bluuebunny/crossref_metadata_2025 huggingface dataset:
Headache in long COVID as disabling condition: A clinical approach
Authors: Rodrigues Arthur Nascimento , Dias Apio Ricardo Nazareth , Paranhos Alna Carolina Mendes , Silva Camilla Costa , Bastos Thalita da Rocha , Brito Bárbara Barros de , da Silva Nívia Monteiro , de Sousa Emanuel de Jesus Soares , Quaresma Juarez Antônio Simões , Falcão Luiz Fábio Magno
Published: March 2023

Background and purpose

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can exacerbate previous headache disorders or change the type of pain experienced from headaches. This study aimed to investigate the clinical features of Long COVID headaches.

Method

This was a cross-sectional, descriptive, and analytical observational study that included 102 patients (with previous headache, n = 50; without previous headache, n = 52) with long COVID and headache complaints. The Migraine Disability Assessment Test and Visual Analog Pain Scale were used to collect participants' headache data according to a standardized protocol.

Results

The patients in this study who reported experiencing headaches before COVID-19 had longer headache duration in the long COVID phase than that in the pre-long COVID phase (p = 0.031), exhibited partial improvement in headache symptoms with analgesics (p = 0.045), and had a duration of long COVID of <1 year (p = 0.030). Patients with moderate or severe disability and those classified as having severe headaches in the long COVID phase were highly likely to develop chronic headaches. Hospital admission [odds ratio (OR) = 3.0082; 95% confidence interval (95% CI): 1.10–8.26], back pain (OR = 4.0017; 95% CI: 1.13–14.17), insomnia (OR = 3.1339; 95% CI: 1.39–7.06), and paraesthesia (OR = 2.7600; 95% CI: 1.20–6.33) were associated with headache in these patients.

Conclusion

Headache is a disabling condition in patients with long COVID-19, exacerbating the conditions of those with headaches prior to contracting COVID-19.
Afterload reduction after non-invasive vagus nerve stimulation in acute heart failure
Authors: Nagai Michiaki , Dote Keigo , Kato Masaya , Sasaki Shota , Oda Noboru , Förster Carola Y.
Published: March 2023

Introduction

While central blood pressure (BP) has been recognized as a major indicator of left ventricular (LV) afterload, the reduction of central pressure decreases LV afterload and may prevent heart failure (HF) decompensation. Non-invasive transcutaneous vagus nerve stimulation (tVNS) was shown to improve cardiac function in HF patients. In this study, the relationship between active tVNS and reduction of central BP was investigated in patients with acute HF (AHF).

Methods

The 22 patients hospitalized for AHF after initial stabilization (median 80 yrs, males 60%) were randomly assigned to active or sham group. For 1 h daily over 5 days, low-level transcutaneous electrical stimulation (LLTS) (20 Hz, 1 mA) was performed after attaching an ear clip to the tragus (active group) or the earlobe (sham control group). Before and after stimulation, central aortic systolic pressure (CASP), brachial systolic BP (SBP), diastolic BP (DBP) as well as heart rate (HR) were noninvasively measured.

Results

No significant differences in baseline characteristics were observed between the active and sham groups. In the active group, CASP, SBP, DBP, and HR each decreased significantly after stimulation (all p < 0.05), whereas in the sham group, CASP, SBP, DBP, and HR each increased significantly after stimulation (all p < 0.05). All the changes in CASP, SBP, DBP and HR before and after stimulation were also significantly different between active and sham groups (all p < 0.01). There were no device-related side effects.

Conclusion

In this study, the left tragus tVNS resulted in an acute afterload reduction in the elderly AHF patients. Non-invasive LLTS may be useful and safe for reducing afterload in AHF.

Clinical trial registration

ClinicalTrials.gov, identifier UMIN000044121.
Abnormal metabolic connectivity in default mode network of right temporal lobe epilepsy
Authors: Wang Xiaoyang , Lin Dandan , Zhao Chunlei , Li Hui , Fu Liyuan , Huang Zhifeng , Xu Shangwen
Published: March 2023

Aims

Temporal lobe epilepsy (TLE) is a common neurological disorder associated with the dysfunction of the default mode network (DMN). Metabolic connectivity measured by 18F-fluorodeoxyglucose Positron Emission Computed Tomography (18F-FDG PET) has been widely used to assess cumulative energy consumption and provide valuable insights into the pathophysiology of TLE. However, the metabolic connectivity mechanism of DMN in TLE is far from fully elucidated. The present study investigated the metabolic connectivity mechanism of DMN in TLE using 18F-FDG PET.

Method

Participants included 40 TLE patients and 41 health controls (HC) who were age- and gender-matched. A weighted undirected metabolic network of each group was constructed based on 14 primary volumes of interest (VOIs) in the DMN, in which Pearson’s correlation coefficients between each pair-wise of the VOIs were calculated in an inter-subject manner. Graph theoretic analysis was then performed to analyze both global (global efficiency and the characteristic path length) and regional (nodal efficiency and degree centrality) network properties.

Results

Metabolic connectivity in DMN showed that regionally networks changed in the TLE group, including bilateral posterior cingulate gyrus, right inferior parietal gyrus, right angular gyrus, and left precuneus. Besides, significantly decreased (P < 0.05, FDR corrected) metabolic connections of DMN in the TLE group were revealed, containing bilateral hippocampus, bilateral posterior cingulate gyrus, bilateral angular gyrus, right medial of superior frontal gyrus, and left inferior parietal gyrus.

Conclusion

Taken together, the present study demonstrated the abnormal metabolic connectivity in DMN of TLE, which might provide further insights into the understanding the dysfunction mechanism and promote the treatment for TLE patients.
Multifaceted microglia during brain development: Models and tools
Authors: Bridlance Cécile , Thion Morgane Sonia
Published: March 2023

Microglia, the brain resident macrophages, are multifaceted glial cells that belong to the central nervous and immune systems. As part of the immune system, they mediate innate immune responses, regulate brain homeostasis and protect the brain in response to inflammation or injury. At the same time, they can perform a wide array of cellular functions that relate to the normal functioning of the brain. Importantly, microglia are key actors of brain development. Indeed, these early brain invaders originate outside of the central nervous system from yolk sac myeloid progenitors, and migrate into the neural folds during early embryogenesis. Before the generation of oligodendrocytes and astrocytes, microglia thus occupy a unique position, constituting the main glial population during early development and participating in a wide array of embryonic and postnatal processes. During this developmental time window, microglia display remarkable features, being highly heterogeneous in time, space, morphology and transcriptional states. Although tremendous progress has been made in our understanding of their ontogeny and roles, there are several limitations for the investigation of specific microglial functions as well as their heterogeneity during development. This review summarizes the current murine tools and models used in the field to study the development of these peculiar cells. In particular, we focus on the methodologies used to label and deplete microglia, monitor their behavior through live-imaging and also discuss the progress currently being made by the community to unravel microglial functions in brain development and disorders.
Revealing the three-dimensional murine brain microstructure by contrast-enhanced computed tomography
Authors: Balcaen Tim , Piens Catherine , Mwema Ariane , Chourrout Matthieu , Vandebroek Laurens , Des Rieux Anne , Chauveau Fabien , De Borggraeve Wim M. , Hoffmann Delia , Kerckhofs Greet
Published: March 2023

To improve our understanding of the brain microstructure, high-resolution 3D imaging is used to complement classical 2D histological assessment techniques. X-ray computed tomography allows high-resolution 3D imaging, but requires methods for enhancing contrast of soft tissues. Applying contrast-enhancing staining agents (CESAs) ameliorates the X-ray attenuating properties of soft tissue constituents and is referred to as contrast-enhanced computed tomography (CECT). Despite the large number of chemical compounds that have successfully been applied as CESAs for imaging brain, they are often toxic for the researcher, destructive for the tissue and without proper characterization of affinity mechanisms. We evaluated two sets of chemically related CESAs (organic, iodinated: Hexabrix and CA4+ and inorganic polyoxometalates: 1:2 hafnium-substituted Wells-Dawson phosphotungstate and Preyssler anion), for CECT imaging of healthy murine hemispheres. We then selected the CESA (Hexabrix) that provided the highest contrast between gray and white matter and applied it to a cuprizone-induced demyelination model. Differences in the penetration rate, effect on tissue integrity and affinity for tissue constituents have been observed for the evaluated CESAs. Cuprizone-induced demyelination could be visualized and quantified after Hexabrix staining. Four new non-toxic and non-destructive CESAs to the field of brain CECT imaging were introduced. The added value of CECT was shown by successfully applying it to a cuprizone-induced demyelination model. This research will prove to be crucial for further development of CESAs for ex vivo brain CECT and 3D histopathology.
Attentional capture by fearful faces requires consciousness and is modulated by task-relevancy: A dot-probe EEG study
Authors: Qiu Zeguo , Jiang Jiaqin , Becker Stefanie I. , Pegna Alan J.
Published: March 2023

In the current EEG study, we used a dot-probe task in conjunction with backward masking to examine the neural activity underlying awareness and spatial processing of fearful faces and the neural processes for subsequent cued spatial targets. We presented face images under different viewing conditions (subliminal and supraliminal) and manipulated the relation between a fearful face in the pair and a subsequent target. Our mass univariate analysis showed that fearful faces elicit the N2-posterior-contralateral, indexing spatial attention capture, only when they are presented supraliminally. Consistent with this, the multivariate pattern analysis revealed a successful decoding of the location of the fearful face only in the supraliminal viewing condition. Additionally, the spatial attention capture by fearful faces modulated the processing of subsequent lateralised targets that were spatially congruent with the fearful face, in both behavioural and electrophysiological data. There was no evidence for nonconscious processing of the fearful faces in the current paradigm. We conclude that spatial attentional capture by fearful faces requires visual awareness and it is modulated by top-down task demands.
Characteristics of culprit intracranial plaque without substantial stenosis in ischemic stroke using three-dimensional high-resolution vessel wall magnetic resonance imaging
Authors: Tian Xia , Shi Zhang , Wang Zhen , Xu Bing , Peng Wen-Jia , Zhang Xue-Feng , Liu Qi , Chen Shi-Yue , Tian Bing , Lu Jian-Ping , Shao Cheng-Wei
Published: March 2023

Background and aims

We aim to analyze the difference in quantitative features between culprit and non-culprit intracranial plaque without substantial stenosis using three-dimensional high-resolution vessel wall MRI (3D hr-vw-MRI).

Methods

The patients with cerebral ischemic symptoms of the unilateral anterior circulation were recruited who had non-stenotic intracranial atherosclerosis (<50%) confirmed by computed tomographic angiographic (CTA) or magnetic resonance angiography (MRA). All patients underwent 3D hr-vw MRI within 1 month after symptom onset. 3D hr-vw-MRI characteristics, including wall thickness, plaque burden, enhancement ratio, plaque volume and intraplaque hemorrhage, and histogram features were analyzed based on T2-, precontrast T1-, and post-contrast T1-weighted images. Univariate and multivariate logistic regression analysis were used to identify key determinates differentiating culprit and non-culprit plaques and to calculate the odds ratios (ORs) with 95% confidence intervals (CIs).

Results

A total of 150 plaques were identified, of which 133 plaques (97 culprit and 36 non-culprit) were in the middle cerebral artery, three plaques (all culprit) were in the anterior cerebral artery (ACA) and 14 (11 culprit and three non-culprit) were in the internal carotid artery (ICA). Of all the quantitative parameters analyzed, plaque volume, maximum wall thickness, minimum wall thickness, plaque burden, enhancement ratio, coefficient of variation of the most stenotic site, enhancement ratio of whole culprit plaque in culprit plaques were significantly higher than those in non-culprit plaques. Multivariate logistic regression analysis found that plaque volume [OR, 1.527 (95% CI, 1.231–1.894); P < 0.001] and enhancement ratio of whole plaque [OR, 1.095 (95% CI, 1.021–1.175); P = 0.011] were significantly associated with culprit plaque. The combination of the two features obtained a better diagnostic efficacy for culprit plaque with sensitivity and specificity (0.910 and 0.897, respectively) than each of the two parameters alone.

Conclusion

3D hr-vw MRI features of intracranial atherosclerotic plaques provided potential values over prediction of ischemic stroke patients with non-stenotic arteries. The plaque volume and enhancement ratio of whole plaque of stenosis site were found to be effective predictive parameters.
Exploring molecular signatures related to the mechanism of aging in different brain regions by integrated bioinformatics
Authors: Su Xie , Xie Lu , Li Jing , Tian Xinyue , Lin Bing , Chen Menghua
Published: March 2023

The mechanism of brain aging is not fully understood. Few studies have attempted to identify molecular changes using bioinformatics at the subregional level in the aging brain. This study aimed to identify the molecular signatures and key genes involved in aging, depending on the brain region. Differentially expressed genes (DEGs) associated with aging of the cerebral cortex (CX), hippocampus (HC), and cerebellum (CB) were identified based on five datasets from the Gene Expression Omnibus (GEO). The molecular signatures of aging were explored using functional and pathway analyses. Hub genes of each brain region were determined by protein–protein interaction network analysis, and commonly expressed DEGs (co-DEGs) were also found. Gene–microRNAs (miRNAs) and gene–disease interactions were constructed using online databases. The expression levels and regional specificity of the hub genes and co-DEGs were validated using animal experiments. In total, 32, 293, and 141 DEGs were identified in aging CX, HC, and CB, respectively. Enrichment analysis indicated molecular changes related to leukocyte invasion, abnormal neurotransmission, and impaired neurogenesis due to inflammation as the major signatures of the CX, HC, and CB. Itgax is a hub gene of cortical aging. Zfp51 and Zfp62 were identified as hub genes involved in hippocampal aging. Itgax and Cxcl10 were identified as hub genes involved in cerebellar aging. S100a8 was the only co-DEG in all three regions. In addition, a series of molecular changes associated with inflammation was observed in all three brain regions. Several miRNAs interact with hub genes and S100a8. The change in gene levels was further validated in an animal experiment. Only the upregulation of Zfp51 and Zfp62 was restricted to the HC. The molecular signatures of aging exhibit regional differences in the brain and seem to be closely related to neuroinflammation. Itgax, Zfp51, Zfp62, Cxcl10, and S100a8 may be key genes and potential targets for the prevention of brain aging.
A longitudinal assessment of appetite loss and nutritional care among postoperative patients in Vietnam
Authors: Nguyen Tu Huu , Ta Nguyet Thi , Dang Anh Kim , Nguyen Tham Thi , Dam Vu Anh Trong , Latkin Carl A. , Ho Cyrus S. H. , Ho Roger C. M.
Published: March 2023

Background

Post-operative appetite loss is an important complication affecting surgical outcomes. It has been estimated that nearly 60% of patients having gastrointestinal or major elective surgeries suffer from malnutrition. Appetite refers to the physical desire for food appetite, and losing appetite after surgery may result in a decrease in body weight, impairment of intestinal absorption and eventually, malnutrition among postoperative patients. This study aims to assess appetite status and other relevant factors among abdominal postoperative patients in Vietnam.

Methods

A cross-sectional study was conducted on 169 abdominal postoperative patients from June 1st to August 30th, 2016 at Hanoi Medical University Hospital, Hanoi, Vietnam. Appetite score was computed by using the Council on Nutrition Appetite Questionnaire (CNAQ). This study used GEE to account for the potential correlation of outcomes of the longitudinal assessment, assuming an independent correlation structure.

Results

The primary and secondary outcome measures: highest average appetite score was recorded in the preoperative day and the score declined throughout seven-day duration. Patients who were female, under general anesthetics and being under open surgery tended to get lower appetite scores. The majority of patients had moderate to good appetite in both the preoperative day and seven days post-operation.

Conclusion

Women should receive more care and help in regaining their appetite after surgery. Treatment for appetite loss through non-pharmaceutical measures should be prioritized. Interventions that increase the appetite of patients after abdominal surgery should be targeted on patients being under general anesthetic as well as open surgery and be undertaken with caution.
Association of prognostic nutritional index with risk of contrast induced nephropathy: A meta-analysis
Authors: Chang Wei-Ting , Sun Cheuk-Kwan , Wu Jheng-Yan , Huang Po-Yu , Liu Ting-Hui , Chang Ying-Jen , Lin Yao-Tsung , Kang Fu-Chi , Hung Kuo-Chuan
Published: March 2023

Background

Although prognostic nutritional index (PNI) has been frequently applied in patients with malignancy or those during postoperative recovery, whether it is also an optimal indicator of the risk of contrast-induced nephropathy (CIN) in patients receiving coronary angiography remains uncertain. This meta-analysis aimed at investigating the clinical association of PNI with the risk of CIN in patients receiving coronary angiography or percutaneous coronary intervention.

Methods

Embase, Medline, Cochrane Library, and Google scholar were searched for studies until January 2023. The relationship between CIN risk and PNI (i.e., low vs. high) (primary outcome) as well as other variables (secondary outcomes) were analyzed using a random-effects model.

Results

Overall, 10 observational studies with 17,590 patients (pooled incidence of CIN: 18%) were eligible for analysis. There was a higher risk of CIN in patients with a low PNI compared to those with a high PNI [odd ratio (OR) = 3.362, 95% confidence interval (CI): 2.054 to 5.505, p < 0.0001, I2 = 89.6%, seven studies, 12,972 patients, certainty of evidence: very low]. Consistently, a lower PNI was noted in patients with CIN compared to those without (Mean difference = −5.1, 95% CI: −6.87 to −3.33, p < 0.00001, I2 = 96%, eight studies, 15,516 patients, certainty of evidence: very low). Other risks of CIN included diabetes and hypertension, while male gender and the use of statins were associated with a lower risk of CIN. Patients with CIN were older, had a higher creatinine level, and received a higher contrast volume compared to those without. On the other hand, pre-procedural albumin, estimated glomerular filtration rate, ejection fraction, hemoglobin, lymphocyte ratio were found to be lower in patients with CIN than in those without.

Conclusion

This meta-analysis highlighted an inverse association of PNI with the risk of CIN, which required further studies for verification.

Systematic review registration

[https://www.crd.york.ac.uk/prospero/], identifier [CRD42023389185].
Machine learning driven prediction of cerebrospinal fluid rhinorrhoea following endonasal skull base surgery: A multicentre prospective observational study
Authors:   CRANIAL Consortium
Published: March 2023

Background

Cerebrospinal fluid rhinorrhoea (CSFR) is a common complication following endonasal skull base surgery, a technique that is fundamental to the treatment of pituitary adenomas and many other skull base tumours. The CRANIAL study explored CSFR incidence and related risk factors, particularly skull base repair techniques, via a multicentre prospective observational study. We sought to use machine learning to leverage this complex multicentre dataset for CSFR prediction and risk factor analysis.

Methods

A dataset of 865 cases - 725 transsphenoidal approach (TSA) and 140 expanded endonasal approach (EEA) - with cerebrospinal fluid rhinorrhoea as the primary outcome, was used. Relevant variables were extracted from the data, and prediction variables were divided into two categories, preoperative risk factors; and repair techniques, with 6 and 11 variables respectively. Three types of machine learning models were developed in order to predict CSFR: logistic regression (LR); decision tree (DT); and neural network (NN). Models were validated using 5-fold cross-validation, compared via their area under the curve (AUC) evaluation metric, and key prediction variables were identified using their Shapley additive explanations (SHAP) score.

Results

CSFR rates were 3.9% (28/725) for the transsphenoidal approach and 7.1% (10/140) for the expanded endonasal approach. NNs outperformed LR and DT for CSFR prediction, with a mean AUC of 0.80 (0.70-0.90) for TSA and 0.78 (0.60-0.96) for EEA, when all risk factor and intraoperative repair data were integrated into the model. The presence of intraoperative CSF leak was the most prominent risk factor for CSFR. Elevated BMI and revision surgery were also associated with CSFR for the transsphenoidal approach. CSF diversion and gasket sealing appear to be strong predictors of the absence of CSFR for both approaches.

Conclusion

Neural networks are effective at predicting CSFR and uncovering key CSFR predictors in patients following endonasal skull base surgery, outperforming traditional statistical methods. These models will be improved further with larger and more granular datasets, improved NN architecture, and external validation. In the future, such predictive models could be used to assist surgical decision-making and support more individualised patient counselling.
The state of cancer research in fragile and conflict-affected settings in the Middle East and North Africa Region: A bibliometric analysis
Authors: Sater Zahi Abdul , Farhat Theresa , Elsayed Mohamed N. , Youssef Yara , Husain Marium , Kaddoura Malak , Jaber Lubna , Mukherji Deborah , Taher Ali
Published: March 2023

Background

Cancer represents a disproportionate burden in LMICs, especially conflict-affected countries in the MENA region. Research output on cancer fails to match the growing burden in the region. This bibliometric study aims to examine the status and trends of cancer research in fragile and conflict-affected settings in the MENA region from 2000 to 2021, while also incorporating economic and demographic indicators as additional factors of analysis.

Methods

The Web of Science databases were searched for publications related to cancer research in Iraq, Lebanon, Libya, Palestine, Syria, and Yemen from January 1, 2000, to December 31, 2021. The retrieved publications were screened based on preset eligibility criteria and the final list was analyzed using the Bibliometrix Package in R to generate the annual scientific production and citations, journals, institutions, authors, collaborations, keywords, and title co-occurrence. Each country’s annual scientific production was analyzed against its annual GDP per capita.

Results

A total of 4,280 documents met the inclusion criteria in this research. The annual number of publications revealed a significant increase over the past 20 years. These publications were mostly published in international journals that had impact factors rated in the 3rd or 4th quartiles. The overall contribution of researchers from Fragile and Conflict-Affected Settings (FCS) to cancer research was 6.5% of the MENA cancer research productivity, despite comprising around 23% of the total MENA region’s population. Lebanon had the highest publication productivity at the country level, followed by Iraq and Syria. GDP per capita was not significantly correlated with cancer research across the countries under investigation. At the institutional level, the American University of Beirut was the most prolific institution and had the highest number of collaborations and the widest range of cooperative partners. Most first authors were male researchers. There is an interest in cancer expression, prevalence, diagnosis, and management in terms of commonly researched topics.

Conclusion

This study underscores the need for a concerted effort to improve cancer research outcomes in FCS, which can be achieved through targeted research, increased investment in research infrastructure and capacity-building initiatives, and greater regional and global collaboration.
Immunotherapy combined with rh-endostatin improved clinical outcomes over immunotherapy plus chemotherapy for second-line treatment of advanced NSCLC
Authors: Huang Hongxiang , Zhong Peiyuan , Zhu Xie , Fu Silv , Li Siling , Peng Sujuan , Liu Yangyang , Lu Zhihui , Chen Li
Published: March 2023

Background

Despite the fact that numerous clinical and preclinical studies have demonstrated the synergistic effects of combining antiangiogenic or chemotherapy with immunotherapy, no data have been found to indicate that combination therapy is more effective and safer as second-line therapy.

Methods

We retrospectively compared the effectiveness and safety of ICIs plus rh-endostatin to ICIs plus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). The evaluation indicators of this study were progression-free survival (PFS), safety profile, objective response rate (ORR), disease control rate (DCR), and 1-year overall survival (OS).

Results

The median PFS with immunotherapy plus rh-endostatin (IE) was 7.10 months (95% CI, 4.64 to 9.56) versus 5.13 months (95% CI, 4.29 to 5.97) with immunotherapy plus chemotherapy (IC) (HR, 0.56; 95%CI, 0.33 to 0.95). Treatment-related adverse events of grade 3 or 4 occurred in 7.5% of the IE group versus 25.0% of the IC group. The ORR in the IE group was 35.0% versus 20.8% in the IC group (P = 0.137), and the DCR in the IE group was 92.5% versus 77.1% in the IC group (P = 0.049). The 1-year OS rate for the IE group was 69.4%, which was higher than the 61.4% of the IC group.

Conclusion

Our study showed that ICI therapy combined with endostatin therapy exhibits high efficacy and safety, suggesting that such a combination might be a viable treatment option for patients with pre-treated NSCLC in the future.
Extracellular vesicles secreted from bone metastatic renal cell carcinoma promote angiogenesis and endothelial gap formation in bone marrow in a time-dependent manner in a preclinical mouse model
Authors: Takeda Masashi , Sakamoto Hiromasa , Shibasaki Noboru , Fukui Tomohiro , Magaribuchi Toshihiro , Sumiyoshi Takayuki , Utsunomiya Noriaki , Sawada Atsuro , Goto Takayuki , Kobayashi Takashi , Ueda Koji , Yamasaki Toshinari , Ogawa Osamu , Akamatsu Shusuke
Published: March 2023

Introduction

Bone is a major metastatic site of renal cell carcinoma (RCC). Recently, it is well recognized that bone metastatic tumor cells remodel bone marrow vasculature. However, the precise mechanism underlying cell-cell communication between bone metastatic RCC and the cells in bone marrow remains unknown. Extracellular vesicles (EVs) reportedly play crucial roles in intercellular communication between metastatic tumor cells and bone marrow. Therefore, we conducted the current study to clarify the histological alteration in vascular endothelium in bone marrow induced by EVs secreted from bone metastatic RCC cells as well as association between angiogenesis in bone marrow and bone metastasis formation.

Materials and methods

We established a bone metastatic RCC cell line (786-O BM) by in vivo selection and observed phenotypic changes in tissues when EVs were intravenously injected into immunodeficient mice. Proteomic analysis was performed to identify the protein cargo of EVs that could contribute to histological changes in bone. Tissue exudative EVs (Te-EVs) from cancer tissues of patients with bone metastatic RCC (BM-EV) and those with locally advanced disease (LA-EV) were compared for in vitro function and protein cargo.

Results

Treatment of mice with EVs from 786-O BM promoted angiogenesis in the bone marrow in a time-dependent manner and increased the gaps of capillary endothelium. 786-O BM EVs also promoted tube formation in vitro. Proteomic analysis of EVs identified aminopeptidase N (APN) as a candidate protein that enhances angiogenesis. APN knockdown in 786-O BM resulted in reduced angiogenesis in vitro and in vivo. When parental 786-O cells were intracardially injected 12 weeks after treatment with786-O BM EVs, more bone metastasis developed compared to those treated with EVs from parental 786-O cells. In patient samples, BM-EVs contained higher APN compared to LA-EV. In addition, BM-EVs promoted tube formation in vitro compared to LA-EVs.

Conclusion

EVs from bone metastatic RCC promote angiogenesis and gap formation in capillary endothelium in bone marrow in a time-dependent manner.
B cells as modulators of HPV+ oropharyngeal cancer in a preclinical model
Authors: Galán-Ortíz Jorge R. , Andino del Valle Kamila A. , Pérez-Rosario Abelardo A. , Castañón Pereira Daniel L. , Díaz-Rivera Jennifer , Merheb-Finianos Pamela A. , Dorta-Estremera Stephanie M.
Published: March 2023

Among the different immune cells present within tumors, B cells also infiltrate human papillomavirus-positive (HPV+) oropharyngeal tumors. However, the role of B cells during programmed death-1 (PD-1) blockade in HPV+ oropharyngeal cancer needs to be better defined. By using the preclinical mouse model for HPV+ oropharyngeal cancer (named mEER), we characterized B cells within tumors and determined their functional role in vivo during PD-1 blockade. We determined that treatment naïve tongue-implanted tumors, which we have previously demonstrated to be sensitive to PD-1 blockade, contained high infiltration of CD8+ T cells and low infiltration of B cells whereas flank-implanted tumors, which are resistant to PD-1 blockade, contain a higher frequency of B cells compared to T cells. Moreover, B cell-deficient mice (µMt) and B cell-depleted mice showed a slower tumor growth rate compared to wild-type (WT) mice, and B cell deficiency increased CD8+ T cell infiltration in tumors. When we compared tongue tumor-bearing mice treated with anti-PD-1, we observed that tumors that responded to the therapy contained more T cells and B cells than the ones that did not respond. However, µMt mice treated with PD-1 blockade showed similar tumor growth rates to WT mice. Our data suggest that in untreated mice, B cells have a more pro-tumorigenic phenotype potentially affecting T cell infiltration in the tumors. In contrast, B cells are dispensable for PD-1 blockade efficacy. Mechanistic studies are needed to identify novel targets to promote the anti-tumorigenic function and/or suppress the immunosuppressive function of B cells in HPV+ oropharyngeal cancer.
The role of CXCL12 axis in pancreatic cancer: New biomarkers and potential targets
Authors: Roberto Michela , Arrivi Giulia , Di Civita Mattia Alberto , Barchiesi Giacomo , Pilozzi Emanuela , Marchetti Paolo , Santini Daniele , Mazzuca Federica , Tomao Silverio
Published: March 2023

Introduction

Chemokines are small, secreted peptides involved in the mediation of the immune cell recruitment. Chemokines have been implicated in several diseases including autoimmune diseases, viral infections and also played a critical role in the genesis and development of several malignant tumors. CXCL12 is a homeostatic CXC chemokine involved in the process of proliferation, and tumor spread. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, that is still lacking effective therapies and with a dramatically poor prognosis.

Method

We conducted a scientific literature search on Pubmed and Google Scholar including retrospective, prospective studies and reviews focused on the current research elucidating the emerging role of CXCL12 and its receptors CXCR4 – CXCR7 in the pathogenesis of pancreatic cancer.

Results

Considering the mechanism of immunomodulation of the CXCL12-CXCR4-CXCR7 axis, as well as the potential interaction with the microenvironment in the PDAC, several combined therapeutic approaches have been studied and developed, to overcome the “cold” immunological setting of PDAC, like combining CXCL12 axis inhibitors with anti PD-1/PDL1 drugs.

Conclusion

Understanding the role of this chemokine’s axis in disease initiation and progression may provide the basis for developing new potential biomarkers as well as therapeutic targets for related pancreatic cancers.
Caryopteris odorata and its metabolite coumarin attenuate characteristic features of cardiometabolic syndrome in high-refined carbohydrate-high fat-cholesterol-loaded feed-fed diet rats
Authors: Ahmed Mobeen Ghulam , Mehmood Malik Hassan , Mehdi Shumaila , Farrukh Maryam
Published: March 2023

Caryopteris odorata (D. Don) B.L. Robinson (Verbenaceae family) is an aromaric shrub traditionally used to treat diabetes and related pathologies (diabetic foot ulcer), cancer/tumors, wound healing, and inflammation. It is enriched with flavonoids and phenolics like coumarins, quercetin, gallic acid, coumaric acid, stigmasterol, α-tocopherol, and iridoids. C. odorata has been reported as having α-glucosidase, anti-inflammatory, and anti-oxidant properties. Its effectiveness in preventing cardiometabolic syndrome has not yet been assessed. This study aims to investigate the potential efficacy of C. odorata and coumarin for characteristic features of cardiometabolic syndrome (CMS), including obesity, dyslipidemia, hyperglycemia, insulin resistance, and hypertension by using high-refined carbohydrate-high fat-cholesterol (HRCHFC)-loaded feed-fed rats. Chronic administration of C. odorata and coumarin for 6 weeks revealed a marked attenuation in body and organ weights, with a consistent decline in feed intake compared to HRCHFC diet fed rats. The test materials also caused a significant reduction in the blood pressure (systolic, diastolic, and mean) and heart rate of HRCHFC-diet fed rats. Improved glucose tolerance and insulin sensitivity tests were also observed in test material administered rats compare to only HRCHFC-diet fed rats. C. odorata and coumarin-treated animals produced a marked decline in serum FBG, TC, TG, LFTs, and RFTs, while an increase in serum HDL-C levels was noticed. C. odorata and coumarin also significantly modulated inflammatory biomarkers (TNFα, IL-6), adipokines (leptin, adiponectin, and chemerin), and HMG-CoA reductase levels, indicating prominent anti-inflammatory, cholesterol-lowering, and anti-hyperglycemic potential. Administration of C. odorata and coumarin exhibited a marked improvement in oxidative stress markers (CAT, SOD, and MDA). Histopathological analysis of liver, heart, kidney, pancreas, aorta, and fat tissues showed a revival of normal tissue architecture in C. odorata and coumarin-treated rats compared to only HRCHFC-diet fed rats. These results suggest that C. odorata and coumarin possess beneficial effects against the characteristic features of CMS (obesity, insulin resistance, hypertension, and dyslipidemia) in HRCHFC feed-administered rats. These effects were possibly mediated through improved adipokines, glucose tolerance, and insulin sensitivity, the attenuation of HMG-CoA reductase and inflammatory biomarkers, and modulated oxidative stress biomarkers. This study thus demonstrates a rationale for the therapeutic potential of C. odorata and coumarin in CMS.
Multi-omics reveals hypertrophy of adipose tissue and lipid metabolism disorder via mitochondria in young mice under real-ambient exposure to air pollution
Authors: Si Honglin , Gao Tianlin , Yang Jing , Zhu Jing , Han Ying , Li Chengwei , Wang Jianxin , Li Jianyu , Zhao Yanjie , Chen Lei , Zheng Yuxin , Jiang Menghui
Published: March 2023

Air pollution has become one of the most serious health risks as a result of industrialization, especially in developing countries. More attention has been drawn to the relationship between obesity/overweight and fine particulate matter (PM2.5). Especially for susceptible populations, the impact of air pollution on children and adolescents has attracted more public attentions. However, the detailed underlying mechanism influencing obesity or overweight under PM2.5 exposure is still unknown. Therefore, young mice were exposed to PM2.5 using the real-ambient exposure system that we previously established in Shijiazhuang city. Compared with the traditionally concentrated air particle (CAP) system, our real-ambient exposure system provides similar PM2.5 concentrations and characteristics as outdoor ambient air and minimizes the influence of external interfering factors. After 8 weeks of exposure to PM2.5, the weight of gonadal white adipose tissue (gWAT) and subcutaneous white adipose tissue (sWAT) was considerably increased, accompanied by a significantly enlarged size of adipocytes in sWAT. Importantly, multiomics analysis indicated altered metabolites involved in the lipid metabolism pathway, and transcriptomic analysis revealed notably changed signaling pathways related to fatty acid metabolism. Moreover, the mtDNA copy number, mitochondrial activity and fatty acid oxidation (FAO) were increased in the liver under PM2.5 exposure. Taken together, our research investigated the hypotrophy of adipose tissue in young mice, supported an imbalance in lipid metabolism based on multiomics analysis, and revealed disordered mitochondrial function under PM2.5 exposure. Our study provided new insight into the hazardous effects of air pollution, and extended our understanding on the underlying mechanism.
IL-17 inhibitor-associated inflammatory bowel disease: A study based on literature and database analysis
Authors: Deng Zhenzhen , Wang Shengfeng , Wu Cuifang , Wang Chunjiang
Published: March 2023

Objective: Few real-world studies have shown clear association between interleukin (IL)-17 inhibitors and inflammatory bowel disease (IBD) onset. This study investigated the reporting prevalence and evaluated the clinical features and management of IL-17 inhibitor-related IBD events.

Methods: We used the US FDA Adverse Event Reporting System database and retrieved data, from 2015 to 2022, on IL-17 inhibitors to identify gastrointestinal inflammatory events and conduct disproportionality analyses by estimating the reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs). Furthermore, case reports and case series, from 2015 to 30 November 2022, on IBD induced by IL-17 inhibitors were collected for retrospective analysis.

Results: A total of 388 cases of primary suspected IL-17 inhibitor-associated gastrointestinal events were reported (268 IBD and 120 colitis), including 348 cases involving secukinumab (SEC), 36 cases involving ixekizumab (IXE), and 4 cases involving brodalumab (BRO). Statistically significant reporting rates of total IBD events were observed for SEC and IXE (ROR = 2.13, 95% CI [1.96-2.30] and ROR = 2.79, 95% CI [2.39-3.27], respectively), whereas BRO did not trigger a safety signal. Twenty-nine studies, which included 34 cases, showed evidence of IBD, following SEC (79.4%) and IXE (20.6%) treatment. The median age was 42 years; typical initial symptoms included diarrhea (90.9%), abdominal pain (57.6%), bloody diarrhea (51.5%), and fever (36.4%). The median time to onset of IBD symptoms was 2.9 months. Some cases were accompanied by elevated white blood cell (WBC) count (87.5%), erythrocyte sedimentation rate (ESR; 85.7%), C-reactive protein (CRP; 100%), and fecal calprotectin (FC; 100%). Cessation of IL-17 inhibitors plus treatment with corticosteroids and TNF antagonists, as either monotherapy or in combination, could lead to complete clinical remission. The median time to remission after IL-17 inhibitor discontinuation was 4 weeks.

Conclusion: IL-17 inhibitor treatment is associated with exacerbation and new onset of IBD and colitis. Obtaining a detailed patient history before initiation of treatment and monitoring gastrointestinal symptoms and intestinal inflammatory biomarkers during IL-17 inhibitor treatment is important for safe use of these drugs.
Design, synthesis and anticancer activity studies of 3-(coumarin-3-yl)-acrolein derivatives: Evidenced by integrating network pharmacology and vitro assay
Authors: Chen Lexian , Lv Qianqian , Cai Jianghong , Liang Jiajie , Liang Ziyan , Lin Jiahui , Xiao Ying , Chen Ruiyao , Zhang Zhiling , Hong Yue , Ji Hong
Published: March 2023

Coumarin derivatives have diverse structures and show various significant biological activities. Aiming to develop more potent coumarin derivatives for cancer treatment, a series of coumarin acrolein hybrids were designed and synthesized by using molecular hybridization approach, and investigated for their antiproliferative activity against A549, KB, Hela and MCF-7 cancer cells as well as HUVEC and LO2 human normal cells. The results indicated that most of the synthesized compounds displayed remarkable inhibitory activity towards cancer cells but low cytotoxicity on normal cells. Among all the compounds, 5d and 6e were the most promising compounds against different cancer cell lines, especially for A549 and KB cells. The preliminary action mechanism studies suggested that compound 6e, the representative compound, was capable of dose-dependently suppressing migration, invasion and inducing significant apoptosis. Furthermore, the combined results of network pharmacology and validation experiments revealed that compound 6e induced mitochondria dependent apoptosis via the PI3K/AKT-mediated Bcl-2 signaling pathway. In summary, our study indicated compound 6e could inhibit cell proliferation, migration, invasion and promote cell apoptosis through inhibition of PI3K/AKT signaling pathway in human oral epidermoid carcinoma cells. These findings demonstrated the potential of 3-(coumarin-3-yl)-acrolein derivatives as novel anticancer chemotherapeutic candidates, providing ideas for further development of drugs for clinical use.
Ensemble of structure and ligand-based classification models for hERG liability profiling
Authors: Vittorio Serena , Lunghini Filippo , Pedretti Alessandro , Vistoli Giulio , Beccari Andrea R.
Published: March 2023

Drug-induced cardiotoxicity represents one of the most critical safety concerns in the early stages of drug development. The blockade of the human ether-à-go-go-related potassium channel (hERG) is the most frequent cause of cardiotoxicity, as it is associated to long QT syndrome which can lead to fatal arrhythmias. Therefore, assessing hERG liability of new drugs candidates is crucial to avoid undesired cardiotoxic effects. In this scenario, computational approaches have emerged as useful tools for the development of predictive models able to identify potential hERG blockers. In the last years, several efforts have been addressed to generate ligand-based (LB) models due to the lack of experimental structural information about hERG channel. However, these methods rely on the structural features of the molecules used to generate the model and often fail in correctly predicting new chemical scaffolds. Recently, the 3D structure of hERG channel has been experimentally solved enabling the use of structure-based (SB) strategies which may overcome the limitations of the LB approaches. In this study, we compared the performances achieved by both LB and SB classifiers for hERG-related cardiotoxicity developed by using Random Forest algorithm and employing a training set containing 12789 hERG binders. The SB models were trained on a set of scoring functions computed by docking and rescoring calculations, while the LB classifiers were built on a set of physicochemical descriptors and fingerprints. Furthermore, models combining the LB and SB features were developed as well. All the generated models were internally validated by ten-fold cross-validation on the TS and further verified on an external test set. The former revealed that the best performance was achieved by the LB model, while the model combining the LB and the SB attributes displayed the best results when applied on the external test set highlighting the usefulness of the integration of LB and SB features in correctly predicting unseen molecules. Overall, our predictive models showed satisfactory performances providing new useful tools to filter out potential cardiotoxic drug candidates in the early phase of drug discovery.
Sampling strategies for the Herman–Kluk propagator of the wavefunction
Authors: Kröninger Fabian , Lasser Caroline , Vaníček Jiří J. L.
Published: March 2023

When the semiclassical Herman–Kluk propagator is used for evaluating quantum-mechanical observables or time-correlation functions, the initial conditions for the guiding trajectories are typically sampled from the Husimi density. Here, we employ this propagator to evolve the wavefunction itself. We investigate two grid-free strategies for the initial sampling of the Herman–Kluk propagator applied to the wavefunction and validate the resulting time-dependent wavefunctions evolved in harmonic and anharmonic potentials. In particular, we consider Monte Carlo quadratures based either on the initial Husimi density or on its square root as possible and most natural sampling densities. We prove analytical convergence error estimates and validate them with numerical experiments on the harmonic oscillator and on a series of Morse potentials with increasing anharmonicity. In all cases, sampling from the square root of Husimi density leads to faster convergence of the wavefunction.
Two-dimensional particle-in-cell simulation of electron heating effect in multiple hollow cathode trenches with curved boundary
Authors: Park Heesung , Sakiyama Yukinori , Lee Hae June
Published: March 2023

A particle-in-cell simulation is suitable for simulating capacitively coupled plasma devices because it calculates the trajectory of particles with arbitrary energy distributions and has the advantage of analyzing sheath dynamics precisely. Implementing the ghost grid method in the Poisson solver makes it possible to simulate a curved structure in the structured grids. The electron transport and heating mechanism are determined according to the two-dimensional (2D) sheath dynamics. The hollow cathode effect on electron transport was analyzed by varying the hole shape and gas pressure. The spatial distributions of electron density and temperature are influenced by the energy relaxation length of electrons, which is affected by the energy distribution function and gas pressure. As a result, a new electron heating mode appears in the 2D structure.