ResearchPad - research-paper https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Can network pharmacology identify the anti-virus and anti- inflammatory activities of Shuanghuanglian oral liquid used in Chinese medicine for respiratory tract infection?]]> https://www.researchpad.co/article/elastic_article_13632 Shuanghuanglian (SHL) oral liquid is a well-known traditional Chinese medicine preparation administered for respiratory tract infections in China. However, the underlying pharmacological mechanisms remain unclear. The present study aims to determine the potential pharmacological mechanisms of SHL oral liquid based on network pharmacology.MethodsA network pharmacology-based strategy including collection and analysis of putative compounds and target genes, network construction, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Gene Ontology (GO) enrichment, identification of key compounds and target genes, and molecule docking was performed in this study.ResultsA total of 82 bioactive compounds and 226 putative target genes of SHL oral liquid were collected. Of note, 28 hub target genes including 4 major hub target genes: estrogen receptor 1 (ESR1), nuclear receptor coactivator 2 (NCOA2), nuclear receptor coactivator 1 (NCOA1), androgen receptor (AR) and 5 key compounds (quercetin, luteolin, baicalein, kaempferol and wogonin) were identified based on network analysis. The hub target genes mainly enriched in pathways including PI3K-Akt signaling pathway, human cytomegalovirus infection, and human papillomavirus infection, which could be the underlying pharmacological mechanisms of SHL oral liquid for treating diseases. Moreover, the key compounds had great molecule docking binding affinity with the major hub target genes.ConclusionUsing network pharmacology analysis, SHL oral liquid was found to contain anti-virus, anti-inflammatory, and “multi-compounds and multi-targets” with therapeutic actions. These findings may provide a valuable direction for further clinical application and research. ]]> <![CDATA[Altered Neural Response Induced by Central-Fatigue in the Cortical Area During High-Intensity Interval Pedaling]]> https://www.researchpad.co/article/elastic_article_13363 The central-governor model explains the mechanism of endurance exercise-induced central fatigue, but high-intensity exercise-induced central fatigue has not been investigated yet. This study aimed to research how central fatigue during high-intensity intermittent pedaling alters the neural response, which results in Electroencephalography (EEG) recordings.Methods:We assessed neural response by measuring the alternation of brainwave spectral power during an intermittent high-intensity 60-minute exercise on an ergometer cycle. The cadences were changed every 10 minutes according to intermittent pattern altering (90-120-60-120-60-90 rpm). EEG was used to analyze altering brain function. Heart Rate (HR), Blood Lactate (BL), and Rating of Perceived Exertion (RPE) were measured after the change in cadences.Results:HR, BL, and RPE increased at a cadence of 120 rpm compared with 60 rpm on the ergometer cycle. The spectral power of EEG, according to cadence × brainwaves, significantly increased (P<0.01) in the alpha and beta frequency ranges with a change in cadences between 60 rpm and 120 rpm. The spectral power of the EEG significantly increased (P<0.01) over the whole frequency range from rest to warming (theta: 251%, alpha: 165%, beta: 145%) and significantly reduced in theta, alpha, and beta (theta: 176%, alpha: 142%, beta: 77%) (P≤0.01).Conclusion:High-intensity exercises (90 and 120 cadences) increased brain function, regardless of fatigue occurrence. High-intensity interval training (HIIT) led to altering the neural response. It would be required to investigate the usefulness of HIIT to treat some of the psychotic disorders. ]]> <![CDATA[Comparing the Efficacy of Anodal, Cathodal, and Sham Transcranial Direct Current Stimulation on Brain-Derived Neurotrophic Factor and Psychological Symptoms in Opioid-Addicted Patients]]> https://www.researchpad.co/article/elastic_article_13362 Today, addiction to opioids is a serious problem all over the world. Unfortunately, the consumption of these drugs and the number of addicted people have drastically increased. This research aimed at comparing the efficacy of anodal, cathodal, and sham transcranial Direct Current Stimulation (tDCS) on the Brain-Derived Neurotrophic Factor (BDNF) and psychological symptoms in opioid-addicted patients.Methods:Thirty opioid-addicted patients were selected based on the Diagnostic and Statistical Manual of Mental Disorders, the Fifth Edition, through the convenience sampling method. They were then randomly assigned to 3 groups (10 in each group). The subjects were evaluated before and after tDCS by their serum level of BDNF, desires for drug questionnaire, and depression anxiety stress scale. The data were analyzed by the Kolmogorov-Smirnov test, one-way analysis of variance, as well as the Bonferroni test.Results:Stimulating the Dorsolateral Prefrontal Cortex (DLPFC) led to a significant change in increasing the level of BDNF (P=0.031) and reducing the degree of depression (P=0.018), anxiety (P=0.001), stress (P=0.012), and decreased the level of craving (P=0.001) in opioid-addicted patients. There was no significant difference between active stimulation groups (anodal left/cathodal right and anodal right/cathodal left). The stimulation of the right DLPFC (group B) significantly increased BDNF in comparison with the sham group (sham tDCS) and decreased anxiety and craving. Nonetheless, no change was observed in depression and stress. The stimulation of the left DLPFC (group A) significantly reduced depression, anxiety, stress, and craving compared with the sham group, while there was no change in BDNF.Conclusion:In addition to the conventional treatments of opioid-addicted patients, tDCS is an effective complementary treatment. ]]> <![CDATA[Partial Improvement of Spatial Memory Damages by Bone Marrow Mesenchymal Stem Cells Transplantation Following Trimethyltin Chloride Administration in the Rat CA1]]> https://www.researchpad.co/article/elastic_article_13360 Trimethyltin Chloride (TMT) is a neurotoxin that can kill neurons in the nervous system and activate astrocytes. This neurotoxin mainly damages the hippocampal neurons. After TMT injection, behavioral changes such as aggression and hyperactivity have been reported in animals along with impaired spatial and learning memory. Hence, TMT is a suitable tool for an experimental model of neurodegeneration. The present study aims to determine the palliative effects of Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs) on the hippocampi of rats damaged from TMT exposure.Methods:We assigned 28 male Wistar rats to the following groups: control, model, vehicle, and treatment. The groups received Intraperitoneal (IP) injections of 8 mg/kg TMT. After one week, stem cells were stereotactically injected into the CA1 of the right rats’ hippocampi. Spatial memory was determined by the Morris Water Maze (MWM) test 6 weeks after cell transplantation. Finally, the rats’ brains were perfused and stained by cresyl violet to determine the numbers of cells in the Cornus Ammonis (CA1) section of the hippocampus. We assessed the expressions of Glial Fibrillary Acidic Protein (GFAP) and Neuronal-specific Nuclear (NeuN) proteins in the right hippocampus by Western blot.Results:The MWM test showed that the treatment group had significantly higher traveled distances in the target quarter compared with the model and vehicle groups (P<0.05). Based on the result of cell count (Nissl staining), the number of cells increased in the treatment group compared with the model and vehicle groups (P<0.05). Western blot results showed up-regulation of GFAP and NeuN proteins in the model, vehicle, and treatment groups compared with the control group.Conclusion:Injection of BM-MSCs may lead to a behavioral and histological improvement in TMT-induced neurotoxicity by increasing the number of pyramidal neurons and improving memory. ]]> <![CDATA[Evaluation of the Anti-apoptotic and Anti-cytotoxic Effect of Epicatechin Gallate and Edaravone on SH-SY5Y Neuroblastoma Cells]]> https://www.researchpad.co/article/elastic_article_13359 Parkinson disease (PD) is the second most common neurodegenerative disease affecting older individuals with signs of motor disability and cognitive impairment. Epicatechin (EC) and edaravone have neuroprotective effects most probably due to their antioxidant activity; however, a limited number of studies have considered their role in PD. This research aimed at investigating the neuroprotective effect of EC and edaravone in a neurotoxin-induced model of PD.Methods:An in vitro model of PD was made by subjecting SH-SY5Y neuroblastoma cells to neurotoxin: 6-hydroxydopamine (6-OHDA) 100 μM/well. The cytoprotective effect of EC and edaravone in five concentrations on cell viability was tested using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The apoptotic assay was done by annexin V and propidium iodide method using flow cytometry.Results:According to the MTT assay analysis, EC and edaravone had protective effects against 6-OH DA-induced cytotoxicity in SH-SY5Y neuroblastoma cells that were much more significant for edaravone and also a relative synergistic effect between EC and edaravone was observed. The apoptotic analysis showed that edaravone alone could decrease early and late apoptosis, whereas EC diminished early apoptosis, but enhanced late apoptosis and necrosis. Besides, co-treatment of edaravone and EC had a synergistic effect on decreasing apoptosis and increasing cell viability.Conclusion:The protective effect of edaravone on apoptosis and cytotoxicity was demonstrated clearly and EC had a synergistic effect with edaravone. ]]> <![CDATA[Protective Role of Apigenin Against Aβ 25–35 Toxicity Via Inhibition of Mitochondrial Cytochrome c Release]]> https://www.researchpad.co/article/elastic_article_13358 Cognitive dysfunction is the most common problem of patients with Alzheimer Disease (AD). The pathological mechanism of cognitive impairment in AD may contribute to neuronal loss, synaptic dysfunction, and alteration in neurotransmitters receptors. Mitochondrial synapses dysfunction due to the accumulation of Amyloid Beta (Aβ) is one of the earliest pathological features of AD. The flavone apigenin has been reported to play some protective roles in AD through the anti-oxidative and anti-inflammatory properties. This study aimed at investigating the effects of apigenin on spatial working memory and neural protection by restoring mitochondrial dysfunction and inhibition of caspase 9.Methods:Intracerebroventricular (ICV) microinjection of Aβ 25–35 was used for AD modeling. Working memory was assessed 21 days later using the Y maze test. Neuronal loss was detected in the hilar area of the hippocampus using Nissl and Fluoro-jade B staining, whereas immunohistochemistry was used to illustrate cytochrome c positive cells and caspase 9.Results:The results revealed that apigenin significantly ameliorated spatial working memory. It also significantly reduced the number of degenerative neurons in the hilus area. Apigenin almost completely blocked the release of cytochrome c and caspase 9 in hilus.Conclusion:Apigenin may improve the spatial working memory deficits and neuronal degeneration through the amelioration of the mitochondrial dysfunction. ]]> <![CDATA[Developing the Persian Version of Sensory Gating Inventory and Assessing Its Validity and Reliability]]> https://www.researchpad.co/article/elastic_article_13357 Sensory Gating Inventory (SGI) measures behavioral aspects of Sensory Gating (SG), which filters irrelevant sensory inputs into the higher cortex. It modifies sensitivity to sensory stimuli. Abnormal SG leads to overloading of information in the brain and its subsequent dysfunction. Electrophysiological techniques cannot assess the behavioral aspects of SG. We aimed to design the Persian version of SGI with high validity and reliability.Methods:After a forward and then backward translation of the original SGI, we assessed the content validity and construct validity of the Persian version. A total of 405 participants filled the Persian version of SGI. To assess test-retest reliability, 100 participants filled the inventory again 7–10 days later. The content validity ratio and index, as well as confirmatory factor analysis, were computed, too. Finally, the Cronbach’s alpha, Cohen’s kappa, and intraclass correlation coefficients were calculated.Results:The content validity ratios of all items of the inventory were more than 60%, which means that they were necessary according to the experts’ opinions. Confirmatory factor analysis confirmed the fitness of the 4-factor structure of the original Inventory. The test-retest reliability using the intraclass correlation coefficient and Cronbach’s alpha coefficients were also high for the four subscales. The Cohen’s kappa coefficients revealed moderate to substantial level of agreement between the first and second scores for all items.Conclusion:The Persian version of SGI has good and acceptable psychometric properties. It can be used as a valid and reliable tool for studying behavioral aspects of SG in Persian speaking population. ]]> <![CDATA[Comparing the Effectiveness of Neurofeedback and Transcranial Direct Current Stimulation on Sleep Quality of Patients With Migraine]]> https://www.researchpad.co/article/elastic_article_13355 Migraine is considered one of the most common primary headache disorders. Migraine attacks may occur due to a lack of sleep. Furthermore, sleep is regarded as one of the smoothing factors of migraine pain. Patients with sleep disorders often suffer from headaches when they wake up compared with healthy individuals.Methods:This research was a quasi-experimental study with a pre-test-post-test design and a 2-month follow-up. The samples included 20 migraine patients within the age range of 15 to 55 years who were selected as volunteers for treatment by the neurologists and psychiatrists during 2017. The initial evaluation was then conducted based on the inclusion and exclusion criteria and using the Ahvaz migraine questionnaire, and Pittsburgh sleep quality index. The patients were randomly assigned to two neurofeedback (n=10) and transcranial Direct Current Stimulation (tDCS) (n=10) groups and evaluated three times. The obtained data were analyzed by the repeated measures ANCOVA and Chi-square test in SPSS.Results:Based on the scores of both groups, no significant difference was observed between neurofeedback and tDCS groups. However, based on the results, neurofeedback decreased sleep latency, whereas tDCS increased sleep efficiency. Overall, these two treatments were effective in improving subjective sleep quality and sleep quality.Conclusion:Both neurofeedback and tDCS treatments could significantly enhance sleep quality of the patients in the post-test and 2-month follow-up. Given the effectiveness of both treatments, neurofeedback and tDCS are recommended to be used for improving the sleep status of patients with migraine. ]]> <![CDATA[Investigating the Role of Brain Lateralization and Gender in Paranormal Beliefs]]> https://www.researchpad.co/article/elastic_article_13354 Brain lateralization is associated with human behavior. Therefore, this study aimed at investigating the effects of brain lateralization on the scores of paranormal beliefs.Methods:The study population included 180 students of Sanandaj universities, Sanandaj City, Iran who were selected with convenience sampling method (100 left-brained males, 6 left-brained females, 56 both left- and right-brained males and 22 both left- and right-brained females). The research tools were the paranormal belief scale developed by Blackmore (1994), as well as the brain lateralization questionnaire (1985).Results:The obtained findings suggested a significant difference between the left-brain and right-brained people in terms of paranormal beliefs. A significant difference was also found between the left-brained males and both left- and right-brained females in terms of paranormal beliefs.Conclusion:The paranormal beliefs of the left-brained cases were different from both left- and right-brained subjects, which can be seen between the left-brained males and both left- and right-brained females. ]]> <![CDATA[Protein Kinase Cɛ in the Platelet and Hippocampal Tissue as a Diagnostic Biological Marker in Alzheimer Disease]]> https://www.researchpad.co/article/elastic_article_13353 Alzheimer Disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory and other cognitive functions. Protein Kinase Cɛ (PKCɛ) is an isoform that most effectively suppresses Amyloid Beta (Aβ) production and synaptic loss.Methods:In this study, spatial learning and memory for treated rats were evaluated by the Morris water maze test. The activity (total PKC), mRNA expression, and protein level of PKCɛ in the platelet and hippocampal tissue were evaluated using immunosorbent assay, real-time qPCR, and western blotting analysis, respectively.Results:The traveled distance was significantly prolonged, and escape latency significantly increased in Aβ-treated groups. PKC activity assay showed that there was a remarkable difference between the Aβ-treated and sham-operated groups on days 10 and 30 in the hippocampus and also day 30 in platelet after the injection of Aβ. A significant effect in PKC activity was observed between days 0 and 10, days 0 and 30, as well as days 5 and 30. Aβ significantly downregulated the PKCɛ mRNA expression in the hippocampus of rats on day 30; however, no significant difference was observed in platelet. Western blot analysis demonstrated that Aβ significantly reduced PKCɛ protein expression in the hippocampus of treated groups on day 30.Conclusion:The expression level of PKCɛ was downregulated following the injection of Aβ in the hippocampus, but no significant difference was observed between the AD and sham groups in platelet that may be due to the low concentration of PKCɛ or duration of Aβ exposure in the rat brain. ]]> <![CDATA[Gendered factors for heated tobacco product use: Focus group interviews with Korean adults]]> https://www.researchpad.co/article/elastic_article_13137 Since June 2017, heated tobacco products (HTPs) have been on sale in Korea, comprising approximately 11.8% of total tobacco sales in April 2019. This research illuminates hitherto unexplored gendered factors influencing the use of HTPs.METHODSThe participants for the focus group interviews (FGI) were recruited among those who use or have used HTPs. Participants were separated into six groups (a total of 38 persons: 20 men and 18 women). Each FGI, lasting for two hours, was audio-recorded and transcribed, and subsequently coded to conduct a content analysis using NVivo V12.RESULTSBoth male and female participants shared the same opinion that HTPs were ‘less smelly’ and that despite their significant merit, HTPs had slightly different usages and places of use. First, male participants used them to avoid family members’ pressure to quit smoking, and female participants used them to avoid the stigma associated with female smoking. Second, men tended to use HTPs indoors, mostly in non-smoking areas, while women used them outdoors, mainly in the streets. Both genders were dissatisfied with the taste of HTPs and often used them in combination with combustible cigarettes (CCs). In terms of taste, dual use, absence of smoking cessation, and perception of harm, no definite gendered difference was found. Almost half of the participants considered HTPs to be less harmful than cigarettes, while others contended that they were equally harmful. Many agreed that there was no strong correlation between the use of HTPs and smoking cessation.CONCLUSIONSSince HTPs have the potential to weaken motivating factors for smoking cessation in both male and female users, an understanding of their characteristics with gendered factors is beneficial to establishing policies to prevent the spread of HTP use and increase the overall rate of smoking cessation. ]]> <![CDATA[Exposure to secondhand smoke in hospitality settings in Ghana: Evidence of changes since implementation of smoke-free legislation]]> https://www.researchpad.co/article/elastic_article_13136 Ghana has a partial smoking ban with smoking allowed in designated smoking areas. Studies evaluating smoke-free laws are scarce in Sub-Saharan Africa. Evaluation of smoke-free laws is an effective means of measuring progress towards a smoke-free society. This study assessed the level of compliance to the provisions of the current smoke-free policy using air quality measurements for fine particulate matter (PM2.5) in hospitality venues in Ghana.METHODSThis was a cross-sectional observational study conducted in 2019 using a structured observational checklist complemented with air quality measurements using Dylos monitors across 152 randomly selected hospitality venues in three large cities in Ghana.RESULTSSmoking was observed in a third of the venues visited. The median indoor PM2.5 concentration was 14.6 μg/m3 (range: 5.2–349). PM2.5 concentrations were higher in venues where smoking was observed (28.3 μg/m3) compared to venues where smoking was not observed (12.3 μg/m3) (p<0.001). Hospitality locations in Accra, Ghana’s capital city, had the lowest compliance levels (59.5%) and poorer air quality compared to the cities of Kumasi and Tamale.CONCLUSIONSThe study shows that while smoking and SHS exposure continues in a substantial number of hospitality venues, there is a marked improvement in PM2.5 concentrations compared to earlier studies in Ghana. There is still a considerable way to go to increase compliance with the law. Efforts are needed to develop an action plan to build upon recent progress in providing smoke-free public spaces in Ghana. ]]> <![CDATA[Aneuploidy in targeted endoscopic biopsies outperforms other tissue biomarkers in the prediction of histologic progression of Barrett's oesophagus: A multi-centre prospective cohort study]]> https://www.researchpad.co/article/elastic_article_12767 The cancer risk in Barrett's oesophagus (BO) is difficult to estimate. Histologic dysplasia has strong predictive power, but can be missed by random biopsies. Other clinical parameters have limited utility for risk stratification. We aimed to assess whether a molecular biomarker panel on targeted biopsies can predict neoplastic progression of BO.Methods203 patients with BO were tested at index endoscopy for 9 biomarkers (p53 and cyclin A expression; aneuploidy and tetraploidy; CDKN2A (p16), RUNX3 and HPP1 hypermethylation; 9p and 17p loss of heterozygosity) on autofluorescence-targeted biopsies and followed-up prospectively. Data comparing progressors to non-progressors were evaluated by univariate and multivariate analyses using survival curves, Cox-proportional hazards and logistic regression models.Findings127 patients without high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC) at index endoscopy were included, of which 42 had evidence of any histologic progression over time. Aneuploidy was the only predictor of progression from non-dysplastic BO (NDBO) to any grade of neoplasia (p = 0.013) and HGD/OAC (p = 0.002). Aberrant p53 expression correlated with risk of short-term progression within 12 months, with an odds ratio of 6.0 (95% CI: 3.1–11.2). A panel comprising aneuploidy and p53 had an area under the receiving operator characteristics curve of 0.68 (95% CI: 0.59–0.77) for prediction of any progression.InterpretationAneuploidy is the only biomarker that predicts neoplastic progression of NDBO. Aberrant p53 expression suggests prevalent dysplasia, which might have been missed by random biopsies, and warrants early follow up. ]]> <![CDATA[Diet quality is associated with reduced risk of hypertension among Inner Mongolia adults in northern China]]> https://www.researchpad.co/article/elastic_article_12757 The present study investigated the association between dietary patterns and hypertension applying the Chinese Dietary Balance Index-07 (DBI-07).Design:A cross-sectional study on adult nutrition and chronic disease in Inner Mongolia. Dietary data were collected using 24 h recall over three consecutive days and weighing method. Dietary patterns were identified using principal components analysis. Generalized linear models and multivariate logistic regression models were used to examine the associations between DBI-07 and dietary patterns, and between dietary patterns and hypertension.Setting:Inner Mongolia (n 1861).Participants:A representative sample of adults aged ≥18 years in Inner Mongolia.Results:Four major dietary patterns were identified: ‘high protein’, ‘traditional northern’, ‘modern’ and ‘condiments’. Generalized linear models showed higher factor scores in the ‘high protein’ pattern were associated with lower DBI-07 (βLBS = −1·993, βHBS = −0·206, βDQD = −2·199; all P < 0·001); the opposite in the ‘condiments’ pattern (βLBS = 0·967, βHBS = 0·751, βDQD = 1·718; all P < 0·001). OR for hypertension in the highest quartile of the ‘high protein’ pattern compared with the lowest was 0·374 (95 % CI 0·244, 0·573; P trend < 0·001) in males. OR for hypertension in the ‘condiments’ pattern was 1·663 (95 % CI 1·113, 2·483; P trend < 0·001) in males, 1·788 (95 % CI 1·155, 2·766; P trend < 0·001) in females.Conclusions:Our findings suggested a higher-quality dietary pattern evaluated by DBI-07 was related to decreased risk for hypertension, whereas a lower-quality dietary pattern was related to increased risk for hypertension in Inner Mongolia. ]]> <![CDATA[Adaptation, acceptability and feasibility of a Short Food Survey to assess the dietary intake of children during attendance at childcare]]> https://www.researchpad.co/article/elastic_article_12756 To (i) describe the adaptation of the Short Food Survey (SFS) for assessing the dietary intake of children (2–5 years) during attendance at Early Childhood Education and Care (SFS-ECEC); (ii) determine the acceptability and feasibility of the SFS-ECEC; and (iii) compare the SFS-ECEC to direct observations for assessing dietary intake of children in care.Design:The adapted forty-seven-item SFS-ECEC was completed by childcare educators to capture individual child’s usual intake over the past month. Acceptability and feasibility were assessed via educator self-report and completion rates. Mean servings of food groups consumed in accordance with dietary guidelines reported in the SFS-ECEC were compared to those obtained by a single-day direct observation via visual estimation conducted by trained personnel. Mean differences, intra-class correlations, Bland–Altman plots, percentage agreement and Cohen’s κ were examined.Setting:Early Childhood Education and Care, NSW, Australia.Participants:Educators and children.Results:213 (98·61 %) SFS-ECECs were returned. Acceptability was high with 86·54 % of educators reporting the tool as easy to understand. Mean differences in servings of food groups between the SFS-ECEC and direct observation were statistically significantly different for five out of six foods and ranged 0·08–1·07, with intra-class correlations ranging 0·00–0·21. Agreement between the methods in the classification of children meeting or not meeting dietary guidelines ranged 42·78–93·01 %, with Cohen’s κ ranging −0·03 to 0·14.Conclusions:The SFS-ECEC is acceptable and feasible for completion by childcare educators. While tool refinement and further validation is warranted, small mean differences suggest the tool may be useful in estimating group-level intakes. ]]> <![CDATA[Four decades of socio-economic inequality and secular change in the physical growth of Guatemalans]]> https://www.researchpad.co/article/elastic_article_12754 To investigate changes in socio-economic inequalities in growth in height, weight, BMI and grip strength in children born during 1955–1993 in Guatemala, a period of marked socio-economic-political change.Design:We modelled longitudinal data on height, weight, BMI and hand grip strength using Super-Imposition by Translation and Rotation (SITAR). Internal Z-scores summarising growth size, timing and intensity (peak growth velocity, e.g. cm/year) were created to investigate inequalities by socio-economic position (SEP; measured by school attended). Interactions of SEP with date of birth were investigated to capture secular changes in inequalities.Setting:Urban and peri-urban schools in the region of Guatemala City, Guatemala.Participants:Participants were 40 484 children and adolescents aged 3–19 years of Ladino and Maya ancestry (nobservations 157 067).Results:The difference in height (SITAR size) between lowest and highest SEP decreased from −2·0 (95 % CI −2·2, −1·9) sd to −1·4 (95 % CI −1·5, −1·3) sd in males, and from −2·0 (95 % CI −2·1, −1·9) sd to −1·2 (95 % CI −1·3, −1·2) sd in females over the study period. Inequalities also reduced for weight, BMI and grip strength, due to greater secular increases in lowest-SEP groups. The puberty period was earlier and shorter in higher-SEP individuals (earlier SITAR timing and higher SITAR intensity). All SEP groups showed increases in BMI intensity over time.Conclusions:Inequality narrowed between the 1960s and 1990s. The lowest-SEP groups were still >1 sd shorter than the highest. Risks remain for reduced human capital and poorer population health for urban Guatemalans. ]]> <![CDATA[CD44+/EPCAM+ cells detect a subpopulation of ALDH<sup>high</sup> cells in human non-small cell lung cancer: A chance for targeting cancer stem cells?]]> https://www.researchpad.co/article/elastic_article_12525 Objectives: Several studies demonstrated that aldehyde dehydrogenase (ALDH) and CD44 are the most considered cancer stem cells (CSC) markers. However, a comparison between ALDH high cells and CD44+ cells have been previously described with no significant correlation. Indeed, the aim of the present research is to identify a superficial marker able to match with ALDH high cells population in freshly isolated human lung cancer cells.

Materials and Methods: This cross-sectional study analyzed the expression of ALDHhigh/low cells and the positivity for CD44 and epithelium cell adhesion molecule (EPCAM) antigens in surgical lung cancer tissues. The main approach was a cytofluorimetric analysis of ALDH expression and positivity for CD44/EPCAM on primary cell population obtained from 23 patients harboring NSCLC.

Results: There was a highly positive correlation between the expressions of ALDHhigh and CD44+/EPCAM+ cells, with a Pearson’s correlation coefficient equal to 0.69 (95% CI 0.39–0.86; P = 0.0002), and Spearman’s correlation coefficient equal to 0.52 (P = 0.0124). The average paired difference between the expression of ALDHhigh and CD44+/EPCAM+ cells was very close to 0, being 0.1% (SD 2.5%); there was no difference between these subpopulations in terms of means (95% CI = –1.0; 1.2%, P = 0.8464). These results highlight a strong similarity between ALDHhigh and CD44+/EPCAM+ cells.

Conclusions: Our study is the first attempt which identifies a high correlation between the ALDHhigh and the CD44+/EPCAM+ cells, thus suggesting the possibility to use this superficial marker for future target treatments against lung cancer stem cells.

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<![CDATA[Lactate induces PD-L1 in HRAS<sup>G12V</sup>-positive oropharyngeal squamous cell carcinoma]]> https://www.researchpad.co/article/elastic_article_12522 Intratumoral lactate production negatively correlates with survival and tumor clearance in the setting of human papillomavirus positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC). Robust anti-tumor immune activity is required for tumor clearance in human patients and animal models of this disease, and intratumoral lactate interferes with this process. While lactate is known to directly inhibit T cell activity, recent evidence has demonstrated that lactate can affect gene expression in multiple cell types. We therefore sought to determine if lactate in the tumor microenvironment could aid immune evasion by inducing the expression of immune checkpoint co-inhibitors. Using a mouse cell line transformed with HPV16 E6, E7, and HRASG12V, we determined that OPSCC cells carrying the HRASG12V mutant showed significantly increased expression of PD-L1 in the presence of extracellular lactate. Furthermore, we demonstrate here that lactate activates the MEK/ERK pathway in Ras-mutated cells.

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<![CDATA[Combined inhibition of PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation and potentiates PI3K inhibition in cancer cells]]> https://www.researchpad.co/article/elastic_article_12520 Aberrant activation of mitogenic signaling pathways in cancer promotes growth and proliferation of cells by activating mTOR and S6 phosphorylation, and D-cyclin kinases and Rb phosphorylation, respectively. Correspondingly, inhibition of phosphorylation of both Rb and S6 is required for robust anti-tumor efficacy of drugs that inhibit cell signaling. The best-established mechanism of mTOR activation in cancer is via PI3K/Akt signaling, but mTOR activity can also be stimulated by CDK4 and PIM kinases. In this study, we show that the CDK4/6 inhibitor abemaciclib inhibits PIM kinase and S6 phosphorylation in cancer cells and concurrent inhibition of PIM, CDK4, and CDK6 suppresses both S6 and Rb phosphorylation. TSC2 or PIK3CA mutations obviate the requirement for PIM kinase and circumvent the inhibition of S6 phosphorylation by abemaciclib. Combination with a PI3K inhibitor restored suppression of S6 phosphorylation and synergized to curtail cell growth. By combining abemaciclib with a PI3K inhibitor, three pathways (Akt, PIM, and CDK4) to mTOR activation are neutralized, suggesting a potential combination strategy for the treatment of PIK3CA-mutant ER+ breast cancer.

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<![CDATA[The cytotoxicity of gallium maltolate in glioblastoma cells is enhanced by metformin through combined action on mitochondrial complex 1]]> https://www.researchpad.co/article/elastic_article_12514 New drugs are needed for glioblastoma, an aggressive brain tumor with a dismal prognosis. We recently reported that gallium maltolate (GaM) retards the growth of glioblastoma in a rat orthotopic brain tumor model by inhibiting mitochondrial function and iron-dependent ribonucleotide reductase (RR). However, GaM’s mechanism of action at the mitochondrial level is not known. Given the interaction between gallium and iron metabolism, we hypothesized that gallium might target iron-sulfur (Fe-S) cluster-containing mitochondrial proteins. Using Extracellular Flux Analyzer technology, we confirmed that after a 24-h incubation, GaM 50 μmol/L inhibited glioblastoma cell growth by <10% but inhibited cellular oxygen consumption rate by 44% and abrogated mitochondrial reserve capacity. GaM blocked mitochondrial complex I activity and produced a 2.9-fold increase in cellular ROS. NMR spectroscopy revealed that gallium binds to IscU, the bacterial scaffold protein for Fe-S cluster assembly and stabilizes its folded state. Gallium inhibited the rate of in vitro cluster assembly catalyzed by bacterial cysteine desulfurase in a reaction mixture containing IscU, Fe (II), DTT, and L-cysteine. Metformin, a complex I inhibitor, enhanced GaM’s inhibition of complex I, further increased cellular ROS levels, and synergistically enhanced GaM’s cytotoxicity in glioblastoma cells in 2-D and 3-D cultures. Metformin did not affect GaM action on cellular iron uptake or transferrin receptor1 expression nor did it enhance the cytotoxicity of the RR inhibitor Didox. Our results show that GaM inhibits complex I by disrupting iron-sulfur cluster assembly and that its cytotoxicity can be synergistically enhanced by metformin through combined action on complex I.

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