Metabolomic signatures of carfilzomib‐related cardiotoxicity in patients with multiple myeloma

As a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib-CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post-baseline plasma samples of 60 MM patients treated with carfilzomib-based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post-baseline/baseline metabolite ratios that differ between the CVAE and no-CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T-UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21-0.94, p = 0.044) compared with the no-CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver-operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31-0.87, p = 0.023) was significantly lower in post-baseline/baseline ratios of CVAE patients compared with no-CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib-CVAE and potential cardioprotective strategies

Perspective Chapter: The Toxic Silver (Hg)

In the late 1950s, residents of a Japanese fishing village known as “Minamata” began falling ill and dying at an alarming rate. The Japanese authorities stated that methyl-mercury-rich seafood and shellfish caused the sickness. Burning fossil fuels represent ≈52.7% of Hg emissions. The majorities of mercury’s compounds are volatile and thus travel hundreds of miles with wind before being deposited on the earth’s surface. High acidity and dissolved organic carbon increase Hg-mobility in soil to enter the food chain. Additionally, Hg is taken up by areal plant parts via gas exchange. Mercury has no identified role in plants while exhibiting high affinity to form complexes with soft ligands such as sulfur and this consequently inactivates amino acids and sulfur-containing antioxidants. Long-term human exposure to Hg leads to neurotoxicity in children and adults, immunological, cardiac, and motor reproductive and genetic disorders. Accordingly, remediating contaminated soils has become an obligation. Mercury, like other potentially toxic elements, is not biodegradable, and therefore, its remediation should encompass either removal of Hg from soils or even its immobilization. This chapter discusses Hg’s chemical behavior, sources, health dangers, and soil remediation methods to lower Hg levels

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Agent-Based Modeling for Construction Resource Positioning Using Digital Twin and BLE Technologies

In response to the critical need for enhanced resource management in the construction industry, this research develops an innovative, integrated methodology that synergistically combines Agent-Based Modeling (ABM), Building Information Modeling (BIM), and Bluetooth Low Energy (BLE) technologies. Central to our approach is a sophisticated technological framework that incorporates a Client Early Warning System (CEWS) and a Decision Support System (DSS). These systems facilitate real-time monitoring and management of construction resources, ensuring operational efficiency and optimal resource utilization. Our methodology was empirically validated through a comprehensive case study at Helwan University’s College of Engineering. The results demonstrated a significant enhancement in operational efficiency, particularly in resource allocation and progress tracking. Key practical outcomes include the development of a CEWS master dashboard that provides in-depth, real-time insights into project metrics. This dashboard was crucial for managing compliance with health protocols during the COVID-19 pandemic, showcasing the framework’s adaptability to critical health standards. Further, the integration of indoor tracking technology revolutionized attendance tracking by replacing outdated manual methods with automated processes. This capability not only underscores the practical applicability of our research but also establishes a new benchmark for future technological advancements in construction project management. Our study sets the stage for subsequent innovations, paving the way for a more connected, efficient, and data-driven approach in the construction industry

[¹²³I]-Celecoxib Analogues as SPECT Tracers of Cyclooxygenase-2 in Inflammation

We report the synthesis and evaluation of a series of iodinated celecoxib analogues as cyclooxygenase-2 (COX-2)-targeted single photon emission computerized tomography (SPECT) imaging agents for the detection of inflammation. The structure−activity relationship identified 5-(4-iodophenyl)-1-{4-(methylsulfonyl)phenyl}-3-(trifluoromethyl)-1<i>H</i>-pyrazole (<b>8</b>) as a promising compound with IC₅₀ values of 0.05 μM against purified COX-2 and 0.03 μM against COX-2 in activated macrophages. The arylstannane of <b>8</b> undergoes facile radio-[¹²³I]-iodination upon treatment with Na¹²³I/NaI and chloramine T using an EtOAc/H₂O two-phase system. The [¹²³I]-<b>8</b> was produced in a radiochemical yield of 85% and a radiochemical purity of 99%. In vivo SPECT imaging demonstrated that the radiotracer was taken up by inflamed rat paws with an average 1.7-fold enrichment over contralateral noninflamed paws. This study suggests that conversion of celecoxib into its isomeric iodo-[¹²³I]-analogues is a useful approach for generating novel and efficacious agents for COX-2-targeted SPECT imaging of inflammation

Aurora Kinase A Promotes Inflammation and Tumorigenesis in Mice and Human Gastric Neoplasia

Chronic inflammation contributes to the pathogenesis of gastric tumorigenesis. The aurora kinase A (AURKA) gene is frequently amplified and overexpressed in gastrointestinal cancers. We investigated the roles of AURKA in inflammation and gastric tumorigenesis. We used quantitative real-time reverse transcription polymerase chain reaction, immunofluorescence, immunohistochemistry, luciferase reporter, immunoblot, co-immunoprecipitation, and in vitro kinase assays to analyze AGS and MKN28 gastric cancer cells. We also analyzed Tff1−/− mice, growth of tumor xenografts, and human tissues. We correlated increased expression of AURKA with increased levels of tumor necrosis factor-α and inflammation in the gastric mucosa of Tff1−/− mice (r = 0.62; P = .0001). MLN8237, an investigational small-molecule selective inhibitor of AURKA, reduced nuclear staining of nuclear factor-κB (NF-κB) p65 in human gastric cancer samples and mouse epithelial cells, suppressed NF-κB reporter activity, and reduced expression of NF-κB target genes that regulate inflammation and cell survival. Inhibition of AURKA also reduced growth of xenograft tumors from human gastric cancer cells in mice and reversed the development of gastric tumors in Tff1−/− mice. AURKA was found to regulate NF-κB activity by binding directly and phosphorylating IκBα in cells. Premalignant and malignant lesions from the gastric mucosa of patients had increased levels of AURKA protein and nuclear NF-κB, compared with healthy gastric tissue. In analyses of gastric cancer cell lines, human tissue samples, and mouse models, we found AURKA to be up-regulated during chronic inflammation to promote activation of NF-κB and tumorigenesis. AURKA inhibitors might be developed as therapeutic agents for gastric cancer

CONVERGENT SYNTHESIS AND EVALUATION OF 18F-LABELED AZULENIC COX2 PROBES FOR CANCER IMAGING

The overall objectives of this research are to (i) develop azulene-based PET probes and (ii) image COX2 as a potential biomarker of breast cancer. Several lines of research have demonstrated that COX2 is overexpressed in breast cancer and that its presence correlates with poor prognoses. While other studies have reported that COX2 inhibition can be modulated and used beneficially as a chemopreventive strategy in cancer, no viable mechanism for achieving that approach has yet been developed. This shortfall could be circumvented through in vivo imaging of COX2 activity, particularly using sensitive imaging techniques such as PET. Toward that goal, our laboratory focuses on the development of novel 18F-labled COX2 probes. We began the synthesis of the probes by transforming tropolone into a lactone, which was subjected to an [8+2] cycloaddition reaction to yield 2-methylazulene as the core ring of the probe. After exploring numerous synthetic routes, the final target molecule and precursor PET compounds were prepared successfully using convergent synthesis. Conventional 18F labeling methods caused precursor decomposition, which prompted us to hypothesize that the acidic protons of the methylene moiety between the azulene and thiazole rings were readily abstracted by a strong base such as potassium carbonate. Ultimately, this caused the precursors to disintegrate. This observation was supported after successfully using an 18F labeling strategy that employed a much milder phosphate buffer. The 18F-labeled COX2 probe was tested in a breast cancer xenograft mouse model. The data obtained via successive whole-body PET/CT scans indicated probe accumulation and retention in the tumor. Overall, the probe was stable in vivo and no defluorination was observed. A biodistribution study and Western blot analysis corroborate with the imaging data. In conclusion, this novel COX2 PET probe was shown to be a promising agent for cancer imaging and deserves further investigation

Brief exposure to obesogenic diet disrupts brain dopamine networks.

OBJECTIVE:We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH). METHODS:We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET). RESULTS:We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate) and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals. CONCLUSION:These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding