bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of the intestinal mucosal and cell-mediated response against natural helminth infection in the African catfish Clarias gariepinus
Authors: Abdel-Hakeem Sara Salah , Fadladdin Yousef Abdal Jalil , Khormi Mohsen A. , Abd-El-Hafeez Hanan H.
Published: July 2024

Fish gut is a versatile organ serving as the primary pathway for invasion by pathogens, particularly parasites, playing a crucial role in modulating the intestinal adaptive immune response. This study aimed to investigate the cellular-mediated reaction, mucosal acidity, and the expression of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), and CD68 in the intestines of catfish, Clarias gariepinus, naturally infected with helminths. Forty catfish were collected from the Nile River and examined for intestinal parasites. The intestinal tissues of the control and infected fish were fixed for histochemical and immunohistochemical studies. Two groups of helminths were found: cestodes Tetracampos ciliotheca and Polyonchobothrium clarias, and nematodes Paracamallanus cyathopharynx, with a prevalence rate of 63.63%, 18.0%, and 18.0%, respectively. Our results showed that the infected fish had a statistically significant rise in the activity of immune cells, including mast cells, eosinophil granular cells, and dendritic cells. This correlated with upregulation in the expressions of PCNA, VEGF, and CD68. Histochemical analyses demonstrated a marked increase in acidic mucus production, Sudan black B, and bromophenol mercury blue. This study enriches our understanding of the evolution of vertebrate immunity in combating intestinal parasitic infections and the host’s adaptive responses.
Uncovering novel mechanisms of chitinase-3-like protein 1 in driving inflammation-associated cancers
Authors: Fan Yan , Meng Yuan , Hu Xingwei , Liu Jianhua , Qin Xiaosong
Published: July 2024

Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein that is induced and regulated by multiple factors during inflammation in enteritis, pneumonia, asthma, arthritis, and other diseases. It is associated with the deterioration of the inflammatory environment in tissues with chronic inflammation caused by microbial infection or autoimmune diseases. The expression of CHI3L1 expression is upregulated in several malignant tumors, underscoring the crucial role of chronic inflammation in the initiation and progression of cancer. While the precise mechanism connecting inflammation and cancer is unclear, the involvement of CHI3L1 is involved in chronic inflammation, suggesting its role as a contributing factor to in the link between inflammation and cancer. CHI3L1 can aggravate DNA oxidative damage, induce the cancerous phenotype, promote the development of a tumor inflammatory environment and angiogenesis, inhibit immune cells, and promote cancer cell growth, invasion, and migration. Furthermore, it participates in the initiation of cancer progression and metastasis by binding with transmembrane receptors to mediate intracellular signal transduction. Based on the current research on CHI3L1, we explore introduce the receptors that interact with CHI3L1 along with the signaling pathways that may be triggered during chronic inflammation to enhance tumorigenesis and progression. In the last section of the article, we provide a brief overview of anti-inflammatory therapies that target CHI3L1.
Targeted nanoparticles triggered by plaque microenvironment for atherosclerosis treatment through cascade effects of reactive oxygen species scavenging and anti-inflammation
Authors: Luo Xianghong , Zhang Mengjiao , Dai Waicong , Xiao Xianghao , Li Xinyi , Zhu Yingjian , Shi Xiangyang , Li Zhaojun
Published: July 2024

Inflammatory factors and reactive oxygen species (ROS) are risk factors for atherosclerosis. Many existing therapies use ROS-sensitive delivery systems to alleviate atherosclerosis, which achieved certain efficacy, but cannot eliminate excessive ROS. Moreover, the potential biological safety concerns of carrier materials through chemical synthesis cannot be ignored. Herein, an amphiphilic low molecular weight heparin- lipoic acid conjugate (LMWH-LA) was used as a ROS-sensitive carrier material, which consisted of injectable drug molecules used clinically, avoiding unknown side effects. LMWH-LA and curcumin (Cur) self-assembled to form LLC nanoparticles (LLC NPs) with LMWH as shell and LA/Cur as core, in which LMWH could target P-selectin on plaque endothelial cells and competitively block the migration of monocytes to endothelial cells to inhibit the origin of ROS and inflammatory factors, and LA could be oxidized to trigger hydrophilic-hydrophobic transformation and accelerate the release of Cur. Cur released within plaques further exerted anti-inflammatory and antioxidant effects, thereby suppressing ROS and inflammatory factors. We used ultrasound imaging, pathology and serum analysis to evaluate the therapeutic effect of nanoparticles on atherosclerotic plaques in apoe−/− mice, and the results showed that LLC showed significant anti-atherosclerotic effects. Our finding provided a promising therapeutic nanomedicine for the treatment of atherosclerosis.
PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy
Authors: Du Li , Gong Yao , Zhang Xiaoying , Sun Jide , Gao Fengxia , Shen Meiying , Bai Huili , Yang Tiantian , Cheng Xiaoxue , Li Siqiao , Peng Jian , Liu Zhangling , Ding Shijia , Chen Junman , Cheng Wei
Published: July 2024

Background

PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems.

Results

We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity.

Conclusions

In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors.

Graphical Abstract
Repolarizing neutrophils via MnO2 nanoparticle-activated STING pathway enhances Salmonella-mediated tumor immunotherapy
Authors: Lu Shan , Mi Ze , Liu Peng , Ding Jinsong , Ma Yiran , Yang Jieru , Rong Pengfei , Zhou Wenhu
Published: July 2024

Engineered Salmonella has emerged as a promising microbial immunotherapy against tumors; however, its clinical effectiveness has encountered limitations. In our investigation, we unveil a non-dose-dependent type of behavior regarding Salmonella’s therapeutic impact and reveal the regulatory role of neutrophils in diminishing the efficacy of this. While Salmonella colonization within tumors recruits a substantial neutrophil population, these neutrophils predominantly polarize into the pro-tumor N2 phenotype, elevating PD-L1 expression and fostering an immunosuppressive milieu within the tumor microenvironment. In order to bypass this challenge, we introduce MnO2 nanoparticles engineered to activate the STING pathway. Harnessing the STING pathway to stimulate IFN-β secretion prompts a shift in neutrophil polarization from the N2 to the N1 phenotype. This strategic repolarization remodels the tumor immune microenvironment, making the infiltration and activation of CD8+ T cells possible. Through these orchestrated mechanisms, the combined employment of Salmonella and MnO2 attains the synergistic enhancement of anti-tumor efficacy, achieving the complete inhibition of tumor growth within 20 days and an impressive 80% survival rate within 40 days, with no discernible signs of significant adverse effects. Our study not only unveils the crucial in vivo constraints obstructing microbial immune therapy but also sets out an innovative strategy to augment its efficacy. These findings pave the way for advancements in cell-based immunotherapy centered on leveraging the potential of neutrophils.

Graphical Abstract
HiViPore: a highly viable in-flow compression for a one-step cell mechanoporation in microfluidics to induce a free delivery of nano- macro-cargoes
Authors: Maremonti Maria Isabella , Panzetta Valeria , Netti Paolo Antonio , Causa Filippo
Published: July 2024

Background

Among mechanoporation techniques for intracellular delivery, microfluidic approaches succeed in high delivery efficiency and throughput. However, especially the entry of large cargoes (e.g. DNA origami, mRNAs, organic/inorganic nanoparticles) is currently impaired since it requires large cell membrane pores with the need to apply multi-step processes and high forces, dramatically reducing cell viability.

Results

Here, HiViPore presents as a microfluidic viscoelastic contactless compression for one-step cell mechanoporation to produce large pores while preserving high cell viability. Inducing an increase of curvature at the equatorial region of cells, formation of a pore with a size of ~ 1 μm is obtained. The poration is coupled to an increase of membrane tension, measured as a raised fluorescence lifetime of 12% of a planarizable push-pull fluorescent probe (Flipper-TR) labelling the cell plasma membrane. Importantly, the local disruptions of cell membrane are transient and non-invasive, with a complete recovery of cell integrity and functions in ~ 10 min. As result, HiViPore guarantees cell viability as high as ~ 90%. In such conditions, an endocytic-free diffusion of large nanoparticles is obtained with typical size up to 500 nm and with a delivery efficiency up to 12 times higher than not-treated cells.

Conclusions

The proposed one-step contactless mechanoporation results in an efficient and safe approach for advancing intracellular delivery strategies. In detail, HiViPore solves the issues of low cell viability when multiple steps of poration are required to obtain large pores across the cell plasma membrane. Moreover, the compression uses a versatile, low-cost, biocompatible viscoelastic fluid, thus also optimizing the operational costs. With HiViPore, we aim to propose an easy-to-use microfluidic device to a wide range of users, involved in biomedical research, imaging techniques and nanotechnology for intracellular delivery applications in cell engineering.
Health and disability – a multi-group latent class analysis of the World Health Organization Disability Assessment Schedule 2.0 among those with mental and physical health conditions
Authors: Seet Vanessa , Abdin Edimansyah , Jeyagurunathan Anitha , Chik Tan Sing , Kit Lum Joon , Sing Lee Eng , Verma Swapna , Ker-Chiah Wei , Ng Pamela , Subramaniam Mythily
Published: July 2024

Background

This study aims to identify disability classes among people with schizophrenia spectrum disorder, depression, anxiety or diabetes via the WHODAS 2.0; investigate the invariance of disability patterns among the four diagnostic groups; and examine associations between disability classes and sociodemographic variables.

Methods

Patients seeking treatment for schizophrenia spectrum disorder, depression, anxiety or diabetes (n=1076) were recruited. Latent class analysis was used to identify disability classes based on WHODAS 2.0 responses. Measurement invariance was tested using multi-group latent class analysis. Associations between classes and sociodemographic variables were tested via multinomial logistic regression.

Results

A five-class solution was identified; examination of model invariance showed that the partially constrained five-class model was most appropriate, suggesting that class structure was consistent while class membership differed across diagnostic groups. Finally, significant associations were found between class membership and ethnicity, education level, and employment status.

Conclusions

The results show the feasibility of using the WHODAS 2.0 to identify and compare different disability classes among people with mental or physical conditions and their sociodemographic correlates. Establishing a typology of different disability profiles will help guide research and treatment plans that tackle not just clinical but also functional aspects of living with either a chronic psychiatric or physical condition.
Nomograms to predict tumor regression grade (TRG) and ypTNM staging in patients with locally advanced esophageal cancer receiving neoadjuvant therapy
Authors: Qiu Jianhao , Zhang Zhan , Liu Junjie , Zhao Yue , Li Yongmeng , Tang Zhanpeng , Li Lin , Tian Yu , Tian Hui
Published: July 2024

Background

Neoadjuvant therapy (NT) has increased survival rates for patients with locally advanced esophageal cancer (EC), but estimating the impact of NT treatment prior to surgery is still very difficult.

Methods

A retrospective study of the clinical information of 150 patients with locally advanced EC who got NT at Qilu Hospital of Shandong University between June 2018 and June 2023. Patients were randomized into training and internal validation groups at a 3:1 ratio. Furthermore, an external validation cohort comprised 38 patients who underwent neoadjuvant therapy at Qianfoshan Hospital in the Shandong Province between June 2021 and June 2023. Independent risk factors were identified using univariate and multivariate logistic regression (forward stepwise regression). Predictive models and dynamic web nomograms were developed by integrating these risk factors.

Results

A total of 188 patients with locally advanced EC were enrolled, of whom 118 achieved stage I of neoadjuvant pathologic TNM (ypTNM) after receiving NT and 129 achieved grades 0-1 in the tumor regression grade (TRG). Logistic regression analysis identified five independent predictors of TRG grades 0-1: pulmonary function tests (PFT), prognostic nutritional index (PNI), triglyceride (TG) levels, squamous cell carcinoma antigen (SCC-Ag) levels, and combination immunotherapy. The areas under the receiver operating characteristic (ROC) curves for the training, internal validation, and external validation groups were 0.87, 0.75, and 0.80, respectively. Meanwhile, two independent predictors of stage I of ypTNM were identified: prealbumin (PA) and SCC antigen. The areas under the ROC curves for the training, internal validation, and external validation groups were 0.78, 0.67, and 0.70, respectively. The Hosmer-Lemeshow test for both predictive models showed excellent calibration, with well-fitted calibration curves. Decision curve analysis (DCA) and clinical impact curves (CIC) have demonstrated that nomograms are of clinical utility.

Conclusion

The nomograms performed well in predicting the likelihood of stage I of ypTNM and TRG grade 0-1 after NT in patients with locally advanced EC. It helps thoracic surgeons to predict the sensitivity of patients to NT before surgery, which enables precise treatment of patients with locally advanced EC.
2-Bromo-1,4-Naphthalenedione promotes CD8+ T cell expansion and limits Th1/Th17 to mitigate experimental autoimmune encephalomyelitis
Authors: Yang Cuixia , Ma Yuanchen , Lu Qiying , Qu Yuliang , Li Yuantao , Cheng Shimei , Xiao Chongjun , Chen Jinshuo , Wang Chuangjia , Wang Feng , Xiang Andy Peng , Huang Weijun , Tang Xiaorong , Zheng Haiqing
Published: July 2024

Treating Multiple sclerosis (MS), a well-known immune-mediated disease characterized by axonal demyelination, is challenging due to its complex causes. Naphthalenedione, present in numerous plants, is being explored as a potential medicine for MS due to its immunomodulatory properties. However, its effects on lymphocytes can vary depending on factors such as the specific compound, concentration, and experimental conditions. In this study, we aim to explore the therapeutic potential of 2-bromo-1,4-naphthalenedione (BrQ), a derivative of naphthalenedione, in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and to elucidate its underlying mechanisms. We observed that mice treated with BrQ exhibited reduced severity of EAE symptoms, including lower clinical scores, decreased leukocyte infiltration, and less extensive demyelination in central nervous system. Furthermore, it was noted that BrQ does not directly affect the remyelination process. Through cell-chat analysis based on bulk RNA-seq data, coupled with validation of flow analysis, we discovered that BrQ significantly promotes the expansion of CD8+ T cells and their interactions with other immune cells in peripheral immune system in EAE mice. Subsequent CD8+ T cell depletion experiments confirmed that BrQ alleviates EAE in a CD8+ T cell-dependent manner. Mechanistically, expanded CD8+ cells were found to selectively reduce antigen-specific CD4+ cells and subsequently inhibit Th1 and Th17 cell development in vivo, ultimately leading to relief from EAE. In summary, our findings highlight the crucial role of BrQ in modulating the pathogenesis of MS, suggesting its potential as a novel drug candidate for treating MS and other autoimmune diseases.
Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy
Authors: Wahl Devin , Risen Sydney J. , Osburn Shelby C. , Emge Tobias , Sharma Sadhana , Gilberto Vincenzo S. , Chatterjee Anushree , Nagpal Prashant , Moreno Julie A. , LaRocca Thomas J.
Published: July 2024

Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. In this study, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old (aged 19 months) wildtype mice, and in rTg4510 tau pathology mice (aged 2 months). We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and rTg4510 mice. These effects of NF-κB/NLRP3-targeting Nanoligomers were also associated with reduced glial cell activation and pathology, favorable changes in transcriptome signatures of glia-associated inflammation (reduced) and neuronal health (increased), and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting both NF-κB and NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegeneration.
Influence of virtual reality and task complexity on digital health metrics assessing upper limb function
Authors: Kanzler Christoph M. , Armand Tom , Simovic Leonardo , Sylvester Ramona , Domnik Nadine , Eilfort Antonia M. , Rohner Carola , Gassert Roger , Gonzenbach Roman , Lambercy Olivier
Published: July 2024

Background

Technology-based assessments using 2D virtual reality (VR) environments and goal-directed instrumented tasks can deliver digital health metrics describing upper limb sensorimotor function that are expected to provide sensitive endpoints for clinical studies. Open questions remain about the influence of the VR environment and task complexity on such metrics and their clinimetric properties.

Methods

We aim to investigate the influence of VR and task complexity on the clinimetric properties of digital health metrics describing upper limb function. We relied on the Virtual Peg Insertion Test (VPIT), a haptic VR-based assessment with a virtual manipulation task. To evaluate the influence of VR and task complexity, we designed two novel tasks derived from the VPIT, the VPIT-2H (VR environment with reduced task complexity) and the PPIT (physical task with reduced task complexity). These were administered in an observational longitudinal study with 27 able-bodied participants and 31 participants with multiple sclerosis (pwMS, VPIT and PPIT only) and the value of kinematic and kinetic metrics, their clinimetric properties, and the usability of the assessment tasks were compared.

Results

Intra-participant variability strongly increased with increasing task complexity (coefficient of variation + 56%) and was higher in the VR compared to the physical environment (+ 27%). Surprisingly, this did not translate into significant differences in the metrics’ measurement error and test–retest reliability across task conditions (p > 0.05). Responsiveness to longitudinal changes in pwMS was even significantly higher (effect size + 0.35, p < 0.05) for the VR task with high task complexity compared to the physical instrumented task with low task complexity. Increased inter-participant variability might have compensated for the increased intra-participant variability to maintain good clinimetric properties. No significant influence of task condition on concurrent validity was present in pwMS. Lastly, pwMS rated the PPIT with higher usability than the VPIT (System Usability Scale + 7.5, p < 0.05).

Conclusion

The metrics of both the VR haptic- and physical task-based instrumented assessments showed adequate clinimetric properties. The VR haptic-based assessment may be superior when longitudinally assessing pwMS due to its increased responsiveness. The physical instrumented task may be advantageous for regular clinical use due to its higher usability. These findings highlight that both assessments should be further validated for their ideal use-cases.
Which government policies to create sustainable food systems have the potential to simultaneously address undernutrition, obesity and environmental sustainability?
Authors: Burgaz Celia , Van-Dam Iris , Garton Kelly , Swinburn Boyd A. , Sacks Gary , Asiki Gershim , Claro Rafael , Diouf Adama , Bartoletto Martins Ana Paula , Vandevijvere Stefanie
Published: July 2024

Introduction

A transformation of food systems is urgently needed, given their contribution to three ongoing and interlinked global health pandemics: (1) undernutrition and food insecurity, (2) obesity and non-communicable diseases (NCDs), and (3) climate change and biodiversity loss. As policymakers make decisions that shape food systems, this study aimed to identify and prioritise policies with double- or triple-duty potential to achieve healthier and more environmentally sustainable food systems.

Methods

This study undertook a 4-step methodological approach, including (i) a compilation of international policy recommendations, (ii) an online survey, (iii) four regional workshops with international experts and (iv) a ranking for prioritisation. Policies were identified and prioritised based on their double- or triple-duty potential, synergies and trade-offs. Using participatory and transdisciplinary approaches, policies were identified to have double- or triple-duty potential if they were deemed effective in tackling two or three of the primary outcomes of interest: (1) undernutrition, (2) obesity/NCDs and (3) environmental degradation.

Results

The desk review identified 291 recommendations for governments, which were merged and classified into 46 initially proposed policies. Based on the results from the online survey, 61% of those policies were perceived to have double- or triple-duty potential. During the workshops, 4 potential synergies and 31 trade-offs of these policies were identified. The final list of 44 proposed policies for healthier and more environmentally sustainable food systems created was divided into two main policy domains: ‘food supply chains’ and ‘food environments’. The outcome with the most trade-offs identified was ‘undernutrition’, followed by ‘environmental sustainability’, and ‘obesity/NCDs’. Of the top five expert-ranked food supply chain policies, two were perceived to have triple-duty potential: (a) incentives for crop diversification; (b) support for start-ups, and small- and medium-sized enterprises. For food environments, three of the top five ranked policies had perceived triple-duty potential: (a) affordability of healthier and more sustainable diets; (b) subsidies for healthier and more sustainable foods; (c) restrictions on children's exposure to marketing through all media.

Conclusion

This study identified and prioritised a comprehensive list of double- and triple-duty government policies for creating healthier and more environmentally sustainable food systems. As some proposed policies may have trade-offs across outcomes, they should be carefully contextualised, designed, implemented and monitored.
Association of increasing gross tumor volume dose with tumor volume reduction and local control in fractionated stereotactic radiosurgery for unresected brain metastases
Authors: Kanayama Naoyuki , Ikawa Toshiki , Takano Koji , Arita Hideyuki , Morimoto Masahiro , Hirata Takero , Ogawa Kazuhiko , Teshima Teruki , Konishi Koji
Published: July 2024

Background

Fractionated stereotactic radiosurgery (fSRS) is an important treatment strategy for unresected brain metastases. We previously reported that a good volumetric response 6 months after fSRS can be the first step for local control. Few studies have reported the association between gross tumor volume (GTV) dose, volumetric response, and local control in patients treated with the same number of fractions. Therefore, in this study, we aimed to investigate the GTV dose and volumetric response 6 months after fSRS in five daily fractions and identify the predictive GTV dose for local failure (LF) for unresected brain metastasis.

Methods

This retrospective study included 115 patients with 241 unresected brain metastases treated using fSRS in five daily fractions at our hospital between January 2013 and April 2022. The median prescription dose was 35 Gy (range, 30–35 Gy) in five fractions. The median follow-up time after fSRS was 16 months (range, 7–66 months).

Results

GTV D80 > 42 Gy and GTV D98 > 39 Gy were prognostic factors for over 65% volume reduction (odds ratio, 3.68, p < 0.01; odds ratio, 4.68, p < 0.01, respectively). GTV D80 > 42 Gy was also a prognostic factor for LF (hazard ratio, 0.37; p = 0.01).

Conclusions

GTV D80 > 42 Gy in five fractions led to better volume reduction and local control. The goal of planning an inhomogeneous dose distribution for fSRS in brain metastases may be to increase the GTV D80 and GTV D98. Further studies on inhomogeneous dose distributions are required.
Injectable bone cement cannulated pedicle screw for lumbar degenerative disease in osteoporosis - clinical follow-up of over 5 years
Authors: Li Cong-can , Yang Xiu-lun , Wu Wen-wen , Zhou Rui , Jiang Yi-fan , Xiao Jun , Zhang Yu-Xuan , Song Lei , Dai Fei
Published: July 2024

Objective

The aim of this study is to evaluate the clinical efficacy of injectable cemented hollow pedicle screw (CICPS) in the treatment of osteoporotic lumbar degenerative diseases through a large sample long-term follow-up study. Additionally, we aim to explore the risk factors affecting interbody fusion.

Methods

A total of 98 patients who underwent CICPS for transforaminal lumbar interbody fusion (TLIF) for osteoporotic lumbar degenerative disease from March 2011 to September 2017 were analyzed. X-ray and electronic computed tomography (CT) imaging data were collected during preoperative, postoperative, and follow-up periods. The data included changes in intervertebral space height (ΔH), screw failure, cement leakage (CL), and intervertebral fusion. The patients were divided into two groups based on their fusion status one year after surgery: satisfied group A and dissatisfied group B. Surgical data such as operation time, intraoperative bleeding volume and surgical complications were recorded, and visual analog scale (VAS) and Oswestry disability index (ODI) were used to evaluate the improvement of lumbar and leg pain.

Results

The mean follow-up time was 101.29 months (ranging from 70 to 128 months). A total of 320 CICPS were used, with 26 screws (8.13%) leaking, 3 screws (0.94%) experiencing cement augmentation failure, and 1 screw (0.31%) becoming loose and breaking. The remaining screws were not loose or pulled out. Female gender, decreased bone density, and CL were identified as risk factors affecting interbody fusion (P < 0.05). Early realization of interbody fusion can effectively prevent the loss of intervertebral space height (P < 0.05) and maintain the surgical treatment effect. Both VAS and ODI scores showed significant improvement during the follow-up period (P < 0.05). Binary logistic regression analysis revealed that decreased bone density and cement leakage were risk factors for prolonged interbody fusion.

Conclusions

The results of long-term follow-up indicate that PMMA enhanced CICPS has unique advantages in achieving good clinical efficacy in the treatment of osteoporosis lumbar degenerative diseases. Attention should be paid to identify female gender, severe osteoporosis, and CL as risk factors affecting interbody fusion.
Biomechanical analysis of patient specific cone vs conventional stem in revision total knee arthroplasty
Authors: Piovan Gianluca , Bori Edoardo , Padalino Marika , Pianigiani Silvia , Innocenti Bernardo
Published: July 2024

Background

In revision total knee arthroplasty, addressing significant bone loss often involves the use of cemented or press-fit stems to ensure implant stability and long-term fixation. A possible alternative to stem was recently introduced utilizing custom-made porous metaphyseal cones, designed to reconstruct the missing tibial and femoral geometries. Early clinical and radiological assessments have shown promising results. The objective of this research was to biomechanically evaluate the performances of these custom-made cones.

Methods

The biomechanical study was conducted using a validated finite element model. The bone geometries of a patient (selected for their history of four knee revisions due to infection and periprosthetic fractures, followed by a successful treatment with custom-made 3D-printed metaphyseal cones) were employed for the study. On these bone models, different revision scenarios were simulated and examined biomechanically: (A) custom-made cementless metaphyseal cones; (B) cemented stems; (C) press-fit stems; (D) distal femoral reconstruction with press-fit stem. All the models were analyzed at 0 °and 90 °of flexion, under physiological load conditions simulating daily activities; stress distribution, average Von-Mises stresses and risk of fracture were then analyzed and compared among configurations.

Results

The use of custom-made 3D-printed cones exhibited the most favorable stress distribution in both femoral and tibial bones. Tibial bone stress was evenly distributed in custom-made cone configurations, while stress concentration was observed in distal regions for the other scenarios. Additionally, custom-made cones displayed overall homogeneity and lower stress levels, potentially contributing to limit pain. Symmetrical stress distribution was observed between the lateral and medial proximal tibia in custom-made cone models, whereas other scenarios exhibited uneven stress, particularly in the anterior tibial bone.

Conclusions

The biomechanical analysis of porous custom-made metaphyseal cones in re-revision arthroplasties is in agreement with the positive clinical and radiological outcomes. These findings provide valuable insights into the potential benefits of using custom-made cones, which offer more uniform stress distribution and may contribute to improve patient outcomes in revision TKA procedures. Further studies in this direction are warranted to validate these biomechanical findings.
Current indications and surgical strategies for myocardial revascularization in patients with left ventricular dysfunction: a scoping review
Authors: Moreno-Angarita Alejandro , Peña Diego , de León Juan David Lopez-Ponce , Estacio Mayra , Vila Lidy Paola , Muñoz Maria Isabel , Cadavid-Alvear Eduardo
Published: July 2024

Background

Ischemic cardiomyopathy (ICM) accounts for more than 60% of congestive heart failure cases and is associated with high morbidity and mortality rates. Myocardial revascularization in patients with left ventricular dysfunction (LVD) and a left ventricular ejection fraction (LVEF) ≤35% aims to improve survival and quality of life and reduce complications associated with heart failure and coronary artery disease. The majority of randomized clinical trials have consistently excluded those patients, resulting in evidence primarily derived from observational studies.

Main body

We performed a scoping review using the Arksey and O'Malley methodology in five stages: 1) formulating the research question; 2) locating relevant studies; 3) choosing studies; 4) organizing and extracting data; and 5) compiling, summarizing, and presenting the findings. This literature review covers primary studies and systematic reviews focusing on surgical revascularization strategies in adult patients with ischemic left ventricular dysfunction (LVD) and a left ventricular ejection fraction (LVEF) of 35% or lower. Through an extensive search of Medline and the Cochrane Library, a systematic review was conducted to address three questions regarding myocardial revascularization in these patients. These questions outline the current knowledge on this topic, current surgical strategies (off-pump vs. on-pump), and graft options (including hybrid techniques) utilized for revascularization.

Three independent reviewers (MAE, DP, and AM) applied the inclusion criteria to all the included studies, obtaining the full texts of the most relevant studies. The reviewers subsequently assessed these articles to make the final decision on their inclusion in the review. Out of the initial 385 references, 156 were chosen for a detailed review. After examining the full articles were examined, 134 were found suitable for scoping review.

Conclusion

The literature notes the scarcity of surgical revascularization in LVD patients in randomized studies, with observational data supporting coronary revascularization's benefits. ONCABG is recommended for multivessel disease in LVD with LVEF < 35%, while OPCAB is proposed for older, high-risk patients. Strategies like internal thoracic artery skeletonization harvesting and postoperative glycemic control mitigate risks with BITA in uncontrolled diabetes. Total arterial revascularization maximizes long-term survival, and hybrid revascularization offers advantages like shorter hospital stays and reduced costs for significant LAD lesions.
Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer
Authors: Cheng Weishi , Kang Kai , Zhao Ailin , Wu Yijun
Published: July 2024

Cancer immunotherapies, represented by immune checkpoint inhibitors (ICIs), have reshaped the treatment paradigm for both advanced non-small cell lung cancer and small cell lung cancer. Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are some of the most common and promising targets in ICIs. Compared to ICI monotherapy, which occasionally demonstrates treatment resistance and limited efficacy, the dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 operates at different stages of T cell activation with synergistically enhancing immune responses against cancer cells. This emerging dual therapy heralds a new direction for cancer immunotherapy, which, however, may increase the risk of drug-related adverse reactions while improving efficacy. Previous clinical trials have explored combination therapy strategy of anti-PD-1/PD-L1 and anti-CTLA-4 agents in lung cancer, yet its efficacy remains to be unclear with the inevitable incidence of immune-related adverse events. The recent advent of bispecific antibodies has made this sort of dual targeting more feasible, aiming to alleviate toxicity without compromising efficacy. Thus, this review highlights the role of dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in treating lung cancer, and further elucidates its pre-clinical mechanisms and current advancements in clinical trials. Besides, we also provide novel insights into the potential combinations of dual blockade therapies with other strategies to optimize the future treatment mode for lung cancer.
SLC14A1 and TGF-β signaling: a feedback loop driving EMT and colorectal cancer metachronous liver metastasis
Authors: Zhang Yixun , Yang Yumeng , Qi Xuan , Cui Peng , Kang Yi , Liu Haiyi , Wei Zhigang , Wang Haibo
Published: July 2024

Background

Colorectal cancer (CRC) metachronous liver metastasis is a significant clinical challenge, largely attributable to the late detection and the intricate molecular mechanisms that remain poorly understood. This study aims to elucidate the role of Solute Carrier Family 14 Member 1 (SLC14A1) in the pathogenesis and progression of CRC metachronous liver metastasis.

Methods

We conducted a comprehensive analysis of CRC patient data from The Cancer Genome Atlas and GSE40967 databases, focusing on the differential expression of genes associated with non-metachronous liver metastasis and metachronous liver metastasis. Functional assays, both in vitro and in vivo, were performed to assess the biological impact of SLC14A1 modulation in CRC cells. Gene set enrichment analysis, molecular assays and immunohistochemical analyses on clinical specimens were employed to unravel the underlying mechanisms through which SLC14A1 exerts its effects.

Results

SLC14A1 was identified as a differentially expressed gene, with its overexpression significantly correlating with poor relapse-free and overall survival. Mechanistically, elevated SLC14A1 levels enhanced CRC cell invasiveness and migratory abilities, corroborated by upregulated TGF-β/Smad signaling and Epithelial-Mesenchymal Transition. SLC14A1 interacted with TβRII and stabilized TβRII protein, impeding its Smurf1-mediated K48-linked ubiquitination and degradation, amplifying TGF-β/Smad signaling. Furthermore, TGF-β1 reciprocally elevated SLC14A1 mRNA expression, with Snail identified as a transcriptional regulator, binding downstream of SLC14A1’s transcription start site, establishing a positive feedback loop. Clinically, SLC14A1, phosphorylated Smad2, and Snail were markedly upregulated in CRC patients with metachronous liver metastasis, underscoring their potential as prognostic markers.

Conclusions

Our findings unveil SLC14A1 as a critical regulator in CRC metachronous liver metastasis, providing novel insights into the molecular crosstalk between SLC14A1 and TGF-β/Smad signaling. These discoveries not only enhance our understanding of CRC metachronous liver metastasis pathogenesis, but also highlight SLC14A1 as a promising target for therapeutic intervention and predictive marker.
IL-33 stimulates the anticancer activities of eosinophils through extracellular vesicle-driven reprogramming of tumor cells
Authors: Gambardella Adriana Rosa , Antonucci Caterina , Zanetti Cristiana , Noto Francesco , Andreone Sara , Vacca Davide , Pellerito Valentina , Sicignano Chiara , Parrottino Giuseppe , Tirelli Valentina , Tinari Antonella , Falchi Mario , De Ninno Adele , Businaro Luca , Loffredo Stefania , Varricchi Gilda , Tripodo Claudio , Afferni Claudia , Parolini Isabella , Mattei Fabrizio , Schiavoni Giovanna
Published: July 2024

Immune cell-derived extracellular vesicles (EV) affect tumor progression and hold promise for therapeutic applications. Eosinophils are major effectors in Th2-related pathologies recently implied in cancer. Here, we evaluated the anti-tumor activities of eosinophil-derived EV following activation with the alarmin IL-33. We demonstrate that IL-33-activated mouse and human eosinophils produce higher quantities of EV with respect to eosinophils stimulated with IL-5. Following incorporation of EV from IL-33-activated eosinophils (Eo33-EV), but not EV from IL-5-treated eosinophils (Eo5-EV), mouse and human tumor cells increased the expression of cyclin-dependent kinase inhibitor (CDKI)-related genes resulting in cell cycle arrest in G0/G1, reduced proliferation and inhibited tumor spheroid formation. Moreover, tumor cells incorporating Eo33-EV acquired an epithelial-like phenotype characterized by E-Cadherin up-regulation, N-Cadherin downregulation, reduced cell elongation and migratory extent in vitro, and impaired capacity to metastasize to lungs when injected in syngeneic mice. RNA sequencing revealed distinct mRNA signatures in Eo33-EV and Eo5-EV with increased presence of tumor suppressor genes and enrichment in pathways related to epithelial phenotypes and negative regulation of cellular processes in Eo33-EV compared to Eo5-EV. Our studies underscore novel IL-33-stimulated anticancer activities of eosinophils through EV-mediated reprogramming of tumor cells opening perspectives on the use of eosinophil-derived EV in cancer therapy.
Unveiling G-protein coupled receptors as potential targets for ovarian cancer nanomedicines: from RNA sequencing data analysis to in vitro validation
Authors: Khetan Riya , Eldi Preethi , Lokman Noor A. , Ricciardelli Carmela , Oehler Martin K. , Blencowe Anton , Garg Sanjay , Pillman Katherine , Albrecht Hugo
Published: July 2024

Genetic heterogeneity in ovarian cancer indicates the need for personalised treatment approaches. Currently, very few G-protein coupled receptors (GPCRs) have been investigated for active targeting with nanomedicines such as antibody-conjugated drugs and drug-loaded nanoparticles, highlighting a neglected potential to develop personalised treatment. To address the genetic heterogeneity of ovarian cancer, a future personalised approach could include the identification of unique GPCRs expressed in cancer biopsies, matched with personalised GPCR-targeted nanomedicines, for the delivery of lethal drugs to tumour tissue before, during and after surgery. Here we report on the systematic analysis of public ribonucleic acid-sequencing (RNA-seq) gene expression data, which led to prioritisation of 13 GPCRs as candidates with frequent overexpression in ovarian cancer tissues. Subsequently, primary ovarian cancer cells derived from ascites and ovarian cancer cell lines were used to confirm frequent gene expression for the selected GPCRs. However, the expression levels showed high variability within our selection of samples, therefore, supporting and emphasising the need for the future development of case-to-case personalised targeting approaches.
Prevalence of delivery mode in an Italian nationwide cohort with celiac disease: a SIGENP multicenter retrospective study (the CD-deliver-IT)
Authors: Iorfida Donatella , Valitutti Francesco , Vestri Annarita , D’Adamo Grazia , Passaro Tiziana , Crocco Marco , Malerba Federica , Monzani Alice , Rabbone Ivana , Pensabene Licia , Giancotti Laura , Graziano Francesco , Citrano Michele , Ferretti Francesca , Trovato Chiara Maria , Pacenza Caterina , Iasevoli Mario , Banzato Claudia , Lubrano Riccardo , Montuori Monica ,   the “Food-induced disease” study group of SIGENP, Principessa Luigi , D’Angelo Elisa , Malamisura Basilio , Calvi Angela , Zampatti Noemi , Montafia Ilaria , Diamanti Antonella , Pisano Pasquale
Published: July 2024

Background

Studies have indicated an association between cesarean section (CS), especially elective CS, and an increased risk of celiac disease (CD), but the conclusions of other studies are contradictory. The primary aim of this study (CD-deliver-IT) was to evaluate the rate of CS in a large population of CD patients throughout Italy. 

Methods

This national multicenter retrospective study was conducted between December 2020 and November 2021. The coordinating center was the Pediatric Gastroenterology and Liver Unit of Policlinico Umberto I, Sapienza, University of Rome, Lazio, Italy. Eleven other referral centers for CD have participated to the study. Each center has collected data on mode of delivery and perinatal period of all CD patients referring to the center in the last 40 years.

Results

Out of 3,259 CD patients recruited in different Italian regions, data on the mode of delivery were obtained from 3,234. One thousand nine hundred forty-one (1,941) patients (60%) were born vaginally and 1,293 (40%) by CS (8.3% emergency CS, 30.1% planned CS, 1.5% undefined CS). A statistically significant difference was found comparing median age at time of CD diagnosis of patients who were born by emergency CS (4 years, CI 95% 3.40–4.59), planned CS (7 years, CI 95% 6.02–7.97) and vaginal delivery (6 years, CI 95% 5.62–6.37) (log rank p < 0.0001).

Conclusions

This is the first Italian multicenter study aiming at evaluating the rate of CS in a large population of CD patients through Italy. The CS rate found in our CD patients is higher than rates reported in the general population over the last 40 years and emergency CS seems to be associated with an earlier onset of CD compared to vaginal delivery or elective CS in our large nationwide retrospective cohort. This suggests a potential role of the mode of delivery on the risk of developing CD and on its age of onset, but it is more likely that it works in concert with other perinatal factors. Further prospective studies on other perinatal factors potentially influencing gut microbiota are awaited in order to address heavy conflicting evidence reaming in this research field.