer Claudia , Mieth Markus , Mehrabi Arianeb , Michalski Christoph , Renders Lutz , Bachmann Quirin , Heemann Uwe , Krautter Markus , Schwenger Vedat , Echterdiek Fabian , Zeier Martin , Morath Christian , Kälble Florian
Published: January 2025

In the face of growing transplant waitlists and aging donors, sound pre-transplant evaluation of organ offers is paramount. However, many transplant centres lack clear criteria on organ acceptance. Often, previous scores for donor characterisation have not been validated for the Eurotransplant population and are not established to support graft acceptance decisions. Here, we investigated 1353 kidney transplantations at three different German centres to develop and validate novel statistical models for the prediction of early adverse graft outcome (EAO), defined as graft loss or CKD ≥4 within three months. The predictive models use generalised estimating equations (GEE) accounting for potential correlations between paired grafts from the same donor. Discriminative accuracy and calibration were determined via internal and external validation in the development (935 recipients, 309 events) and validation cohort (418 recipients, 162 events) respectively. The expert model is based on predictor ratings by senior transplant nephrologists, while for the data-driven model variables were selected via high-dimensional lasso generalised estimating equations (LassoGee). Both models show moderate discrimination for EAO (C-statistic expert model: 0,699, data-driven model 0,698) with good calibration. In summary, we developed novel statistical models that represent current clinical consensus and are tailored to the older deceased donor population. Compared to KDRI, our described models are sparse with only four and three predictors respectively and account for paired grafts from the same donor, while maintaining a discriminative accuracy equal or better than the established KDRI-score.
Frailty assessment in adults undergoing allogeneic hematopoietic cell transplantation: insights from a multicenter GETH-TC study to optimize outcomes and care
Authors: Salas María Queralt , Solano María Teresa , Baile González Mónica , Acera Gómez Marina , Fox Laura , Pérez Artigas María del Mar , Santamaría Ana , Quintela González María del Carmen , Sánchez Salinas Andrés , Salmerón Camacho Joaquina M. , Illana Álvaro Verónica , Abdallahi-Lefdil Zahra , Cornago Navascues Javier , Pardo Laura , Fernández-Luis Sara , Vega Suárez Leddy Patricia , Villar Sara , Beorlegui-Murillo Patricia , Esquirol Albert , Izquierdo García Isabel , Rodríguez González Sonia , Mussetti Alberto , Lavilla Esperanza , Lopez-Marín Javier , Filaferro Silvia , Cedillo Ángel , Bento Leyre , Sureda Anna
Published: January 2025

Introduction

This multicenter prospective study sponsored by the Grupo Español de Transplante Hematopoyético y Terapia Celular (GETH-TC) explores the use of frailty assessments in allo-HCT candidates.

Methods

Frailty was measured using the HCT Frailty Scale at first consultation and HCT admission in 404 adults from 15 HCT programs in Spain. Based on the results, patients were classified into fit, pre-frail and frail categories. Allo-HCT outcomes were analyzed according to the results obtained from the HCT Frailty Scale. Data was collected prospectively and all patients signed informed consent.

Results

At first consultation, 102 (26.2%) patients were classified as fit, 248 (61.4%) as pre-frail, and 50 (12.4%) as frail. During the study, 62 (15.2%) patients participated in a pre-habilitation program. Among non-pre-habilitated patients (n=342), the proportion of fit patients decreased from 26.6% to 16.7%, while frail patients increased from 12.7% to 19.9%. In contrast, pre-habilitated patients (n=62) showed improvements, with fit patients increasing from 24.2% to 46.8%, and frail patients decreasing from 9.7% to 3.2%. Multivariate analysis confirmed lower OS (HR 2.52, P=0.002) and higher NRM (HR 2.69, P=0.013) in frail patients at HCT admission compared to fit ones, with a trend towards lower OS in pre-frail patients (HR 1.54, P=0.097).

Conclusion

This study highlights the feasibility of incorporating the HCT Frailty Scale into clinical practice, confirms its negative impact of frailty on transplant outcomes, and suggests that frailty is dynamic and potentially reversible through pre-transplant interventions.
Understanding the role of the gut microbiome in solid tumor responses to immune checkpoint inhibitors for personalized therapeutic strategies: a review
Authors: Lim Mi Young , Hong Seungpyo , Nam Young-Do
Published: January 2025

Immunotherapy, especially immune checkpoint inhibitor (ICI) therapy, has yielded remarkable outcomes for some patients with solid cancers, but others do not respond to these treatments. Recent research has identified the gut microbiota as a key modulator of immune responses, suggesting that its composition is closely linked to responses to ICI therapy in cancer treatment. As a result, the gut microbiome is gaining attention as a potential biomarker for predicting individual responses to ICI therapy and as a target for enhancing treatment efficacy. In this review, we discuss key findings from human observational studies assessing the effect of antibiotic use prior to ICI therapy on outcomes and identifying specific gut bacteria associated with favorable and unfavorable responses. Moreover, we review studies investigating the possibility of patient outcome prediction using machine learning models based on gut microbiome data before starting ICI therapy and clinical trials exploring whether gut microbiota modulation, for example via fecal microbiota transplantation or live biotherapeutic products, can improve results of ICI therapy in patients with cancer. We also briefly discuss the mechanisms through which the gut microbial-derived products influence immunotherapy effectiveness. Further research is necessary to fully understand the complex interactions between the host, gut microbiota, and immunotherapy and to develop personalized strategies that optimize responses to ICI therapy.
Role of tertiary lymphoid structures and B cells in clinical immunotherapy of gastric cancer
Authors: Chen Weiyi , Zhang Lingli , Gao Man , Zhang Ning , Wang Rumeng , Liu Yang , Niu Yan , Jia Lizhou
Published: January 2025

Gastric cancer is a common malignant tumor of the digestive tract, and its treatment remains a significant challenge. In recent years, the role of various immune cells in the tumor microenvironment in cancer progression and treatment has gained increasing attention. Immunotherapy, primarily based on immune checkpoint inhibitors, has notably improved the prognosis of patients with gastric cancer; however, challenges regarding therapeutic efficacy persist. Histological features within the tumor microenvironment, such as tertiary lymphoid structures (TLSs), tumor-infiltrating lymphocytes, and the proportion of intratumoral stroma, are emerging as potentially effective prognostic factors. In gastric cancer, TLSs may serve as local immune hubs, enhancing the ability of immune cells to interact with and recognize tumor antigens, which is closely linked to the effectiveness of immunotherapy and improved survival rates in patients. However, the specific cell type driving TLS formation in tumors has not yet been elucidated. Mature TLSs are B-cell regions containing germinal centers. During germinal center formation, B cells undergo transformations to become mature cells with immune function, exerting anti-tumor effects. Therefore, targeting B cells within TLSs could provide new avenues for gastric cancer immunotherapy. This review, combined with current research on TLSs and B cells in gastric cancer, elaborates on the relationship between TLSs and B cells in the prognosis and immunotherapy of patients with gastric cancer, aiming to provide effective guidance for precise immunotherapy.
Single-cell RNA sequencing and immune microenvironment analysis reveal PLOD2-driven malignant transformation in cervical cancer
Authors: Lin Zhiheng , Wang Fengxin , Yin Renwu , Li Shengnan , Bai Yuquan , Zhang Baofang , Sui Chenlin , Cao Hengjie , Su Dune , Xu Lianwei , Wang Honghong
Published: January 2025

Background

Cervical cancer is the fourth most common cancer in women globally, and the main cause of the disease has been found to be ongoing HPV infection. Cervical cancer remains the primary cause of cancer-related death despite major improvements in screening and treatment approaches, especially in low- and middle-income nations. Therefore, it is crucial to investigate the tumor microenvironment in advanced cervical cancer in order to identify possible treatment targets.

Materials and methods

In order to better understand malignant cervical cancer epithelial cells (EPCs), this study used bulk RNA-seq data from UCSC in conjunction with single-cell RNA sequencing data from the ArrayExpress database. After putting quality control procedures into place, cell type identification and clustering analysis using the Seurat software were carried out. To clarify functional pathways, enrichment analysis and differential gene expression were carried out. The CIBERSORT and ESTIMATE R packages were used to evaluate the immune microenvironment characteristics, and univariate and multivariate Cox regression analyses were used to extract prognostic features. Furthermore, assessments of drug sensitivity and functional enrichment were carried out.

Results

Eight cell types were identified, with EPCs showing high proliferative and stemness features. Five EPC subpopulations were defined, with C1 NNMT+ CAEPCs driving tumor differentiation. A NNMT CAEPCs Risk Score (NCRS) model was developed, revealing a correlation between elevated NCRS scores and adverse patient outcomes characterized by immune evasion. In vitro experiments validated that the prognostic gene PLOD2 significantly enhances proliferation, migration, and invasion of cervical cancer cells.

Conclusion

This investigation delineated eight cell types and five subpopulations of malignant EPCs in cervical cancer, establishing the C1 NNMT+ CAEPCs as a crucial therapeutic target. The NCRS model demonstrated its prognostic capability, indicating that higher scores are associated with poorer clinical outcomes. The validation of PLOD2 as a prognostic gene highlights its therapeutic potential, underscoring the critical need for integrating immunotherapy and targeted treatment strategies to enhance diagnostic and therapeutic approaches in cervical cancer.
A revisit of the semi-geostrophic eddy east of the Sri Lanka dome with anisotropy insight
Authors: Le Zhou , Subrahmanyam M. V. , Raju Pemmani Venkata Subba , Pathirana Gayan , Wang Dongxiao , Song Wei
Published: January 2025

During boreal summer, the Southwest Monsoon Current (SMC) turns northeastward, transporting highly saline water into the Bay of Bengal (BOB) and significantly influencing the dynamics of the upper ocean. Previous studies have shown that an anticyclonic semi-geostrophic (SG) eddy forms on the eastern flank of the SMC, this formation associated with the kinetic energy transfer via the barotropic instability (BTI). The presence of such an eddy can attenuate the meridional salinity flux, potentially affecting the development of the circulation within the BOB. Acknowledging the importance of this phenomenon, this study revisits the SG eddy using satellite altimetry data, reanalysis datasets and in-situ observations from the Research Moored Array for African-Asian-Australian Monsoon Analysis and Prediction (RAMA) project. Our results show that a cyclonic eddy-like (CE-like) negative Sea Level Anomaly (SLA), generated in the eastern BOB due to regional anomalous wind stress curl, also contributes to the formation of the SG eddy. During the formation, mean flows on the northern edge of the SG eddy are strengthened, while southeastward currents on the eastern edge are structured influenced by CE-like SLA. Further instability analyses indicate that the anisotropic component of BTI is significantly larger than the isotropic component, which is attributed to the weak nonlinear planetary geostrophic convergence of the SG eddy and the strong horizontal shear in mean flow field induced by CE-like SLA. Additionally, our results point out that anomalies in wind stress curl over the eastern BOB and subsequent formation of negative SLA are likely influenced by the Indian Ocean Dipole. These findings suggest that the coupling between SMC instability and regional wind stress curl may play a pivotal role in the generation of SG eddy on interannual timescale, with important implications for regional ocean dynamics.
Global surface eddy mixing ellipses: spatio-temporal variability and machine learning prediction
Authors: Jing Tian , Chen Ru , Liu Chuanyu , Qiu Chunhua , Zhang Cuicui , Hong Mei
Published: January 2025

Mesoscale eddy mixing significantly influences ocean circulation and climate system. Coarse-resolution climate models are sensitive to the specification of eddy diffusivity tensor. Mixing ellipses, derived from eddy diffusivity tensor, illustrate mixing geometry, i.e., the magnitude, anisotropy, and dominant direction of eddy mixing. Using satellite altimetry data and the Lagrangian single-particle method, we estimate eddy mixing ellipses across the global surface ocean, revealing substantial spatio-temporal variability. Notably, large mixing ellipses predominantly occur in eddy-rich and energetic ocean regions. We also assessed the predictability of global mixing ellipses using machine learning algorithms, including Spatial Transformer Networks (STN), Convolutional Neural Network (CNN) and Random Forest (RF), with mean-flow and eddy- properties as features. All three models effectively represent and predict spatiotemporal variations, with the STN model, which incorporates an adaptive spatial attention mechanism, outperforming RF and CNN models in predicting mixing anisotropy. Feature importance rankings indicate that eddy velocity magnitude and eddy size are the most significant factors in predicting the major axis and anisotropy. Furthermore, training the models with a 2-year temporal duration, aligned with the El Niño Southern Oscillation (ENSO) timescale, improved predictions in the northern equatorial central Pacific region compared to models trained with a 12-year duration. This resulted in a spatially averaged correlation increase of over 0.5 for predicting the minor axis and anisotropy, along with a reduction of more than 0.15 in the Normalized Root Mean Square Error. These findings highlight the considerable potential of machine learning algorithms in predicting mixing ellipses and parameterizing eddy mixing processes within climate models.
Marine environmental regulation and green technology innovation: evidence from enterprises in coastal areas of China
Authors: Jiang Junchen , Sun Han
Published: January 2025

It is of great significance to explore the effect of marine environmental policies to promote the sustainable development of the marine economy. This article takes the ‘National Marine Ecological Civilization Demoznstration Zone’ (hereinafter referred to as the ‘Demonstration Zone’) as a quasi-natural experiment and adopts the difference-in-difference method to explore the effects of marine environmental regulation on green technology innovation of micro-enterprises in coastal areas and on the high-quality development of the regional economy. This article finds that marine environmental regulation can promote the green technology innovation of enterprises in coastal areas. The mechanism analyses show that marine environmental regulation increases the government’s attention to the environment and promotes industrial structure upgrading, thus positively affecting local enterprises’ green technology innovation. Cross-sectional analyses show that the increase in green technology innovation is more pronounced in resource-based cities, areas with high marine economic dependence and high green finance development, as well as in enterprises with low financial constraints and marine-related enterprises. Additionally, marine environmental regulation significantly increases green invention patents and independent green innovation by enterprises in coastal areas. At the macro level, we find that the impact of marine environmental regulation on green technology innovation ultimately leads to high-quality development of the local economy. Based on the above results, this article suggests that the government should actively explore and practice the construction of marine environmental ecological civilization, and further improve marine environmental regulation to encourage firms to carry out green technological innovation activities.
Potential renoprotective effects and possible underlying mechanisms of angiotensin receptor-neprilysin inhibitors in cardiorenal syndrome
Authors: Rahman Md. Moshiur , Rahman Asadur , Nishiyama Akira
Published: January 2025

Angiotensin receptor-neprilysin inhibitors (ARNIs) represent a novel class of medications characterized by their dual action on major cardiorenal regulators, specifically the renin–angiotensin system (RAS) and the natriuretic peptide (NP) system. Sacubitril/valsartan, a pioneering ARNI, has demonstrated strong antihypertensive effect as well as superior efficacy in preserving renal function compared to RAS inhibitors in heart failure patients with reduced ejection fraction. Here, we gathered evidence on the impact of sacubitril/valsartan on the preservation of kidney function in patients with cardiorenal syndrome (CRS). In particular, we present a comprehensive summary of the latest advancements and findings from clinical trials, studies, and meta-analyses on the impact of ARNIs in maintaining or improving renal function. We also discussed the pre-clinical evidence supporting the use of sacubitril/valsartan for improving renal function, along with the underlying molecular mechanisms in animal models mimicking various clinical scenarios. Altogether, the analysis of published data from both pre-clinical and clinical studies provides substantial support for the usefulness of ARNIs in enhancing renal protection in subjects with CRS.
Integrating competency-based, interprofessional teamwork education for students: guiding principles to support current needs and future directions
Authors: Williams Kimberly N. , Lazzara Elizabeth H. , Hernandez Jessica , Klocko David , Chandran Neethu , Paquette Shannon L. , Preble Richard , Sadighi Mozhdeh , Tran Bau , Kilcullen Molly , Rege Robert , Reed Gary , Salas Eduardo , Tannenbaum Scott I. , Greilich Philip E.
Published: January 2025

Interprofessional teamwork is vital to effective patient care, and targeting healthcare learners earlier in their education can lead to greater improvement in confidence and competence in teamwork skills. Despite this, institutions have continued struggling to integrate competency-based interprofessional teamwork curriculum in undergraduate health care professions’ education. The current article provides guidance related to design, implementation, and assessment for institutions seeking to implement competency-based teamwork education and training strategies for healthcare students. Guiding principles and strategies for curricular design focus on conducting thorough interprofessional needs analyses and building transportable, evidence-based competencies that apply across professions. For implementation, key principles center on strategies to ensure adequate professional representation and faculty development. Assessment considerations focus on building infrastructure for evaluation that spans professional schools. These strategies aim to create a robust, effective, and sustainable IPE curriculum that enhances collaboration and teamwork among future healthcare professionals. By addressing the key areas of design, implementation, and assessment, this article offers comprehensive guidelines for advancing interprofessional education. We believe incorporating the key guiding principles and strategies from this paper will enable institutions to integrate teamwork education and training more effectively into undergraduate healthcare training, which will facilitate institutions’ ability to ensure learners are “team ready” as they transition into the workforce after graduation.
Positive end-expiratory pressure increases intracranial pressure but not pressure reactivity index in supine and prone positions: a porcine model study
Authors: Hammervold Rønnaug , Beqiri Erta , Smielewski Peter , Storm Benjamin S. , Nielsen Erik W. , Guérin Claude , Frisvold Shirin K.
Published: January 2025

Introduction

Positive end-expiratory pressure (PEEP) and prone positioning can improve gas exchange by promoting uniform lung aeration. However, elevated ventilation pressures may increase intracranial pressure (ICP) and disrupt cerebral autoregulation. This study investigated the effects of PEEP on ICP and cerebral autoregulation in a porcine model with healthy lungs and normal ICP, comparing prone and supine positions. Cerebral autoregulation was assessed through cerebrovascular reactivity using the pressure reactivity index (PRx). We also explored whether other baseline variables influenced potential variances in ICP and PRx.

Methodology

Twelve anesthetized pigs were randomized to begin in either supine or prone position, across PEEP of 5, 10, 15, and 20 cmH2O. Continuous monitoring included esophageal pressure to calculate end-inspiratory and end-expiratory transpulmonary pressures. The ICM+® software (University of Cambridge Enterprise, Cambridge, United Kingdom) was used for high-resolution data collection, signal processing and ICP curve analysis. Linear mixed-effects models and ANOVA were used to analyze changes in ICP and PRx and the influence of position. An exploratory correlation analysis was conducted on baseline variables potentially related to the ICP increase.

Results

Mean ICP increase was 1.0 mmHg ± 0.9 at 10 cmH2O PEEP, 2.0 mmHg ± 1.7 at 15 cmH2O PEEP, and 3.1 mmHg ± 1.6 at 20 cmH2O PEEP compared to a baseline PEEP of 5 cmH2O (p < 0.001). The effect of PEEP increase on ICP was not influenced by body position. PRx remained unaffected by PEEP. PEEP-induced increases in ICP were higher in cases of higher baseline ICP, higher central venous pressure, lower respiratory system elastance and lower end-inspiratory and end-expiratory transpulmonary pressures.

Conclusion

Increasing PEEP elevates ICP regardless of body position without adversely affecting cerebral autoregulation in a healthy porcine model. Baseline ICP, central venous pressure, respiratory system elastance and end-inspiratory and end-expiratory transpulmonary pressure may influence the magnitude of ICP changes.
Unmet medical needs definition and incentives: stakeholders perspectives on the reform of the EU pharmaceutical legislation
Authors: Wens Io , Claessens Zilke , Vanneste Alice , Barbier Liese , Janssens Rosanne , Huys Isabelle
Published: January 2025

Introduction

The 2020 pharmaceutical strategy for Europe stressed that rethinking regulatory policies to foster innovation in disease areas with unmet medical needs (UMN) is one of the European Commission’s (EC) priority areas. To understand stakeholders’ views regarding appropriate UMN criteria and incentives, the EC developed a survey and launched it for public consultation between September and December 2021. This study aims to assess stakeholders’ views on the policy revisions proposed by the EC, particularly those regarding the definition of UMN, its criteria and incentives and evaluate how stakeholders’ views are reflected in the proposed reform of the EU pharmaceutical legislation of 2023.

Methods

The public consultation survey comprised 14 questions including multiple-choice and open answer questions about the reform of the pharmaceutical legislation. A mixed-method analysis was conducted on publicly available data of stakeholders’ responses, including descriptive and quantitative statistics for multiple-choice questions and a qualitative thematic framework analysis for open answer questions. A subgroup analysis was performed to assess differences and similarities in stakeholders’ views, and results were compared with the proposed reform of the EU pharmaceutical legislation.

Results

A total of 478 participants completed the survey consisting of 36% industry, 19% end-users, 17% healthcare providers, 7.5% researchers and 7.5% public bodies. All stakeholder groups favored including “absence of satisfactory authorized treatment” and “disease seriousness” as defining criteria for UMN. However, stakeholders disagreed on including the criterion “lack of access for patients,” with public bodies and industry being less in favour. Industry favored maintaining or having additional incentives like transferable exclusivity vouchers on top of current intellectual property rights to foster innovation. In contrast, other stakeholders supported alternative proposals, namely enhancing the use of scientific advice and implementing expediting measures for regulatory evaluation of medicines targeting UMN.

Conclusion

Stakeholders agreed on including availability of alternatives and disease seriousness in the UMN definition but highlighted its ambiguity. Industry participants supported additional incentives like transferable exclusivity vouchers, whereas others preferred scientific and regulatory support. These findings underscore the need for further discussion on UMN criteria and incentives to stimulate innovation while ensuring patient-centric outcomes and equitable access to medicines across Europe.
Advances in the genetics of myasthenia gravis: insights from cutting-edge neuroscience research
Authors: Yixian Zheng , Hai Wang , Xiuying Liu , Jichun Yan
Published: January 2025

Myasthenia gravis (MG) is an autoimmune disorder involving complex interactions between genetic and environmental factors. Genome-wide association studies (GWAS), transcriptome-wide association studies (TWAS), and other methods have identified multiple novel susceptibility loci and genes, providing crucial insights into the genetic etiology of MG. Moreover, the pivotal roles of epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, in the pathogenesis of MG are gradually being unveiled. This review comprehensively summarizes the latest advances in MG genetic research, focusing on the discovery and validation of susceptibility genes, genetic heterogeneity and subtype-specific genetic factors, gene–environment interactions, epigenetic mechanisms, and progress in genetics-based diagnostic and prognostic biomarkers.
Effects of Chenpi (Citrus reticulata cv. Chachiensis) on serum antioxidant enzymes, inflammatory factors, and intestinal health in Beagle dogs
Authors: Wang Wencan , Xu Ling , Zhang Yan , Cao Yong , Yang Yixue , Liu Guo , Mao Xin
Published: January 2025

Ensuring companion animal welfare is a top priority for the pet industry and owners alike. The health of the pets can be directly and effectively improved through diet. Chenpi includes beneficial ingredients with proven anti-inflammatory, antioxidant, and immunomodulatory properties. The present investigation involved feeding snacks infused with Chenpi powder (CPP) to dogs for 42 days to examine the potential health benefits of CPP. The research evidenced a notable increase in serum superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity in dogs, accompanied by a decrease in malondialdehyde (MDA), interleukin-8 (IL-8), and interferon-gamma (IFN-γ) level. Additionally, CPP increased fecal scores and significantly reduced fecal odors due to inhibition of 3-methylindole, hydrogen sulfide (H2S), and ammonia nitrogen (NH4+-N), and also raised the levels of fecal secretory immunoglobulin A (SIgA). Analysis of the microbial composition via 16S rRNA sequencing showed that CPP increased Bacteroidota and decreased Firmicutes in the gut flora at the phylum level. Functional prediction study of microbial communities also showed that the CPP group enriched metabolic and genetic information processing pathways. In addition, there were significant correlations between serum indicators and several significantly altered microorganisms. These findings suggest that CPP can potentially enhance the overall health of dogs by reducing fecal odorants, enhancing antioxidant and immunological capabilities, and modulating intestinal flora. This study establishes a solid scientific foundation regarding the application of CPP in functional pet foods.