Evaluation of deformed image-based dose calculations for adaptive radiotherapy of nasopharyngeal carcinoma

The ultimate goal of adaptive radiotherapy (ART) is to deliver truly customized radiation treatments. Currently, the quality of cone-beam computed tomography (CBCT) images is still inferior to that of conventional CT images in contour delineations and dose calculations for replanning purposes. This retrospective study aims to evaluate the dosimetric accuracy of using deformed conventional CT images for dose calculations, in the hope of inferring the feasibility of ART using planning CT (PCT) images that deformed to up-to-date CBCT images for patients with nasopharyngeal carcinoma (NPC). Thirty consecutive patients with NPC who had undergone 1 replan in their radiotherapy treatments were selected. The pretreatment PCT images were deformed to match the mid-treatment PCT images by deformable image registration. The same volumetric modulated arc therapy plan was then calculated on the deformed PCT images. The resulting dose distributions and dose volume histograms of the tumors and organs at risk (OARs) were compared with the original plan. Five dose levels, D98%, D95%, D50%, D5%, and D2%, were recorded for 9 NPC targets. Four dose levels, Dmax, D10%, D50%, and Dmean, were recorded for 15 OARs. The greatest percentage difference in observed dose for D98%, D95%, D50%, D5%, and D2% of the targets were 1.71%, 1.55%, 0.64%, 0.97%, and 1.13%, respectively. The greatest percentage difference in observed dose for Dmax, D10%, D50%, and Dmean of the OARs were -26.51% (left optic nerve), -17.06% (left optic nerve), 56.70% (spinal cord), and 18.97% (spinal cord), respectively. In addition, 29 of 45 (64%) dosimetric end points of the targets showed statistically significant dose differences (p < 0.05) between the original plan and the plan calculated on deformed images. Forty-nine of 60 (82%) dosimetric end points of the OARs also showed statistically significant dose differences (p < 0.05). Dose calculations using deformed PCT images could result in significant dose uncertainties in target volumes and OARs. Larger dose deviations were found in OARs in comparison with target volumes. The spinal cord and optic nerve showed the greatest percentage dose differences and the clinical significance has yet to be determined. Deformable registration error was believed to be the problem causing the dose deviations. Owing to unknown clinical significanceof dose deviation results obtained from this study, a conventional CT scan is still required for replanning in patients with NPC who are experiencing significant anatomical changes during the course of radiation treatment. [Abstract copyright: Copyright © 2017 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Aurora kinase A in urological cancers

Aurora kinases are a family of serine/threonine kinases of whom function to preserve the integrity and fidelity of chromosomal segregation. In mammals, aurora kinase A (AurkA) is vital to the mitotic phase of the cell cycle as a consequence of its spatial and timely interactions with various types of cell cycle substrates. Since AurkA is present in all of the mammalian somatic cell cycles, it is also detectable in many different types and stages of cancers. Specific activation sites, feedback loops, and substrate interactions have been identified and linked to the progression of urological cancers. It is inarguable that the slightest hint of disorder among AurkA can disrupt the cell cycle’s ability to regulate the growth and progression of cells in all conditions due to its direct interactions with tumor suppressing molecules. Discovering that AurkA interacts with FOXO3a, PLK1, TPX2, TPX2, SPOP, YBX1 and CXCR7 in ways that were unknown before 2019 has revealed new targeted treatment options that may surpass current methodology in efficiency and length of remission. The aim of this paper is to highlight AurkA’s oncogenic role in urological cancers, in addition to emphasizing newfound pathways and mechanisms that introduce the prostate cancer research field to more options for therapeutic approaches

Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models: an effect mediated by EGFR inhibition, p53 acetylation and oxidative stress

BACKGROUND: The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its chemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC). METHODS: Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of PA-2. RESULTS: PA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established subcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect, resulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented the development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the activation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades, including PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced its DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the thioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-κB. These molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer effect of PA-2. CONCLUSIONS: Our findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC, and is also effective in its chemoprevention, warranting further evaluation as an anticancer agent

Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice

(a) Immunoblotting analysis of IRβ in the hippocampus and frontal cortex of 18-month old wildtype and APN-KO mice. (b) Densitometric analysis of the ratio of IRβ. Mean ± S.E.M.; ***p < 0.001, n.s. statistically not significant; Scale bar: 100 μm. (JPG 30 kb

Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in Hepatocellular carcinoma development

Background: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. Methods: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. Results: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. Conclusion: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis. © 2011 Yip et al.published_or_final_versio

A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10-6) had not been highlighted in previous studies. While rs56137030was correlated at r2>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations

Renal and Splenic Micro-Infarctions Following Bronchial Artery Embolization with Tris-Acryl Microspheres

A bronchial artery embolization (BAE) is an important therapeutic method used to control acute and chronic hemoptysis. We report a case of multiple micro-infarcts involving both the kidneys and spleen, following a BAE with 500-700 µm crossed-linked tris-acryl microspheres (Embospheres) in a patient with bronchial artery pulmonary vein shunts. The superior penetration characteristics of the microspheres may have resulted in the greater tendency to cross the bronchial artery pulmonary vein shunts, which subsequently caused the systemic infarcts in our patient. We propose the use of larger sized microspheres (700-900 µm), which may aid in avoiding this complication

Comparisons of the risk of myopericarditis between COVID-19 patients and individuals receiving COVID-19 vaccines: a population-based study.

Both COVID-19 infection and COVID-19 vaccines have been associated with the development of myopericarditis. The objective of this study is to (1) analyse the rates of myopericarditis after COVID-19 infection and COVID-19 vaccination in Hong Kong, (2) compared to the background rates, and (3) compare the rates of myopericarditis after COVID-19 vaccination to those reported in other countries. This was a population-based cohort study from Hong Kong, China. Patients with positive RT-PCR test for COVID-19 between 1st January 2020 and 30th June 2021 or individuals who received COVID-19 vaccination until 31st August were included. The main exposures were COVID-19 positivity or COVID-19 vaccination. The primary outcome was myopericarditis. This study included 11,441 COVID-19 patients from Hong Kong, four of whom suffered from myopericarditis (rate per million: 326; 95% confidence interval [CI] 127-838). The rate was higher than the pre-COVID-19 background rate in 2019 (rate per million: 5.5, 95% CI 4.1-7.4) with a rate ratio of 55.0 (95% CI 21.4-141). Compared to the background rate, the rate of myopericarditis among vaccinated subjects in Hong Kong was similar (rate per million: 5.5; 95% CI 4.1-7.4) with a rate ratio of 0.93 (95% CI 0.69-1.26). The rates of myocarditis after vaccination in Hong Kong were comparable to those vaccinated in the United States, Israel, and the United Kingdom. COVID-19 infection was associated with significantly higher rate of myopericarditis compared to the vaccine-associated myopericarditis. [Abstract copyright: © 2022. The Author(s).

Automatic Ultrasound Curve Angle Measurement via Affinity Clustering for Adolescent Idiopathic Scoliosis Evaluation

The current clinical gold standard for evaluating adolescent idiopathic scoliosis (AIS) is X-ray radiography, using Cobb angle measurement. However, the frequent monitoring of the AIS progression using X-rays poses a challenge due to the cumulative radiation exposure. Although 3D ultrasound has been validated as a reliable and radiation-free alternative for scoliosis assessment, the process of measuring spinal curvature is still carried out manually. Consequently, there is a considerable demand for a fully automatic system that can locate bony landmarks and perform angle measurements. To this end, we introduce an estimation model for automatic ultrasound curve angle (UCA) measurement. The model employs a dual-branch network to detect candidate landmarks and perform vertebra segmentation on ultrasound coronal images. An affinity clustering strategy is utilized within the vertebral segmentation area to illustrate the affinity relationship between candidate landmarks. Subsequently, we can efficiently perform line delineation from a clustered affinity map for UCA measurement. As our method is specifically designed for UCA calculation, this method outperforms other state-of-the-art methods for landmark and line detection tasks. The high correlation between the automatic UCA and Cobb angle (R$^2$=0.858) suggests that our proposed method can potentially replace manual UCA measurement in ultrasound scoliosis assessment

Sulfonylurea is associated with higher risks of ventricular arrhythmia or sudden cardiac death compared with metformin: A population-based cohort study

Background Commonly prescribed diabetic medications such as metformin and sulfonylurea may be associated with different arrhythmogenic risks. This study compared the risk of ventricular arrhythmia or sudden cardiac death between metformin and sulfonylurea users in patients with type 2 diabetes. Methods and Results Patients aged ≥40 years who were diagnosed with type 2 diabetes or prescribed antidiabetic agents in Hong Kong between January 1, 2009, and December 31, 2009, were included and followed up until December 31, 2019. Patients prescribed with both metformin and sulfonylurea or had prior myocardial infarction were excluded. The study outcome was a composite of ventricular arrhythmia or sudden cardiac death. Metformin users and sulfonylurea users were matched at a 1:1 ratio by propensity score matching. The matched cohort consisted of 16 596 metformin users (47.70% men; age, 68±11 years; mean follow‐up, 4.92±2.55 years) and 16 596 sulfonylurea users (49.80% men; age, 70±11 years; mean follow‐up, 4.93±2.55 years). Sulfonylurea was associated with higher risk of ventricular arrhythmia or sudden cardiac death than metformin hazard ratio (HR, 1.90 [95% CI, 1.73–2.08]). Such difference was consistently observed in subgroup analyses stratifying for insulin usage or known coronary heart disease. Conclusions Sulfonylurea use is associated with higher risk of ventricular arrhythmia or sudden cardiac death than metformin in patients with type 2 diabetes