Changes In Levels Research Articles

Cancer Pathways Targeted by Berberine: Role of microRNAs.

Cancer is a complex and heterogeneous malignant disease. Due to its multifactorial nature, including progressive changes in genetic, epigenetic, transcript, and protein levels, conventional therapeutics fail to save cancer patients. Evidence indicates that dysregulation of microRNA (miRNA) expression plays a crucial role in tumorigenesis, metastasis, cell proliferation, differentiation, metabolism, and signaling pathways. Moreover, miRNAs can be used as diagnostic and prognostic markers and therapeutic targets in cancer. Berberine, a naturally occurring plant alkaloid, has a wide spectrum of biological activities in different types of cancers. Inhibition of cell proliferation, metastasis, migration, invasion, and angiogenesis, as well as induction of cell cycle arrest and apoptosis in cancer cells, is reported by berberine. Recent studies suggested that berberine regulates many oncogenic and tumor suppressor miRNAs implicated in different phases of cancer. This review discussed how berberine inhibits cancer growth and propagation and regulates miRNAs in cancer cells. And how berberine-mediated miRNA regulation changes the landscape of transcripts and proteins that promote or suppress cancer progression. Overall, the underlying molecular pathways altered by berberine and miRNA influencing the tumor pathophysiology will enhance our understanding to combat the malignancy.

YTHDC2 serves a distinct late role in spermatocytes during germ cell differentiation.

Post-transcriptional regulation of gene expression by RNA-binding proteins can enhance the speed and robustness of cell state transitions by controlling RNA stability, localization, or if, when or where mRNAs are translated. The RNA helicase YTHDC2 is required to shut down components of the mitotic program to facilitate a proper switch from mitosis to meiosis in mouse germ cells. Here we show that YTHDC2 has a second essential role in promoting meiotic progression in late spermatocytes. Inducing conditional knockout of Ythdc2 during the first wave of spermatogenesis, after initiation of meiotic prophase, allowed Ythdc2-deficient germ cells to advance to the pachytene stage and properly express many meiotic markers. However, the Ythdc2-deficient spermatocytes mis-expressed a number of genes, some up-regulated and some down-regulated, failed to transition to the diplotene stage, then quickly died. Co-immunoprecipitation experiments revealed that YTHDC2 interacts with several RNA-binding proteins in early or late spermatocytes, with many of the interacting proteins, including MEIOC, localizing to granules, similar to YTHDC2. Our findings suggest that YTHDC2 collaborates with other RNA granule components to facilitate proper progression of germ cells through multiple steps of meiosis via mechanisms influencing post-transcriptional regulation of RNAs.

PP1β opposes classic PP1 function, inhibiting spine maturation and promoting LTP.

Protein phosphatase 1 (PP1) regulates synaptic plasticity and has been described as a molecular constraint on learning and memory. There are three neuronal isoforms, PP1α, PP1β, and PP1γ, but little is known about their individual functions. PP1α and PP1γ are assumed to mediate the effects of PP1 on learning and memory based on their enrichment at dendritic spines and their preferential binding to neurabin and spinophilin, major PP1 synaptic scaffolding proteins. However, it was recently discovered that human de novo PP1β mutations cause intellectual disability, suggesting an important but ill-defined role for PP1β. In this study, we investigated the functions of each PP1 isoform in hippocampal synaptic physiology using conditional CA1-specific knockout mice. In stark contrast to classic PP1 function, we found that PP1β promotes synaptic plasticity as well as spatial memory. These changes in synaptic plasticity and memory are accompanied by changes in GluA1 phosphorylation, GluN2A levels, and dendritic spine density and morphology, including silent synapse number. These functions of PP1β reveal a previously unidentified signaling pathway regulating spine maturation and plasticity, broadening our understanding of the complex role of PP1 in synaptic physiology.

Study on the influence of rainfall infiltration on the stability of dump slope

The present strength reduction finite element methods usually only reduce strength parameters, which result in the deformation state of earth-rock aggregate slope are different from the practical ones. The article holds that under rainfall infiltration, not only the strength parameters of earth-rock aggregate slope will reduce, but also the deformation parameters will also change with the changing of soils stress levels and strength parameters. Using the developed FDM (Finite Difference Method), the numerical simulation for earth-rock aggregate slope deformation under different rainfall infiltration depths are conducted, and the results of numerical calculation are compared with those of the laboratory model tests. Then the influence law of rainfall infiltration depths on the road-embankment slope stability and sliding arc changing characteristics are analyzed by strength reduction finite element methods.

Impact of alcohol control policy on hemorrhagic and ischemic stroke mortality rates in Lithuania: An interrupted time series analysis.

Given the causal impact of alcohol use on stroke, alcohol control policies should presumably reduce stroke mortality rates. This study aimed to test the impact of three major Lithuanian alcohol control policies implemented in 2008, 2017 and 2018 on sex- and stroke subtype-specific mortality rates, among individuals 15+ years-old. Joinpoint regression analyses were performed for each sex- and stroke subtype-specific group to identify timepoints corresponding with significant changes in mortality rate trends. To estimate the impact of each policy, interrupted time series analyses using a generalized additive mixed model were performed on monthly sex- and stroke subtype-specific age-standardized mortality rates from January 2001-December 2018. Significant average annual percent decreases were found for all sex- and stroke subtype-specific mortality rate trends. The alcohol control policies were most impactful on ischemic stroke mortality rates among women. The 2008 policy was followed by a positive level change of 4,498 ischemic stroke deaths per 100,000 women and a negative monthly slope change of -0.048 ischemic stroke deaths per 100,000 women. Both the 2017 and 2018 policy enactment timepoints coincided with a significant negative level change for ischemic stroke mortality rates among women, at -0.901 deaths and -1.431 deaths per 100,000 population, respectively. Hemorrhagic stroke mortality among men was not affected by any of the policies, and hemorrhagic stroke mortality among women and ischemic stroke mortality among men were only associated with the 2008 policy. Our study findings suggest that the impact of alcohol control policies on stroke mortality may vary by sex and subtype.

Change in eating habits after 2 years of pandemic restrictions among adolescents living in a city in northern Italy: results of the COALESCENT Observational Study (Change amOng ItAlian adoLESCENTs)

BackgroundLockdown measures during the recent pandemic, due to the novel COVID-19, affected several other aspects of lifestyle, but little is known about their long-term impact, especially among adolescents. Our study...

Effect of Metformin on Plasma and Cerebrospinal Fluid Biomarkers in Non-Diabetic Older Adults with Mild Cognitive Impairment Related to Alzheimer's Disease.

Alzheimer's disease (AD) is a complicated condition involving multiple metabolic and immunologic pathophysiological processes that can occur with the hallmark pathologies of amyloid-β, tau, and neurodegeneration. Metformin, an anti-diabetes drug, targets several of these disease processes in in vitro and animal studies. However, the effects of metformin on human cerebrospinal fluid (CSF) and plasma proteins as potential biomarkers of treatment remain unexplored. Using proteomics data from a metformin clinical trial, identify the impact of metformin on plasma and CSF proteins. We analyzed plasma and CSF proteomics data collected previously (ClinicalTrials.gov identifier: NCT01965756, conducted between 2013 and 2015), and conduced bioinformatics analyses to compare the plasma and CSF protein levels after 8 weeks of metformin or placebo use to their baseline levels in 20 non-diabetic patients with mild cognitive impairment (MCI) and positive AD biomarkers participants. 50 proteins were significantly (unadjusted p < 0.05) altered in plasma and 26 in CSF after 8 weeks of metformin use, with 7 proteins in common (AZU1, CASP-3, CCL11, CCL20, IL32, PRTN3, and REG1A). The correlation between changes in plasma and CSF levels of these 7 proteins after metformin use relative to baseline levels was high (r = 0.98). The proteins also demonstrated temporal stability. Our pilot study is the first to investigate the effect of metformin on plasma and CSF proteins in non-diabetic patients with MCI and positive AD biomarkers and identifies several candidate plasma biomarkers for future clinical trials after confirmatory studies.

Assessing Tidal Models in the Ryukyu Islands Region Using the ENOPF Method

Abstract Satellite remote sensing can monitor sea level changes at temporal and spatial scales, plays an important role in the study of tides, and is widely used in numerical tidal models. However, these tidal models are usually computationally expensive. The equidistant nodes orthogonal polynomial fitting (ENOPF) method may overcome that drawback. This study evaluates the accuracy of the ENOPF method in fitting the major tidal constituents in the region near the Ryukyu Islands, where the water depth on either side of the islands varies significantly. The results show that the ENOPF method can accurately fit the major tidal constituents in the presence of complex topography. Furthermore, this approach can also be used to generate reasonable cotidal charts and provide valuable tidal information for hydrodynamic model simulations in the East China Sea. For the high-resolution hydrodynamic model of the East China Sea in particular, reasonable open boundary conditions can be provided by the ENOPF method.

Impact of the State of Emergency Declaration for Severe Acute Respiratory Syndrome Coronavirus-2 Pandemic Suppression on Individuals with Type 1 Diabetes Mellitus.

Objective To examine the impact of lifestyle changes caused by the first emergency declaration issued in 2020 on glycemic control and body weight changes in Japanese individuals with type 1 diabetes mellitus. Methods This study included Japanese individuals with type 1 diabetes mellitus who visited Tokyo Women's Medical University Hospital between January 2019 and September 2020 (n=278). Seasonal changes in glycated hemoglobin (HbA1c) levels and the body mass index (BMI) were compared. A self-administered questionnaire regarding changes in treatment, diet, exercise, sleep, and telecommuting was used to assess lifestyle changes. Results Although HbA1c levels decreased from winter to summer in 2019 and 2020, the annual change was slightly but significantly greater in 2020 than in 2019. Seasonal changes in the BMI between 2019 and 2020 were also significantly different. An increase in the daily insulin dose, overall blood glucose level, diurnal change in blood glucose level, and food intake were significantly associated with increased HbA1c levels. Furthermore, HbA1c levels decreased with increasing moderate physical activity and sleep duration. The change in the BMI increased with increasing insulin dose, overall high blood glucose levels, and food intake. However, an increase in moderate physical activity was associated with a decrease in the BMI. HbA1c levels were significantly lower after the first emergency declaration in individuals with type 1 diabetes mellitus than that before the emergency declaration, even after accounting for seasonal variations. Conclusion Decreased HbA1c levels were associated with a decreased food intake, increased moderate exercise, and increased sleep duration during the state of emergency. The BMI remained relatively unchanged.

Lower Melatonin Indicates Poor Short-term Prognosis in Patients with Acute Ischemic Stroke.

We evaluated endogenous melatonin levels in the acute phase of cerebral infarction and explored the impact of possible changes in melatonin levels on the prognosis of patients. This study recruited acute ischemic stroke (AIS) patients from the Department of the Second Affiliated Hospital of Soochow University between December 2019 and June 2021, along with healthy control subjects. Salivary melatonin samples were collected from each participant between 7 pm and 10 pm, and fasting plasma was collected the following morning to measure the levels of inflammatory markers. The prognosis was assessed through follow-up three months after discharge. The relationship between melatonin levels and plasma inflammatory markers was assessed, followed by an analysis of the effect of melatonin levels on patient prognosis. The study enrolled a total of 160 participants, including 120 AIS patients aged 50 years or older (61.7% male) and 40 age-matched controls (55.0% male). The AIS group exhibited lower salivary melatonin levels at 19 (P = 0.002), 20 (P < 0.001), 21 (P < 0.001), and 22 (P < 0.001) o'clock, and the average melatonin level was also lower (P < 0.001). Logistic regression analysis models indicated an association between low melatonin levels and poor prognosis. Salivary melatonin levels demonstrated good predictive ability for the prognosis of AIS patients. Melatonin levels were lower in AIS patients compared to controls. In addition, lower melatonin levels were associated with a poorer prognosis among AIS patients.

Role of Thioredoxin System in Regulating Cellular Redox Status in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia and a public health problem. It exhibits significant oxidative stress and redox alterations. The antioxidant enzyme systems defend the cellular environment from oxidative stress. One of the redox systems is the thioredoxin system (TS), which exerts decisive control over the cellular redox environment. We aimed to review the protective effects of TS, which include thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH. In the following, we discussed the physiological functioning and the role of the TS in maintaining the cellular redox-homeostasis in the AD-damaged brain. Trx protects the cellular environment from oxidative stress, while TrxR is crucial for the cellular detoxification of reactive oxygen species in the brain. However, TS dysregulation increases the susceptibility to cellular death. The changes in Trx and TrxR levels are significantly associated with AD progression. Though the data from human, animal, and cellular models support the neuroprotective role of TS in the brain of AD patients, the translational potential of these findings to clinical settings is not yet applied. This review summarizes the current knowledge on the emerging role of the TrxR-Trx system in AD.

Systematic analysis of expression and prognostic significance for MCM family in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSC) is a common malignant tumor in the world and has a poor prognosis. The family of minichromosome maintenance proteins (MCM) improves the stability of genome replication by inhibiting the rate of DNA replication in eukaryotic cells, thus, small changes in physiological MCM levels would increase the instability of gene replication and increase the incidence of tumor formation, most of which are significantly elevated in multiple cancers. However, the expression of different MCM families in HNSC and their prognostic value remain unclear. ONCOMINE and GEPIA databases were used to analyze the expression of MCMs in HNSC. The Kaplan-Meier plotter database was used to identify molecules with prognostic values. We collected 77 HNSC tissues and 50 normal tissues to validate the results of the bioinformatics analysis by immunohistochemical staining. The expression of MCM3, MCM5 and MCM6 in mRNA and protein levels were higher in HNSC. Moreover, the increased expression of MCM3, MCM5 and MCM6 in mRNA and protein levels predicted better prognosis of HNSC patients. Furthermore, multivariate analysis showed that high expressions of MCM3, MCM5 and MCM6 in protein level may be independent prognostic factors for HNSC patients. The results of this study indicated that MCM3, MCM5 and MCM6 play an important role in occurrence and development in HNSC and might be risk factors for the survival of HNSC patients.

TGF-β1 Drives Integrin-Dependent Pericyte Migration and Microvascular Destabilization in Fibrotic Disease

Interactions between endothelial cells (EC) and mural pericytes (PC) are critical to maintaining the stability and function of the microvascular wall. Abnormal interactions between these two cell types are a hallmark of progressive fibrotic diseases, such as systemic sclerosis (SSc, scleroderma). However, the role that PCs play in signaling microvascular dysfunction remains underexplored. It is hypothesized that integrin-matrix interactions contribute to PC migration from the vascular wall and conversion into interstitial myofibroblasts. Using pro-inflammatory TNF alpha (TNFα) or fibrotic growth factor TGF beta-1 (TGFβ1), human PC inflammatory and fibrotic phenotypes were evaluated by assessing their migration, matrix deposition, integrin expression, and subsequent effects on endothelial dysfunction. Both TNFα and TGFβ1 treatment altered integrin expression and matrix protein deposition, but only fibrotic TGFβ1 drove PC migration in an integrin-dependent manner. In addition, integrin-dependent PC migration was correlated to changes in EC angiopoietin-2 levels, a marker of vascular instability. Finally, there was evidence of changes in vascular stability corresponding to disease state in human SSc skin. The work presented demonstrates that TNFα and TGFβ1 induce changes in PC integrin expression and matrix deposition that facilitate migration and reduce vascular stability, providing evidence that microvascular destabilization can be an early indicator of tissue fibrosis.

Abstract 5682: Micro RNA level changes in prostate cancer cells treated with MDMX and MDM2 inhibitors

Abstract INTRODUCTION: Prostate Cancer (PCa) is the most common non-cutaneous cancer and the second leading cause of cancer death among men in the United States. Most of the PCa cases are diagnosed in men between the ages of 65-74. Due to the recent push for frequent prostate screenings, these cancers are being detected early and treated much faster, leading to a 5-year survival of a localized or regional PCa to &amp;gt;99%. However, the 5-year survival of PCa with distant metastasis is significantly reduced to 32%, especially with involvement of osteoblastic bone lesions, lung lesions, and brain lesions. Therefore, there is a clinical need to identify prognostic markers and new targets for developing therapies and effectively treating advanced PCa. Previous studies have shown that levels of MDMX and MDM2, oncogenic inhibitors of p53 tumor suppressor protein, are significantly elevated in PCa cells. Inhibition of MDM2 and MDMX using specific inhibitors has been shown to elevate the levels of p21, p27, and p53 in LNCaP (Lymph Node Carcinoma of the Prostate) cells leading to cell death. Recent studies have demonstrated that micro RNAs (miRNAs) play an important role in supporting the tumor suppressor function of p53 through regulating the balance between p53 and MDM2. In this regard, several miRNAs were found to be significantly altered to modulate the level and intracellular mechanisms of p53 and MDM2 in various cancers. OBJECTIVES: To determine the relative levels of miRNA31, miRNA-34a and miRNA-128 in LNCaP cells that were treated with NSC-207895 (MDMX inhibitor), SJ-172550 (MDMX inhibitor), and RG-7388 (MDM2 inhibitor). METHODS: LNCaP cells were treated with NSC-207895 (20 uM), SJ-172550 (20 uM) or RG-7388 (2 uM) for 24 hrs. After completing the treatments, the miRNAs were extracted from the LNCaP cells using the miRNeasy Tissue/Cells Advanced Kit from Qiagen. We analyzed the levels of miRNA-31, miRNA-34a, and miRNA-128 in the treated samples using qRT-PCR analysis method and compared the levels to the control. During the qRT-PCR analysis the cDNA was amplified using Meridian Biosciences qPCR Master Mix and specific primers for miRNAs from Origene were used according to the manufacturer's protocol. RESULTS: Our experimental results indicate that inhibition of MDMX using NSC-207895 and SJ-172550 can elevate the levels of p21, p27, and p53 leading to cell death. Determination of cell death markers in the past revealed induction of necroptosis following drug treatments. Our current results indicate measurable changes in the levels of miRNA-31 and miRNA-34a following inhibition of MDMX using SJ-172550. We are in the process of determining the possible link between the changes in the levels of miRNAs and cell death. ACKNOWLEDGEMENT: This research was supported by the Royal Dames of Cancer Research, Ft. Lauderdale, Florida. Citation Format: Rojin Fatirkhorani, Ahmed Saleh Alsarrani, Shyam Sundar Jaganathan, Umamaheswari Natarajan, Appu Rathinavelu. Micro RNA level changes in prostate cancer cells treated with MDMX and MDM2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5682.

Abstract 468: Associations of circulating miRNAs with pancreatic cancer risk differ by years between blood collection &amp; and cancer diagnosis

Abstract Pancreatic adenocarcinoma (PDAC) is one of the most fatal cancers and currently used biomarkers for PDAC diagnosis are not adequate for early detection. Therefore, new biomarkers for PDAC early detection are urgently needed. We conducted a large-scale study to prospectively evaluate the association of circulating miRNAs with PDAC risk. Specially, we aimed to examine whether the associations of miRNAs expression levels and changes of those levels from blood collection to cancer diagnosis (BCCD) with PDAC risk. We used pre-diagnostic plasma samples of 1307 PDAC cases from 5 cohort studies (290 from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, 395 from the Shanghai Women’s and Men’s Health Studies, 154 from the Southern Community Cohort Study, and 468 from the Multiethnic Cohort). Cancer free controls (n=1307) were selected and individually matched to index cases in each cohort. All miRNAs were measured by the NanoString nCounter Analysis System using the Human v3 miRNA Expression panel (798 miRNAs total). Data were pooled and quantile normalized prior to analysis. Associations of circulating miRNAs with PDAC risk were assessed by odds ratio per decile change in miRNA levels using conditional logistic regression. Fold-change of miRNA for cases versus controls by BCCD was analyzed via linear regression. Median time of BCCD was 7.13 years (range: 0.03-19.61 years). We first conducted the association analysis stratified by BCCD: &amp;lt; 5 years, 5-10 years, and &amp;gt;10 years. We found 20 miRNAs were significantly associated with PDAC risk in the &amp;lt;5 years after FDR correction. In the analysis of regressing fold-change of these 20 miRNAs on BCCD, we found the fold change of miR-155-5p was inversely associated with BCCD (β=-0.04, P&amp;lt;0.01), i.e., the case-control difference was larger when blood was drawn closer to PDAC diagnosis, suggesting its potential utility as disease biomarkers for early detection. Conversely, the fold-change of miR-93-5p (β=0.04, P=0.01), miR-223-3p (β=0.03, P=0.02), let-7i-5p (β=0.03, P&amp;lt;0.01), and miR-191-5p (β=0.05, P&amp;lt;0.01) were positively associated with BCCD, i.e., the case-control difference increased with an increasing the time interval of BCCD, indicating they are more likely biomarkers for PDAC risk. Ingenuity pathway analyses of these five significant miRNAs revealed that they were significantly enriched in ribonucleotide reductase signaling pathways at p&amp;lt;0.05. Notably, the silencing of ribonucleotide reductase M2 subunit suppresses tumorigenesis in pancreatic cancer by deactivating the PI3K/AKT/mTOR pathway, further supporting our findings. Findings of this large-scale multiethnic study suggest that changes in circulating levels of let-7i-5p, miR-155-5p, miR-93-5p, miR-191-5p, and miR-223-3p may help identify individuals at an elevated risk of developing PDAC, allowing for screening tests and close surveillance. Citation Format: Hui Cai, Veronica Wendy Setiawan, Xingyi Guo, Jie Wu, Rachael Z Stolzenberg-Solomon, Claire Zhu, Yu-Tang Gao, Jordan Berlin, Fei Ye, Qiuyin Cai, Wei Zheng, Xiao-ou Shu. Associations of circulating miRNAs with pancreatic cancer risk differ by years between blood collection &amp; and cancer diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 468.

Abstract 3270: SH3GLB1 is involved with hydrogen peroxide/akt signaling in glioblastoma multiforme cells

Abstract Glioblastoma (GBM), a malignant brain tumor, has poor survival outcomes due to recurrence or drug resistance. In our previous studies, it was found that superoxide dismutase 2 (SOD2) was associated with temozolomide (TMZ) resistance. Moreover, SOD2 can convert O2 •− to H2O2, and H2O2 redox signaling is vital for physiological reactions and promotes tumor progression. We used cell lines, patient primary cells and pharmacological inhibitors/activators to confirm the significance of H2O2 signaling. We used the cultured cells to verify roles of H2O2 signaling in the plasticity of cell fate and did animal experiments to identify the optimal treatment strategy. In the present study, SOD2 was found to be the upstream mediator, and combining SOD inhibitor and TMZ, the cells showed reduced SH3GLB1 and autophagy levels. We then found that SH3GLB1 was regulated by H2O2 through AKT signaling using experiments of regulating redox homeostasis. The change of intracellular H2O2 levels in mitochondria following the treatments is similar to that in cytosol, however, the cell fate of parental or resistant cells was quite diverse. Notably, CCCP, a mitochondrial membrane potential disrupter, increased endogenous H2O2 production, and TMZ-increased SH3GLB1 levels can be reversed by HgCl2, reflecting the aquaporin function. In animal models, a combination of TMZ and 4-hydroxynonenal reduced growth of the SH3GLB1-knockdown resistant cells, along with suppressed autophagy levels. Our results characterizing the mechanism of H2O2-SH3GLB1 axis signaling in acquired TMZ resistance of GBM cells will provide new therapeutic strategies against the disease in the future. Citation Format: Chia-Hung Chien, Kwang-Yu Chang. SH3GLB1 is involved with hydrogen peroxide/akt signaling in glioblastoma multiforme cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3270.

Abstract 561: Targeting Y box binding protein 1 (YBX1) in MYC-amplified medulloblastoma

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Patients diagnosed with MYC-amplified group 3 medulloblastoma (G3 MB) have a devastating prognosis with a 5-year survival rate of &amp;lt;50%. Standard of care (SOC) consists of maximal resection surgery followed by chemoradiotherapy, but these extensive treatments leave patients with neurocognitive and developmental deficits. Therefore, the identification of novel targets that can be used alone or in combination with SOC is of utmost importance. Using a batch-normalized bulk RNA-seq dataset (GSE124814) comprised of 1350 MB samples and 291 normal cerebella, we reveal upregulation of Y-box binding protein 1 (YBX1) in MB compared to normal cerebellum. Further analysis of this dataset and others demonstrates G3 tumors that display high MYC levels also have the highest YBX1 expression. Analysis of ChIP-seq data shows strong binding of MYC to the YBX1 promoter in G3 MB, concurrent with H3K27ac and H3K4me3 histone modifications. Using a well-established ex vivo model, we demonstrate increased YBX1 expression as normal cerebellar progenitor cells transition to tumorigenic G3 MB stem-like cells. Recent work in leukemia reveals a reciprocal regulation of MYC by YBX1, however, this mechanism is not well established in G3 MB. We utilized an orthogonal pharmacogenetic approach to inhibit YBX1 function and determine its effects on G3 MB tumor biology. Suppression of YBX1 significantly reduced the proliferation and decreased MYC protein expression of G3 MB cells in vitro. These findings support a reciprocal MYC-YBX1 axis, which could influence tumor growth in vivo. Orthotopic implantation of YBX1 KO G3 MB cells leads to increased animal survival. We next evaluated the therapeutic potential of two recently characterized YBX1 inhibitors which display single agent efficacy in vitro and in vivo. YBX1 inhibitors synergized with SOC in vitro lowering the IC50 for both chemo and radiotherapy, which could reduce adverse effects experienced by patients. In silico molecular docking using PyMOL predicts YBX1 inhibitors interact with amino acids within the cold shock domain of YBX1, likely impairing its ability to bind RNA. We performed formaldehyde RNA immunoprecipitation (fRIP)-sequencing to identify changes in RNA transcript levels following YBX1 pharmacological inhibition. Disruption of YBX1-RNA binding impacts the stability of known oncogenic transcripts which may be required for tumorigenesis. Our findings impart an alluring prospect of targeting YBX1 in combination with standard-of-care, and possibly other compounds to improve patients’ outcomes. Citation Format: Stephen Carney, John Hemenway, Ashmitha Rajendran, Matt Hathaway, Eric Nealy, Christian Bonatto, Dhanir Tailor, Sanjay Malhotra, Myron Evans. Targeting Y box binding protein 1 (YBX1) in MYC-amplified medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 561.

Protective role of kallistatin in oxygen-glucose deprivation and reoxygenation in human umbilical vein endothelial cells.

Ischemia-reperfusion (IR) injury is implicated in various clinical diseases. Kallistatin attenuates oxidative stress, and its deficiency has been associated with poor neurological outcomes after cardiac arrest. The present study investigated the antioxidant mechanism through which kallistatin prevents IR injury. Human umbilical vein endothelial cells (HUVECs) were transfected with small interfering RNA (siRNA) targeting the human kallistatin gene (SERPINA4). Following SERPINA4 knockdown, the level of kallistatin expression was measured. To induce IR injury, HUVECs were exposed to 24 h of oxygen-glucose deprivation and reoxygenation (OGD/R). To evaluate the effect of SERPINA4 knockdown on OGD/R, cell viability and the concentration of kallistatin, endothelial nitric oxide synthase (eNOS) and total NO were measured. SERPINA4 siRNA transfection suppressed the expression of kallistatin in HUVECs. Exposure to OGD/R reduced cell viability, and this effect was more pronounced in SERPINA4 knockdown cells compared with controls. SERPINA4 knockdown significantly reduced kallistatin concentration regardless of OGD/R, with a more pronounced effect observed without OGD/R. Furthermore, SERPINA4 knockdown significantly decreased eNOS concentrations induced by OGD/R (P<0.01) but did not significantly affect the change in total NO concentration (P=0.728). The knockdown of SERPINA4 resulted in increased vulnerability of HUVECs to OGD/R and significantly affected the change in eNOS level induced by OGD/R. These findings suggest that the protective effect of kallistatin against IR injury may contribute to its eNOS-promoting effect.

Pengaruh Hypnobreastfeeding Terhadap Tingkat Kecemasan Ibu Menyusui Pada Ibu Post Partum Sectio Caesarrea Dalam Meningkatkan Produksi ASI Di RS. Simpangan Depok

Introduction: This study highlights the level of anxiety of breastfeeding mothers in post partum caesarean section mothers. The cause that can influence the success of breastfeeding is the mother's psychological changes, mothers who give birth using the Sectio Caesarea method have a higher level of anxiety than mothers who give birth spontaneously. The importance of breast milk for babies contains the most optimal nutritional content to provide immune protection for the baby, for this reason hypnobreastfeeding intervention is given which is expected to reduce the level of maternal packaging. Objective: The aim of this research is to determine the effect of Hypnobreastfeeding on the level of anxiety of breastfeeding mothers in post partum sectio caessarea mothers in increasing breast milk production in hospitals. Depok intersection. Method: This research uses a quasi-experimental design with a one group pretest-posttest design without control group. The data collection method involved using the Hamilton Rating Scale For Anxiety (HARS) questionnaire to measure students' anxiety levels before and after the hypnobreastfeeding intervention. This study aims to assess the effect of hypnobreastfeeding on the anxiety level of breastfeeding mothers in post partum mothers. Results: The results of the research obtained a P-valeu value of 0.000 p &lt; 0.05 which states that the Ha hypothesis was accepted and H0 was rejected, thus there was a significant change between before and after the hypnobreastfeeding intervention on changes in anxiety levels.&#x0D;

MicroRNAs as biomarkers of brain injury in neonatal encephalopathy: an observational cohort study

Neonatal Encephalopathy (NE) is a major cause of lifelong disability and neurological complications in affected infants. Identifying novel diagnostic biomarkers in this population may assist in predicting MRI injury and differentiate neonates with NE from those with low-cord pH or healthy neonates and may help clinicians make real-time decisions. To compare the microRNA (miRNA) profiles between neonates with NE, healthy controls, and neonates with low cord pH. Moreover, miRNA concentrations were compared to brain injury severity in neonates with NE. This is a retrospective analysis of miRNA profiles from select samples in the biorepository and data registry at the University of Florida Health Gainesville. The Firefly miRNA assay was used to screen a total of 65 neurological miRNA targets in neonates with NE (n = 36), low cord pH (n = 18) and healthy controls (n = 37). Multivariate statistical techniques, including principal component analysis and orthogonal partial least squares discriminant analysis, and miRNA Enrichment Analysis and Annotation were used to identify miRNA markers and their pathobiological relevance. A set of 10 highly influential miRNAs were identified, which were significantly upregulated in the NE group compared to healthy controls. Of these, miR-323a-3p and mir-30e-5p displayed the highest fold change in expression levels. Moreover, miR-34c-5p, miR-491-5p, and miR-346 were significantly higher in the NE group compared to the low cord pH group. Furthermore, several miRNAs were identified that can differentiate between no/mild and moderate/severe injury in the NE group as measured by MRI. MiRNAs represent promising diagnostic and prognostic tools for improving the management of NE.