bluuebunny/crossref_metadata_2025 huggingface dataset:
3D organoid cultivation improves the maturation and functional differentiation of cholangiocytes from human pluripotent stem cells
Authors: Budi Nova Yuli Prasetyo , Lai Wei-Yu , Huang Yen-Hua , Ho Hong-Nerng
Published: July 2024

Idiopathic cholangiopathies are diseases that affect cholangiocytes, and they have unknown etiologies. Currently, orthotopic liver transplantation is the only treatment available for end-stage liver disease. Limited access to the bile duct makes it difficult to model cholangiocyte diseases. In this study, by mimicking the embryonic development of cholangiocytes and using a robust, feeder- and serum-free protocol, we first demonstrate the generation of unique functional 3D organoids consisting of small and large cholangiocytes derived from human pluripotent stem cells (PSCs), as opposed to traditional 2D culture systems. At day 28 of differentiation, the human PSC–derived cholangiocytes expressed markers of mature cholangiocytes, such as CK7, CK19, and cystic fibrosis transmembrane conductance regulator (CFTR). Compared with the 2D culture system–generated cholangiocytes, the 3D cholangiocyte organoids (COs) showed higher expression of the region-specific markers of intrahepatic cholangiocytes YAP1 and JAG1 and extrahepatic cholangiocytes AQP1 and MUC1. Furthermore, the COs had small-large tube-like structures and functional assays revealed that they exhibited characteristics of mature cholangiocytes, such as multidrug resistance protein 1 transporter function and CFTR channel activity. In addition to the extracellular matrix supports, the epidermal growth factor receptor (EGFR)-mediated signaling regulation might be involved in this cholangiocyte maturation and differentiation. These results indicated the successful generation of intrahepatic and extrahepatic cholangiocytes by using our 3D organoid protocol. The results highlight the advantages of our 3D culture system over the 2D culture system in promoting the functional differentiation and maturation of cholangiocytes. In summary, in advance of the previous works, our study provides a possible concept of small-large cholangiocyte transdifferentiation of human PSCs under cost-effective 3D culture conditions. The study findings have implications for the development of effective cell-based therapy using COs for patients with cholangiopathies.
Exploring the multifaceted role of obesity in breast cancer progression
Authors: Kakkat Sooraj , Suman Prabhat , Turbat- Herrera Elba A. , Singh Seema , Chakroborty Debanjan , Sarkar Chandrani
Published: July 2024

Obesity is a multifaceted metabolic disorder characterized by excessive accumulation of adipose tissue. It is a well-established risk factor for the development and progression of breast cancer. Adipose tissue, which was once regarded solely as a passive energy storage depot, is now acknowledged as an active endocrine organ producing a plethora of bioactive molecules known as adipokines that contribute to the elevation of proinflammatory cytokines and estrogen production due to enhanced aromatase activity. In the context of breast cancer, the crosstalk between adipocytes and cancer cells within the adipose microenvironment exerts profound effects on tumor initiation, progression, and therapeutic resistance. Moreover, adipocytes can engage in direct interactions with breast cancer cells through physical contact and paracrine signaling, thereby facilitating cancer cell survival and invasion. This review endeavors to summarize the current understanding of the intricate interplay between adipocyte-associated factors and breast cancer progression. Furthermore, by discussing the different aspects of breast cancer that can be adversely affected by obesity, this review aims to shed light on potential avenues for new and novel therapeutic interventions.
Differential role of M cells in enteroid infection by Mycobacterium avium subsp. paratuberculosis and Salmonella enterica serovar Typhimurium
Authors: Alfituri Omar A. , Blake Rosemary , Jensen Kirsty , Mabbott Neil A. , Hope Jayne , Stevens Joanne M.
Published: July 2024

Infection of ruminants such as cattle with Mycobacterium avium subsp. paratuberculosis (MAP) causes Johne’s disease, a disease characterized by chronic inflammation of the small intestine and diarrhoea. Infection with MAP is acquired via the faecal-to-oral route and the pathogen initially invades the epithelial lining of the small intestine. In this study we used an in vitro 3D mouse enteroid model to determine the influence of M cells in infection of the gut epithelia by MAP, in comparison with another bacterial intestinal pathogen of veterinary importance, Salmonella enterica serovar Typhimurium. The differentiation of M cells in the enteroid cultures was induced by stimulation with the cytokine receptor activator of nuclear factor-κB ligand (RANKL), and the effects on MAP and Salmonella uptake and intracellular survival were determined. The presence of M cells in the cultures correlated with increased uptake and intracellular survival of Salmonella, but had no effect on MAP. Interestingly neither pathogen was observed to preferentially accumulate within GP2-positive M cells.
The search for optimal nocturnal diurnal heart rate Index targets in ICU patients: a retrospective observational study from large ICU database
Authors: Gao Lan , Shi QinDong , Zhang XiaoYu , Bu Xiang , Zheng PeiYing , Zhou LinJing , Yan JinQi , Li Hao , Tian Gang
Published: July 2024

Background

Circadian rhythms play a crucial role in cardiovascular health, with the nocturnal diurnal heart rate index (NDHRI) reflecting significant circadian variations. However, the optimal NDHRI target in Intensive Care Unit (ICU) patients remains undefined. This study aims to establish an evidence-based NDHRI target range and assess its association with mortality.

Methods

Data from the eICU Collaborative Research Database (n = 32,412) were analyzed. NDHRI was calculated by dividing cumulative nighttime heart rate area by daytime area. Generalized additive models (GAMs) explored the non-linear relationship between mean NDHRI and mortality, adjusting for confounders. Subgroup analyses were conducted based on ethnicity, ICU type, and comorbidities.

Results

A U-shaped association was observed between hospital mortality and mean NDHRI (P < 0.001). The optimal NDHRI range (40.0%–45.0%) demonstrated the lowest mortality rates. The duration spent within this range correlated inversely with mortality (P < 0.001). Subgroup analyses consistently supported these findings across diverse patient profiles.

Conclusions

Our findings suggest an association between maintaining NDHRI within the 40.0%–45.0% range and lower mortality rates in critically ill patients, highlighting the potential utility of monitoring circadian heart rate variations in the ICU. Further research and future randomized controlled trials are essential to confirm causality and should consider this NDHRI range as a pivotal reference target.
The impact of Chinese university music teachers’ teaching beliefs on creative teaching behaviors: the mediating role of technological acceptance
Authors: Zhang Rong , Wang Hsuan-Po
Published: July 2024

This study focuses on college teachers in the Ningxia Hui Autonomous Region of China, aiming to explore the relationships among teaching beliefs, creative teaching behaviors, and technology acceptance. The research adopts a questionnaire survey method, using scales for teaching beliefs, creative teaching behaviors, and technology acceptance to conduct online surveys of college teachers in the Ningxia Hui Autonomous Region of China. Convenience sampling is employed during the survey. The study mainly verifies the theoretical model proposed by using statistical analysis software such as SPSS and AMOS. The results reveal that teaching beliefs of college teachers in the Ningxia Hui Autonomous Region of China positively predict creative teaching behaviors; teaching beliefs positively predict technology acceptance; technology acceptance positively predicts creative teaching behaviors; and technology acceptance has a significant mediating effect between teaching beliefs and creative teaching behaviors.
Optimal power flow method with consideration of uncertainty sources of renewable energy and demand response
Authors: Zhang Wenjia , Peng Zhuyi , Wang Quanquan , Qi Wanchun , Ge Yi
Published: July 2024

Optimal power flow (OPF) calculation methods are important for the power system operation and mainly focus on the deterministic power flow calculation, neglecting the impact of demand response on online security calculation of power systems with renewable energy sources. Therefore, this paper proposes an OPF calculation method that considers the uncertainties of wind power, photovoltaic (PV) power generation and demand-side response. Firstly, the research focuses on the renewable energy grid, considering the uncertainties of wind power and PV power generation, and establishes uncertainty models for wind power and PV output. Secondly, based on cloud model theory, an uncertainty model for demand response is established. According to the established models, an efficient OPF model is constructed with a linearized submodels considering multiple uncertainties. By testing on the IEEE 30-bus system as a typical example, we found the effectiveness and superiority of the proposed OPF calculation method can benefit the power system economic operation and demand side resource utilization.
Development of an equivalent system frequency response model based on aggregation of distributed energy storage systems
Authors: Duan Shuyin , Zhang Jinjia , Yu Lei , Cai Zexiang
Published: July 2024

Energy storage systems (ESSs) installed in distribution networks have been widely adopted for frequency regulation services due to their rapid response and flexibility. Unlike existing ESS design methods which focus on control strategies, this paper proposes a new method based on an ESS equivalent aggregated model (EAM) for calculating the capacity and the droop of an ESS to maintain the system frequency nadir and quasi-steady state frequency using low-order functions. The proposed method 1) uses first-order functions to describe the frequency response (FR) of synchronous generators (SGs); 2) ignores the control strategies of SGs, making the method systematic and allowing it to avoid analyzing complex high-order functions; and 3) is suitable for low inertia systems. The applicability and accuracy of the method is demonstrated using a modified four-generator two-area (4G2A) system.
Coarse to superfine: can hyperspectral soil organic carbon models predict higher-resolution information?
Authors: Kabiri Shayan , O’Rourke Sharon M.
Published: July 2024

Introduction: Modeling and mapping of soil organic carbon concentration and distribution at the pedon scale is a current knowledge gap that can be addressed by laboratory-based hyperspectral imaging and chemometric analysis of soil cores. Despite the advancements in soil organic carbon models based on hyperspectral images, it is not clear how these models will perform upon input with images at higher resolutions than those of their training sets. This study aims to measure the generalizability of a soil organic carbon model based on a test set with higher resolution hyperspectral images than that of its training set.

Methods: Organic carbon contents were measured at 10 cm intervals on eight soil cores for use as the training set and at 1 cm intervals on a single core for use as the test set. Three regression models, namely, multilayer perceptron, partial least-squares, and support vector regressions, were trained and tested with the median of each hyperspectral image for each of these intervals as the training and test predictors. Permutation importance analysis was performed to explain the models.

Results: The results show that although all three models had the same validation R2 of 0.92 for cross-validation on the 10 cm data, multilayer perceptron regression allowed the best generalization with a test R2 of 0.96 compared to the partial least-squares regression (0.81) and support vector regression (0.86). It was demonstrated that the multilayer perceptron model is more robust to soil surface anomalies and that it predicts soil organic carbon on the test set by learning the spectral features related to soil organic matter chromophore activity in the 950–1,150 nm region along with clay mineralogy derived from peaks at 1,400, 1,900, 2,200, 2,250, and 2,350 nm.

Conclusions: This study shows that while the regression models based on hyperspectral images perform well at the 10-cm-resolution cross validation, multilayer perceptron regression shows superior generalization and robustness for a higher 1-cm-resolution test set without much loss of prediction power.
Integrative analysis of the ovarian metabolome and transcriptome of the Yaoshan chicken and its improved hybrids
Authors: Miao Xiaomeng , Wu Tian , Pan Hongyuan , Zhang Yalan , Liu Jia , Fan Ying , Du Lin , Gong Yu , Li Liang , Huang Tengda , Ning Zhonghua
Published: July 2024

Introduction: Laying performance is a key factor affecting production efficiency in poultry, but its molecular mechanism is still indistinct. In this study, Yaoshan chickens, a local breed in Guizhou, China, and merchant chickens (GYR) with higher egg yield after the three-line cross improvement hybridization of Yaoshan chickens were used as animal samples.

Methods: To explore the regulatory mechanism of the diversities in laying performance, RNA-seq and ultra-performance liquid chromatographytandem mass spectrometry (UPLC—MS/MS) were used to describe the transcriptional and metabolic profiles of the ovaries of Yaoshan and GYR chickens.

Results: At the transcriptional level, 288 differentially expressed genes were upregulated in Yaoshan chickens and 353 differentially expressed genes were upregulated in GYR chickens. In addition, GSEA showed that ECM-receptor interactions and the TGF-β signaling pathway were restrained, resulting in increased egg production in GYR chickens. Furthermore, the upregulation of thiamine and carnitine was identified by metabolomic analysis to facilitate the laying performance of hens. Finally, comprehensive analyses of the transcriptome and metabolome found that thiamine and carnitine were negatively correlated with ECM-receptor interactions and the TGF-β signaling pathway, which jointly regulate the laying performance of Yaoshan chickens and GYR chickens.

Discussion: Taken together, our research delineates differences in the transcriptional and metabolic profiles of the ovaries of Yaoshan and GYR chickens during the peak egg production period and provides new hypotheses and clues for further research on poultry egg production performance and the improvement of economic benefits.
Timing of maternal vaccination against COVID-19 for effective protection of neonates: cohort study
Authors: Nowakowska Aleksandra , Lee Seung Mi , Kim Minjee , Chun Jungmin , Kim Sehyun , Kim Byung Chul , In Hyun Ju , Lee Eunji , Lee Chanyeong , Lee Hyeondong , Jang Yuyeon , Cho Hansam , Kim Jinha , Lee Jeesun , Lee Hee-Jung , Lee Yoo-Kyoung , Park Joong Shin , Kim Young Bong
Published: July 2024

Introduction

Although the safety and effectiveness of COVID-19 vaccination during pregnancy have been proven, there is still little data explaining neonatal outcomes of maternal pre-pregnancy vaccination.

Methods

Here, we investigated the impact of vaccination and SARS-CoV-2 infection on maternal-neonate immune response in a cohort study involving 141 pregnant individuals, and defined the importance of maternal COVID-19 vaccination timing for its effectiveness.

Results and discussion

Our data indicate that vertically transferred maternal hybrid immunity provides significantly better antiviral protection for a neonate than either maternal post-infection or post-vaccination immunity alone. Higher neutralization potency among mothers immunized before pregnancy and their newborns highlights the promising role of pre-pregnancy vaccination in neonatal protection. A comparison of neutralizing antibody titers calculated for each dyad suggests that infection and pre-/during-pregnancy vaccination all support transplacental transfer, providing the offspring with strong passive immunity against SARS-CoV-2. Analysis of neutralizing antibody levels in maternal sera collected during pregnancy and later during delivery shows that immunization may exert a positive effect on maternal protection.
Gastric cancer fibroblasts affect the effect of immunotherapy and patient prognosis by inducing micro-vascular production
Authors: Xia Yan , Wang Xiaolu , Lin Jie , Li Yuan , Dong Lidan , Liang Xue , Wang Huai-Yu , Ding Xia , Wang Qi
Published: July 2024

Introduction

Immunotherapy is critical for treating many cancers, and its therapeutic success is linked to the tumor microenvironment. Although anti-angiogenic drugs are used to treat gastric cancer (GC), their efficacy remains limited. Cancer-associated fibroblast (CAF)-targeted therapies complement immunotherapy; however, the lack of CAF-specific markers poses a challenge. Therefore, we developed a CAF angiogenesis prognostic score (CAPS) system to evaluate prognosis and immunotherapy response in patients with GC, aiming to improve patient stratification and treatment efficacy.

Methods

We assessed patient-derived GC CAFs for promoting angiogenesis using EdU, cell cycle, apoptosis, wound healing, and angiogenesis analysis.

Results

We then identified CAF-angiogenesis-associated differentially-expressed genes, leading to the development of CAPS, which included THBS1, SPARC, EDNRA, and VCAN. We used RT-qPCR to conduct gene-level validation, and eight GEO datasets and the HPA database to validate the CAPS system at the gene and protein levels. Six independent GEO datasets were utilized for validation. Overall survival time was shorter in the high- than the low-CAPS group. Immune microenvironment and immunotherapy response analysis showed that the high-CAPS group had a greater tendency toward immune escape and reduced immunotherapy efficacy than the low-CAPS group.

Discussion

CAPS is closely associated with GC prognosis and immunotherapy outcomes. It is therefore an independent predictor of GC prognosis and immunotherapy efficacy.
Lactococcus lactis subsp. cremoris YRC3780 modifies function of mesenteric lymph node dendritic cells to modulate the balance of T cell differentiation inducing regulatory T cells
Authors: Nakagawa Ryogo , Gu Wenting , Mizobuchi Hibine , Kodera Shuhei , Takano Tomohiro , Wang Yimei , Fujioka Ikumi , Uchida Kenji , Nakajima-Adachi Haruyo , Hachimura Satoshi
Published: July 2024

Introduction

The intestinal immune system plays a pivotal role in the induction of immune responses against food. In the case of T cell response, dendritic cells (DCs) are especially important. However, the regulation of immune responses to food by intestinal DCs has been poorly described. In this study, we analyzed the effect of Lactococcus lactis subsp. cremoris YRC3780, a lactic acid bacterial strain isolated from kefir, a traditional fermented milk product, on the immune responses induced by antigen presentation by intestinal DCs to T cells as well as the mechanism of action of these immunomodulatory effects. It has been shown that L. cremoris YRC3780 ameliorates the symptoms of pollinosis in both animal and human studies.

Methods

CD11c+ cells from mesenteric lymph nodes (MLNs) of BALB/c mice were cultured as MLN DCs with L. cremoris YRC3780 and expression of genes inducing regulatory T cells (Tregs) was examined by qPCR. In addition, MLN DCs were cocultured with CD4+ T cells from DO11.10 transgenic mice expressing an ovalbumin (OVA)-specific TCR and the OVA antigen peptide and L. cremoris YRC3780. Induction of Tregs was examined by flow cytometry, gene expression was analyzed by DNA microarray and qPCR, and the production of cytokines was measured by ELISA. MLN DCs from TLR2-deficient mice and components of L. cremoris YRC3780 were used to examine the recognition of YRC3780 by MLN DCs.

Results

L. cremoris YRC3780 enhanced the expression of genes involved in Treg induction in MLN DCs and induced Foxp3+CD4+T cells in an MLN DC and CD4+ T-cell co-culture system. The effect on MLN DCs was likely mediated by receptors other than TLR2. Together with microarray analyses of CD4+ T cell gene expression and cytokine ELISA, it was demonstrated that L. cremoris YRC3780 promoted the induction of Th1 and Tregs, and regulated the balance of Th1/Th2 and Treg/Th17 cells involving multiple genes via the antigen-presentation of MLN DCs.

Discussion

Our findings provide insights into the modulation of intestinal immune responses mediated by DCs and the antiallergic effects of lactic acid bacteria.
Novel predictors of intravenous immunoglobulin resistance in patients with Kawasaki disease: a retrospective study
Authors: Yi Cong , Zhou Yu-Neng , Guo Jun , Chen Jia , She Xiang
Published: July 2024

Objective

The aim of this study was to investigate the predictive value of systemic immune inflammation index (SII), systemic inflammatory response index (SIRI), and pan-immune inflammation value (PIV) in predicting intravenous immunoglobulin (IVIG) resistance in children diagnosed with Kawasaki disease (KD).

Methods

The clinical data of pediatric patients diagnosed with Kawasaki disease and admitted to our hospital between January 2006 and December 2022 were retrospectively analyzed.

Results

In total, 771 children diagnosed with KD were included in this study, 86 (11.2%) of whom were diagnosed with IVIG resistance. The correlation between SII, SIRI, PIV and IVIG resistance was evaluated using univariate testing, binary logistic regression analysis, and receiver operating characteristic (ROC) curve analysis. Our study found that the SII, SIRI, and PIV were independent risk factors (p=0.001, p<0.001, and p=0.02, respectively). The area under the ROC curve (AUC) values of the SII, SIRI, and PIV were 0.626 (95% confidence interval (CI): 0.553–0.698, p<0.001), 0.571 (95% CI: 0.500–0.642, p=0.032), and 0.568 (95% CI: 0.495–0.641, p=0.040), respectively, and the cutoff values were 2209.66, 3.77, and 1387.825, respectively.

Conclusion

The SII, SIRI, and PIV have potential value in predicting IVIG resistance in patients with KD.
Expanding CXCR4 variant landscape in WHIM syndrome: integrating clinical and functional data for variant interpretation
Authors: Zmajkovicova Katarina , Nykamp Keith , Blair Grace , Yilmaz Melis , Walter Jolan E.
Published: July 2024

Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency disease predominantly caused by gain-of-function variants in the CXCR4 gene that typically results in truncation of the carboxyl terminus of C-X-C chemokine receptor type 4 (CXCR4) leading to impaired leukocyte egress from bone marrow to peripheral blood. Diagnosis of WHIM syndrome continues to be challenging and is often made through clinical observations and/or genetic testing. Detection of a pathogenic CXCR4 variant in an affected individual supports the diagnosis of WHIM syndrome but relies on an appropriate annotation of disease-causing variants. Understanding the genotypic-phenotypic associations in WHIM syndrome has the potential to improve time to diagnosis and guide appropriate clinical management, resulting in a true example of precision medicine. This article provides an overview of the spectrum of CXCR4 variants in WHIM syndrome and summarizes the various lines of clinical and functional evidence that can support interpretation of newly identified variants.
Progress in mitochondrial and omics studies in Alzheimer’s disease research: from molecular mechanisms to therapeutic interventions
Authors: Liao Zuning , Zhang Qiying , Ren Na , Zhao Haiyan , Zheng Xueyan
Published: July 2024

Alzheimer’s disease (Alzheimer’s disease, AD) is a progressive neurological disorder characterized by memory loss and cognitive impairment. It is characterized by the formation of tau protein neurofibrillary tangles and β-amyloid plaques. Recent studies have found that mitochondria in neuronal cells of AD patients exhibit various dysfunctions, including reduced numbers, ultrastructural changes, reduced enzyme activity, and abnormal kinetics. These abnormal mitochondria not only lead to the loss of normal neuronal cell function, but are also a major driver of AD progression. In this review, we will focus on the advances of mitochondria and their multi-omics in AD research, with particular emphasis on how mitochondrial dysfunction in AD drives disease progression. At the same time, we will focus on summarizing how mitochondrial genomics technologies have revealed specific details of these dysfunctions and how therapeutic strategies targeting mitochondria may provide new directions for future AD treatments. By delving into the key mechanisms of mitochondria in AD related to energy metabolism, altered kinetics, regulation of cell death, and dysregulation of calcium-ion homeostasis, and how mitochondrial multi-omics technologies can be utilized to provide us with a better understanding of these processes. In the future, mitochondria-centered therapeutic strategies will be a key idea in the treatment of AD.
Exosome-derived microRNAs: emerging players in vitiligo
Authors: li Wenquan , Pang Yaobin , He Qingying , Song Zongzou , Xie Xin , Zeng Jinhao , Guo Jing
Published: July 2024

Exosome-derived microRNAs (miRNAs) are biomacromolecules and nanoscale extracellular vesicles originating from intracellular compartments that are secreted by most cells into the extracellular space. This review examines the formation and function of exosomal miRNAs in biological information transfer, explores the pathogenesis of vitiligo, and highlights the relationship between exosomal miRNAs and vitiligo. The aim is to deepen the understanding of how exosomal miRNAs influence immune imbalance, oxidative stress damage, melanocyte-keratinocyte interactions, and melanogenesis disorders in the development of vitiligo. This enhanced understanding may contribute to the development of potential diagnostic and therapeutic options for vitiligo.
Insights into the efficient degradation mechanism of extracellular proteases mediated by Purpureocillium lilacinum
Authors: Zhang Xiujun , Yang Yuhong , Liu Li , Sui Xin , Bermudez Ramon Santos , Wang Lushan , He Wenxing , Xu Huilian
Published: July 2024

Protease secretion is crucial for degrading nematode cuticles using nematophagous fungus Purpureocillium lilacinum, but the secretion pattern of protease remains poorly understood. This study aimed to explore the degradation mechanism of proteases by investigating the characteristics of protease secretion under various carbon and nitrogen sources, and different carbon to nitrogen (C:N) ratios in P. lilacinum. The results showed that corn flour as a carbon source and yeast extract as a nitrogen source specifically induced protease secretion in P. lilacinum. P. lilacinum produced significant amounts of gelatinase and casein enzyme at C:N ratios of 10:1, 20:1, and 40:1, indicating that higher C:N ratios were more beneficial for secreting extracellular proteases. Proteomic analysis revealed 14 proteases, including 4 S8 serine endopeptidases and one M28 aminopeptidase. Among four S8 serine peptidases, Alp1 exhibited a high secretion level at C:N ratio less than 5:1, whereas PR1C, PR1D, and P32 displayed higher secretion levels at higher C:N ratios. In addition, the transcription levels of GATA transcription factors were investigated, revealing that Asd-4, A0A179G170, and A0A179HGL4 were more prevalent at a C:N ratio of 40:1. In contrast, the transcription levels of SREP, AreA, and NsdD were higher at lower C:N ratios. The putative regulatory profile of extracellular protease production in P. lilacinum, induced by different C:N ratios, was analyzed. The findings offered insights into the complexity of protease production and aided in the hydrolytic degradation of nematode cuticles.
Puppies as the primary causal animal for human rabies cases: three-year prospective study of human rabies in the Philippines
Authors: Saito Nobuo , Inton Karren L. , Mauhay Jaira D. , Solante Rontgene M. , Guzman Ferdinand D. , Yamada Kentaro , Kamiya Yasuhiko , Saito-Obata Mariko , Quiambao Beatriz P. , Yahiro Takaaki , Kimitsuki Kazunori , Nishizono Akira
Published: July 2024

Introduction

While rabies remains a global concern, detailed studies on human rabies, particularly regarding causal animals and the reasons for not receiving postexposure prophylaxis (PEP), are lacking.

Methods

We conducted a 3-year prospective study (October 2019–September 2022) at the Philippines’ largest rabies referral center. We interviewed patients with suspected rabies and their families. We used LN34 qRT-PCR and rapid fluorescent focus inhibition test on saliva samples. We also compared our findings with two retrospective studies at the same hospital.

Results

We enrolled 151 patients, including 131 with potential rabies exposure. Similar to retrospective studies, the participants were predominantly males (75.5%), adults (76.8%), low-income individuals (91.4%), and rural dwellers (62.3%). The causal animals were mainly dogs (97.0%), with similar incubation periods, clinical symptoms, and a high proportion not receiving vaccines or immunoglobulins (93.2%). Most causal animals were owned by either the patients’ households or their neighbors (60.2%), with a significant proportion being puppies (58.8%). Most patients had knowledge of rabies; however, reasons for not seeking PEP included misconceptions about minor bites not causing rabies (51.3%), beliefs in traditional healers (33.9%), and economic constraints (22.6%). Despite completing the WHO regimen, two PEP failures were observed. LN34 qRT-PCR detected 98 positive cases (sensitivity, 64.9%; 95% CI 56.7–72.5). These strains belong to the Southeast Asia 4 subclade.

Discussion

In conclusion, this study highlights the role of puppies as primary causal animals and the presence of misconceptions that preclude patients from acquiring PEP.
A promising metabolite, 9-aminominocycline, restores the sensitivity of tigecycline against tet(X4)-positive Escherichia coli
Authors: Sun Feifei , Zhang Lin , Ma Xuan , Ali Tariq , Wu Yongning , Li Lin
Published: July 2024

The emergence and widespread of tigecycline resistance undoubtedly poses a serious threat to public health globally. The exploration of combination therapies has become preferred antibacterial strategies to alleviate this global burden. In this study, tigecycline-resistant tet(X4)-positive Escherichia coli were selected for adjuvant screening. Interestingly, 9-aminominocycline (9-AMC), one of the tigecycline metabolites, exhibits synergistic antibacterial activity with tigecycline using checkerboard assay. The efficacy in vitro and in vivo was evaluated, and the synergistic mechanism was further explored. The results suggested that 9-AMC combined with tigecycline could inhibit the growth of antibiotic resistant bacteria, efficiently retard the evolution of tet(X4) gene and narrow the drug mutant selection window. In addition, the combination of tigecycline and 9-AMC could destroy the normal membrane structure of bacteria, inhibit the formation of biofilm, remarkably reduce the level of intracellular ATP level, and accelerate the oxidative damage of bacteria. Furthermore, 9-AMC is more stable in the bind of Tet(X4) inactivating enzyme. The transcriptomics analysis revealed that the genes related to the 9-AMC and tigecycline were mainly enriched in ABC transporters. Collectively, the results reveal the potentiation effects on tigecycline and the probability of 9-AMC as a novel tigecycline adjuvant against tet(X4)-positive Escherichia coli, which provides new insights for adjuvant screening.
Repeating late-phase pseudo-progression in a patient with non-small cell lung cancer treated with long-term nivolumab monotherapy; a case report
Authors: Ebisuda Rikako , Furuya Naoki , Inoue Takeo , Kaneko Shotaro , Numata Yu , Shinozaki Yusuke , Mineshita Masamichi
Published: July 2024

Background

Immune check point inhibitors (ICIs) are standard treatment for patients with non-small cell lung cancer (NSCLC). Nearly a decade has passed since nivolumab was approved by the FDA for NSCLC patients. However, long-term outcomes and clinical features remain unclear for individual cases. Pseudo-progression is a well-known paradoxical radiological response pattern under ICI treatment which occurs when tumor index lesions regress after apparent initial progression. We herein report a unique case of NSCLC with repeating pseudo-progression in late phase treated with nivolumab monotherapy for 8.5 years.

Case presentation

A 56-year-old male diagnosed with Non-sq NSCLC clinical stage IVA, at the left upper lobe primary lesion. The primary lesion was PD-L1 negative with no oncogenic driver mutations. He had multiple pulmonary metastases and a left adrenal gland metastasis, and subsequently, received nivolumab as third-line therapy. After initiation of nivolumab, the lung lesion and adrenal metastasis shrank rapidly; however, the patient experienced three late-phase pseudo-progressions in the mediastinal lymph node (LN). This patient is still receiving nivolumab with no symptoms and PS 0. Acquired resistance should be judged carefully in patients with LN-only oligo-progression to avoid unnecessary local therapies and the misjudgment of treatment.
Safety of immune checkpoint inhibitor rechallenge after severe immune-related adverse events: a retrospective analysis
Authors: Eldani Céline , Kostine Marie , Faure Maxime , Lazaro Estibaliz , Rigothier Claire , Hiriart Jean Baptiste , Teulières Bérénice , Poullenot Florian , Haissaguerre Magalie , Zysman Maeva , Veillon Rémi , Vergnenegre Charlotte , Issa Nahema , Domblides Charlotte , Mary-Prey Sorilla , Beylot-Barry Marie , Pham-Ledard Anne , Dutriaux Caroline , Sole Guilhem , Duval Fanny , Gerard Emilie
Published: July 2024

Immune checkpoint inhibitors (ICIs) present clinicians with the challenge of managing immune-related adverse events (irAEs), which can range from mild to severe due to immune system activation 1. While guidelines recommend discontinuing ICIs for grade 3 partial and all grade 4 irAEs, there is growing interest in rechallenging patients based on oncological outcomes, particularly for cardiovascular and neurological irAEs where data remains scarce 1,2. We retrospectively evaluated the safety of ICI rechallenge following grade 3-4 irAEs, specifically focusing on cardiovascular and neurological events, in patients discussed at our multidisciplinary immunotoxicity assessment board between 2019 and 2021. Fifteen patients were included, with a median time to severe irAE onset of 49 days. Among them, five patients experienced neurological adverse events (NAEs): aseptic meningitis (3), inflammatory polyradiculoneuropathy (1), and ophthalmoplegia (1), while one patient presented with myocarditis. Of the 15 patients retreated with ICIs after initial severe irAEs, 11 (73%) remained free of subsequent irAEs, two (13%) experienced recurrence of the initial irAE, and two (13%) developed new irAEs distinct from the initial event. The median time to event recurrence was 69 days, occurring no earlier than the initial severe irAE. In the subset analysis focusing on severe cardiovascular and neurological irAEs, rechallenge with ICIs was generally well tolerated. However, one patient treated with anti-PD1 experienced a relapse of grade 2 aseptic meningitis. Overall, our findings suggest that rechallenging with ICIs after severe irAEs, including those affecting the cardiovascular and neurological systems, may be safe, particularly after irAE regression and corticosteroid withdrawal.
Fibroblast growth factor receptor signaling in estrogen receptor-positive breast cancer: mechanisms and role in endocrine resistance
Authors: Marin Arnaldo , Morales Fernanda , Walbaum Benjamín
Published: July 2024

Fibroblast Growth Factor Receptors (FGFRs) play a significant role in Estrogen Receptor-positive (ER+) breast cancer by contributing to tumorigenesis and endocrine resistance. This review explores the structure, signaling pathways, and implications of FGFRs, particularly FGFR1, FGFR2, FGFR3, and FGFR4, in ER+ breast cancer. FGFR1 is frequently amplified, especially in aggressive Luminal B-like tumors, and its amplification is associated with poor prognosis and treatment resistance. The co-amplification of FGFR1 with oncogenes like EIF4EBP1 and NSD3 complicates its role as a standalone oncogenic driver. FGFR2 amplification, though less common, is critical in hormone receptor regulation, driving proliferation and treatment resistance. FGFR3 and FGFR4 also contribute to endocrine resistance through various mechanisms, including the activation of alternate signaling pathways like PI3K/AKT/mTOR and RAS/RAF/MEK/ERK. Endocrine resistance remains a major clinical challenge, with around 70% of breast cancers initially hormone receptor positive. Despite the success of CDK 4/6 inhibitors in combination with endocrine therapy (ET), resistance often develops, necessitating new treatment strategies. FGFR inhibitors have shown potential in preclinical studies, but clinical trials have yielded limited success due to off-target toxicities and lack of predictive biomarkers. Current clinical trials, including those evaluating FGFR inhibitors like erdafitinib, lucitanib, and dovitinib, have demonstrated mixed outcomes, underscoring the complexity of FGFR signaling in breast cancer. The interplay between FGFR and other signaling pathways highlights the need for comprehensive molecular profiling and personalized treatment approaches. Future research should focus on identifying robust biomarkers and developing combination therapies to enhance the efficacy of FGFR-targeted treatments. In conclusion, targeting FGFR signaling in ER+ breast cancer presents both challenges and opportunities. A deeper understanding of the molecular mechanisms and resistance pathways is crucial for the successful integration of FGFR inhibitors into clinical practice, aiming to improve outcomes for patients with endocrine-resistant breast cancer.
ECM1 and ANXA1 in urinary extracellular vesicles serve as biomarkers for breast cancer
Authors: Huang Hai , Wan Jingyu , Ao Xudong , Qu Shuang , Jia Meng , Zhao Keyu , Liang Junqing , Zen Ke , Liang Hongwei
Published: July 2024

Objective

Although urinary extracellular vesicles (uEVs) have been extensively studied in various cancers, their involvement in breast cancer (BC) remains largely unexplored. The non-invasive nature of urine as a biofluid and its abundant protein content offer considerable potential for the early detection of breast cancer.

Methods

This study analyzed the proteomic profiles of uEVs from BC patients and healthy controls (HC). The dysregulation of ECM1 and ANXA1 in the uEVs was validated in a larger cohort of 128 BC patients, 25 HC and 25 benign breast nodules (BBN) by chemiluminescence assay (CLIA). The expression levels of ECM1 and ANXA1 were also confirmed in the uEVs of MMTV-PyMT transgenic breast cancer mouse models.

Results

LC-MS/MS analysis identified 571 dysregulated proteins in the uEVs of BC patients. ECM1 and ANXA1 were selected for validation in 128 BC patients, 25 HC and 25 BBN using CLIA, as their fold change showed a significant difference of more than 10 with p-value<0.05. Protein levels of ECM1 and ANXA1 in uEVs were significantly increased in BC patients. In addition, the protein levels of ECM1 and ANXA1 in the uEVs of MMTV-PyMT transgenic mice were observed to increase progressively with the progression of breast cancer.

Conclusion

We developed a simple and purification-free assay platform to isolate uEVs and quantitatively detect ECM1 and ANXA1 in uEVs by WGA-coupled magnetic beads and CLIA. Our results suggest that ECM1 and ANXA1 in uEVs could potentially serve as diagnostic biomarkers for breast cancer.
Unveiling the landscape of pathomics in personalized immunotherapy for lung cancer: a bibliometric analysis
Authors: Yuan Lei , Shen Zhiming , Shan Yibo , Zhu Jianwei , Wang Qi , Lu Yi , Shi Hongcan
Published: July 2024

Background

Pathomics has emerged as a promising biomarker that could facilitate personalized immunotherapy in lung cancer. It is essential to elucidate the global research trends and emerging prospects in this domain.

Methods

The annual distribution, journals, authors, countries, institutions, and keywords of articles published between 2018 and 2023 were visualized and analyzed using CiteSpace and other bibliometric tools.

Results

A total of 109 relevant articles or reviews were included, demonstrating an overall upward trend; The terms “deep learning”, “tumor microenvironment”, “biomarkers”, “image analysis”, “immunotherapy”, and “survival prediction”, etc. are hot keywords in this field.

Conclusion

In future research endeavors, advanced methodologies involving artificial intelligence and pathomics will be deployed for the digital analysis of tumor tissues and the tumor microenvironment in lung cancer patients, leveraging histopathological tissue sections. Through the integration of comprehensive multi-omics data, this strategy aims to enhance the depth of assessment, characterization, and understanding of the tumor microenvironment, thereby elucidating a broader spectrum of tumor features. Consequently, the development of a multimodal fusion model will ensue, enabling precise evaluation of personalized immunotherapy efficacy and prognosis for lung cancer patients, potentially establishing a pivotal frontier in this domain of investigation.
Primary thyroid squamous cell carcinoma diagnosed with 18F-FDG PET/CT: a case report
Authors: Liao Taiping , Long Yongjun , Li Lingxiao , Qi Qinlin , Li Li , Fu Guoxu
Published: July 2024

Primary thyroid squamous cell carcinoma is extremely rare. We report a case of primary thyroid squamous cell carcinoma diagnosed using 18F-FDG PET/CT. The patient presented with left axillary lymphadenopathy as the initial symptom. Fine-needle aspiration of the axillary lymph nodes indicated metastatic squamous cell carcinoma. To identify the primary tumor, the patient underwent an 18F-FDG PET/CT scan, which revealed a mass in the thyroid and multiple enlarged lymph nodes with abnormal FDG uptake. Pathological examination of the axillary lymph nodes and thyroid biopsy confirmed the diagnosis of primary thyroid squamous cell carcinoma with lymph node metastasis.
Laparoscopic-assisted sclerotherapy in pediatric retroperitoneal lymphatic malformations
Authors: Shi Hao , Lv Zhibao , Xu Weijue , Liu Jiangbin , Sheng Qingfeng , Ren Xiang , Chen Zhou
Published: July 2024

Background

Retroperitoneal lymphatic malformations (LMs) are rare. Currently, the treatment of retroperitoneal LMs remains challenging. This study aimed to examine the safety and efficacy of laparoscopic-assisted sclerotherapy for retroperitoneal LMs in pediatric patients.

Methods

We retrospectively reviewed patients treated with laparoscopic-assisted sclerotherapy for retroperitoneal LMs in a single tertiary medical center between July 2020 and February 2023. Doxycycline was prepared into a solution with a concentration of 10 mg/ml for use in sclerotherapy. Demographic data, clinical features, details of management, and outcomes were collected and analyzed.

Results

A total of six patients, comprising three males and three females, were identified. The LMs were categorized into four macrocystic and two mixed-cystic types. The mean age and weight were 52.2 months (range, 11–108 months) and 20 kg (range, 12.5–27.5 kg), respectively. Three patients presented with abdominal pain or distension, while the other three patients were asymptomatic. All six patients underwent a total of eight sclerotherapy sessions. Two patients experienced intra-cystic hemorrhage and required a second sclerotherapy session. Only one patient presented with vomiting after sclerotherapy, which resolved spontaneously. Five patients met the complete response criteria, and one patient met the effective criteria. The mean reduction in lesion size was 92.3% (range, 69.9%–99.6%). No further complications or recurrence were recorded during follow-up.

Conclusion

Laparoscopic-assisted sclerotherapy is a safe and effective approach for treating retroperitoneal LMs. This technique is applicable for both macrocystic and mixed-cystic retroperitoneal LMs.
Knockout of C1q/tumor necrosis factor-related protein-9 aggravates cardiac fibrosis in diabetic mice by regulating YAP-mediated autophagy
Authors: Ruan Shiyan , Li Jun , Lei Shengyun , Zhang Shaomeng , Xu Dan , Zuo Anju , Li Linxi , Guo Yuan
Published: July 2024

Introduction

Diabetic cardiomyopathy (DCM) is predominantly distinguished by impairment in ventricular function and myocardial fibrosis. Previous studies revealed the cardioprotective properties of C1q/tumor necrosis factor-related protein 9 (CTRP9). However, whether CTRP9 affects diabetic myocardial fibrosis and its underlying mechanisms remains unclear.

Methods

We developed a type 1 diabetes (T1DM) model in CTRP9-KO mice via streptozotocin (STZ) induction to examine cardiac function, histopathology, fibrosis extent, Yes-associated protein (YAP) expression, and the expression of markers for autophagy such LC3-II and p62. Additionally, we analyzed the direct impact of CTRP9 on high glucose (HG)-induced transdifferentiation, autophagic activity, and YAP protein levels in cardiac fibroblasts.

Results

In diabetic mice, CTRP9 expression was decreased in the heart. The absence of CTRP9 aggravated cardiac dysfunction and fibrosis in mice with diabetes, alongside increased YAP expression and impaired autophagy. In vitro, HG induced the activation of myocardial fibroblasts, which demonstrated elevated cell proliferation, collagen production, and α-smooth muscle actin (α-SMA) expression. CTRP9 countered these adverse effects by restoring autophagy and reducing YAP protein levels in cardiac fibroblasts. Notably, the protective effects of CTRP9 were negated by the inhibition of autophagy with chloroquine (CQ) or by YAP overexpression through plasmid intervention. Notably, the protective effect of CTRP9 was negated by inhibition of autophagy caused by chloroquine (CQ) or plasmid intervention with YAP overexpression.

Discussion

Our findings suggest that CTRP9 can enhance cardiac function and mitigate cardiac remodeling in DCM through the regulation of YAP-mediated autophagy. CTRP9 holds promise as a potential candidate for pharmacotherapy in managing diabetic cardiac fibrosis.