bluuebunny/crossref_metadata_2025 huggingface dataset:
First-line combination therapy of immunotherapy plus anti-angiogenic drug for thoracic SMARCA4-deficient undifferentiated tumors in AIDS: a case report and review of the literature
Authors: Wei Xiaoling , Xing Xiangju , Yao Wei , Wang Changzheng , Xiao Yajie , Du Xianzhi
Published: January 2025

Background

Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) exhibit a notably aggressive phenotype, which is associated with poor patient survival outcomes. These tumors are generally resistant to conventional cytotoxic chemotherapy, thereby limiting the availability of effective treatment options.

Case presentation

We describe a 69-year-old AIDS patient who initially presented with a fused, enlarged lymph node on the right clavicle and mild, unexplained pain under the right axilla that worsened with severe coughing episodes. An initial chest CT scan revealed multiple nodular and mass shadows in the mediastinum and multiple nodules in both lungs, as well as a small amount of pericardial effusion. Additionally, serum biomarkers of lung cancer were abnormal as follows: carcinoembryonic antigen (CEA) at 13.74 ng/mL, cytokeratin 19 fragment (CYFRA21-1) at 6.82 ng/mL, neuron-specific enolase (NSE) at 25.49 ng/mL, and progastrin-releasing peptide precursor (ProGRP) at 89.35 pg/mL. Subsequent pathology confirmed SMARCA4-deficient undifferentiated tumors. Considering that the weak immune status and intermediate PD-L1 level, the patient was treated with a first-line combination therapy of immunotherapy and anti-angiogenic drug instead of chemo-immunotherapy. The patient responded well to immunotherapy combining anti-angiogenic drugs and achieved an overall survival for more than 22 months.

Conclusion

Our study presented a rare case of thoracic SMARCA4-deficient undifferentiated tumors and AIDS, suggesting that first-line immunotherapy plus anti-angiogenic drugs as a potential therapeutic option for SMARCA4-UT patients under specific conditions.
Injecting hope: the potential of intratumoral immunotherapy for locally advanced and metastatic cancer
Authors: Skalickova Marketa , Hadrava Vanova Katerina , Uher Ondrej , Leischner Fialova Jindriska , Petrlakova Katerina , Masarik Michal , Kejík Zdeněk , Martasek Pavel , Pacak Karel , Jakubek Milan
Published: January 2025

Despite enormous progress, advanced cancers are still one of the most serious medical problems in current society. Although various agents and therapeutic strategies with anticancer activity are known and used, they often fail to achieve satisfactory long-term patient outcomes and survival. Recently, immunotherapy has shown success in patients by harnessing important interactions between the immune system and cancer. However, many of these therapies lead to frequent side effects when administered systemically, prompting treatment modifications or discontinuation or, in severe cases, fatalities. New therapeutic approaches like intratumoral immunotherapy, characterized by reduced side effects, cost, and systemic toxicity, offer promising prospects for future applications in clinical oncology. In the context of locally advanced or metastatic cancer, combining diverse immunotherapeutic and other treatment strategies targeting multiple cancer hallmarks appears crucial. Such combination therapies hold promise for improving patient outcomes and survival and for promoting a sustained systemic response. This review aims to provide a current overview of immunotherapeutic approaches, specifically focusing on the intratumoral administration of drugs in patients with locally advanced and metastatic cancers. It also explores the integration of intratumoral administration with other modalities to maximize therapeutic response. Additionally, the review summarizes recent advances in intratumoral immunotherapy and discusses novel therapeutic approaches, outlining future directions in the field.
Macrophage heterogeneity and oncogenic mechanisms in lung adenocarcinoma: insights from scRNA-seq analysis and predictive modeling
Authors: Zhang Han , Dai Jiaxing , Mu Qiuqiao , Zhao Xiaojiang , Lin Ziao , Wang Kai , Wang Meng , Sun Daqiang
Published: January 2025

Background

Macrophages play a dual role in the tumor microenvironment(TME), capable of secreting pro-inflammatory factors to combat tumors while also promoting tumor growth through angiogenesis and immune suppression. This study aims to explore the characteristics of macrophages in lung adenocarcinoma (LUAD) and establish a prognostic model based on macrophage-related genes.

Method

We performed scRNA-seq analysis to investigate macrophage heterogeneity and their potential pseudotime evolutionary processes. Specifically, we used scRNA-seq data processing, intercellular communication analysis, pseudotime trajectory analysis, and transcription factor regulatory analysis to reveal the complexity of macrophage subpopulations. Data from The Cancer Genome Atlas (TCGA) was used to assess the impact of various macrophage subtypes on LUAD prognosis. Univariate Cox regression was applied to select prognostic-related genes from macrophage markers. We constructed a prognostic model using Lasso regression and multivariate Cox regression, categorizing LUAD patients into high and low-risk groups based on the median risk score. The model’s performance was validated across multiple external datasets. We also examined differences between high and low-risk groups in terms of pathway enrichment, mutation information, tumor microenvironment(TME), and immunotherapy efficacy. Finally, RT-PCR confirmed the expression of model genes in LUAD, and cellular experiments explored the carcinogenic mechanism of COL5A1.

Results

We found that signals such as SPP1 and MIF were more active in tumor tissues, indicating potential oncogenic roles of macrophages. Using macrophage marker genes, we developed a robust prognostic model for LUAD that effectively predicts prognosis and immunotherapy efficacy. A nomogram was constructed to predict LUAD prognosis based on the model’s risk score and other clinical features. Differences between high and low-risk groups in terms of TME, enrichment analysis, mutational landscape, and immunotherapy efficacy were systematically analyzed. RT-PCR and cellular experiments supported the oncogenic role of COL5A1.

Conclusion

Our study identified potential oncogenic mechanisms of macrophages and their impact on LUAD prognosis. We developed a prognostic model based on macrophage marker genes, demonstrating strong performance in predicting prognosis and immunotherapy efficacy. Finally, cellular experiments suggested COL5A1 as a potential therapeutic target for LUAD.
The role and therapeutic targeting of the CCL2/CCR2 signaling axis in inflammatory and fibrotic diseases
Authors: Guo Shan , Zhang Qi , Guo Yingjie , Yin Xiaoyan , Zhang Peng , Mao Tao , Tian Zibin , Li Xiaoyu
Published: January 2025

CCL2, a pivotal cytokine within the chemokine family, functions by binding to its receptor CCR2. The CCL2/CCR2 signaling pathway plays a crucial role in the development of fibrosis across multiple organ systems by modulating the recruitment and activation of immune cells, which in turn influences the progression of fibrotic diseases in the liver, intestines, pancreas, heart, lungs, kidneys, and other organs. This paper introduces the biological functions of CCL2 and CCR2, highlighting their similarities and differences concerning fibrotic disorders in various organ systems, and reviews recent progress in the diagnosis and treatment of clinical fibrotic diseases linked to the CCL2/CCR2 signaling pathway. Additionally, further in-depth research is needed to explore the clinical significance of the CCL2/CCR2 axis in fibrotic conditions affecting different organs.
Immune response profiling of HERV-W envelope proteins in multiple sclerosis: potential biomarkers for disease progression
Authors: Ruberto Stefano , Domınguez-Mozo María I. , Garcıa-Martınez M. Angel , Cossu Davide , Sechi Leonardo A. , Alvarez-Lafuente Roberto
Published: January 2025

Introduction

The envelope proteins syncytin-1 and pHERV-W from the Human Endogenous Retroviral family ‘W’ (HERV-W) have been identified as potential risk factors in multiple sclerosis (MS). This study aims to evaluate both humoral and cell-mediated immune response to antigenic peptides derived from these proteins across different clinical forms and inflammatory phases of MS.

Methods

Indirect enzyme-linked immunosorbent assay (ELISA) was employed to measure immunoglobulin G (IgG) responses to syncytin-1env 486-500 and pHERV-Wenv 486-504 peptides in MS patients. Discriminant analysis was used to assess whether clinical course prediction could be enhanced by integrating clinical variables with humoral response data against other MS-associated viral factors. Additionally, peripheral blood mononuclear cells from MS patients and healthy controls (HC) were analyzed for inflammatory responses following stimulation with these peptides.

Results

MS patients exhibited significantly elevated antibody titers against -pHERV-Wenv 486-504 and syncytin-1env 486-500 compared to HCs, with the highest levels observed in progressive MS forms. Discriminant analysis accurately predicted the clinical course in 75.3% of the cases, with an 85% accuracy rate for progressive MS. In vitro, stimulation with pHERV-Wenv 486-504 led to a notable increase in pro-inflammatory cytokine production by CD4, CD8, and CD19 cells compared to syncytin-1env 486-500. A strong correlation was found between pHERV- Wenv 486-504 induced cytokine production and EBV and CMV titers in MS patients.

Discussion

These findings suggest that the pHERV-W envelope protein could be a valuable biomarker for monitoring peripheral inflammation in MS.
ZBP1 senses Brucella abortus DNA triggering type I interferon signaling pathway and unfolded protein response activation
Authors: Gomes Marco Túlio R. , Guimarães Erika S. , Oliveira Sergio C.
Published: January 2025

The innate immune system promptly detects and responds to invading pathogens, with a key role played by the recognition of bacterial-derived DNA through pattern recognition receptors. The Z-DNA binding protein 1 (ZBP1) functions as a DNA sensor inducing type I interferon (IFN) production, innate immune responses and also inflammatory cell death. ZBP1 interacts with cytosolic DNA via its DNA-binding domains, crucial for its activation. Brucella abortus is the etiologic agent of brucellosis in livestock and humans, leading to significant economic losses and public health impact. Despite other innate immune sensors that recognize B. abortus DNA, including Toll-like receptor 9 and the Stimulator of interferon genes (STING), here we evaluated the ZBP1 participation as a cytosolic receptor sensing Brucella infection. Using macrophages derived from ZBP1 knockout (KO) mice we demonstrated that ZBP1 partially contributes to IFN-β expression upon B. abortus infection or Brucella DNA transfection. The knockdown of STING by siRNA decreased the residual IFN-β signal elicited by B. abortus infection, demonstrating the presence of a redundant cytosolic DNA-sensing mechanism driving type I IFN production. Furthermore, ZBP1 is involved in type I IFN signaling inducing IRF-1 expression. Additionally, ZBP1 also contributes to Unfolded Protein Response (UPR) activation during infection. However, ZBP1 does not influence the production of proinflammatory mediators, inflammasome activation and it is dispensable to control bacterial infection in mice or replication in macrophages. This study highlights the complex interactions of Brucella components with innate immune receptors and identifies ZBP1 as a sensor for B. abortus DNA-induced IFN-β response.
Low skeletal muscle mass as a proxy marker of sarcopenia is a risk factor for major complications in older patients undergoing curative colon resections for colon cancer
Authors: Tırnova İsmail , Gasimova Maya , Akay Hatice , Sarıtürk Çağla , Güven Mert Aslıhan , Yenidünya Özlem , Karakayalı Feza Yarbuğ
Published: January 2025

Introduction

Various reports have confirmed that low skeletal muscle mass, a proxy marker of sarcopenia, can be a risk factor for surgical and oncological outcomes in colon cancer. We aimed to investigate the effects of skeletal muscle mass index (SMMI) on postoperative complications, overall survival (OS), and disease-free survival (DFS) in older patients with colon cancer who underwent elective curative colon resections.

Materials and methods

Patients over 65 years old with stage I-III colon cancer who underwent elective curative colon resections between January 2015 and December 2023 were included in this single-center retrospective longitudinal study. Demographics, comorbidities, laboratory data, pathological features, malignant lymph node ratio (MLNR), OS, and DFS were recorded. Controlling Nutritional Status (CONUT) Score was used to assess the nutritional status. An axial portal-phase image was obtained at the level of the third lumbar vertebra, and muscle areas were calculated. SMMI was calculated by dividing the muscle area (cm2) by the square of the patient’s height (m2). Low SMMI was defined as SMMI<41 cm2/m2 in women and < 43 cm2/m2 in men with body mass index (BMI) <25 kg/m2, and as SMMI <53 cm2/m2 in patients with a BMI >25 kg/m2. Postoperative complications were classified according to the Clavien-Dindo system. Univariate and multivariate analyses were performed to investigate the factors related to the postoperative complications, OS and DFS.

Results

In total, 98 cases (mean age 75.2 ± 6.9, 55.1% male) were included in the study. The median follow-up time was 38.3 (0.5–113) months. There were 64 patients (65.3%) in the Low SMMI group and 34 patients (34.7%) in the Normal SMMI group. Logistic regression analysis demonstrated that low SMMI was associated with a higher risk of major complications, with an odds ratio of 5.3 (95% CI, 1.1–20.1; p = 0.037). Cox regression analysis revealed no significant differences in OS and DFS.

Conclusion

Low SMMI as a proxy marker of sarcopenia was found to be an independent risk factor for postoperative major complications. Additional prospective studies are warranted to obtain more reliable results.
Prognostic value of HSP27 in 28-day mortality in septic ICU patients: a retrospective cohort study
Authors: Yao Lihua , Fan Zaiwei , Yao Fangyi , Wang Xiaozhong
Published: January 2025

Background

This study aimed to investigate the association between serum heat shock protein 27 (HSP27) levels and 28-day mortality in patients with sepsis.

Methods

This retrospective study analyzed the clinical data of 76 septic patients admitted to the intensive care unit (ICU). Fifty non-septic ICU patients and 50 healthy individuals served as control groups. Serum HSP27 levels were measured on the day of ICU admission and compared to sepsis severity and survival outcomes.

Results

Median serum HSP27 levels in septic patients (4.70 ng/mL, IQR: 2.10–13.48 ng/mL) were significantly higher than those in both non-septic ICU controls and healthy controls (all p < 0.05). Moreover, non-survivors exhibited significantly higher median HSP27 levels (9.30 ng/mL, IQR: 3.62–25.91 ng/mL) compared to survivors (3.03 ng/mL, IQR: 1.48–7.39 ng/mL, p < 0.05). Multivariate logistic regression analysis confirmed the association between HSP27 levels and 28-day mortality in sepsis patients. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve (AUC) of 0.720 (95% CI: 0.605–0.817, p < 0.001) for HSP27 in predicting sepsis prognosis. Survival analysis demonstrated that patients with high serum HSP27 levels (≥2.61 ng/mL) had a worse prognosis than those with low levels (<2.61 ng/mL).

Conclusion

HSP27 shows potential as a biomarker for the diagnosis and prognosis of sepsis, however, further research is necessary to solidify its clinical utility.
Shotgun metagenomics reveals the interplay between microbiome diversity and environmental gradients in the first marine protected area in the northern Arabian Gulf
Authors: Fakhraldeen Saja A. , Madhusoodhanan Rakhesh , Habibi Nazima , Al-Haddad Sakinah , Alagarsamy Surendraraj , Habeebullah Sabeena F. K. , Al-Zakri Walid M. , Thuslim Fathima , Fernandes Loreta , Al-Yamani Faiza , Al-Said Turki
Published: January 2025

Introduction

The northwest Arabian Gulf encounters significant anthropogenic pressures, including nutrient enrichment from coastal development and effluent discharge.

Methods

This study presents the first shotgun metagenomics-based characterization of microbial communities in Kuwaiti waters of the northwest Arabian Gulf, focusing on Kuwait’s first Marine Protected Area (MPA) in Sulaibikhat Bay, a vital nursery ground for commercially important fish.

Results

Analysis revealed significantly higher microbial diversity within the MPA compared to adjacent waters, with Rhodobacteraceae (27.8%) and Flavobacteriaceae (15.3%) being dominant. Elevated inorganic phosphorus, nitrogen, and salinity were key factors driving this diversity. Multivariate analysis highlighted phosphate as a critical component affecting the MPA microbial community structure, particularly for the families Microbacteriaceae, Flavobacteriaceae, and Rhodobacteraceae.

Discussion

This study underscores the ecological importance of MPAs and highlights the impact of nutrient enrichment and other environmental stressors on microbial diversity, emphasizing the need to reduce nutrient influx to mitigate eutrophication and enhance marine ecosystem resilience in stressed environments.
Prevalence and characterization of IncQ1α-mediated multi-drug resistance in Proteus mirabilis Isolated from pigs in Kunming, Yunnan, China
Authors: Liu Hongmei , Xia Na , Suksawat Fanan , Tengjaroenkul Bundit , Hu Yue , Zhou Xiaofeng , Li Xiaojiang , Huang Cuiqin , Bao Yinli , Wu Qiong , Zhang Chunrong , Angkititrakul Sunpetch , Xiang Bin , Wu Xin
Published: January 2025

Background

Proteus mirabilis is a conditionally pathogenic bacterium that is inherently resistant to polymyxin and tigecycline, largely due to antibiotic resistance genes (ARGs). These ARGs can be horizontally transferred to other bacteria, raising concerns about the Inc plasmid-mediated ARG transmission from Proteus mirabilis, which poses a serious public health threat. This study aims to investigate the presence of Inc plasmid types in pig-derived Proteus mirabilis in Kunming, Yunnan, China.

Methods

Fecal samples were collected from pig farms across six districts of Kunming (Luquan, Jinning, Yiliang, Anning, Songming, and Xundian) from 2022 to 2023. Proteus mirabilis isolates were identified using IDS and 16S rRNA gene sequencing. Then, positive strains underwent antimicrobial susceptibility testing and incompatibility plasmid typing. Multi-drug-resistant isolates with positive incompatibility plasmid genes were selected for whole-genome sequencing. Resistance and Inc group data were then isolated and compared with 126 complete genome sequences from public databases. Whole-genome multi-locus sequence typing, resistance group analysis, genomic island prediction, and plasmid structural gene analysis were performed.

Results

A total of 30 isolates were obtained from 230 samples, yielding a prevalence of 13.04%. All isolates exhibited multi-drug resistance, with 100% resistance to cotrimoxazole, erythromycin, penicillin G, chloramphenicol, ampicillin, and streptomycin. Among these, 15 isolates tested positive for the IncQ1α plasmid repC gene. The two most multi-drug-resistant and repC-positive strains, NO. 15 and 21, were sequenced to compare genomic features on Inc groups and ARGs with public data. Genome analysis revealed that the repC gene was primarily associated with IncQ1α, with structural genes from other F-type plasmids (TraV, TraU, TraN, TraL, TraK, TraI, TraH, TraG, TraF, TraE/GumN, and TraA) also present. Strain NO. 15 carried 33 ARGs, and strain NO. 21 carried 38 ARGs, conferring resistance to tetracyclines, fluoroquinolones, aminoglycosides, sulfonamides, peptides, chloramphenicol, cephalosporins, lincomycins, macrolides, and 2-aminopyrimidines.

Conclusion

The repC gene is primarily associated with IncQ1α, with structural genes from other F-type plasmids. A comparison with 126 public genome datasets confirmed this association.
Mitochondrial disease and epilepsy in children
Authors: Zhang Xuan , Zhang Bo , Tao Zhiming , Liang Jianmin
Published: January 2025

Mitochondria is the cell’s powerhouse. Mitochondrial disease refers to a group of clinically heterogeneous disorders caused by dysfunction in the mitochondrial respiratory chain, often due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that encodes mitochondrial proteins. This dysfunction can lead to a variety of clinical phenotypes, particularly affecting organs with high energy demands, such as the brain and muscles. Epilepsy is a prevalent neurological disorder in children and is also a frequent manifestation of mitochondrial disease. The exact mechanisms underlying epilepsy in mitochondrial disease remain unclear and are thought to involve multiple contributing factors. This review explores common mitochondrial diseases associated with epilepsy, focusing on their prevalence, seizure types, EEG features, therapeutic strategies, and outcomes. It also summarizes the relationship between the molecular genetics of mitochondrial respiratory chain components and the development of epilepsy.
Single-channel attention classification algorithm based on robust Kalman filtering and norm-constrained ELM
Authors: He Jing , Huang Zijun , Li Yunde , Shi Jiangfeng , Chen Yehang , Jiang Chengliang , Feng Jin
Published: January 2025

Introduction

Attention classification based on EEG signals is crucial for brain-computer interface (BCI) applications. However, noise interference and real-time signal fluctuations hinder accuracy, especially in portable single-channel devices. This study proposes a robust Kalman filtering method combined with a norm-constrained extreme learning machine (ELM) to address these challenges.

Methods

The proposed method integrates Discrete Wavelet Transformation (DWT) and Independent Component Analysis (ICA) for noise removal, followed by a robust Kalman filter enhanced with convex optimization to preserve critical EEG components. The norm-constrained ELM employs L1/L2 regularization to improve generalization and classification performance. Experimental data were collected using a Schulte Grid paradigm and TGAM sensors, along with publicly available datasets for validation.

Results

The robust Kalman filter demonstrated superior denoising performance, achieving an average AUC of 0.8167 and a maximum AUC of 0.8678 on self-collected datasets, and an average AUC of 0.8344 with a maximum of 0.8950 on public datasets. The method outperformed traditional Kalman filtering, LMS adaptive filtering, and TGAM’s eSense algorithm in both noise reduction and attention classification accuracy.

Discussion

The study highlights the effectiveness of combining advanced signal processing and machine learning techniques to improve the robustness and generalization of EEG-based attention classification. Limitations include the small sample size and limited demographic diversity, suggesting future research should expand participant groups and explore broader applications, such as mental health monitoring and neurofeedback.
Preoperative prediction of pituitary neuroendocrine tumor invasion using multiparametric MRI radiomics
Authors: Yang Qiuyuan , Ke Tengfei , Wu Jialei , Wang Yubo , Li Jiageng , He Yimin , Yang Jianxian , Xu Nan , Yang Bin
Published: January 2025

Objective

The invasiveness of pituitary neuroendocrine tumor is an important basis for formulating individualized treatment plans and improving the prognosis of patients. Radiomics can predict invasiveness preoperatively. To investigate the value of multiparameter magnetic resonance imaging (mpMRI) radiomics in predicting pituitary neuroendocrine tumor invasion into the cavernous sinus (CS) before surgery.

Patients and methods

The clinical data of 133 patients with pituitary neuroendocrine tumor (62 invasive and 71 non-invasive) confirmed by surgery and pathology who underwent preoperative mpMRI examination were retrospectively analyzed. Data were divided into training set and testing set according to different field strength equipment. Radiomics features were extracted from the manually delineated regions of interest in T1WI, T2WI and CE-T1, and the best radiomics features were screened by LASSO algorithm. Single radiomics model (T1WI, T2WI, CE-T1) and combined radiomics model (T1WI+T2WI+CE-T1) were constructed respectively. In addition, clinical features were screened to establish clinical model. Finally, the prediction model was evaluated by ROC curve, calibration curve and decision curve analysis (DCA).

Results

A total of 10 radiomics features were selected from 306 primitive features. The combined radiomics model had the highest prediction efficiency. The area under curve (AUC) of the training set was 0.885 (95% CI, 0.819-0.952), and the accuracy, sensitivity, and specificity were 0.951,0.826, and 0.725. The AUC of the testing set was 0.864 (95% CI, 0.744-0.985), and the accuracy, sensitivity, and specificity were 0.829,0.952, and 0.700. DCA showed that the combined radiomics model had higher clinical net benefit.

Conclusion

The combined radiomics model based on mpMRI can effectively and accurately predict the invasiveness of pituitary neuroendocrine tumor to CS preoperatively, and provide decision-making basis for clinical individualized treatment.
Mechanistic insights into HPV-positivity in non-smokers and HPV-negativity in smokers with head and neck cancer
Authors: Hoffmann Markus , Hille Susanne , Fazel Asita , Laudien Martin , Wiegand Susanne , Müller Martin , Müller Oliver J. , Quabius Elgar Susanne
Published: January 2025

Introduction

Several aspects of the involvement of HPV in the pathogenesis of HPV-associated diseases remain poorly understood including mechanistic aspects of infection and the question of why the majority of HPV-positive HNSCC-patients are non-smokers, whereas HPV-negatives are smokers. Our previous research, based on 1,100 patient samples, hypothesized an explanation for this phenomenon: Smoking induces upregulation of a mucosal protective protein (SLPI), which competes with HPV for binding to Annexin A2 (AnxA2), pivotal for HPV cell entry. Here we investigate the mechanistic aspects of our hypothesis using transfection assays.

Methods

HaCaT and HeLa cell lines were used to investigate the effects of shRNA transfection and nicotine exposure on HPV16-PsV-uptake. Cells were treated with Lipofectamine™ RNAiMAX for 48 or 72 hours with specific shRNA-concentrations, while nicotine was added to the cell medium at the indicated concentrations. Protein isolation, SLPI- and AnxA2-quantification, LDH cytotoxicity assessment, HPV16-PsV-uptake measurement, mRNA-isolation, cDNA-synthesis and RT-qPCR were performed.

Results

In vitro transfection experiments with HPV16 pseudovirions (PsVs) showed that PsVs entered cells significantly better when SLPI was downregulated and significantly less when AnxA2 was downregulated. Nicotine exposure increased SLPI levels and reduced PsV uptake.

Conclusions

The overexpression of SLPI caused by tobacco-smoking can hinder HPV cell entry by binding to AnxA2 and thus prevent successful HPV infection. Conversely, non-smokers have lower SLPI-levels, associated with an excess of unbound AnxA2, favoring HPV cell-entry. These findings support our hypothesis, suggesting a paradigm shift in understanding virus-related pathogenesis, particularly in the head and neck region, and the nature of HPV infection.
Copper in the colorectal cancer microenvironment: pioneering a new era of cuproptosis-based therapy
Authors: Feng Qixuan , Sun Yue , Yang Zhe , Wang Zhiyu , Chen Zhangyi , Liu Fang , Liu Lingxiang
Published: January 2025

Copper, an essential trace element and biochemical cofactor in humans plays a critical role in maintaining health. Recent studies have identified a significant association between copper levels and the progression and metastasis of cancer. Copper is primarily absorbed in the intestinal tract, often leading to an imbalance of copper ions in the body. Colorectal cancer (CRC), the most common cancer originating in the intestines, thrives in an environment with elevated copper concentrations. Current research is focused on uncovering the relationship between copper and CRC which has introduced new concepts such as cuproplasia and cuproptosis, significantly deepening our understanding of copper’s influence on cell proliferation and death. Cuproplasia is a kind of cell proliferation mediated by the co-regulatory activities of enzymes and non-enzymatic factors, while cuproptosis refers to cell death induced by excessive copper, which results in abnormal oligomerization of lipacylated proteins and the reduction of iron-sulfur cluster proteins. Exploring cuproplasia and cuproptosis opens new avenues for treating CRC. This review aims to summarize the critical role of copper in promoting colorectal cancer, the dual effects of copper in the tumor microenvironment (TME), and strategies for leveraging this unique microenvironment to induce cuproptosis in colorectal cancer. Understanding the relationship between copper and CRC holds promise for establishing a theoretical foundation for innovative therapeutic strategies in CRC.
A nomogram for predicting neonatal acute respiratory distress syndrome in patients with neonatal pneumonia after 34 weeks of gestation
Authors: Yu Aosong , Hou Huanhuan , Ran Lingyi , Sun Xiaojia , Xin Wanchun , Feng Tong
Published: January 2025

Objective

To establish a prediction nomogram for early prediction of neonatal acute respiratory distress syndrome (NARDS).

Methods

This is a retrospective cross-sectional study conducted between January 2021 and December 2023. Clinical characteristics and laboratory results of cases with neonatal pneumonia were compared in terms of presence of NARDS diagnosis based on the Montreux Definition. The NARDS group and non-NARDS group were then compared to establish a prediction nomogram for early prediction of NARDS. The predictive accuracy and compliance of the model were evaluated using subject operating characteristic curves, area under the ROC curve, and calibration curves, and the model performance was estimated by self-lifting weight sampling. The Hosmer–Lemeshow test was used to assess the goodness of fit of the model.

Findings

NARDS group consisted of 104, non-NARDS group consisted of 238 newborns in our study. Gestational age, triple concave sign, blood glucose measurement after birth (Glu), Apgar score at the 5th minute (Apgar5), neutrophil count (ANC) and platelet count (PLT) are independent predictors of NARDS in late preterm and term newborns who present with progressive respiratory distress and require varying degrees of respiratory support within the first 24 h of life to minimize work of breathing and restore organismal oxygenation. The area under the ROC curve was 0.829 (95% CI = 0.785–0.873), indicating the model's strong predictive power. In addition, decision curve analysis showed that the model had significantly better net benefits.

Conclusion

In this study, a predictive column-line plot was constructed based on six clinically accessible conventional variables. Early application of this model has a better predictive effect on the early diagnosis of NARDS, thus facilitating more timely and effective interventions.
Duvelisib is a novel NFAT inhibitor that mitigates adalimumab-induced immunogenicity
Authors: Bhingarkar Aboli , Wang Yuyin , Hoshitsuki Keito , Eichinger Katherine Marie , Rathod Sanjay , Zhu Yin , Lyu He , McNutt Andrew T. , Moreland Larry W. , McDermott Lee , Koes David R. , Fernandez Christian A.
Published: January 2025

Introduction

TNFα inhibitor (TNFi) immunogenicity in rheumatoid arthritis (RA) is a major obstacle to its therapeutic effectiveness. Although methotrexate (MTX) can mitigate TNFi immunogenicity, its adverse effects necessitate alternative strategies. Targeting nuclear factor of activated T cells (NFAT) transcription factors may protect against biologic immunogenicity. Therefore, developing a potent NFAT inhibitor to suppress this immunogenicity may offer an alternative to MTX.

Methods

We performed a structure-based virtual screen of the NFATC2 crystal structure to identify potential small molecules that could interact with NFATC2. For validation, we investigated the effect of the identified compound on NFAT transcriptional activity, nuclear localization, and binding to the NFAT consensus sequence. In vivo studies assessed the ability of the compound to protect against TNFi immunogenicity, while ex vivo studies evaluated its effect on CD4+ T cell proliferation and B cell antibody secretion.

Results

We identified duvelisib (DV) as a novel NFATC2 and NFATC1 inhibitor that attenuates NFAT transcriptional activity without inhibiting calcineurin or NFAT nuclear localization. Our results suggest that DV inhibits NFAT independently of PI3K by interfering with nuclear NFAT binding to the NFAT consensus promoter sequence. DV significantly protected mice from adalimumab immunogenicity and attenuated ex vivo CD4+ T cell proliferation and B cell antibody secretion.

Discussion

DV is a promising NFAT inhibitor that can protect against TNFi immunogenicity without inhibiting calcineurin phosphatase activity. Our results suggest that the future development of DV analogs may be of interest as agents to attenuate unwanted immune responses.
Protective effects of Cordyceps militaris against hepatocyte apoptosis and liver fibrosis induced by high palmitic acid diet
Authors: Tsai Wan-Ting , Situmorang Jiro Hasegawa , Kuo Wei-Wen , Kuo Chia-Hua , Lin Shinn-Zong , Huang Chih-Yang , Ho Tsung-Jung
Published: January 2025

Background

Fatty Liver Disease (FLD) progresses from steatosis to steatohepatitis and, if left untreated, can lead to irreversible conditions such as cirrhosis and hepatocarcinoma. The etiology of FLD remains unclear, but factors such as overconsumption, poor diet, obesity, and diabetes contribute to its development. Palmitic acid (PA) plays a significant role in FLD progression by inducing apoptosis, inflammation, oxidative stress, and endoplasmic reticulum (ER) stress in hepatocytes. Cordyceps militaris (CM), a fungus with various biological activities, including antioxidant properties is examined both in vitro and in vivo to assess its effectiveness in mitigating PA-induced hepatocyte apoptosis and preventing FLD progression.

Purpose

This study aims to investigate the potential and mechanism of CM in combating FLD, particularly in inhibiting hepatocyte apoptosis.

Methods

In vitro studies utilized Clone9 hepatocytes treated with PA to simulate FLD conditions. The effects of CM ethyl acetate extract (EAECM) on apoptosis, mitochondrial function, ER stress, inflammation, and oxidative stress were evaluated. In vivo experiments involved FVB mice fed a NASH diet containing high levels of PA to induce FLD, with powdered CM administered orally to assess its impact on body weight, fasting blood glucose level, liver health, fibrosis, and markers of ER stress, inflammation, and oxidative stress.

Results

EAECM demonstrated protective effects against PA-induced apoptosis, mitochondrial dysfunction, ER stress, inflammation, and oxidative stress in vitro. In vivo, powdered CM supplementation attenuated body weight gain, improved fasting blood glucose level, prevented hepatomegaly, reduced serum triglycerides, and inhibited liver fibrosis. Furthermore, powdered CM treatment mitigated ER stress, inflammation, and oxidative stress in the liver of mice receiving a NASH diet.

Conclusion

C. militaris holds promise as a therapeutic agent for FLD, as evidenced by its ability to alleviate PA-induced hepatocytes damage and hinder FLD progression in mice. Further research is warranted to identify the active compounds responsible for its beneficial effects and to explore its potential clinical applications in treating FLD.
High-risk adverse events in two types of single inhaler triple-therapy: a pharmacovigilance study based on the FAERS database
Authors: Ruan Zhishen , Wang Chunbin , Yuan Shasha , Fan Yiling , Xu Bo , Cong Xiaodong , Li Dan , Miao Qing
Published: January 2025

Objective

Single inhaler triple therapy is widely used in Chronic Obstructive Pulmonary Disease (COPD) and asthma. This research aimed to analyze adverse events (AEs) associated with Budesonide/Glycopyrronium/Formoterol Fumarate (BUD/GLY/FOR) and Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI).

Methods

This is a cross-sectional study. BUD/GLY/FOR (2020Q3-2024Q3) and FF/UMEC/VI (2018Q1-2024Q3) report files were downloaded from the U.S. Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) database. We use reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) for disproportionality analysis. The aim was to explore associations between drugs and preferred term (PT) and system organ classification (SOC) levels. We focused on exploring the top 10 PTs of each drug’s BCPNN (IC) effect value and the PT of pneumonia.

Results

16,355 AEs in BUD/GLY/FOR and 39,110 AEs in FF/UMEC/VI were extracted. Device use issues, oropharyngeal and vocal problems, pneumonia, candida infections, and urinary retention were the standard PTs present in drug leaflets. The risk of device use issues was higher in BUD/GLY/FOR, whereas the risk of pneumonia and candida infection in FF/UMEC/ VI had higher risk. Outside of the drug leaflets, both drugs were associated with a higher risk of AEs in vascular disorders. BUD/GLY/FOR group had a higher risk of AEs in body height decreased and hypoacusis. Notably, this study found an association between the above PTs and drugs, and the causal relationship needs to be verified by further longitudinal studies.

Conclusion

Our study provides a preliminary exploration of the safety of clinical use of BUD/GLY/FOR and FF/UMEC/VI, and clinicians should be alert to potential adverse effects.
Role of copper homeostasis and cuproptosis in heart failure pathogenesis: implications for therapeutic strategies
Authors: Liu Zhichao , Gan Yongkang , Shen Zhen , Cai Siqi , Wang Xizhen , Li Yong , Li Xiaofeng , Fu Huanjie , Chen Jinhong , Li Ningcen
Published: January 2025

Copper is an essential micronutrient involved in various physiological processes in various cell types. Consequently, dysregulation of copper homeostasis—either excessive or deficient—can lead to pathological changes, such as heart failure (HF). Recently, a new type of copper-dependent cell death known as cuproptosis has drawn increasing attention to the impact of copper dyshomeostasis on HF. Notably, copper dyshomeostasis was associated with the occurrence of HF. Hence, this review aimed to investigate the biological processes involved in copper uptake, transport, excretion, and storage at both the cellular and systemic levels in terms of cuproptosis and HF, along with the underlying mechanisms of action. Additionally, the role of cuproptosis and its related mitochondrial dysfunction in HF pathogenesis was analyzed. Finally, we reviewed the therapeutic potential of current drugs that target copper metabolism for treating HF. Overall, the conclusions of this review revealed the therapeutic potential of copper-based therapies that target cuproptosis for the development of strategies for the treatment of HF.
Targeted lipidomics analysis of possible molecular mechanisms of lipid changes in temporal lobe epilepsy models
Authors: Sun Huaiyu , Li Xuewei , Chen Zhiqing , Meng Hongmei
Published: January 2025

Background

Lipids are vital biomolecules involved in the formation of various biofilms. Seizures can cause changes in lipid metabolism in the brain. In-depth studies at multiple levels are urgently needed to elucidate lipid composition, distribution, and metabolic pathways in the brain after seizure.

Methods

In this research, a cutting-edge targeted quantitative lipidomics study was conducted on the hippocampal tissues of six rats with temporal lobe epilepsy and six normal rats. Accurate lipid quantification based on linear equations was calculated using an internal standard. The lipids were quantitatively and qualitatively analyzed by ultra-high performance liquid chromatography (UPLC) and mass spectrometry (MS).

Results

A total of 21 lipid classes were identified. Among them, the most abundant were triacylglycerol (TG), phosphatidyl ethanolamine (PE-P), and fatty acids (FA). Cholesteryl ester (ChE) exhibits the most considerable difference between the normal and epileptic samples. ChE was found to be the most significantly upregulated lipid, while FA was observed to be the most significantly downregulated lipid.

Conclusion

Based on the absolute quantitative analysis of lipids in rat hippocampal specimens, the contents and change trends of different lipids were observed. Upregulation of ChE and dihydroceramide (DHCer) was observed, and an analysis of the distribution changes elucidated the causes and possible molecular mechanisms of lipid accumulation in temporal lobe epilepsy. The results and methods described provide a comprehensive analysis of lipid metabolism in temporal lobe epilepsy and a new therapeutic target for the treatment of epilepsy.
Regional simulations of equatorial spread F driven with, and an analysis of, WAM-IPE electric fields
Authors: Kirchman Aaron , Hysell David , Fang Tzu-Wei
Published: January 2025

A three-dimensional, regional simulation is used to investigate ionospheric plasma density irregularities associated with Equatorial Spread F. This simulation is first driven with background electric fields derived from ISR observations. Next, the simulation is driven with electric fields taken from the WAM-IPE global model. The discrepancies between the two electric fields, particularly in the evening prereversal enhancement, produce disagreeing simulation results. The WAM-IPE electric fields are then studied through a simple sensitivity analysis of a field-line integrated electrodynamics model similar to the one used in WAM-IPE. This analysis suggests there is no simple tuning of ion composition or neutral winds that accurately reproduce ISR-observed electric fields on a day-to-day basis. Additionally, the persistency of the prereversal enhancement structure over time is studied and compared to measurements from the ICON satellite. These results suggest that WAM-IPE electric fields generally have a shorter and more variable correlation time than those measured by ICON.
Acute effects of proprioceptive neuromuscular facilitation stretching on rectus femoris muscle stiffness: a dose-response shear-wave elastography study
Authors: Kranjc Sara , Fink Mojca , Nakamura Masatoshi , Kozinc Žiga
Published: January 2025

Introduction

Proprioceptive neuromuscular facilitation (PNF) stretching is widely used to increase range of motion, but its underlying mechanisms are not well understood. This experimental, parallel group design study investigated the acute effects of PNF stretching on rectus femoris muscle stiffness and explored a potential dose-response relationship.

Methods

Thirty healthy young adults (23 females, 7 males) were randomly assigned to either a PNF stretching group (n = 15; 22.96 ± 2.2 years) or a control group (n = 15; 23.3 ± 2.1 years). Rectus femoris stiffness was measured using shear-wave elastography (Resona 7, Mindray, China) at two locations (distal and proximal) before and after the second, fourth, and sixth sets of PNF stretching. The protocol involved six sets, each with three 10-s stretches and 5-s maximal contractions.

Results

The results indicate that PNF stretching had no statistically significant effect on muscle stiffness, with no main effects of group (F = 0.05; p = 0.830) or time (F = 0.545; p = 0.653), and no significant interactions. However, the proximal location showed a substantially higher shear modulus compared to the distal location (F = 63.6; p < 0.001; η2 = 0.69), independent of group or time.

Discussion

These findings highlight a location-specific difference in muscle stiffness that was unaffected by the intervention. In conclusion, PNF stretching did not acutely reduce rectus femoris stiffness compared to passive rest, regardless of the number of stretching sets performed. Further research is needed to understand the muscle-specific effects of PNF stretching.
Application and development of CRISPR technology in the secondary metabolic pathway of the active ingredients of phytopharmaceuticals
Authors: Gao Haixin , Pei Xinyi , Song Xianshui , Wang Shiying , Yang Zisong , Zhu Jianjun , Lin Qiupeng , Zhu Qinlong , Yang Xiangna
Published: January 2025

As an efficient gene editing tool, the CRISPR/Cas9 system has been widely employed to investigate and regulate the biosynthetic pathways of active ingredients in medicinal plants. CRISPR technology holds significant potential for enhancing both the yield and quality of active ingredients in medicinal plants. By precisely regulating the expression of key enzymes and transcription factors, CRISPR technology not only deepens our understanding of secondary metabolic pathways in medicinal plants but also opens new avenues for drug development and the modernization of traditional Chinese medicine. This article introduces the principles of CRISPR technology and its efficacy in gene editing, followed by a detailed discussion of its applications in the secondary metabolism of medicinal plants. This includes an examination of the composition of active ingredients and the implementation of CRISPR strategies within metabolic pathways, as well as the influence of Cas9 protein variants and advanced CRISPR systems in the field. In addition, this article examines the long-term impact of CRISPR technology on the progress of medicinal plant research and development. It also raises existing issues in research, including off-target effects, complexity of genome structure, low transformation efficiency, and insufficient understanding of metabolic pathways. At the same time, this article puts forward some insights in order to provide new ideas for the subsequent application of CRISPR in medicinal plants. In summary, CRISPR technology presents broad application prospects in the study of secondary metabolism in medicinal plants and is poised to facilitate further advancements in biomedicine and agricultural science. As technological advancements continue and challenges are progressively addressed, CRISPR technology is expected to play an increasingly vital role in the research of active ingredients in medicinal plants.
Tunes that move us: the impact of music-induced emotions on prosocial decision-making
Authors: Wu Hongwei , Wang Danni , Zhou Linshu
Published: January 2025

Introduction

The significance of music might be attributed to its role in social bonding, a function that has likely influenced the evolution of human musicality. Although there is substantial evidence for the relationship between prosocial songs and prosocial behavior, it remains unclear whether music alone, independent of lyrics, can influence prosocial behaviors. This study investigates whether music and the emotions it induces can influence prosocial decision-making, utilizing the classical two-dimensional model of emotion (mood and arousal).

Methods

In Experiment 1,42 undergraduate students listened to happy music (positive, high arousal), sad music (negative, low arousal), and white noise while reading stories describing helping scenarios and then assessed their willingness to help. Experiments 2 and 3 further explore mood and arousal effects by manipulating the mode (major vs. minor) and tempo (fast vs. slow) of the music.

Results

Experiment 1’s results indicated that sad music increases willingness to help more than happy music or white noise, suggesting that music-induced emotions influence prosocial behavior through immediate prosocial emotions like empathy. Experiments 2 and 3 demonstrated that only mood, influenced by the music mode, affects prosocial decision-making, while tempo-induced arousal does not. Additionally, Theory of Mind and memory strength do not mediate these effects.

Discussion

These findings reveal the role of pure music listening and specific emotional dimensions on prosocial decision-making, providing evidence to support the music-social bonding hypothesis.