Tag: statistics

Int J Cancer. 2021 Aug 30. doi: 10.1002/ijc.33786. Online ahead of print.

ABSTRACT

Acidity in the tumor microenvironment has been reported to promote cancer growth and metastasis. In this study, we examined a potential relation between extracellular acidity and expression level of the immune checkpoint molecule PD-L1 in murine squamous cell carcinoma (SCC) and melanoma cell lines. PD-L1 expression in the tumor cells was upregulated by culturing in a low pH culture medium. Tumor-bearing mice were allowed to ingest sodium bicarbonate, resulting in neutralization of acidity in the tumor tissue, a decrease in PD-L1 expression in tumor cells, and suppression of tumor growth in vivo. Proton-sensing G protein-coupled receptors (GPCRs), T cell death-associated gene 8 (TDAG8) and ovarian cancer G-protein-coupled receptor 1 (OGR1), were upregulated by low pH, and essentially involved in the acidity-induced elevation of PD-L1 expression in the tumor cells. Human head and neck SCC RNAseq data from the Cancer Genome Atlas also suggested a statistically significant correlation between expression levels of the proton sensors and PD-L1 mRNA expression. These findings strongly suggest that neutralization of acidity in tumor tissue may result in reduction of PD-L1 expression, potentially leading to inhibition of an immune check point and augmentation of anti-tumor immunity.

PMID:34460096 | DOI:10.1002/ijc.33786

Inflammation. 2021 Aug 30. doi: 10.1007/s10753-021-01520-0. Online ahead of print.

ABSTRACT

Plasminogen activator inhibitor-1 (PAI-1) antagonists are known for their neuroprotective effects. In this study, it was aimed to investigate the possible protective effects of PAI-1 antagonists in a rat mild traumatic brain injury (TBI) model. Sprague-Dawley male rats were grouped as sham (n = 7), TBI (n = 9), and TBI + PAI-1 antagonist (5 and 10 mg/kg TM5441 and TM5484; n = 6-7). Under anesthesia, TBI was induced by dropping a metal 300-g weight from a height of 1 m on the skull. Before and 24-h after trauma neurological examination, tail suspension, Y-maze, and novel object recognition tests were performed. Twenty-four hours after TBI, the rats were decapitated and activities of myeloperoxidase, nitric oxide release, luminol-, and lucigenin-enhanced chemiluminescence were measured. Also, interleukin-1β, interleukin-6, tumor necrosis factor, interleukin-10, tumor growth factor-β, caspase-3, cleaved caspase-3, and PAI levels were measured with the ELISA method in the brain tissue. Brain injury was graded histopathologically following hematoxylin-eosin staining. Western blot and immunohistochemical investigation for low-density lipoprotein receptor, matrix metalloproteinase-3, and nuclear factor-κB were also performed. Data were analyzed using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA) and expressed as means ± SEM. Values of p < 0.05 were considered to be statistically significant. Higher levels of myeloperoxidase activity in the TBI group (p < 0.05) were found to be suppressed in 5 and 10 mg/kg TM5441 treatment groups (p < 0.05-p < 0.01). The tail suspension test score was increased in the TBI group (p < 0.001) and decreased in all treatment groups (p < 0.05-0.001). The histologic damage score was increased statistically significantly in the cortex, dentate gyrus, and CA3 regions in the TBI group (p < 0.01-0.001), decreased in the treatment groups in the cortex and dentate gyrus (p < 0.05-0.001). PAI antagonists, especially TM5441, have antioxidant and anti-inflammatory properties against mild TBI in the acute period. Behavioral test results were also improved after PAI antagonist treatment after mild TBI.

PMID:34460025 | DOI:10.1007/s10753-021-01520-0

Neurol Ther. 2021 Aug 30. doi: 10.1007/s40120-021-00277-w. Online ahead of print.

ABSTRACT

INTRODUCTION: According to the official Russian source, in 2017 only 0.27% of the population of Russia was diagnosed with International Classification of Diseases, tenth revision (ICD-10) F4 category disorders (neurotic, stress-related and somatoform disorders), despite these disorders being among the most prevalent mental disorders worldwide. Here we report the results of a large-scale survey among Russian psychiatrists with the primary objective to assess the proportion of psychiatrists who use the diagnoses of interest (mixed anxiety and depression disorder [MADD], adjustment disorder [AdD], panic disorder [PD], agoraphobia, generalized anxiety disorder [GAD], social phobia, simple phobia, acute stress disorder and posttraumatic stress disorder) and compare results with those of a recent World Psychiatric Association (WPA) and World Health Organization (WHO) survey. We also compared the incidence of these diagnoses between state and non-state psychiatric services in Russia.

METHODS: Mean proportions and distribution of proportions of participants who made diagnoses of interest at different rates were calculated and compared with the results of the recent WPA and WHO survey. Risk ratios (RR) of the incidence of these diagnoses made at a frequency of at least once a week were calculated to compare state and non-state psychiatric services. The 95% confidence intervals of the RRs were calculated using the Koopman asymptotic score method.

RESULTS: Responses of 960 Russian psychiatrists were included in the analysis. Of these 95, 89 and 87% reported making diagnoses of MADD, AdD and PD, respectively, during the preceding 12 months, a far larger proportion compared to other disorders of interest. In general, a significantly smaller proportion of participants in our survey made diagnoses of anxiety disorders compared to respondents in the international WPA-WHO survey. Based on RRs, diagnoses of MADD, AdD, PD, GAD and acute stress disorder were less frequently made in the state-operated psychiatric service.

CONCLUSION: Our survey revealed a serious underdiagnosis of anxiety disorders in Russia that may be associated with complex factors that include, but are not limited to the current stigma associated with the state-operated psychiatric service, which is still the exclusive source of official statistical data in Russia.

PMID:34460079 | DOI:10.1007/s40120-021-00277-w

Bull Math Biol. 2021 Aug 30;83(10):102. doi: 10.1007/s11538-021-00931-2.

NO ABSTRACT

PMID:34460011 | DOI:10.1007/s11538-021-00931-2

AMB Express. 2021 Aug 30;11(1):122. doi: 10.1186/s13568-021-01282-w.

ABSTRACT

Klebsiella pneumoniae is a multidrug-resistant (MDR) opportunistic pathogen that causes nosocomial infections. Virulence analysis and molecular typing as powerful approaches can provide relevant information on K. pneumoniae infection. In the current study, antibiotic resistance, virulence-associated genes analysis, as well as molecular typing of K. pneumoniae strains were investigated. Out of 505 clinical samples collected from hospitalized patients, 100 K. pneumoniae strains were isolated by standard microbiological methods and subjected to the phenotypic and genotyping analysis. The highest prevalence of resistance was observed against ciprofloxacin (75%), trimethoprim-sulfamethoxazole (73%) and nitrofurantoin (68%). Virulence associated genes including entB, traT, ybts, magA, iucC, htrA and rmpA were found in 80%, 62%, 75%, 5%, 30%, 72% and 48%, of the isolates, respectively. The prevalence of biofilm-associated genes including mrkA, fimH, and mrkD were equally 88% for all tested isolates. Moreover, the efflux pump genes including AcrAB, TolC and mdtK were observed in 41 (41%), 33 (33%) and 26 (26%) of the strains respectively. A significant statistical association was observed between MDR strains and high expression of efflux pump and biofilm genes. The K. pneumoniae strains were differentiated into 11 different genetic patterns using the repetitive element sequence-based PCR (rep-PCR) technique. High prevalence of resistance, presence of various virulence factors, high level of efflux pump, and biofilm gene expression in diverse clones of K. pneumoniae strains pose an important health issue in clinical settings.

PMID:34460016 | DOI:10.1186/s13568-021-01282-w

Clin Oral Investig. 2021 Aug 30. doi: 10.1007/s00784-021-04152-8. Online ahead of print.

ABSTRACT

OBJECTIVES: The aim of this study was to evaluate the in vitro effect of enamel matrix derivative (EMD) and hyaluronic acid (HA) and their synergistic combination on lipopolysaccharides (LPS)-induced inflammation in human keratinocytes and osteoblasts.

MATERIAL AND METHODS: Cells were challenged with LPS (1 μg/ml) and cultured in the following treatment groups with EMD (30 mg/ml) and HA (30 mg/ml): LPS, EMD, HA, EMD + HA, EMD + LPS, HA + LPS, and EMD + HA + LPS. Cell viability, inflammatory cytokine expression, and cell migration were determined using colorimetric assay, quantitative real-time polymerase chain reaction (qPCR), and scratch wound healing assay, respectively.

RESULTS: Cell viability was decreased when exposed to LPS compared to the controls. Overall, LPS treatment expressed upregulation on inflammatory cytokine tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6). EMD and HA reduced up to 3.0-fold the cytokine expression caused by LPS (p < 0.05). EMD and HA statistically induced higher migration in osteoblasts and keratinocytes, respectively. Migration was impaired by LPS, whereas it significantly increased after addition of EMD and HA.

CONCLUSIONS: EMD and HA are advantageous biomaterials that individually generate strong directional migratory keratinocyte and osteoblast response. Their combination also enhances cell viability, and anti-inflammatory and migratory abilities to promote healing specially under LPS inflammatory stimulus. Future in vivo and animal research is necessary to further characterize the effect of EMD and HA on periodontal regeneration.

CLINICAL RELEVANCE: The use of EMD in conjunction with HA resulted in a reduction of inflammation and improvement of tissue healing at wound sites. Both biomaterials combined may potentially improve the effectiveness of bone regeneration in periodontal bone defects, pointing to the potential clinical relevance of both materials in regenerative periodontal surgery.

PMID:34460002 | DOI:10.1007/s00784-021-04152-8

J Anesth. 2021 Aug 28. doi: 10.1007/s00540-021-02993-x. Online ahead of print.

ABSTRACT

PURPOSE: Angiogenesis, one of regenerative medicine, is essential in the process of wound healing. The detailed effects of intravenous anesthetics and sedatives used during perioperative period have not yet been clarified. We investigated the effects of benzodiazepines and propofol on in vitro capillary tube formation.

METHODS: The effects of midazolam, diazepam and propofol (1, 10, 50 µM each) on proliferation of human umbilical vein endothelial cells (HUVEC) and normal human diploid fibroblasts (NHDF) were determined. Quantitation of migration was achieved by measuring the fluorescence of migrating HUVEC using angiogenesis system. The effects of midazolam, diazepam and propofol on in vitro angiogenesis were investigated in co-cultured HUVEC and NHDF incubated. The effects of midazolam on activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases were examined by Western blot analysis using phospho-specific antibodies. Parametric data were analyzed with one-way repeated measures analysis of variance followed by the Scheffé test. A value of P < 0.05 was considered statistically significant.

RESULTS: Fifty µM of midazolam significantly impaired endothelial cell proliferation, migration, and in vitro capillary tube formation. Propofol, diazepam or lower dose midazolam did not show any enhancing or suppressive effects on in vitro angiogenesis. Fifty µM of midazolam remarkably activated ERK, but not p38 MAPK in HUVEC.

CONCLUSION: Propofol and benzodiazepines except high-dose midazolam did not affect in vitro angiogenesis. High-dose midazolam may impair in vitro capillary tube formation due to by suppressing proliferation and migration of endothelial cells via activation of ERK.

PMID:34460008 | DOI:10.1007/s00540-021-02993-x

Bull Math Biol. 2021 Aug 30;83(10):103. doi: 10.1007/s11538-021-00935-y.

ABSTRACT

We combine a systems pharmacology approach with an agent-based modelling approach to simulate LoVo cells subjected to AZD6738, an ATR (ataxia-telangiectasia-mutated and rad3-related kinase) inhibiting anti-cancer drug that can hinder tumour proliferation by targeting cellular DNA damage responses. The agent-based model used in this study is governed by a set of empirically observable rules. By adjusting only the rules when moving between monolayer and multi-cellular tumour spheroid simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model is first parameterised by monolayer in vitro data and is thereafter used to simulate treatment responses in in vitro tumour spheroids subjected to dynamic drug delivery. Spheroid simulations are subsequently compared to in vivo data from xenografts in mice. The spheroid simulations are able to capture the dynamics of in vivo tumour growth and regression for approximately 8 days post-tumour injection. Translating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and in this article, we exemplify how data-driven, agent-based models can be used to bridge the gap between in vitro and in vivo research. We further highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.

PMID:34459993 | DOI:10.1007/s11538-021-00935-y

Eur J Pediatr. 2021 Aug 30. doi: 10.1007/s00431-021-04215-8. Online ahead of print.

ABSTRACT

A retrospective study that compared children younger than 6 months versus older children of a Spanish cohort of patients diagnosed with Kawasaki disease between 2011 and 2016 (Kawa-Race study). From the 598 patients recruited, 42 patients were younger than 6 months (7%) and presented more frequently with an incomplete diagnosis of Kawasaki disease (52.4 vs 27.9%, p = 0.001). Cardiac abnormalities detected by echocardiography were more common in younger patients (52.4 vs 30%, p = 0.002). These younger patients presented with a higher proportion of coronary aneurysms as well (19 vs 8.6%, p < 0.001). Shock at diagnosis (9.5 vs 1.9%, p = 0.016) and admission to intensive care units (17.7 vs 4.1%, p = 0.003) were more frequent in patients younger than 6 months. There were no statistically significant differences in relation to infections, non-response to IVIG, or mid- or long-term outcomes.Conclusion: Data of the Spanish cohort are consistent with other American and Asian studies, although Spanish children younger than 6 months had a lower rate of non-response to IVIG and better clinical outcomes. A high index of suspicion should be considered for this population due to a higher risk of coronary abnormalities, presentation of shock, and admission to the intensive care unit. What is Known: •Children below 6 months of age with Kawasaki disease (KD) have different features compared to older. •Younger patients usually have an incomplete form of KD and coronary artery abnormalities. What is New: •Younger than 6 months with KD presented with shock and required admission to PICU more frequently compared to older. •Infections play a similar role in KD despite the age of the patients.

PMID:34459958 | DOI:10.1007/s00431-021-04215-8

Surg Endosc. 2021 Aug 30. doi: 10.1007/s00464-021-08697-3. Online ahead of print.

ABSTRACT

BACKGROUND: Gender disparities in surgical leadership have come under increased scrutiny, and in order to better understand why these disparities exist, it is important to study the disparities across surgical fellowship programs.

METHODS: Data derived from the Fellowship Council (FC) database for fellows completing training from academic years 2015-2019 were analyzed. Available information included institution, fellowship type, program director (PD), associate program director (APD), faculty, and fellow names for all FC Fellowships. Faculty and fellow gender were determined from personal knowledge or publicly available online biographical information.

RESULTS: A total of 1023 fellows and 221 programs were analyzed. The advanced gastrointestinal (GI)/minimally invasive surgery (MIS) fellowship programs included 321 fellows, with a small increase in the percentage of female fellows from 28 to 31% over 5 years. Advanced GI/MIS/bariatric fellowship programs had a total of 262 fellows, also with a small increase in the percent of female fellows, from 29 to 38% in the study period. The gender of program directors, assistant program directors, and faculty for the fellowship programs studied were analyzed as well. Of the 221 programs in the Fellowship Council data, 13.6% of program directors, 18.3% of associate program directors, and 19.9% of faculty were female. Advanced GI/MIS fellowship programs had the lowest percentage of female PDs, with only 9.3% of the program directors being female. Colorectal surgery fellowships had the highest percentage of female PDs, with 33% being female.

CONCLUSIONS: In conclusion, women are underrepresented in gastrointestinal surgery fellowships among both trainees and educators. It is likely that a significant contributing factor to this underrepresentation of female fellows is the underrepresentation of female program directors and faculty; although neither our study nor any previously published study has proven that statistically.

PMID:34459975 | DOI:10.1007/s00464-021-08697-3