bluuebunny/crossref_metadata_2025_split huggingface dataset:
A perspective on emerging therapies in metastatic colorectal cancer: Focusing on molecular medicine and drug resistance
Authors: Kusumaningrum Anggraeni E. , Makaba Sarce , Ali Eyhab , Singh Mandeep , Fenjan Mohammed N. , Rasulova Irodakhon , Misra Neeti , Al‐ Musawi Sada G. , Alsalamy Ali 
Published: January 2024

AbstractThe majority of cancer cases are colorectal cancer, which is also the second largest cause of cancer‐related deaths worldwide. Metastasis is the leading cause of death for patients with colorectal cancer. Metastatic colorectal cancer incidence are on the rise due to a tiny percentage of tumors developing resistant to medicines despite advances in treatment tactics. Cutting‐edge targeted medications are now the go‐to option for customized and all‐encompassing CRC care. Specifically, multitarget kinase inhibitors, antivascular endothelial growth factors, and epidermal growth factor receptors are widely used in clinical practice for CRC‐targeted treatments. Rare targets in metastatic colorectal cancer are becoming more well‐known due to developments in precision diagnostics and the extensive use of second‐generation sequencing technology. These targets include the KRAS mutation, the BRAF V600E mutation, the HER2 overexpression/amplification, and the MSI‐H/dMMR. Incorporating certain medications into clinical trials has significantly increased patient survival rates, opening new avenues and bringing fresh viewpoints for treating metastatic colorectal cancer. These focused therapies change how cancer is treated, giving patients new hope and better results. These markers can significantly transform and individualize therapy regimens. They could open the door to precisely customized and more effective medicines, improving patient outcomes and quality of life. The fast‐growing body of knowledge regarding the molecular biology of colorectal cancer and the latest developments in gene sequencing and molecular diagnostics are directly responsible for this advancement.
Antidiabetic features of AdipoAI, a novel AdipoR agonist
Authors: Ahuja Akash , Zboinski Elissa , das Siddhartha , Zhu Xiaofang , Ma Qian , Xie Ying , Tu Qisheng , Chen Jake 
Published: January 2024

AbstractAdiponectin is an antidiabetic endogenous adipokine that plays a protective role against the unfavorable metabolic sequelae of obesity. Recent evidence suggests a sinister link between hypoadiponectinemia and development of insulin resistance/type 2 diabetes (T2D). Adiponectin's insulin‐sensitizing property is mediated through the specific adiponectin receptors R1 and R2, which activate the AMP‐activated protein kinase (AMPK) and peroxisome proliferator‐activated receptor (PPAR) α pathways. AdipoAI is a novel synthetic analogue of endogenous adiponectin with possibly similar pharmacological effects. Thus, there is a need of orally active small molecules that activate Adipoq subunits, and their downstream signaling, which could ameliorate obesity related type 2 diabetes. In the study we aim to investigate the effects of AdipoAI on obesity and T2D. Through in‐vitro and in‐vivo analyses, we investigated the antidiabetic potentials of AdipoAI and compared it with AdipoRON, another orally active adiponectin receptors agonist. Our results showed that in‐vitro treatment of AdipoAI (0–5 µM) increased adiponectin receptor subunits AdipoR1/R2 with increase in AMPK and APPL1 protein expression in C2C12 myotubes. Similarly, in‐vivo, oral administration of AdipoAI (25 mg/kg) observed similar effects as that of AdipoRON (50 mg/kg) with improved control of blood glucose and insulin sensitivity in diet‐induced obesity (DIO) mice models. Further, AdipoAI significantly reduced epididymal fat content with decrease in inflammatory markers and increase in PPAR‐α and AMPK levels and exhibited hepatoprotective effects in liver. Further, AdipoAI and AdipoRON also observed similar results in adipose tissue. Thus, our results suggest that low doses of orally active small molecule agonist of adiponectin AdipoAI can be a promising therapeutic target for obesity and T2D.
Prognostic impact of in‐stent restenosis in normal weight, overweight, and obese patients undergoing percutaneous coronary intervention
Authors: Jones Davis , Spirito Alessandro , Sartori Samantha , Vogel Birgit , Edens Madison , Kamaleldin Karim , Pileggi Brunna , Baber Usman , Dangas George , Sharma Samin K. , Kini Annapoorna , Mehran Roxana 
Published: January 2024

AbstractBackgroundAmong patients undergoing percutaneous coronary intervention (PCI), in‐stent restenosis (ISR) is related with a worse prognosis, while higher body mass index (BMI) values are associated with better outcomes. It is unclear whether the prognostic impact of ISR varies in function of BMI.MethodsPatients undergoing PCI at a large center from 2012 to 2019 not presenting with an acute myocardial infarction (MI) were included. Subjects with BMI < 18.5 kg/m2 or treated with bare metal stents were excluded. Patients were stratified according to type of lesion treated (ISR vs. no‐ISR) and into four BMI categories: normal weight (BMI 18.5–25 kg/m2), overweight (25.0–29.9 kg/m2), class I obesity (30.0–34.9 kg/m2), class II–III obesity (≥35.0 kg/m2). The primary outcome was major adverse cardiovascular events (MACE), a composite of all‐cause death, MI, and target vessel revascularization (TVR) at 1 year.ResultsOut of 16,234 patients, 3694 (23%) underwent PCI for ISR. ISR as compared to no‐ISR was associated with a consistent increased risk of MACE within the normal weight (18.8% vs. 7.8%, adj. hazard ratio (HR): 1.99, 95% confidence interval [CI]: 1.51–2.64), overweight (19.1% vs. 6.4%, adj. HR: 2.35, 95% CI: 1.91–2.88), class I obesity (18.3% vs. 6.8%, adj. HR: 1.95, 95% CI: 1.47–2.57), and class II–III obesity (16.4% vs. 7.4%, adj. HR: 1.61, 95% CI: 1.09–2.37) groups (interaction p‐value: 0.192). The ISR‐related risks were mostly driven by an excess of TVR.ConclusionsAt 1 year, ISR was associated with an increased risk of MACE irrespective of BMI, mostly due to an excess of TVR after ISR.
Development of Platinum Complexes for Tumor Chemoimmunotherapy
Authors: Jin Suxing , Guo Yan , Wang Xiaoyong 
Published: January 2024

AbstractPlatinum complexes are potential antitumor drugs in chemotherapy. Their impact on tumor treatment could be greatly strengthened by combining with immunotherapy. Increasing evidences indicate that the antitumor activity of platinum complexes is not limited to chemical killing effects, but also extends to immunomodulatory actions. This review introduced the general concept of chemoimmunotherapy and summarized the progress of platinum complexes as chemoimmunotherapeutic agents in recent years. Platinum complexes could be developed into inducers of immunogenic cell death, blockers of immune checkpoint, regulators of immune signaling pathway, and modulators of tumor immune microenvironment, etc. The synergy between chemotherapeutic and immunomodulatory effects reinforces the antitumor activity of platinum complexes, and helps them circumvent the drug resistance and systemic toxicity. The exploration of platinum complexes for chemoimmunotherapy may create new opportunities to revive the discovery of metal anticancer drugs.
A systematic review of present and future pharmaco‐structural therapies for hypertrophic cardiomyopathy
Authors: Sawan Mariem A. , Prabakaran Sindhu , D'Souza Melroy , Behbahani‐Nejad Omid , Gold Matthew E. , Williams Byron Robinson , Bilen Ozlem 
Published: January 2024

AbstractHypertrophic cardiomyopathy (HCM) is a common contemporary, treatable, genetic disorder that can be compatible with normal longevity. While current medical therapies are ubiquitous, they are limited by a lack of solid evidence, are often inadequate, poorly tolerated, and do not alter the natural disease course. As such, there has long been a need for effective, evidence‐based, and targeted disease‐modifying therapies for HCM. In this review, we redefine HCM as a treatable condition, evaluate current strategies for therapeutic intervention, and discuss novel myosin inhibitors. The majority of patients with HCM have elevated left ventricular outflow tract gradients, which predicts worse symptoms and adverse outcomes. Conventional pharmacological therapies for symptomatic HCM can help improve symptoms but are often inadequate and poorly tolerated. Septal reduction therapies (surgical myectomy and alcohol septal ablation) can safely and effectively reduce refractory symptoms and improve outcomes in patients with obstructive HCM. However, they require expertise that is not universally available and are not without risks. Currently, available therapies do not alter the disease course or the progressive cardiac remodeling that ensues, nor subsequent heart failure and arrhythmias. This has been regarded as an unmet need in the care of HCM patients. Novel targeted pharmacotherapies, namely cardiac myosin inhibitors, have emerged to reverse key pathophysiological changes and alter disease course. Their favorable outcomes led to the early Food and Drug Administration approval of mavacamten, a first‐in‐class myosin modulator, changing the paradigm for the pharmacological treatment of HCM.
A Drug‐Drug Interaction Study to Evaluate the Impact of Rimegepant on OCT2‐ and MATE1‐Mediated Transport of Metformin in Healthy Participants
Authors: Bhardwaj Rajinder , Morris Beth , Matschke Kyle , Bertz Richard , Croop Robert , Liu Jing 
Published: January 2024

AbstractRimegepant is a calcitonin gene‐related peptide receptor antagonist approved for migraine treatment. This phase 1, open‐label, single‐center, fixed‐sequence study evaluated the effect of rimegepant on the pharmacokinetics (PK) of metformin. Twenty‐eight healthy participants received metformin 500 mg twice daily from Days 1 to 4 and Days 7 to 10, and once daily on Days 5 and 11. Rimegepant, 75 mg tablet, was administered once daily from Days 9 to 12. At pre‐specified time points, plasma metformin concentration, serum glucose levels, and safety and tolerability were evaluated. A 16% increase in the area under the plasma metformin concentration‐time curve (AUC) for 1 dosing interval (AUC0‐τ,ss), a statistically insignificant increase in maximum and minimum steady‐state metformin concentration (Cmax,ss and Cmin,ss), and a decrease in metformin renal clearance were observed on Day 11 following metformin‐rimegepant coadministration compared with metformin alone; however, the changes were not clinically relevant. Additionally, coadministration of rimegepant with metformin did not induce clinically meaningful change in the maximum observed glucose concentration (Gmax) or AUCgluc compared with metformin alone. Overall, rimegepant and metformin coadministration did not result in clinically relevant changes in metformin PK, renal clearance, or the antihyperglycemic effects of metformin. Rimegepant is considered safe for use with metformin.
Utility of Cytochrome P450 4F2 Genotyping to Assess Drug Interaction Risk for Brincidovovir, a Cytochrome P450 4F2 Substrate
Authors: Tippin Tim , Faison Shamia , Schuck Virna , Dunn John , Naderer Odin 
Published: January 2024

AbstractSmallpox was eradicated in 1980 but remains a biothreat due to the potential release of variola virus into the general population. Brincidofovir, the second medicine approved by the US Food and Drug Administration to treat smallpox, is metabolized by oxidative and hydrolytic pathways. The oxidative pathway is initiated by cytochrome P450 4F2 (CYP4F2), an enzyme lacking clinical probes for drug interaction studies. The aim of this work was to assess the impact of reduced activity CYP4F2 variants (rs2108622, C/T and T/T) on brincidofovir pharmacokinetics as a surrogate for drug inhibition.Genotyping was performed on blood from healthy participants receiving oral (n = 261) and intravenous (IV, n = 49) brincidofovir across 6 phase 1 trials. Plasma concentrations were measured by validated liquid chromatography tandem mass spectrometry methods.After oral administration, subjects with the lowest activity CYP4F2 genotype (T/T) had up to 36% higher AUCinf and 29% higher Cmax while subjects with the moderate activity CYP4F2 genotype (C/T) had similar Cmax and AUCinf compared to those with the wild‐type genotype. Little to no increase in brincidofovir exposure parameters was observed following IV administration.Based on the lack of significant increases in brincidofovir plasma concentrations in subjects with low activity CYP4F2, a clinically meaningful drug–drug interaction is not expected with CYP4F2 inhibitor and brincidofovir coadministration.
Exploiting hashing for concurrent query processing and indexing of current location of moving objects
Authors: Chaudhry Natalia , Yousaf Muhammad Murtaza 
Published: January 2024

SummaryDue to recent developments in location‐based services and mobile computing, the need for indices for moving objects has been strengthened to improve the response time of a query operation. With a single index in place for managing both the update and query operations for moving objects, the index needs to be updated each time the object moves. This deteriorates the performance of concurrent query operations. It is critical to handle the conflicts between continuous update and query operations effectively using appropriate concurrency control protocol otherwise, inconsistent results will be reported. Many indices have been proposed in the literature for moving objects but they lack the support for processing concurrent operations. Further, the consistent indices in the literature are based on tree structure that have computationally expensive split/merge operations that can negatively affect the response time of query processing algorithms. Moreover such tree based indices are proposed for historical and future timeline data. As the scope of this article is on current timeline and concurrent continuous query operations, therefore, we exploit state of the art hash‐based indices in the literature and presented the two consistent versions. The comparative analysis of the indices is performed and meaningful findings are also presented along.
A transdiagnostic and translational framework for delineating the neuronal mechanisms of compulsive exercise in anorexia nervosa
Authors: Conn K. , Huang K. , Gorrell S. , Foldi C. J. 
Published: January 2024

AbstractObjectiveThe development of novel treatments for anorexia nervosa (AN) requires a detailed understanding of the biological underpinnings of specific, commonly occurring symptoms, including compulsive exercise. There is considerable bio‐behavioral overlap between AN and obsessive‐compulsive disorder (OCD), therefore it is plausible that similar mechanisms underlie compulsive behavior in both populations. While the association between these conditions is widely acknowledged, defining the shared mechanisms for compulsive behavior in AN and OCD requires a novel approach.MethodsWe present an argument that a better understanding of the neurobiological mechanisms that underpin compulsive exercise in AN can be achieved in two critical ways. First, by applying a framework of the neuronal control of OCD to exercise behavior in AN, and second, by taking better advantage of the activity‐based anorexia (ABA) rodent model to directly test this framework in the context of feeding pathology.ResultsA cross‐disciplinary approach that spans preclinical, neuroimaging, and clinical research as well as compulsive neurocircuitry and behavior can advance our understanding of when, why, and how compulsive exercise develops in the context of AN and provide targets for novel treatment strategies.DiscussionIn this article, we (i) link the expression of compulsive behavior in AN and OCD via a transition between goal‐directed and habitual behavior, (ii) present disrupted cortico‐striatal circuitry as a key substrate for the development of compulsive behavior in both conditions, and (iii) highlight the utility of the ABA rodent model to better understand the mechanisms of compulsive behavior relevant to AN.Public SignificanceIndividuals with AN who exercise compulsively are at risk of worse health outcomes and have poorer responses to standard treatments. However, when, why, and how compulsive exercise develops in AN remains inadequately understood. Identifying whether the neural circuitry underlying compulsive behavior in OCD also controls hyperactivity in the activity‐based anorexia model will aid in the development of novel eating disorder treatment strategies for this high‐risk population.
Valorization of spent coffee ground as a natural antioxidant and its use for sunflower oil shelf‐life extension
Authors: Bijla Laila , Hmitti Asma , Fadda Angela , Oubannin Samira , Gagour Jamila , Aissa Rabha , Laknifli Abdellatif , Sakar El Hassan , Gharby Said 
Published: January 2024

AbstractIn the present paper, spent coffee grounds (SCG) were investigated for their antioxidant capacity, chemical profiling, and their potential to extend the shelf‐life of refined sunflower oil (RSO). Ethanolic SCG extract (SCGE) ability to enhance RSO oxidation, during accelerated aging conditions, was examined at 60°C for 120 days. To this end, oxidative stability was evaluated for RSO added with SCGE (at 0.01%, 0.02%, and 0.03%) in the presence of a negative control (RSO without SCGE) and a positive one consisting in vitamin E (VE, a synthetic antioxidant) using the same concentrations (0.01%–0.03%). Our outcomes reveal that SCG were an important source of oil, protein, carbohydrates, minerals, pigments, phenolics, and flavonoid compounds, and they have high antioxidant capacity. SCGE at 0.03% increased RSO oxidative stability by reducing free fatty acids (FFA), peroxide value (PV), and conjugated dienes (CD) and trienes (CT) compared to the unenriched oil. However, both SCGE and VE had no significant effect (p < 0.05) on the fatty acids profile and iodine value. Furthermore, RSO enriched with SCGE had overall acceptability in the sensory evaluation. In conclusion, SCGE improved RSO oxidative stability, and therefore, it could be used as an efficient natural antioxidant to substitute VE during industrial processes.Practical Application: It is widely accepted that synthetic antioxidants may be harmful to human health. In such a context, plant‐based natural antioxidants proved to be an excellent alternative. The valorization of SCG as a natural antioxidant may represent a cost‐effective and sustainable approach for the food industry. The addition of used coffee grounds to refined sunflower oil could enhance its shelf‐life, offering a potential alternative to synthetic antioxidants. This may also help to reduce the quantity of coffee waste produced, promoting a circular economy.
Characteristics of deceased subjects transported to a postmortem imaging center due to unusual death related to epilepsy
Authors: Ito Yoshiki , Hata Nobuhiro , Maesawa Satoshi , Tanei Takafumi , Ishizaki Tomotaka , Mutoh Manabu , Hashida Miki , Kobayashi Yutaka , Saito Ryuta 
Published: January 2024

AbstractObjectivePatients with epilepsy have high risk of experiencing uncommon causes of death. This study aimed to evaluate patients who underwent unusual deaths related to epilepsy and identify factors that may contribute to these deaths and may also include sudden unexpected death in epilepsy (SUDEP).MethodsWe analyzed 5291 cases in which a postmortem imaging (PMI) study was performed using plane CT, because of an unexplained death. A rapid troponin T assay was performed using peripheral blood samples. Clinical information including the cause of death suspected by the attending physician, body position, place of death, medical history, and antiseizure medications was evaluated.ResultsA total of 132 (2.6%) patients had an obvious history of epilepsy, while 5159 individuals had no history of epilepsy (97.4%). Cerebrovascular disease was the cause of death in 1.6% of patients in the group with epilepsy, and this was significantly lower than that in the non‐epilepsy group. However, drowning was significantly higher (9.1% vs. 4.4%). Unspecified cause of death was significantly more frequent in the epilepsy group (78.0% vs. 57.8%). Furthermore, the proportion of patients who demonstrated elevation of troponin T levels without prior cardiac disease was significantly higher in the epilepsy group (37.9% vs. 31.1%). At discovery of death, prone position was dominant (30.3%), with deaths occurring most commonly in the bedroom (49.2%). No antiseizure medication had been prescribed in 12% of cases, while 29.5% of patients were taking multiple antiseizure medications.SignificanceThe prevalence of epilepsy in individuals experiencing unusual death was higher than in the general population. Despite PMI studies, no definitive cause of death was identified in a significant proportion of cases. The high troponin T levels may be explained by long intervals between death and examination or by higher incidence of myocardial damage at the time of death.Plain Language SummaryThis study investigated unusual deaths in epilepsy patients, analyzing 5291 postmortem imaging cases. The results showed that 132 cases (2.6%) had a clear history of epilepsy. In these cases, only 22% cases were explained after postmortem examination, which is less than in non‐epilepsy group (42.2%). Cerebrovascular disease was less common in the epilepsy group, while drowning was more common. Elevated troponin T levels, which suggest possibility of myocardial damage or long intervals between death and examination, were also more frequent in the epilepsy group compared to non‐epilepsy group.
Coal price forecasting using complete ensemble empirical mode decomposition and stacking‐based ensemble learning with semisupervised data processing
Authors: Tang Jing , Guo Yida , Han Yilin 
Published: January 2024

AbstractGlobally, coal is a critical energy source, and the profits of related enterprises are highly related to changes in the coal price. A robust coal purchasing cost forecasting method may enhance the coal purchasing strategies of coal‐consuming enterprises and obtain key information for reducing global carbon emissions. However, forecasting the price of coal is a challenging task due to the noise and high random fluctuation of coal price data. To overcome these obstacles, this research proposes a novel forecasting method combining data decomposition, semisupervised feature engineering, and ensemble learning to forecast coal prices. Initially, the Complete Ensemble Empirical Mode Decomposition with Adaptive Noise (CEEMDAN) method is employed to decompose the coal price series to reduce the complexity. Second, considering the fluctuation of coal price is influenced by various factors (such as transportation cost and coal mine production), the proposed system incorporates an adaptive data fusion module to fuse data from multiple sources. Finally, a stacking‐based ensemble learning model is adopted in the method to increase the forecasting accuracy by combining the forecasting results of multiple models. The Bohai‐Rim Steam‐Coal Price Index was used to validate the proposed method, and the result of the case study shows that the proposed method provides superior performance than the other nine baseline models in all measured indices. The outcomes of ablation tests indicate the precision of each algorithm is improved by combining CEEMDAN, which proves that the decomposition algorithm is necessary.