Mechanistic Correlation Research Articles

Abstract 4067: Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14)

Abstract Translocation t(11;14) positive multiple myeloma (MM) is sensitive to venetoclax, yet the drug lacks FDA approval in MM. Selinexor is an inhibitor of nuclear exporter XPO1 and is approved in relapsed refractory MM. We recently analyzed RNA-seq from 859 MM patient samples (MMRF CoMMpass study) and compared them to healthy bone marrow samples (GSE114922). After correcting for batch effects, differential gene expression analysis found apoptosis and cell cycle regulation amongst the top upregulated gene pathways in MM. We therefore hypothesized that MM would be sensitive to the combination of the pro-apoptotic drug, venetoclax, and selinexor, which causes cell cycle arrest. Using a panel of 8 MM cell lines (U266-B1, KMS12BM, SKMM2, RPMI-8226, LP1, OPM2, KMS12PE, and NCIH929), we performed cell viability assays in increasing concentrations of selinexor, venetoclax, and a combination of the two drugs at 72 hours. Overall, the combination showed synergy in MM cell lines but strikingly, cell lines that possessed t(11;14) were more sensitive to the drug combination and showed enhanced synergy compared to the non-t(11;14). Average Bliss model synergy score were 0.5 in non-t(11;14) and 10.2 in t(11;14) MM cells (>10 indicates synergistic effects and <-10 indicates antagonistic drug effects). To better understand molecular mechanisms underlying the observed synergistic effect in t(11;14), we performed western blot analysis in these cell lines treated with selinexor, venetoclax, the combination, or DMSO control for 24 hours. We measured protein levels of Cyclin D1, which is overexpressed in t(11;14) and a cargo of XPO1. We confirmed Cyclin D1 overexpression in t(11;14) cells lines but not in non-t(11;14) cells. Cyclin D1 levels decreased with selinexor, and the reduction was enhanced by adding venetoclax. Additionally, we measured levels of XPO1, p53, MCL-1, and p65, which we have previously shown to be altered by selinexor treatment. While venetoclax monotherapy caused increased MCL-1 expression, this was abrogated by combining with selinexor and the effects were statistically more significant in t(11;14) cell lines. Concurrently, two patients with relapsed, refractory t(11;14) MM and disease progression after multiple lines of therapy were treated with venetoclax; however, after initial response, they developed resistance and progressive disease. Based off our preclinical results, selinexor was added to venetoclax and recaptured responses (VGPR and MR, respectively) suggesting a beneficial effect of the combination over single agent venetoclax. To our knowledge, this is the first report of patients with MM treated with the combination of selinexor and venetoclax. Further clinical evaluation of this combination in t(11;14) MM is planned and samples will be collected to better understand the mechanistic correlation between XPO1, BCL2/MCL-1, and Cyclin D1 levels and response. Citation Format: Sana Chaudhry, Nina Nguyen, Rimpi Khurana, Tulasigeri M. Totiger, Skye Montoya, Jumana Afaghani, Terrence Bradley, Francesco Maura, Dickran Kazandjian, Jennifer Chapman, Stephan Schürer, Ola Landgren, James Hoffman, Justin Taylor. Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4067.

PHF13 epigenetically activates TGFβ driven epithelial to mesenchymal transition

Epigenetic alteration is a pivotal factor in tumor metastasis. PHD finger protein 13 (PHF13) is a recently identified epigenetic reader of H3K4me2/3 that functions as a transcriptional co-regulator. In this study, we demonstrate that PHF13 is required for pancreatic-cancer-cell growth and metastasis. Integrative analysis of transcriptome and epigenetic profiles provide further mechanistic insights into the epigenetic regulation of genes associated with cell metastasis during the epithelial-to-mesenchymal transition (EMT) induced by transforming growth factor β (TGFβ). Our data suggest PHF13 depletion impairs activation of TGFβ stimulated genes and correlates with a loss of active epigenetic marks (H3K4me3 and H3K27ac) at these genomic regions. These observations argue for a dependency of TGFβ target activation on PHF13. Furthermore, PHF13-dependent chromatin regions are enriched in broad H3K4me3 domains and super-enhancers, which control genes critical to cancer-cell migration and invasion, such as SNAI1 and SOX9. Overall, our data indicate a functional and mechanistic correlation between PHF13 and EMT.

Multimodality Characterization of Cancer-Associated Fibroblasts in Tumor Microenvironment and Its Correlation With Ultrasound Shear Wave-Measured Tissue Stiffness in Localized Prostate Cancer.

IntroductionGrowing evidence suggests that the tumor microenvironment (TME) represented by cellular and acellular components plays a key role in the multistep process of metastases and response to therapies. However, imaging and molecular characterization of the TME in prostate cancer (PCa) and its role in predicting aggressive tumor behavior and disease progression is largely unexplored. The study explores the PCa TME through the characterization of cancer-associated fibroblasts (CAFs) using both immunohistochemistry (IHC) and genomics approaches. This is then correlated with transrectal ultrasound shear wave elastography (USWE)-measured tissue stiffness.Patients and MethodsThirty patients with clinically localized PCa undergoing radical prostatectomy for different risk categories of tumor (low, intermediate, and high) defined by Gleason score (GS) were prospectively recruited into this study. Prostatic tissue stiffness was measured using USWE prior to surgery. The CAFs within the TME were identified by IHC using a panel of six antibodies (FAP, SMAα, FSP1, CD36, PDGFRα, and PDGFRβ) as well as gene expression profiling using TempO-sequence analysis. Whether the pattern and degree of immunohistochemical positivity (measured by Quick score method) and expression of genes characterizing CAFs were correlated with USWE- and GS-measured tissue stiffnesses were tested using Spearman’s rank correlation and Pearson correlation.ResultsThere was a statistically significant correlation between GS of cancers, the pattern of staining for CAFs by immunohistochemical staining, and tissue stiffness measured in kPa using USWE (p < 0.001). Significant differences were also observed in immunohistochemical staining patterns between normal prostate and prostatic cancerous tissue. PDGFRβ and SMAα immunostaining scores increased linearly with increasing the USWE stiffness and the GS of PCa. There was a significant positive correlation between increasing tissue stiffness in tumor stroma and SMAα and PDGFRβ gene expression in the fibromuscular stroma (p < 0.001).ConclusionUSWE-measured tissue stiffness correlates with increased SMAα and PDGFRβ expressing CAFs and PCa GSs. This mechanistic correlation could be used for predicting the upgrading of GS from biopsies to radical surgery and response to novel treatments.

ERK inhibition in glioblastoma is associated with autophagy activation and tumorigenesis suppression.

Autophagy-dependent tumorigenic growth is one of the most commonly reported molecular mechanisms in glioblastoma (GBM) progression. However, the mechanistic correlation between autophagy and GBM is still largely unexplored, especially the roles of autophagy-related genes involved in GBM oncogenesis. In this study, we aimed to explore the genetic alterations that interact with both autophagic activity and GBM tumorigenesis, and to investigate the molecular mechanisms of autophagy involved in GBM cell death and survival. For this purpose, we systematically explored the alterations of autophagic molecules at the genome level in human GBM samples through deep RNA sequencing. The effect of genetic and pharmacologic inhibition of ERK on GBM growth in vitro and in vivo was researched. An image-based tracking analysis of LC3 using mCherry-eGFP-LC3 plasmid, and transmission electron microscopy were utilized to monitor autophagic flux. Immunoblot analysis was used to measure the related proteins. MAPK ERK expression was identified as one of the most probable autophagy-related transcriptional responses during GBM growth. The genetic and pharmacologic inhibition of ERK in vivo and in vitro led to cell death, demonstrating its critical role for GBM proliferation and survival. To our surprise, autophagic activities were excessively activated and resulted in cytodestructive effects on GBM cells upon ERK inhibitor treatment. Furthermore, based on the observation of downregulation of mTOR signaling, we speculated the ERK inhibitor-induced GBM cells death might depend on mTOR-mediated pathway, leading to autophagy dysregulation. Accordingly, the in vivo and in vitro experiments revealed that the mTOR inhibitor rapamycin further increased cell mortality and exhibited enhanced antitumor effect on GBM cells when co-treated with the ERK inhibitor. Our data creatively demonstrated that the autophagy-related regulator ERK maintains autophagic activity during GBM tumorigenesis via mTOR signaling pathway. The pharmacologic inhibition of both mTOR and ERK signaling exhibited synergistic therapeutic effect on GBM growth in vivo and in vitro, which has certain novelty and may provide a potential therapeutic approach for GBM treatment in the future.

Microbes, metabolites and (synaptic) malleability, oh my! The effect of the microbiome on synaptic plasticity.

ABSTRACTThe microbiome influences the emotional and cognitive phenotype of its host, as well as the neurodevelopment and pathophysiology of various brain processes and disorders, via the well‐established microbiome–gut–brain axis. Rapidly accumulating data link the microbiome to severe neuropsychiatric disorders in humans, including schizophrenia, Alzheimer's and Parkinson's. Moreover, preclinical work has shown that perturbation of the microbiome is closely associated with social, cognitive and behavioural deficits. The potential of the microbiome as a diagnostic and therapeutic tool is currently undercut by a lack of clear mechanistic understanding of the microbiome–gut–brain axis. This review establishes the hypothesis that the mechanism by which this influence is carried out is synaptic plasticity – long‐term changes to the physical and functional neuronal structures that enable the brain to undertake learning, memory formation, emotional regulation and more. By examining the different constituents of the microbiome–gut–brain axis through the lens of synaptic plasticity, this review explores the diverse aspects by which the microbiome shapes the behaviour and mental wellbeing of the host. Key elements of this complex bi‐directional relationship include neurotransmitters, neuronal electrophysiology, immune mediators that engage with both the central and enteric nervous systems and signalling cascades that trigger long‐term potentiation of synapses. The importance of establishing mechanistic correlations along the microbiome–gut–brain axis cannot be overstated as they hold the potential for furthering current understanding regarding the vast fields of neuroscience and neuropsychiatry. This review strives to elucidate the promising theory of microbiome‐driven synaptic plasticity in the hope of enlightening current researchers and inspiring future ones.

A Dose-Escalation Phase Ib International Study to Evaluate the Safety, Pharmacokinetics and Efficacy of ST-617 for the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for H&N Cancer

Oral Mucositis (OM) is a common, painful, and costly toxicity associated with cytotoxic chemoradiation regimens used to treat H&N cancer, which may interfere with planned treatment and negatively impact tumor control. There are currently no approved interventions to mitigate the incidence, severity or duration of OM. Oxidative stress is a critical event in OM's pathogenesis. Through its effect on Nrf2, ST-617 has marked anti-oxidative activity/properties. Supportive Therapeutics is developing ST-617, a dithioethione, for the attenuation of OM. The objective of this trial was to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of ST-617 in patients at high risk of severe OM (SOM).A dose escalation trial was performed in which ST-617, administered as an oral suspension, 1-2 hours before the administration of daily RT fractions at 9 study sites in South Africa and Australia. Eighteen patients with diagnoses of oral or oropharyngeal CA were enrolled (up to 6 pts/dose). Patients received concomitant cisplatin either weekly or tri-weekly. ST-617 was administered 3 days prior to CRT, and then continuing daily concomitant with BSC (Best Supportive Care) until the end of treatment. Safety outcomes, using CTCAE criteria (v 4.03) were used. Dose escalation occurred in the absence of toxicity. OM occurrence and severity were assessed by trained and validated evaluators using WHO, NCI-CTC and RTOG criteria; scores were centrally assigned. The primary efficacy endpoints included the incidence and duration of SOM (WHO grades 3 or 4) vs historical controls. PD tracking measured total ROS/RNS, GSH/GSSG, regulation in plasma and buccal epithelial cells.17 pts completed the 50, 100 and 150mg/day with no safety issues. No early dose limiting toxicity (DLT) or serious Adverse Event linked to ST-617 were observed. AEs observed were mainly nausea which is usually associated with CRT as expected. As overall SOM incidence (baseline to the last day of radiation) of 50% was less than expected and was related to ST-617 dose: 50 mg/day 83% (n = 6); 100 mg/day 33% (n = 9); 200 mg/day 33% (n = 3). The 100 mg/day dose was well tolerated with no grade 4 OM. No CRT dose interruptions or delays due to OM were noted Total ROS/RNS levels in plasma and buccal samples show significant decrease with increased ST-617 dosing from 50 to 100 mg/day. ST-617 did not alter tumor response at 1 year post-CRT (n = 17).ST-617 administration was safe at all doses tested. The course and severity of patients treated with ST-617 compared favorably with historical controls. A dose-response effect on SOM incidence was noted. Mechanistic correlation between ROS/RNS levels was seen. A randomized, controlled, double blind trial is planned with the recommended dose of 100mg/day.

A Novel Mechanistic Cell Survival Model to Replace Linear-Quadratic Model for Relative Biological Effectiveness (RBE) in Proton Therapy

<h3>Purpose/Objective(s)</h3> Relative biological effectiveness (RBE) is important in proton therapy. Although a large amount of in vitro cell experimental data exists for various linear energy transfers (LETs) and various cell lines, it is difficult to derive a reliable RBE model from these data using the classic linear-quadratic (LQ) model, mainly because its parameters, α_LQ and β_LQ, have no clear mechanistic correlation with LET. In this study, we hypothesize that a mechanistic model with parameters directly relate to LET can be developed to replace the LQ model for cell survival description, and it would be better than the LQ model for RBE model derivation. The 2 parameters in the model are α_M, which represents the ability to generate cell damage and may linearly increase with LET, and β_M, which represents the ability to repair cell damage and may linearly decrease with LET (because higher LET generates more clustered DNA damages, which are difficult to repair). <h3>Materials/Methods</h3> We used the number of unit damages to score the severity of radiation-generated damage in a cell. Assuming that a dose of D generated an average number of α_M*D unit damages, the probability of cells having n (n = 0, 1, 2, ...m) unit damages was thus determined using the Poisson Equation, P(n) = [(α_MD)ⁿ/n!]*exp(-α_MD). We further assumed that a cell with n unit damages has a probability of β_Mⁿ to be repaired, and cells having 4 or more unit damages would not be repaired. Thus, the survival fraction of cells after a dose of D was derived as SF(D) = [1+α_Mβ_MD+(α_Mβ_MD)²/2+(α_Mβ_MD)³/6]*exp(-α_MD). A total of 47 experimental cell survival datasets for 3 cell lines in the literature were used to test this mechanistic model. Correlations of α_M and β_M with LET were determined in terms of RBE_α and RBE_β, which is the ratio of α_M (or β_M) in proton and photon. A RBE model was consequently derived. <h3>Results</h3> The mechanistic model fitted well with all experimental data, similar as the LQ model. Interestingly, for two cell lines with pristine proton beam data, both α_M and β_M were perfect linear functions of LET, with R² = 0.98∼1.0. On the other hand, the linearity was greatly degraded for the corresponding spread-out Bragg Peak (SOBP) data, with same data points deviating at same directions for 2 cell lines, suggesting that the LET values calculated in SOBP were not as accurate as pristine beam. For the 3^rd cell line with majority data points of SOBP beams, R² = 0.89∼0.91. The correlation of α_M and β_M with LET were expressed as RBE_α = 1.1+k_α*LET and RBE_β = 1.0-k_β*LET, where k_α = 0.018, 0.009 and 0.005, k_β = 0.031, 0.028, and 0.027 for 3 cell lines, respectively. A RBE model depending on LET, dose and cell type (represented by α_M and β_M in photon) was finally derived. <h3>Conclusion</h3> A mechanistic cell survival model was developed and it appeared to have advantage over the LQ model in deriving a reliable RBE model.

VALVULAR BILE ACIDS CORRELATE WITH THE DEGREE OF STENOSIS IN PATIENTS WITH CALCIFIC AORTIC VALVE STENOSIS

<h3>BACKGROUND</h3> Calcific aortic valve stenosis (CAVS) is the most common valvular pathology seen in the Western world. The pathological mechanism of CAVS is still unclear and currently no medical therapy to prevent or reduce the progression of CAVS exists. Our recent metabolomics analysis of human aortic valve tissue identified bile acid biosynthesis as a potential mitigator of valvular stenosis. In this study, we sought to build on these preliminary results by conducting a targeted bile acid analysis of human calcific aortic valve tissues. <h3>METHODS AND RESULTS</h3> Human aortic tissue valves from 102 patients undergoing aortic valve replacement surgery were collected from St. Boniface Hospital. Bile acid profiling (80 bile acids) of valvular tissues along with 19 plasma samples was carried out by liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Three bile acids namely nordeoxycholic acid, norcholic acid and glycodeoxycholic acids were significantly altered (p < 0.05) between different degrees of CAVS severity based on the mean pressure gradient. Similarly, nordeoxycholic acid and norcholic acid, as well as 4 other bile acids namely 3β,7α-diOH-5-cholestenoic acid, 3β-OH-5-cholestenoic acid, glycolithocholic acid, and glycoallocholic acid were significantly altered (p < 0.05) across CAVS severity based on the valvular calcification score. In addition, the levels of these bile acids in valvular tissues correlate significantly with plasma levels. <h3>CONCLUSION</h3> In this report, we present a novel mechanistic pathway correlation for bile acids in the pathogenies of CAVS. Our goal is to validate these findings in a large cohort of patients with CAVS. Given that bile acid modulating therapies are already used in clinical practice, the bile acid pathway may be a potential therapeutic target to prevent or delay the progression of CAVS.

NSD1: A Lysine Methyltransferase between Developmental Disorders and Cancer.

Recurrent epigenomic alterations associated with multiple human pathologies have increased the interest in the nuclear receptor binding SET domain protein 1 (NSD1) lysine methyltransferase. Here, we review the current knowledge about the biochemistry, cellular function and role of NSD1 in human diseases. Several studies have shown that NSD1 controls gene expression by methylation of lysine 36 of histone 3 (H3K36me1/2) in a complex crosstalk with de novo DNA methylation. Inactivation in flies and mice revealed that NSD1 is essential for normal development and that it regulates multiple cell type-specific functions by interfering with transcriptional master regulators. In humans, putative loss of function NSD1 mutations characterize developmental syndromes, such as SOTOS, as well as cancer from different organs. In pediatric hematological malignancies, a recurrent chromosomal translocation forms a NUP98-NSD1 fusion with SET-dependent leukemogenic activity, which seems targetable by small molecule inhibitors. To treat or prevent diseases driven by aberrant NSD1 activity, future research will need to pinpoint the mechanistic correlation between the NSD1 gene dosage and/or mutational status with development, homeostasis, and malignant transformation.

Humoral Immune Response of SARS-CoV-2-Infected Patients with Cancer: Influencing Factors and Mechanisms.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)–infected patients with cancer show worse outcomes compared with patients without cancer. The humoral immune response (HIR) of patients with cancer against SARS‐CoV‐2 is not well characterized. To better understand it, we conducted a serological study of hospitalized patients with cancer infected with SARS‐CoV‐2.Materials and MethodsThis was a unicentric, retrospective study enrolling adult patients with SARS‐CoV‐2 admitted to a central hospital from March 15 to June 17, 2020, whose serum samples were quantified for anti–SARS‐CoV‐2 receptor‐binding domain or spike protein IgM, IgG, and IgA antibodies. The aims of the study were to assess the HIR to SARS‐CoV‐2; correlate it with different cancer types, stages, and treatments; clarify the interplay between the HIR and clinical outcomes of patients with cancer; and compare the HIR of SARS‐CoV‐2–infected patients with and without cancer.ResultsWe included 72 SARS‐CoV‐2–positive subjects (19 with cancer, 53 controls). About 90% of controls revealed a robust serological response. Among patients with cancer, a strong response was verified in 57.9%, with 42.1% showing a persistently weak response. Treatment with chemotherapy within 14 days before positivity was the only factor statistically shown to be associated with persistently weak serological responses among patients with cancer. No significant differences in outcomes were observed between patients with strong and weak responses. All IgG, IgM, IgA, and total Ig antibody titers were significantly lower in patients with cancer compared with those without.ConclusionA significant portion of patients with cancer develop a proper HIR. Recent chemotherapy treatment may be associated with weak serological responses among patients with cancer. Patients with cancer have a weaker SARS‐CoV‐2 antibody response compared with those without cancer.Implications for PracticeThese results place the spotlight on patients with cancer, particularly those actively treated with chemotherapy. These patients may potentially be more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, so it is important to provide oncologists further theoretical support (with concrete examples and respective mechanistic correlations) for the decision of starting, maintaining, or stopping antineoplastic treatments (particularly chemotherapy) not only on noninfected but also on infected patients with cancer in accordance with cancer type, stage and prognosis, treatment agents, treatment setting, and SARS‐CoV‐2 infection risks.

Phase Ib, international, dose-escalation study to evaluate the safety, pharmacokinetics (PK) and efficacy of ST-617 for the attenuation of oral mucositis (OM) in patients receiving chemoradiation (CRT) for head and neck (H&amp;N) cancer.

6075 Background: OM is a common, painful, and costly toxicity associated with cytotoxic regimens used to treat H&amp;N cancers, which may result in radiotherapy treatment interruptions to negatively impact tumor control. There are currently no approved interventions to successfully prevent or delay OM onset among patients being treated with radiation therapy, with or without concomitant chemotherapy (CRT). Oxidative stress is a critical event in OM’s pathogenesis. Through its effect on Nrf2, ST-617 has marked anti-oxidative activity/properties. Supportive Therapeutics is developing ST-617, a dithioethione, for the attenuation of OM onset, duration and severity. The objective of this trial was to assess the safety, tolerability, PK, PD and efficacy of ST-617 in patients at high risk of severe OM (SOM). Methods: A dose escalation trial in which ST-617 administered as an oral suspension, 1-2 hours before the administration of daily RT fractions was performed at 9 study sites in South Africa and Australia. Eighteen patients with diagnoses of oral or oropharyngeal CA were enrolled (up to 6 pts/dose). Patients received concomitant cisplatin either weekly or tri-weekly. ST-617 was administered 3 days prior to CRT, and then continuing daily until the end of treatment. Safety outcomes, using CTCAE criteria (v 4.03) were used. Dose escalation occurred in the absence of toxicity. OM occurrence and severity were assessed by trained and validated evaluators using WHO, NCI-CTC and RTOG criteria; scores were centrally assigned. The primary efficacy endpoints included the incidence and duration of SOM (WHO grades 3 or 4) vs historical controls. PD tracking measured total ROS/RNS, GSH/GSSG, regulation in plasma and buccal epithelial cells. Results: 17 pts completed the 50, 100 and 150mg/day with no safety issues. No early dose limiting toxicity (DLT) or serious Adverse Event linked to ST-617 were observed. AEs observed were mainly nausea which is usually associated with CRT as expected. The 100 mg/day dose has been well tolerated with no grade 4 OM. No CRT dose interruptions or delays due to OM has been observed. Total ROS/RNS levels in plasma and buccal samples show significant decrease with increased ST-617 dosing from 50 to 100 mg/day. Conclusions: ST-617 administration was safe at all doses tested. The course and severity of patients treated with ST-617 compared favorably with historical controls. Mechanistic correlation between ROS/RNS levels was seen. A randomized, controlled, double blind trial is planned with the recommended dose of 100mg/day. Clinical trial information: 20180138.

Damage progression and acoustic emission in brittle failure of granite and sandstone

This paper experimentally evaluates and quantitatively compares stress-induced damage progression and acoustic emission (AE) in granite and sandstone based on continuous acousto-optic-mechanical (AOM) observations. Experimental results reveal that the step-rise characteristics of the AE event rate preceding the entire macrofracturing process and the apparent white patching phenomena are the most significant acousto-optical evidences for process zone nucleation in granite but not in sandstone. During the unstable crack growth stage in granite, the robustly high AE event rate level has been mechanically correlated with the reactivation and intensification of fracture process zones (FPZs) by the stress build-up, and the relatively low AE event rate level has been revealed as a result of the progression of FPZs into macrocracks. It is the first time that the process zone nucleation in granite has been mechanistically related to the clustering of three types of grain-scale microcracks, i.e., grain boundary cracks, intragranular cracks and transgranular cracks, due to the grain interlocking effect. Comparatively, the clustering of microcracks is insignificant in the brittle failure of sandstone. Mechanistic correlations among the AOM characteristics in the two rock types are also investigated in detail.

Selective adsorption of cationic/anionic tritoluene dyes on functionalized amorphous silica: A mechanistic correlation between the precursor, modifier and adsorbate

Selective adsorption of synthetic and functionalized amorphous silica (silica nanosheets and silica nanoparticles (SiNSs and SiNPs) modified by hexadecyl trimethyl ammonium bromide (HDTAB) and hexadecyl trimethoxysilane (HDTMS)) towards dyes is investigated to obtain a mechanistic correlation between the silica precursor, modifier and adsorbate. Structures of the parent and functionalized counterparts are revealed by series of characterizations. Modifier has a clogging effect in the interlayer space of 2D SiNSs, resulting in the decrease of thermostability and surface area. 3D SiNPs with higher cationic exchange capacity (CEC) and greater activity is more prone to surface functionalization and higher modifier availability. Adsorption performances are tested by malachite green (MG), crystal violet (CV) and bromophenol blue (BPB) through combined batch experiment and density functional theory (DFT) calculation. Selective adsorption of HDTAB-SiNSs/SiNPs towards MG (287.36 and 289.86 mg/g), HDTAB/HDTMS-SiNSs for CV (196.91 and 260.64 mg/g) and BPB on HDTAB/HDTMS-SiNPs (211.54 and 149.94 mg/g) are obtained. Pseudo-second-order and Freundlich models are agreeable for the adsorption processes, holding for significant role of π-π stacking. The inherent mechanistic correlation is further concluded: (i) Electrostatic interaction play a dominant role for the adsorption of cationic MG/CV on silica, whereas the adsorption of anionic BPB is mainly through partition process. (ii) Affecting strength on the adsorption capacity: Adsorbate charge >functionalization manner >steric hindrance >additional interactions. (iii) Organic modification with flexible alkyl chain and tunable space is preferential for the accommodation of smaller dyes. Dye with greater steric hindrance is favorable for particle diffusion. (iv) Multidimensional structured silica and modifiers are inductive to stronger interactions towards target adsorbate, which deserve further explorations in the future.

Synergising biomass growth kinetics and transport mechanisms to simulate light/dark cycle effects on photo-production systems.

Light attenuation is a primary challenge limiting the upscaling of photobioreactors for sustainable bio-production. One key to this challenge, is to model and optimise the light/dark cycles so that cells within the dark region can be frequently transferred to the light region for photosynthesis. Therefore, this study proposes the first mechanistic model to integrate the light/dark cycle effects into biomass growth kinetics. This model was initially constructed through theoretical derivation based on the intracellular reaction kinetics, and was subsequently modified by embedding a new parameter, effective light coefficient, to account for the effects of culture mixing. To generate in silico process data, a new multiscale reactive transport modelling strategy was developed to couple fluid dynamics with biomass growth kinetics and light transmission. By comparing against previous experimental and computational studies, the multiscale model shows to be of high accuracy. Based on its simulation result, an original correlation was proposed to link effective light coefficient with photobioreactor gas inflow rate; this has not been done before. The impact of this study is that by using the proposed mechanistic model and correlation, we can easily control and optimise photobioreactor gas inflow rates to alleviate light attenuation and maintain a high biomass growth rate.

Accurate artificial intelligence-based methods in predicting bottom-hole pressure in multiphase flow wells, a comparison approach

Determining bottom-hole pressure in producing multiphase flow petroleum wells is a crucial issue that directly affects plans, infrastructures, and all the equipment required to develop an oil field. This study attempted to introduce the best method regarding accuracy and codes applicable in vertical oil and gas wells. Therefore, with the aid of genetic programming (GP), least-square support vector machines (LSSVM), and radial basis function (RBF) neural networks and using 450 producing wells data, three models are trained. Besides, five experimental and mechanistic correlations were used for taking more approaches into account to evaluate the accuracy of simulations. LSSVM and GP had the highest precision models among all the methods, proved by several analyses and calculation of the coefficient of determination (R2), average relative error (ARE), average absolute relative error (AARE), and root mean square error (RMSE). The models mentioned above performed better than previously developed correlations, where Ansari et al.'s (1994) model had the nearest outcomes to GP results. In addition to the generated models, the analyses' results introduced a new correlation for predicting wellbore pressure using available measurements of the wellhead data.

Irisin: A Promising Target for Ischemia-Reperfusion Injury Therapy.

Ischemia-reperfusion injury (IRI) is defined as the total combined damage that occurs during a period of ischemia and following the recovery of blood flow. Oxidative stress, mitochondrial dysfunction, and an inflammatory response are factors contributing to IRI-related damage that can each result in cell death. Irisin is a polypeptide that is proteolytically cleaved from the extracellular domain of fibronectin type III domain-containing protein 5 (FNDC5). Irisin acts as a myokine that potentially mediates beneficial effects of exercise by reducing oxidative stress, improving mitochondrial fitness, and suppressing inflammation. The existing literature also suggests a possible link between irisin and IRI, involving mechanisms similar to those associated with exercise. This article will review the pathogenesis of IRI and the potential benefits and current limitations of irisin as a therapeutic strategy for IRI, while highlighting the mechanistic correlations between irisin and IRI.

Onset of Nucleate Boiling Model for Rectangular Upward Narrow Channel: CFD Based Approach

Despite that mechanistic and accurate correlations predicting the Onset of Nucleate Boiling (ONB) for pool boiling are widely presented in the literature, models for forced convective boiling remain few. These models do not provide the desired quality, principally because they do not consider important features of convective boiling. In this work, numerical investigations of the ONB for water boiling flow at atmospheric pressure upward a narrow rectangular channel (3 mm × 100 mm × 400 mm) are carried out based on Computational Fluid Dynamics (CFD) simulations. The predictions of the CFD calculations are validated with the available experimental data. A new ONB model incorporating the convective boiling features is developed and proposed. This model is derived based on several CFD simulation data, covering wide operating conditions. The flow Reynolds number ranges from 959 to 13500, inlet subcooling from 2.5 to 30 K and applied heat flux from 5 to 90 kW/m2. The new model predictions have a standard deviation of 2.7% where its performance is better than ±0.3 K when compared with additional simulation data that are provided for validation.

Are spliced ncRNA host genes distinct classes of lncRNAs?

Many small nucleolar RNAs and many of the hairpin precursors of miRNAs are processed from long non-protein-coding host genes. In contrast to their highly conserved and heavily structured payload, the host genes feature poorly conserved sequences. Nevertheless, there is mounting evidence that the host genes have biological functions beyond their primary task of carrying a ncRNA as payload. So far, no connections between the function of the host genes and the function of their payloads have been reported. Here we investigate whether there is evidence for an association of host gene function or mechanisms with the type of payload. To assess this hypothesis we test whether the miRNA host genes (MIRHGs), snoRNA host genes (SNHGs), and other lncRNA host genes can be distinguished based on sequence and/or structure features unrelated to their payload. A positive answer would imply a functional and mechanistic correlation between host genes and their payload, provided the classification does not depend on the presence and type of the payload. A negative answer would indicate that to the extent that secondary functions are acquired, they are not strongly constrained by the prior, primary function of the payload. We find that the three classes can be distinguished reliably when the classifier is allowed to extract features from the payloads. They become virtually indistinguishable, however, as soon as only sequence and structure of parts of the host gene distal from the snoRNAs or miRNA payload is used for classification. This indicates that the functions of MIRHGs and SNHGs are largely independent of the functions of their payloads. Furthermore, there is no evidence that the MIRHGs and SNHGs form coherent classes of long non-coding RNAs distinguished by features other than their payloads.

Abstract 14687: Achieved Eicosapentaenoic Acid (EPA) Levels Predicts Regression of Coronary Plaque Volumes by Coronary Computed Tomography Angiography (CCTA) in the EVAPORATE Trial

Background: Despite the beneficial effects of statins on progression of coronary atherosclerosis and cardiovascular (CV) events, significant CV risk persists in patients with hypertriglyceridemia. In REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), icosapent ethyl (IPE) added to statins reduced initial and total CV events by 25% and 30%, but the mechanisms of benefit are unclear. In a follow-up analysis, degree of CV benefit from IPE was predominantly related to achieved serum EPA levels. Methods: EVAPORATE is a randomized, placebo-controlled trial, using CCTA to evaluate the effects of IPE as an adjunct to statins on coronary plaque volumes in a cohort with elevated triglycerides. Here, we present the 18-month, pre-specified secondary end-point analysis on association of achieved serum EPA levels, and change in coronary plaque volumes in the pooled cohort. Results: 80 patients were enrolled, and 68 completed the 18-month visit. Median (IQR) level of serum EPA for the pooled cohort was 20.6 (13.8) ug/ml at baseline and 25.3 (55.5) ug/ml at follow up. At 18 months, EPA levels &gt; 26 ug/ml predicted regression of fibro-fatty plaque (logβ: - 0.75± 0.36), total non-calcified plaque (TNCP) (logβ: - 0.77± 0.33), and total plaque (TP) (logβ: - 0.63± 0.28) volumes (mm3), after adjustment for age, sex, diabetes, hypertension, and baseline TGL levels (p &lt; 0.05 for all). Conclusions: Higher serum EPA levels predict regression of prognostically relevant coronary plaque volumes, TNCP, and TP on CCTA. This provides important mechanistic correlation to the CV benefits of IPE.

Acoustic analysis of starting jets in an anechoic chamber: implications for volcano monitoring

Explosive volcanic eruptions are associated with a plethora of geophysical signals. Among them, acoustic signals provide ample information about eruptive dynamics and are widely used for monitoring purposes. However, a mechanistic correlation of monitoring signals, underlying source processes and reasons for short-term variations is incomplete. Scaled laboratory experiments can mimic a wide range of explosive volcanic eruption conditions. Here, starting (non-steady) compressible gas jets are created using a shock tube in an anechoic chamber and their acoustic signature is recorded with a microphone array. Noise sources are mapped in time and frequency using wavelet analysis and their dependence from pressure ratio, non-dimensional mass supply and exit-to-throat area ratio is deciphered. We observed that the pressure ratio controls the establishment of supersonic conditions and their duration, and influences the interaction between shock, shear layer, and vortex ring. The non-dimensional mass supply affects the duration of the discharge, the maximum velocity of the flow, and the existence of a trailing jet. Lower values of exit-to-throat area ratio induce a faster decay of the acoustic fingerprint of the jet flow. The simplistic experiments presented here, and their acoustic analysis will serve as an essential starting point to infer source conditions prior to and during impulsive volcanic eruptions.