bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of MMPs supports amoeboid angiogenesis hampering VEGF-targeted therapies via MLC and ERK 1/2 signaling
Authors: Chillà Anastasia , Anceschi Cecilia , Frediani Elena , Scavone Francesca , Del Rosso Tommaso , Pelagio Giuseppe , Tufaro Antonio , De Palma Giuseppe , Del Rosso Mario , Fibbi Gabriella , Chiarugi Paola , Laurenzana Anna , Margheri Francesca 
Published: February 2023

Abstract
Background
In the past decades studies on anti-tumoral drugs inhibiting matrix metalloproteinase (MMPs) were disappointing. Recently, we demonstrated that mature endothelial cells (ECs) and endothelial colony forming cells (ECFCs) can switch between invasion modes to cope with challenging environments, performing the “amoeboid angiogenesis” in the absence of proteases activity.

Methods
We first set out to investigate by ELISA if the inhibitors of the main protease family involved in angiogenesis were differently expressed during breast cancer progression. We used Marimastat, a broad-spectrum MMP inhibitor, as a means of inducing amoeboid characteristics and studied VEGF role in amoeboid angiogenesis. Thus, we performed invasion and capillary morphogenesis assay, morphological, cell signaling and in vivo mouse studies.

Results
Our data showed that TIMP1, TIMP2, alpha2-antiplasmin, PAI-1 and cystatin increase in breast cancer serum of patients with primary cancer and lymph node positive compared to healthy women. In vitro results revealed that the most high-powered protease inhibitors able to induce amoeboid invasion of ECFCs were TIMP1, 2 and 3. Surprisingly, Marimastat promotes ECFC invasion and tubular formation in vitro and in vivo, inducing amoeboid characteristics. We observed that the combination of Marimastat plus VEGF doesn’t boost neither cell invasion nor vessel formation capacity. Moreover, inhibition of VEGF activity with Bevacizumab in the presence of Marimastat confirmed that amoeboid angiogenesis is independent from the stimulus of the main vascular growth factor, VEGF.

Conclusions
We underline the importance to consider the amoeboid mechanism of endothelial and cancer cell invasion, probably responsible for the failure of synthetic metalloproteinase inhibitors as cancer therapy and tumor resistance to VEGF-targeted therapies, to set-up new drugs to be used in cancer therapy.
Enteric neuroanatomy and smooth muscle activity in the western diamondback rattlesnake (Crotalus atrox)
Authors: Kohl Tobias , Ridzal Lejla , Kuch Birgit , Hartel Marlene , Kreft Corinna , Musoski Ahmed , Michel Klaus , Luksch Harald , Schemann Michael , Annaházi Anita 
Published: February 2023

Abstract
Background
Gastrointestinal (GI) functions are controlled by the enteric nervous system (ENS) in vertebrates, but data on snakes are scarce, as most studies were done in mammals. However, the feeding of many snakes, including Crotalus atrox, is in strong contrast with mammals, as it consumes an immense, intact prey that is forwarded, stored, and processed by the GI tract. We performed immunohistochemistry in different regions of the GI tract to assess the neuronal density and to quantify cholinergic, nitrergic, and VIPergic enteric neurons. We recorded motility patterns and determined the role of different neurotransmitters in the control of motility. Neuroimaging experiments complemented motility findings.

Results
A well-developed ganglionated myenteric plexus (MP) was found in the oesophagus, stomach, and small and large intestines. In the submucous plexus (SMP) most neurons were scattered individually without forming ganglia. The lowest number of neurons was present in the SMP of the proximal colon, while the highest was in the MP of the oesophagus. The total number of neurons in the ENS was estimated to be approx. 1.5 million. In all regions of the SMP except for the oesophagus more nitric oxide synthase+ than choline-acetyltransferase (ChAT)+ neurons were counted, while in the MP ChAT+ neurons dominated. In the SMP most nerve cells were VIP+, contrary to the MP, where numerous VIP+ nerve fibers but hardly any VIP+ neuronal cell bodies were seen. Regular contractions were observed in muscle strips from the distal stomach, but not from the proximal stomach or the colon. We identified acetylcholine as the main excitatory and nitric oxide as the main inhibitory neurotransmitter. Furthermore, 5-HT and dopamine stimulated, while VIP and the ß-receptor-agonist isoproterenol inhibited motility. ATP had only a minor inhibitory effect. Nerve-evoked contractile responses were sodium-dependent, insensitive to tetrodotoxin (TTX), but sensitive to lidocaine, supported by neuroimaging experiments.

Conclusions
The structure of the ENS, and patterns of gastric and colonic contractile activity of Crotalus atrox are strikingly different from mammalian models. However, the main excitatory and inhibitory pathways appear to be conserved. Future studies have to explore how the observed differences are an adaptation to the particular feeding strategy of the snake.
Gastrodin ameliorates atherosclerosis by inhibiting foam cells formation and inflammation through down-regulating NF-κB pathway
Authors: Xue Xiaofei , Li Fulei , Xu Mengke , Chen Bowen , Zhao Yanyan , Wang Mengyu , Li Ling 
Published: February 2023

Abstract
Background
Gastrodin is an effective polyphenol extracted from Chinese natural herbal Gastrodiae elata Blume, which exhibits antioxidant and anti-inflammatory effects. It has been reported to benefit neurodegenerative diseases, but the effect of Gastrodin on atherosclerosis and the underlying mechanisms remain elusive. The aim of this study is to investigate the function and mechanism of Gastrodin in atherosclerosis.

Methods
Atherosclerosis mouse model was established by fed low density lipoprotein receptor-deficient (Ldlr−/−) mice with a high fat diet (HFD, 20% fat and 0.5 cholesterol) for 8 weeks and Gastrodin was administered daily via oral gavage. Plasma lipid levels were measured using commercial kits. En face and aortic sinus lipid accumulation were analyzed with Oil Red O staining. In vitro cell models using foam cell formation model and classical atherosclerosis inflammation model, macrophages were incubated with oxygenized low-density lipoproteins (ox-LDL) or lipopolysaccharide (LPS) in the presence of different concentration of Gastrodin or vehicle solution. Foam cell formation and cellular lipid content were evaluated by Oil Red O staining and intracellular lipids extraction analysis. Gene expression and proteins related to cholesterol influx and efflux were examined by quantitative reverse transcription PCR (RT-qPCR) and western blotting analysis. Furthermore, the effect of Gastrodin on LPS induced macrophage inflammatory responses and NF-κB pathway were evaluated by RT-qPCR and western blotting analysis.

Results
Gastrodin administration reduced the body weight, plasma lipid levels in Ldlr−/− mice after fed a high fat diet. Oil Red O staining showed Gastrodin-treated mice displayed less atherosclerosis lesion area. Furthermore, Gastrodin treatment significantly ameliorated ox-LDL-induced macrophage-derived foam cells formation through suppressing genes expression related to cholesterol efflux including scavenger receptor class B and ATP-binding cassette transporter A1. Moreover, Gastrodin markedly suppressed pro-inflammatory cytokines secretion and LPS induced inflammatory response in macrophage through downregulating NF-κB pathway.

Conclusions
Our study demonstrated that Gastrodin attenuates atherosclerosis by suppressing foam cells formation and LPS-induced inflammatory response and represents a novel therapeutic target for the treatment of atherosclerosis.
Establishing relationships between particle-induced in vitro and in vivo inflammation endpoints to better extrapolate between in vitro markers and in vivo fibrosis
Authors: McLean Polly , Mueller William , Gosens Ilse , Cassee Flemming R. , Rothen-Rutishauser Barbara , Boyles Matthew , Tran Lang 
Published: February 2023

Abstract
Background
Toxicity assessment for regulatory purposes is starting to move away from traditional in vivo methods and towards new approach methodologies (NAM) such as high-throughput in vitro models and computational tools. For materials with limited hazard information, utilising quantitative Adverse Outcome Pathways (AOPs) in a testing strategy involving NAM can produce information relevant for risk assessment. The aim of this work was to determine the feasibility of linking in vitro endpoints to in vivo events, and moreover to key events associated with the onset of a chosen adverse outcome to aid in the development of NAM testing strategies. To do this, we focussed on the adverse outcome pathway (AOP) relating to the onset of pulmonary fibrosis.

Results
We extracted in vivo and in vitro dose–response information for particles known to induce this pulmonary fibrosis (crystalline silica, specifically α-quartz). To test the in vivo–in vitro extrapolation (IVIVE) determined for crystalline silica, cerium dioxide nanoparticles (nano-CeO2) were used as a case study allowing us to evaluate our findings with a less studied substance. The IVIVE methodology outlined in this paper is formed of five steps, which can be more generally summarised into two categories (i) aligning the in vivo and in vitro dosimetry, (ii) comparing the dose–response curves and derivation of conversion factors.

Conclusion
Our analysis shows promising results with regards to correlation of in vitro cytokine secretion to in vivo acute pulmonary inflammation assessed by polymorphonuclear leukocyte influx, most notable is the potential of using IL-6 and IL-1β cytokine secretion from simple in vitro submerged models as a screening tool to assess the likelihood of lung inflammation at an early stage in product development, hence allowing a more targeted investigation using either a smaller, more targeted in vivo study or in the future a more complex in vitro protocol. This paper also highlights the strengths and limitations as well as the current difficulties in performing IVIVE assessment and suggestions for overcoming these issues.
Preoperative pericardial hematoma in patients with acute type A aortic dissection (AAAD): Do we need an adjusted treatment?
Authors: Kaufeld Tim , Beckmann Erik , Rudolph Linda , Krüger Heike , Natanov Ruslan , Arar Morsi , Korte Wilhelm , Schilling Tobias , Haverich Axel , Martens Andreas , Shrestha Malakh 
Published: February 2023

Abstract
Objective
An acute type A aortic dissection (AAAD) is a critical emergency and remains one of the most challenging diseases in cardiothoracic surgery. The existence of a pericardial hematoma caused by an aortic rupture can dramatically reduce the chances of survival (Jerzewski and Kulik in J Card Surg 29(4):529–530, 2014; Mehta et al. in Circulation 105(2):200–206, 2002; Gilon et al. in Am J Cardiol 103(7):1029–1031, 2009; Isselbacher et al. in Circulation 90(5):2375–2378, 1994). We assessed the surgical outcome of a high-risk group of patients with AAAD and a pericardial hematoma.

Methods
In this study we included 430 Patients (67% male; median age: 64 years) who received surgical treatment between January 2000 and January 2018 at our facility for acute aortic dissection DeBakey type I. We divided the cohort in two groups: Group A consisted of high-risk patients with a pericardial hematoma (n = 162) and Group B of patients without pericardial hematoma (n = 268).

Results
Patients with a preoperative pericardial hematoma had a significantly higher requirement for preoperative mechanical resuscitation (A: 21%; B: 1.5%; P: < 0.001) and were relevantly more frequently admitted to the operation theater with an intubated status (A: 19.8%; B: 8.6%; P: < 0.001). The incidence of visceral malperfusion differed significantly between both groups (A. 11.7%, B. 6:0%; P: 0.034). Limited aortic arch repair (proximal aortic arch replacement) was preferred in the high-risk group (A: 51.9%; B: 40.3%; P: 0.020). However, survival time was generally reduced in these patients (A: 7.5 y; B: 9.9 y).

Conclusion
AAAD patients with preoperative pericardial hematoma present themselves in potentially lethal conditions, with a significantly higher rate of visceral malperfusion. Despite the existence of this risk factor, a limited arch repair was favored. We have proven that cardiac compression is associated with preoperative intubation and mechanical resuscitation. Patients with pericardial hematoma must be further evaluated for preoperative pericardial drainage. In the event of long transfer times to an aortic center a slow drainage should be discussed to prevent early mortality.
Procoxacin bidirectionally inhibits osteoblastic and osteoclastic activity in bone and suppresses bone metastasis of prostate cancer
Authors: Kong Depei , Ye Chen , Zhang Chenxi , Sun Xiaochen , Wang Fubo , Chen Rui , Xiao Guangan , He Shipeng , Xu Jianrong , Rao Xiwu , Ai Jianzhong , Gao Xu , Li Hong , Su Li 
Published: February 2023

Abstract
Background
Bone is the most common site of metastasis of prostate cancer (PCa). PCa invasion leads to a disruption of osteogenic-osteolytic balance and causes abnormal bone formation. The interaction between PCa and bone stromal cells, especially osteoblasts (OB), is considered essential for the disease progression. However, drugs that effectively block the cancer-bone interaction and regulate the osteogenic-osteolytic balance remain undiscovered.

Methods
A reporter gene system was constructed to screen compounds that could inhibit PCa-induced OB activation from 631 compounds. Then, the pharmacological effects of a candidate drug, Procoxacin (Pro), on OBs, osteoclasts (OCs) and cancer-bone interaction were studied in cellular models. Intratibial inoculation, micro-CT and histological analysis were used to explore the effect of Pro on osteogenic and osteolytic metastatic lesions. Bioinformatic analysis and experiments including qPCR, western blotting and ELISA assay were used to identify the effector molecules of Pro in the cancer-bone microenvironment. Virtual screening, molecular docking, surface plasmon resonance assay and RNA knockdown were utilized to identify the drug target of Pro. Experiments including co-IP, western blotting and immunofluorescence were performed to reveal the role of Pro binding to its target. Intracardiac inoculation metastasis model and survival analysis were used to investigate the therapeutic effect of Pro on metastatic cancer.

Results
Luciferase reporter gene consisted of Runx2 binding sequence, OSE2, and Alp promotor could sensitively reflect the intensity of PCa-OB interaction. Pro best matched the screening criteria among 631 compounds in drug screening. Further study demonstrated that Pro effectively inhibited the PCa-induced osteoblastic changes without killing OBs or PCa cells and directly killed OCs or suppressed osteoclastic functions at very low concentrations. Mechanism study revealed that Pro broke the feedback loop of TGF-β/C-Raf/MAPK pathway by sandwiching into 14–3-3ζ/C-Raf complex and prevented its disassociation. Pro treatment alleviated both osteogenic and osteolytic lesions in PCa-involved bones and reduced the number of metastases of PCa in vivo.

Conclusions
In summary, our study provides a drug screening strategy based on the cancer-host microenvironment and demonstrates that Pro effectively inhibits both osteoblastic and osteoclastic lesions in PCa-involved bones, which makes it a promising therapeutic agent for PCa bone metastasis.

Graphical Abstract
The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma
Authors: Feng Mei , Xu Hao , Zhou Wenyuan , Pan Yisheng 
Published: February 2023

Abstract
Background
Advanced gastric cancer (GC) is a lethal malignancy, harboring recurrent alterations in cell cycle pathway, especially the CDKN2A-CDK4/CDK6/CCND1 axis. However, monotherapy of CDK4/6 inhibitors has shown limited antitumor effects for GC, and combination treatments were urgently needed for CDK4/6 inhibitors.

Methods
Here, we performed a comprehensive analysis, including drug screening, pan-cancer genomic dependency analysis, and epigenetic sequencing to identify the candidate combination with CDK4/6 inhibitors. Mechanisms were investigated by bulk RNA-sequencing and experimental validation was conducted on diverse in vitro or in vivo preclinical GC models.

Results
We found that the BRD4 inhibitor JQ1 augments the antitumor efficacy of the CDK4/6 inhibitor abemaciclib (ABE). Diverse in vitro and in vivo preclinical GC models are examined and synergistic benefits from the combination therapy are obtained consistently. Mechanistically, the combination of ABE and JQ1 enhances the cell cycle arrest of GC cells and induces unique characteristics of cellular senescence through the induction of DNA damage, which is revealed by transcriptomic profiling and further validated by substantial in vitro and in vivo GC models.

Conclusion
This study thus proposes a candidate combination therapy of ABE and JQ1 to improve the therapeutic efficacy and worth further investigation in clinical trials for GC.
Effect of hysterectomy on ovarian function: a systematic review and meta-analysis
Authors: Huang Yibao , Wu Meng , Wu Chuqing , Zhu Qingqing , Wu Tong , Zhu Xiaoran , Wu Mingfu , Wang Shixuan 
Published: February 2023

Abstract
Background
Hysterectomy is one of the most frequently gynecologic surgeries performed in premenopausal women. Many premenopausal patients are unwilling to undergo hysterectomy due to the probable decreased ovarian function. The aim of this study is to determine the effect of hysterectomy on ovarian function.

Methods
A meta-analysis has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) guidelines. We mainly searched the Embase, PubMed and Web of Science databases for eligible studies. The outcomes were the levels of common indicators of ovarian function, such as anti-müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, estradiol (E2) and luteinizing hormone (LH). The evidence was synthesized using meta-analysis via fixed or random effect model according to heterogeneity. Subgroup analyses were performed to examine the potential sources of heterogeneity.

Results
The 14 included studies were conducted between 1989 and 2021, involving a total of 1,457 premenopausal women with 760 and 697 in the hysterectomy and control group, respectively. We found that hysterectomy damage ovarian function compared to the control group, with lower AMH level [Weighted mean difference (WMD) = -0.56, 95% confidence interval (95% CI): -0.72 to -0.39, P = 0.000], higher FSH levels (WMD = 2.96, 95% CI: 1.47 to 4.44, P = 0.000), lower inhibin B levels (WMD = -14.34, 95% CI: -24.69 to -3.99, P = 0.000) and higher LH levels (WMD = 4.07, 95% CI: 1.78 to 6.37, P = 0.000). In addition, E2 levels have a decreasing trend (WMD = -17.13, 95% CI: -35.10 to 0.85, P = 0.631) in the hysterectomy group but were not statistically significant.

Conclusion
Hysterectomy has a negative impact on ovarian function, especially in female patients over 40 years old. So, the older patients should closely monitor their ovarian function for early diagnosis and treatment of menopausal symptoms.
The end-tidal alveolar dead space fraction for risk stratification during the first week of invasive mechanical ventilation: an observational cohort study
Authors: Bhalla Anoopindar K. , Chau Ariya , Khemani Robinder G. , Newth Christopher J. L. 
Published: February 2023

Abstract
Background
The end-tidal alveolar dead space fraction (AVDSf = [PaCO2−PETCO2]/PaCO2) is a metric used to estimate alveolar dead space. Higher AVDSf on the first day of mechanical ventilation is associated with mortality and fewer ventilator-free days. It is not clear if AVDSf is associated with length of ventilation in survivors, how AVDSf performs for risk stratification beyond the first day of ventilation, or whether AVDSf adds predictive value to oxygenation (oxygenation index [OI]) or severity of illness (Pediatric Risk of Mortality [PRISM III]) markers.

Methods
Retrospective single-center observational cohort study of children and young adults receiving invasive mechanical ventilation. In those with arterial or capillary blood gases, AVDSf was calculated at the time of every blood gas for the first week of mechanical ventilation.

Results
There were 2335 children and young adults (median age 5.8 years [IQR 1.2, 13.2]) enrolled with 8004 analyzed AVDSf values. Higher AVDSf was associated with mortality and longer length of ventilation in survivors throughout the first week of ventilation after controlling for OI and PRISM III. Higher OI was not associated with increased mortality until ≥ 48 h of ventilation after controlling for AVDSf and PRISM III. When using standardized variables, AVDSf effect estimates were generally higher than OI for mortality, whereas OI effect estimates were generally higher than AVDSf for the length of ventilation in survivors. An AVDSf > 0.3 was associated with a higher mortality than an AVDSf < 0.2 within each pediatric acute respiratory distress syndrome severity category.
The maximum AVDSf within 12 h of intensive care unit admission demonstrated good risk stratification for mortality (AUC 0.768 [95% CI 0.732, 0.803]). AVDSf did not improve mortality risk stratification when added to PRISM III but did improve mortality risk stratification when added to the gas exchange components of PRISM III (minimum 12-h PaO2 and maximum 12-h PCO2) (p < 0.00001).

Conclusions
AVDSf is associated with mortality and length of ventilation in survivors throughout the first week of invasive mechanical ventilation. Some analyses suggest AVDSf may better stratify mortality risk than OI, whereas OI may better stratify risk for prolonged ventilation in survivors than AVDSf.
Inter-vendor and inter-observer reliability of diffusion tensor imaging in the musculoskeletal system: a multiscanner MR study
Authors: Chianca Vito , Albano Domenico , Rizzo Stefania , Maas Mario , Sconfienza Luca Maria , Del Grande Filippo 
Published: February 2023

Abstract
Background
To evaluate the inter-observer and inter-vendor reliability of diffusion tensor imaging parameters in the musculoskeletal system.

Methods
This prospective study included six healthy volunteers three men (mean age: 42; range: 31–52 years) and three women (mean age: 36; range: 30–44 years).
Each subject was scanned using different 3 Tesla magnetic resonance scanners from three different vendors at three different sites bilaterally. First, the intra-class correlation coefficient was used to determine between-observers agreement for overall measurements and clinical sites. Next, between-group comparisons were made through the nonparametric Friedman’s test. Finally, the Bland–Altman method was used to determine agreement among the three scanner measurements, comparing them two by two.

Results
A total of 792 measurement were calculated. ICC reported high levels of agreement between the two observers. ICC related to MD, FA, and RD measurements ranged from 0.88 (95% CI 0.85–0.90) to 0.95 (95% CI 0.94–0.96), from 0.85 (95% CI 0.81–0.88) to 0.95 (95% CI 0.93–0.96), and from 0.89 (0.85–0.90) to 0.92 (0.90–0.94).
No statistically significant inter-vendor differences were observed. The Bland–Altmann method confirmed a high correlation between parameter values.

Conclusion
An excellent inter-observer and inter-vendor reliability was found in our study.