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Medical Dosimetry : Official Journal of...Stereotactic body radiotherapy (SBRT) treatment of oligometastatic lesions via single-isocenter/multi-target (SIMT) plan is more efficient than using...
Stereotactic body radiotherapy (SBRT) treatment of oligometastatic lesions via single-isocenter/multi-target (SIMT) plan is more efficient than using multi-isocenter/multitarget SBRT. This study quantifies the spatial positioning accuracy of 2 commercially available LINAC systems for SIMT treatment pertaining to the potential amplification of error as a function of the target's distance-to-isocenter. We compare the Ring-Gantry Halcyon LINAC equipped with the fast iterative conebeam-CT (iCBCT) for image-guided SIMT treatment, and the SBRT-dedicated C-Arm TrueBeam with standard pretreatment CBCT imaging. For both systems, Sun Nuclear's MultiMet Winston-Lutz Cube phantom with 6 metallic BBs distributed at different planes up to 7 cm away from the isocenter was used. The phantom was aligned and imaged via CBCT, and then couch corrections were applied. To treat all 6 BBs, an Eclipse 10-field 3D-conformal Field-in-Field (2×2 cm MLC field to each BB) plan for varying gantry, collimator, and couch (TrueBeam only) positions was developed for both machines with 6MV-FFF beam. The plan was delivered through ARIA once a week. The EPID images were analyzed via Sun Nuclear's software for spatial positioning accuracy. On TrueBeam, the treatment plan was delivered twice: once with 3DoF translational corrections and once with PerfectPitch 6DoF couch corrections. The average 3D spatial positioning accuracy was 0.55 ± 0.30 mm, 0.54 ± 0.24 mm, and 0.56 ± 0.28 mm at isocenter, and 0.59 ± 0.30 mm, 0.69 ± 0.30 mm, and 0.70 ± 0.35 mm at 7 cm distance-to-isocenter for Halcyon, TrueBeam 3DoF, and TrueBeam 6DoF, respectively. This suggests there are no clinically significant deviations of spatial uncertainty between the platforms with the distance-to-isocenter. On both platforms, our weekly independent measurements demonstrated the reproducibility for less than 1.0 mm positional accuracy of off-axis targets up to 7 cm from the isocenter. Due to this, no additional PTV-margin is suggested for lesions within 7 cm of isocenter. This study confirms that Halcyon can deliver similar positional accuracy to SBRT-dedicated TrueBeam to off-axis targets up to 7 cm from isocenter. These results further benchmark the spatial uncertainty of our extensively used SBRT-dedicated TrueBeam LINAC for SIMT SBRT treatments.
PubMed: 37059628
DOI: 10.1016/j.meddos.2023.03.005 -
Cells Mar 2023Aggresomes are collections of intracellular protein aggregates. In liver cells of patients with alcoholic hepatitis, aggresomes appear histologically as cellular...
BACKGROUND
Aggresomes are collections of intracellular protein aggregates. In liver cells of patients with alcoholic hepatitis, aggresomes appear histologically as cellular inclusions known as Mallory-Denk (M-D) bodies. The proteasome is a multicatalytic intracellular protease that catalyzes the degradation of both normal (native) and abnormal (misfolded and/or damaged) proteins. The enzyme minimizes intracellular protein aggregate formation by rapidly degrading abnormal proteins before they form aggregates. When proteasome activity is blocked, either by specific inhibitors or by intracellular oxidants (e.g., peroxynitrite, acetaldehyde), aggresome formation is enhanced. Here, we sought to verify whether inhibition of proteasome activity by ethanol exposure enhances protein aggregate formation in VL-17A cells, which are recombinant, ethanol-oxidizing HepG2 cells that express both alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1).
METHODS
We exposed ethanol-non-oxidizing HepG2 cells () or ethanol-oxidizing VL-17A () to varying levels of ethanol for 24 h or 72 h. After these treatments, we stained cells for aggresomes (detected microscopically) and quantified their numbers and sizes. We also conducted flow cytometric analyses to confirm our microscopic findings. Additionally, aggresome content in liver cells of patients with alcohol-induced hepatitis was quantified.
RESULTS
After we exposed VL-17A cells to increasing doses of ethanol for 24 h or 72 h, 20S proteasome activity declined in response to rising ethanol concentrations. After 24 h of ethanol exposure, aggresome numbers in VL-17A cells were 1.8-fold higher than their untreated controls at all ethanol concentrations employed. After 72 h of ethanol exposure, mean aggresome numbers were 2.5-fold higher than unexposed control cells. The mean aggregate size in all ethanol-exposed VL-17A cells was significantly higher than in unexposed control cells but was unaffected by the duration of ethanol exposure. Co-exposure of cells to EtOH and rapamycin, the latter an autophagy activator, completely prevented EtOH-induced aggresome formation. In the livers of patients with alcohol-induced hepatitis (AH), the staining intensity of aggresomes was 2.2-fold higher than in the livers of patients without alcohol use disorder (AUD).
CONCLUSIONS
We conclude that ethanol-induced proteasome inhibition in ethanol-metabolizing VL-17A hepatoma cells causes accumulation of protein aggregates. Notably, autophagy activation removes such aggregates. The significance of these findings is discussed.
Topics: Humans; Ethanol; Hep G2 Cells; Protein Aggregates; Cytochrome P-450 CYP2E1; Proteasome Endopeptidase Complex; Hepatitis
PubMed: 37048086
DOI: 10.3390/cells12071013 -
Liver International : Official Journal... Jun 2023Hepatocytic ballooning is a key histological feature in the diagnosis of non-alcoholic steatohepatitis (NASH) and is an essential component of the two most widely used... (Review)
Review
Hepatocytic ballooning is a key histological feature in the diagnosis of non-alcoholic steatohepatitis (NASH) and is an essential component of the two most widely used histological scoring systems for diagnosing and staging non-alcoholic fatty liver disease (NAFLD) [namely, the NAFLD activity score (NAS), and the steatosis, activity and fibrosis (SAF) scoring system]. As a result of the increasing incidence of NASH globally, the diagnostic challenges of hepatocytic ballooning are unprecedented. Despite the clear pathological concept of hepatocytic ballooning, there are still challenges in assessing hepatocytic ballooning in 'real life' situations. Hepatocytic ballooning can be confused with cellular oedema and microvesicular steatosis. Significant inter-observer variability does exist in assessing the presence and severity of hepatocytic ballooning. In this review article, we describe the underlying mechanisms associated with hepatocytic ballooning. Specifically, we discuss the increased endoplasmic reticulum stress and the unfolded protein response, as well as the rearrangement of the intermediate filament cytoskeleton, the appearance of Mallory-Denk bodies and activation of the sonic Hedgehog pathway. We also discuss the use of artificial intelligence in the detection and interpretation of hepatocytic ballooning, which may provide new possibilities for future diagnosis and treatment.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver; Artificial Intelligence; Hedgehog Proteins; Severity of Illness Index; Biopsy
PubMed: 37017559
DOI: 10.1111/liv.15571 -
Do foraging ecology and contaminants interactively predict parenting hormone levels in common eider?General and Comparative Endocrinology Jun 2023Global climate change is causing abiotic shifts such as higher air and ocean temperatures, and disappearing sea ice in Arctic ecosystems. These changes influence...
Global climate change is causing abiotic shifts such as higher air and ocean temperatures, and disappearing sea ice in Arctic ecosystems. These changes influence Arctic-breeding seabird foraging ecology by altering prey availability and selection, affecting individual body condition, reproductive success, and exposure to contaminants such as mercury (Hg). The cumulative effects of alterations to foraging ecology and Hg exposure may interactively alter the secretion of key reproductive hormones such as prolactin (PRL), important for parental attachment to eggs and offspring and overall reproductive success. However, more research is needed to investigate the relationships between these potential links. Using data collected from 106 incubating female common eiders (Somateria mollissima) at six Arctic and sub-Arctic colonies, we examined whether the relationship between individual foraging ecology (assessed using δC, δN) and total Hg (THg) exposure predicted PRL levels. We found a significant, complex interaction between δC, δN and THg on PRL, suggesting that individuals cumulatively foraging at lower trophic levels, in phytoplankton-dominant environments, and with the highest THg levels had the most constant significant relationship PRL levels. Cumulatively, these three interactive variables resulted in lowered PRL. Overall, results demonstrate the potential downstream and cumulative implications of environmentally induced changes in foraging ecology, in combination with THg exposure, on hormones known to influence reproductive success in seabirds. These findings are notable in the context of continuing environmental and food web changes in Arctic systems, which may make seabird populations more susceptible to ongoing stressors.
Topics: Humans; Animals; Female; Ecosystem; Parenting; Ducks; Food Chain; Aquatic Organisms; Arctic Regions; Mercury; Hormones; Environmental Monitoring
PubMed: 36907529
DOI: 10.1016/j.ygcen.2023.114261 -
The American Journal of Pathology Oct 2023Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light... (Review)
Review
Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease-related cellular inclusion bodies, such as Mallory-Denk bodies, intracytoplasmic hyaline bodies, α-antitrypsin aggregates, as well as p62 bodies and condensates. p62 also acts as an intracellular signaling hub, and it involves multiple signaling pathways, including nuclear factor erythroid 2-related factor 2, NF-κB, and the mechanistic target of rapamycin, which are critical for oxidative stress, inflammation, cell survival, metabolism, and liver tumorigenesis. This review discusses the recent insights of p62 in protein quality control, including the role of p62 in the formation and degradation of p62 stress granules and protein aggregates as well as regulation of multiple signaling pathways in the pathogenesis of alcohol-associated liver disease.
Topics: Humans; Sequestosome-1 Protein; Signal Transduction; Liver Neoplasms; NF-kappa B; Liver Diseases, Alcoholic; Autophagy
PubMed: 36906265
DOI: 10.1016/j.ajpath.2023.02.015 -
Cell Death Discovery Feb 2023Hepatotoxins activate the hepatic survival pathway, but it is unclear whether impaired survival pathways contribute to liver injury caused by hepatotoxins. We...
Hepatotoxins activate the hepatic survival pathway, but it is unclear whether impaired survival pathways contribute to liver injury caused by hepatotoxins. We investigated the role of hepatic autophagy, a cellular survival pathway, in cholestatic liver injury driven by a hepatotoxin. Here we demonstrate that hepatotoxin contained DDC diet impaired autophagic flux, resulting in the accumulation of p62-Ub-intrahyaline bodies (IHBs) but not the Mallory Denk-Bodies (MDBs). An impaired autophagic flux was associated with a deregulated hepatic protein-chaperonin system and significant decline in Rab family proteins. Additionally, p62-Ub-IHB accumulation activated the NRF2 pathway rather than the proteostasis-related ER stress signaling pathway and suppressed the FXR nuclear receptor. Moreover, we demonstrate that heterozygous deletion of Atg7, a key autophagy gene, aggravated the IHB accumulation and cholestatic liver injury. Conclusion: Impaired autophagy exacerbates hepatotoxin-induced cholestatic liver injury. The promotion of autophagy may represent a new therapeutic approach for hepatotoxin-induced liver damage.
PubMed: 36810855
DOI: 10.1038/s41420-023-01368-3 -
Global Spine Journal Feb 2023Retrospective Cohort Study.
STUDY DESIGN
Retrospective Cohort Study.
OBJECTIVE
To determine whether 3D-printed porous titanium (3DPT) interbody cages offer any clinical or radiographic advantage over standard solid titanium (ST) interbody cages in transforaminal lumbar interbody fusions (TLIF).
METHODS
A consecutive series of adult patients undergoing one- or two-level TLIF with either 3DPT or ST "banana" cages were analyzed for patient reported outcome measures (PROMs), radiographic complications, and clinical complications. Exclusion criteria included clinical or radiographic follow-up less than 1 year.
RESULTS
The final cohort included 90 ST interbody levels from 74 patients, and 73 3DPT interbody levels from 50 patients for a total of 124 patients. Baseline demographic variables and comorbidity rates were similar between groups ( > .05). Subsidence of any grade occurred more frequently in the ST group compared with the 3DPT group (24.4% vs 5.5%, respectively, = .001). Further, the ST group was more likely to have higher grades of subsidence than the 3DPT group ( = .009). All PROMs improved similarly after surgery and revision rates did not differ between groups (both > .05). On multivariate analysis, significant positive correlators with increasing subsidence grade included greater age ( = .015), greater body mass index ( = .043), osteoporosis/osteopenia ( < .027), and ST cage type ( = .019).
CONCLUSIONS
When considering interbody material for TLIF, both ST and 3DPT cages performed well; however, 3DPT cages were associated with lower rates of subsidence. The clinical relevance of these findings deserves further randomized, prospective investigation.
PubMed: 36786680
DOI: 10.1177/21925682231157762 -
Sovremennye Tekhnologii V Meditsine 2023is to study the cellular and molecular features of toxic liver fibrosis in rats and its dependence on development stages of this pathological condition.
UNLABELLED
is to study the cellular and molecular features of toxic liver fibrosis in rats and its dependence on development stages of this pathological condition.
MATERIALS AND METHODS
Liver fibrogenesis in male Wistar rats was induced with the thioacetamide solution by introducing into the stomach with a probe at a dose of 200 mg/kg of animal body weight 2 times per week. The process dynamics was studied at 5 time points (control, week 3, week 5, week 7, and week 9). The mRNA levels of , , , , , and genes in liver were detected by real-time polymerase chain reaction. Immunohistochemical study was performed on paraffin sections. The CD31, CD34, CK19, α-SMA, FAP, CD68, CD206, CX3CR1, and CD45 cells were used as markers. Fibrosis degree was determined in histological sections, stained in line with the Mallory technique, according to the Ishak's semi-quantitative scale.
RESULTS
Two simultaneously existing morphologically heterogeneous populations of myofibroblasts expressing different types of markers (FAP, α-SMA) were identified in rat liver. Prior to the onset of transformation of fibrosis into cirrhosis (F1-F4, weeks 3-7), FAP and SMA cells were localized in different places on histological specimens. All stages of liver fibrosis development were accompanied by an increase in the number (p=0.0000), a change in the phenotypic structure and functional properties of macrophages. The CK19 cells of the portal areas differentiated into cholangiocytes that formed interlobular bile ducts and ductules, as well as hepatocytes that formed rudiments of new hepatic microlobules. Pathological venous angiogenesis and heterogeneity of endotheliocytes of the intrahepatic vascular bed were detected. Two options for changes in mRNA expression of the selected genes were identified. The level of the and mRNAs at all stages of fibrosis was higher (p=0.0000) than in control rats. For , , , and mRNAs, the situation was the opposite - the level of genes decreased (p=0.0000). There were strong and moderate correlations between the studied target genes (p<0.05).
CONCLUSION
It was established that the stages of toxic fibrosis had morphological and molecular genetic features. The FAP cells make the main contribution to development of portal and initial stage of bridging fibrosis. The stellate macrophages and infiltrating monocytes/ macrophages can potentially be used for development of new therapeutic strategies for liver pathology treatment. One should take into account the features of the markers' expression by endothelial cells during the study of the intrahepatic vascular bed. Joint study of genes is a necessary parameter in fundamental and preclinical research.
Topics: Male; Rats; Animals; Matrix Metalloproteinase 9; Endothelial Cells; Rats, Wistar; Liver Cirrhosis; RNA, Messenger
PubMed: 38434195
DOI: 10.17691/stm2023.15.4.05 -
Respiratory Physiology & Neurobiology Mar 2023Coronavirus disease-2019 (COVID-19) may severely affect respiratory function and evolve to life-threatening hypoxia. The clinical experience led to the implementation of... (Review)
Review
Coronavirus disease-2019 (COVID-19) may severely affect respiratory function and evolve to life-threatening hypoxia. The clinical experience led to the implementation of standardized protocols assuming similarity to severe acute respiratory syndrome (SARS-CoV-2). Understanding the histopathological and functional patterns is essential to better understand the pathophysiology of COVID-19 and then develop new therapeutic strategies. Epithelial and endothelial cell damage can result from the virus attack, thus leading to immune-mediated response. Pulmonary histopathological findings show the presence of Mallory bodies, alveolar coating cells with nuclear atypia, reactive pneumocytes, reparative fibrosis, intra-alveolar hemorrhage, moderate inflammatory infiltrates, micro-abscesses, microthrombus, hyaline membrane fragments, and emphysema-like lung areas. COVID-19 patients may present different respiratory stages from silent to critical hypoxemia, are associated with the degree of pulmonary parenchymal involvement, thus yielding alteration of ventilation and perfusion relationships. This review aims to: discuss the morphological (histopathological and radiological) and functional findings of COVID-19 compared to acute interstitial pneumonia, acute respiratory distress syndrome (ARDS), and high-altitude pulmonary edema (HAPE), four entities that share common clinical traits, but have peculiar pathophysiological features with potential implications to their clinical management.
Topics: Humans; COVID-19; SARS-CoV-2; Altitude; Pulmonary Edema; Pneumonia; Respiratory Distress Syndrome
PubMed: 36460252
DOI: 10.1016/j.resp.2022.104000