Structural Determinants of CX-4945 Derivatives as Protein Kinase CK2 Inhibitors: A Computational Study

Protein kinase CK2, also known as casein kinase-2, is involved in a broad range of physiological events including cell growth, proliferation and suppression of apoptosis which are related to human cancers. A series of compounds were identified as CK2 inhibitors and their inhibitory activities varied depending on their structures. In order to explore the structure-activity correlation of CX-4945 derivatives as inhibitors of CK2, in the present study, a set of ligand- and receptor-based 3D-QSAR models were developed employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). The optimum CoMFA (Rcv2 = 0.618, Rpred2 = 0.892) and CoMSIA (Rcv2 = 0.681, Rpred2 = 0.843) models exhibited reasonable statistical characteristics for CX-4945 derivatives. The results indicated that electrostatic effects contributed the most to both CoMFA and CoMSIA models. The combination of docking analysis and molecular dynamics (MD) simulation showed that Leu45, Lys68, Glu81, Val116, Asp175 and Trp176 of CK2 which formed several direct or water-bridged H-bonds with CX-4945 are crucial for CX-4945 derivatives recognition to CK2. These results can offer useful theoretical references for designing more potent CK2 inhibitors

A comprehensive analysis of adverse drug reactions in 2020–2023: case studies

IntroductionAdverse drug reactions (ADRs) have posed significant threats to patient safety and could potentially result in adverse clinical outcomes.MethodsIn this study, we analyzed ADRs data reported by a large hospital spanning from 2020 to 2023, with a particular focus on identifying demographic and clinical factors associated with severe ADRs. The dataset encompassed 5,644 cases, incorporating variables such as patient age, gender, smoking and drinking history, allergies, medication type, and administration route.ResultsAmong these, 408 cases of severe ADRs underwent detailed examination. Additionally, the study delved into the correlation between adverse drug reactions symptoms (ADRS) and various drug types. According to research statistics, individuals in the middle-aged group (46–65 years) exhibited the highest proportion of severe ADRs at 36.77%. Females were significantly more affected than males, accounting for 66.67% of severe ADRs. Anti-tumor drugs emerged as the primary cause of severe ADRs, responsible for 52.70% of such incidents. Compared with other administration methods, intravenous injection was more prone to causing severe ADRs, with a likelihood of 53.92%. Furthermore, the blood system was identified as the ADRS where severe ADRs occurred at a significantly higher rate than other parts of the body, at 53.19%. Correlation analysis reveals a strong association between medication type and factors such as patient age, administration route, and ADRS. Notably, ADRS was also strongly linked to drug type, gender, and age.ConclusionThese findings collectively highlight the critical need for personalized treatment plans and targeted monitoring. Particular attention should be directed towards high-risk groups, such as middle-aged females and patients undergoing anti-tumor therapies. By doing so, it is possible to enhance drug safety and minimize the occurrence of severe ADRs

A pilot study of pancreatic islet amyloid PET imaging with [¹⁸F]FDDNP

Objectives Pancreatic islet amyloid deposition occurs before β-cell damage in type 2 diabetes mellitus patients. The islet and Alzheimer’s disease β-amyloid shares similar secondary structures. The Alzheimer’s disease β-amyloid targeting tracer [18F]FDDNP could be used to image pancreatic islet amyloid with PET.Patients and methods Consecutive pancreatic tissue sections from a 69-year-old male type 2 diabetes mellitus patient were stained by hematoxylin and eosin, anti-amylin antibody, Congo Red, periodic acid-Schiff, and [18F]FDDNP reference compound, respectively. The pancreatic tissue sections were also incubated with [18F]FDDNP with and without its reference compound for autoradiography. Subsequently, we performed control [18F]FDDNP pancreatic PET/CT imaging in four healthy individuals. The mean standardized uptake values of [18F]FDDNP uptake in the pancreatic head, neck, body, and tail, blood pool, liver, and vertebral bone from 5 to 120 min after injection were determined.Results Islet amyloid was observed in all four standard staining methods in the pancreas tissue. Similar islet amyloid distribution and phenotypes were observed clearly in the [18F]FDDNP reference compound-stained pancreas tissue. [18F]FDDNP was intensively accumulated in the same pancreatic tissue in autoradiography, which was largely blocked by its reference compound. In the PET/CT scans of control human participants, the mean standardized uptake values in pancreas decreased to the blood pool level in 30 min and all parts of the pancreas had similar [18F]FDDNP uptake. The pancreas could be distinguished clearly from the liver at all-time points.Conclusion These results suggested that [18F]FDDNP is a potential tracer for pancreatic islet amyloid PET imaging

Targeting Amyloids with [¹⁸F]AV-45 for Medullary Thyroid Carcinoma Positron Emission Tomography/Computed Tomography Imaging: A Pilot Clinical Study

Medullary thyroid carcinoma (MTC) is a malignant neuroendocrine tumor with a high recurrence rate. Amyloid plaques formed from the misfolding of calcitonin are the key characteristics of MTC. Herein, we conducted a first-in-human pilot clinical study by applying a β-amyloid-specific radiotracer, [ F]AV-45, to positron emission tomography (PET)/computed tomography (CT) imaging of MTC. The presence of amyloid plaques in the tumor tissue sections from five MTC patients was confirmed by hematoxylin and eosin (H&E) and Congo Red staining. [ F]AV-45 selectively accumulated in the amyloid plaques in the continued tumor tissue sections with similar distribution patterns to the H&E and Congo Red staining. In addition, the [ F]AV-45 uptake can be largely blocked by its nonradioactive reference compound. The [ F]AV-45 accumulation in the thyroid, neck lymph nodes, and muscles in healthy human subjects is close to the background indicated by PET/CT imaging. In the comparison PET/CT imaging study of a recurrent MTC patient, 2-deoxy-2-[ F]fluoro-d-glucose ([ F]FDG) showed an elevated uptake by multiple neck lymph nodes. In contrast, only one of these neck lymph nodes had increased [ F]AV-45 uptake. Postoperative histopathological analysis confirmed the [ F]AV-45 PET-positive lymph node as MTC with amyloid deposition, while other [ F]FDG positive lymph nodes were free from MTC and amyloid plaques. Thus, [ F]AV-45 showed the promise for the clinical PET/CT imaging of MTC

COSTA: A Multi-center Multi-vendor TOF-MRA Dataset and A Novel Cerebrovascular Segmentation Network

Time-of-flight magnetic resonance angiography(TOF-MRA) is the least invasive and ionizing radiation free approach for cerebrovascular imaging, but variations in imaging artifacts across different clinical centers andimaging vendors result in inter-site and inter-vendor heterogeneity, making its accurate and robust cerebrovascular segmentation challenging. Moreover, the limited availabilityand quality of annotated data pose further challenges for segmentation methods to generalize well to unseen datasets. In this paper, we construct the largest and mostdiverse TOF-MRA dataset (COSTA) from 8 individual imaging centers, with all the volumes manually annotated. Then we propose a novel network for cerebrovascular segmentation,namely CESAR, with the ability to tackle featuregranularity and image style heterogeneity issues. Specifically, a coarse-to-fine architecture is implemented to refine cerebrovascular segmentation in an iterative manner.An automatic feature selection module is proposed to selectively fuse global long-range dependencies and local contextual information of cerebrovascular structures. A style self-consistency loss is then introduced to explicitlyalign diverse styles of TOF-MRA images to a standardized one. Extensive experimental results on the COSTA dataset demonstrate the effectiveness of our CESAR network against state-of-the-art methods. We have made 6subsets of COSTA with the source code online available, in order to promote relevant research in the community

Bone Mineral Density Reference Standards for Chinese Children Aged 3-18: Cross-Sectional Results of the 2013-2015 China Child and Adolescent Cardiovascular Health (CCACH) Study

Objectives: No nationwide paediatric reference standards for bone mineral density (BMD) are available in China. We aimed to provide sex-specific BMD reference values for Chinese children and adolescents (3-18 years). Methods: Data (10 818 participants aged 3-18 years) were obtained from cross-sectional surveys of the China Child and Adolescent Cardiovascular Health in 2015, which included four municipality cities and three provinces. BMD was measured using Hologic Discovery Dual Energy X-ray Absorptiometry (DXA) scanner. The DXA measures were modelled against age, with height as an independent variable. The LMS statistical method using a curve fitting procedure was used to construct reference smooth cross-sectional centile curves for dependent versus independent variables. Results: Children residing in Northeast China had the highest total body less head (TBLH) BMD while children residing in Shandong Province had the lowest values. Among children, TBLH BMD was higher for boys as compared with girls; but, it increased with age and height in both sexes. Furthermore, TBLH BMD was higher among US children as compared with Chinese children. There was a large difference in BMD for height among children from these two countries. US children had a much higher BMD at each percentile (P) than Chinese children; the largest observed difference was at P50 and P3 and the smallest difference was at P97. Conclusions: This is the first study to present a sex-specific reference dataset for Chinese children aged 3-18 years. The data can help clinicians improve interpretation, assessment and monitoring of densitometry results

Revealing the roles of narrow electronic band near Fermi level in 1T-TaS2 related layered materials

Here we use low-temperature scanning tunneling microscopy and spectroscopy to reveal the roles of the narrow electronic band in two 1$T$-TaS$_2$ related materials (bulk 1$T$-TaS$_2$ and 4$H_{\rm b}$-TaS$_2$). 4$H_{\rm b}$-TaS$_2$ is a superconducting compound with alternating 1$T$-TaS$_2$ and 1$H$-TaS$_2$ layers, where the 1$H$-TaS$_2$ layer has weak charge density wave (CDW) pattern and reduces the CDW coupling between the adjacent 1$T$-TaS$_2$ layers. In the 1$T$-TaS$_2$ layer of 4$H_{\rm b}$-TaS$_2$, we observe a narrow electronic band located near Fermi level, and its spatial distribution is consistent with the tight-binding calculations for two-dimensional 1$T$-TaS$_2$ layers. The weak electronic hybridization between the 1$T$-TaS$_2$ and 1$H$-TaS$_2$ layers in 4$H_{\rm b}$-TaS$_2$ shifts the narrow electronic band to be slightly above the Fermi level, which suppresses the electronic correlation induced band splitting. In contrast, in bulk 1$T$-TaS$_2$, there is an interlayer CDW coupling induced insulating gap. In comparison with the spatial distributions of the electronic states in bulk 1$T$-TaS$_2$ and 4$H_{\rm b}$-TaS$_2$, the insulating gap in bulk 1$T$-TaS$_2$ results from the formation of a bonding band and an antibonding band due to the overlap of the narrow electronic bands in the dimerized 1$T$-TaS$_2$ layers.Comment: 5 pages, 4 figure