OBJECTIVE: The goal of this study was to characterize local tumor control (LC), overall survival (OS), and safety of stereotactic radiosurgery for colorectal brain metastasis (CRBM). METHODS: Ten international institutions participating in the International Radiosurgery Research Foundation provided data for this retrospective case series. This study included 187 patients with CRBM (281 tumors), with a median age of 62 years and 56.7% being male. Most patients (53.5%) had solitary tumors, although 10.7% had > 5 tumors. The median tumor volume was 2.7 cm3 (IQR 0.22-8.1 cm3), and the median margin dose was 20 Gy (IQR 18-22 Gy). RESULTS: The 3-year LC and OS rates were 72% and 20%, respectively. Symptomatic adverse radiation effects occurred in 1.6% of patients. In the multivariate analysis, age > 65 years and tumor volume > 4.0 cm3 were significant predictors of tumor progression (hazard ratio [HR] 2.6, 95% CI 1.4-4.9; p = 0.003 and HR 3.4, 95% CI 1.7-6.9; p < 0.001, respectively). Better performance status (Karnofsky Performance Scale score > 80) was associated with a reduced risk of tumor progression (HR 0.38, 95% CI 0.19-0.73; p = 0.004). Patient age > 62 years (HR 1.6, 95% CI 1.1-2.3; p = 0.03) and the presence of active extracranial disease (HR 1.7, 95% CI 1.1-2.4; p = 0.009) were significantly associated with worse OS. CONCLUSIONS: Stereotactic radiosurgery offers a high LC rate and a low rate of symptomatic adverse radiation effects for the majority of CRBMs. The OS and LC favored younger patients with high functional performance scores and inactive extracranial disease.
- MeSH
- Adult MeSH
- Colorectal Neoplasms * pathology mortality MeSH
- Middle Aged MeSH
- Humans MeSH
- Survival Rate MeSH
- Brain Neoplasms * secondary radiotherapy mortality surgery MeSH
- Radiosurgery * adverse effects MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
BACKGROUND: Radiation-induced intestinal injury (RIII) interrupts the scheduled processes of abdominal and pelvic radiotherapy (RT) and compromises the quality of life of cancer survivors. However, the specific regulators and mechanisms underlying the effects of RIII remain unknown. The biological effects of RT are caused primarily by DNA damage, and ataxia telangiectasia mutated (ATM) is a core protein of the DNA damage response (DDR). However, whether ATM is regulated by deubiquitination signaling remains unclear. METHODS: We established animal and cellular models of RIII. The effects of ubiquitin-specific protease 15 (USP15) on DNA damage and radion-induced intestinal injury were evaluated. Mass spectrometry analysis, truncation tests, and immunoprecipitation were used to identify USP15 as a binding partner of ATM and to investigate the ubiquitination of ATM. Finally, the relationship between the USP15/ATM axes was further determined via subsequent experiments. RESULTS: In this study, we identified the deubiquitylating enzyme USP15 as a regulator of DNA damage and the pathological progression of RIII. Irradiation upregulates the expression of USP15, whereas pharmacological inhibition of USP15 exacerbates radiation-induced DNA damage and RIII both in vivo and in vitro. Mechanistically, USP15 interacts with, deubiquitinates, and stabilises ATM via K48-linked deubiquitination. Notably, ATM overexpression blocks the effect of USP15 genetic inhibition on DNA damage and RIII progression. CONCLUSIONS: These findings describe ATM as a novel deubiquitination target of USP15 upon radiation-induced DNA damage and intestinal injury, and provides experimental support for USP15/ATM axis as a potential target for developing strategies that mitigate RIII.
- MeSH
- Ataxia Telangiectasia Mutated Proteins * metabolism genetics MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- DNA Damage * MeSH
- Radiation Injuries metabolism genetics MeSH
- Ubiquitin-Specific Proteases * metabolism genetics MeSH
- Intestines radiation effects pathology MeSH
- Ubiquitination * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The combination of aminophylline and salbutamol is frequently used in clinical practice in the treatment of obstructive lung diseases. While the side effects (including arrhythmias) of the individual bronchodilator drugs were well described previously, the side effects of combined treatment are almost unknown. We aimed to study the arrhythmogenic potential of combined aminophylline and salbutamol treatment in vitro. For this purpose, we used the established atomic force microscopy (AFM) model coupled with cardiac organoids derived from human pluripotent stem cells (hPSC-CMs). We focused on the chronotropic, inotropic, and arrhythmogenic effects of salbutamol alone and aminophylline and salbutamol combined treatment. We used a method based on heart rate/beat rate variability (HRV/BRV) analysis to detect arrhythmic events in the hPSC-CM based AFM recordings. Salbutamol and aminophylline had a synergistic chronotropic and inotropic effect compared to the effects of monotherapy. Our main finding was that salbutamol reduced the arrhythmogenic effect of aminophylline, most likely mediated by endothelial nitric oxide synthase activated by beta-2 adrenergic receptors. These findings were replicated and confirmed using hPSC-CM derived from two cell lines (CCTL4 and CCTL12). Data suggest that salbutamol as an add-on therapy may not only deliver a bronchodilator effect but also increase the cardiovascular safety of aminophylline, as salbutamol reduces its arrhythmogenic potential.
- MeSH
- Albuterol * pharmacology MeSH
- Aminophylline * pharmacology MeSH
- Bronchodilator Agents pharmacology MeSH
- Cell Line MeSH
- Myocytes, Cardiac drug effects metabolism MeSH
- Humans MeSH
- Microscopy, Atomic Force MeSH
- Pluripotent Stem Cells drug effects cytology MeSH
- Arrhythmias, Cardiac * drug therapy MeSH
- Heart Rate drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: In today's digital age, demanding to interpret vast quantities of visual information with speed and accuracy, nonverbal Intelligence has become increasingly crucial for children, as it plays a key role in cognitive development and learning. While motor proficiency has been positively linked to various cognitive functions in children, its relationship with nonverbal Intelligence remains an open question. This study, therefore, explored the structural associations between motor proficiency and nonverbal Intelligence in school-aged children (6 to 11 years), focusing on potential age and sex-specific patterns. METHODS: Data were obtained from 396 children aged 6 to 11 (214 boys, 182 girls; mean age 8.9 years ±1.3) divided into younger children 6-8 years and older Children 9-11 years. Motor proficiency was assessed using the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2), and non-verbal Intelligence was evaluated with the Raven Progressive Matrices (RPM). We conducted multigroup structural modelling with non-verbal Intelligence as a dependent latent variable. RESULTS: The BOT-2 and RPM models demonstrated an acceptable fit in Czech children. Strength-agility and Fine motor control emerged as the strongest predictors of nonverbal intelligence level assessed by five sets of RPM. Age-specific analyses revealed that the Strength-agility construct was consistently a significant predictor of nonverbal intelligence level in both age categories. However, in older children, also Fine motor control was significantly linked to nonverbal intelligence level. Sex-specific differences were also observed in the structural modelling results, indicating significant predictor non-invariance based on participants' sex. In girls, both Fine motor control and the Strength-agility constructs were significant predictors of nonverbal Intelligence level, showing stronger associations with nonverbal Intelligence than boys. For boys, only the Strength-agility construct was a significant predictor of RPM performance. CONCLUSION: This study reveals a nuanced age- and sex-specific relationship between children's motor proficiency and nonverbal Intelligence. The findings underscore the need for targeted physical interventions, particularly those emphasising fine motor and strength-agility exercises, to ensure equitable opportunities for motor skill development. Such interventions may enhance physical abilities and support cognitive development in an increasingly digital world.
- MeSH
- Latent Class Analysis MeSH
- Child MeSH
- Intelligence * physiology MeSH
- Humans MeSH
- Motor Skills * physiology MeSH
- Sex Factors MeSH
- Age Factors MeSH
- Child Development physiology MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
Although the identification of animal species and muscles have been reported previously, no studies have been found on the use of NIR spectroscopy to identify individual animals from the analysis of commercial meat cuts. The aim of this study was to evaluate the use of a portable near infrared (NIR) instrument combined with classical chemometrics methods [principal component analysis (PCA) and partial least squares discriminant analysis PLS-DA)] to identify the origin of individual goat animals using the spectral signature of their commercial cut. Samples were collected from several carcasses (6 commercial cuts x 24 animals) sourced from a commercial abattoir in Queensland (Australia). The NIR spectra of the samples were collected using a portable NIR instrument in the wavelength range between 950 and 1600 nm. Overall, the PLS-DA models correctly classify 82% and 79% of the individual goat samples using either the goat rack or loin cut samples, respectively. The study demonstrated that NIR spectroscopy was able to identify individual goat animals based on the spectra properties of some of the commercial cut samples analysed (e.g. loin and rack). These results showed the potential of this technique to identify individual animals as an alternative to other laboratory methods and techniques commonly used in meat traceability.
- Publication type
- Journal Article MeSH
UNLABELLED: We would like to provide an updated comprehensive perspective and identify the components linked to chronic spontaneous urticaria (CSU) without specific triggers in autoimmune atrophic gastritis (AAG). AAG is an organ-specific autoimmune disease that affects the corpus-fundus gastric mucosa. Although we lack a unified explanation of the underlying pathways, when considering all paediatric patients reported in the literature, alterations result in gastric neuroendocrine enterochromaffin-like (ECL) cell proliferation and paracrine release of histamine. Several mechanisms have been proposed for the pathogenesis of CSU, with much evidence pointing towards AAG and ECL cell responses, which may be implicated as potential factors contributing to CSU. The excessive production/release of histamine into the bloodstream could cause or trigger exacerbations of CSU in AAG, independent of Helicobacter pylori; thus, the release of histamine from ECL cells may be the primary modulator. CONCLUSION: Considering the understanding of these interactions, recognising the respective roles of AAG in the pathogenesis of CSU may strongly impact the diagnostic workup and management of unexplained/refractory CSU and may inform future research and interventions in the paediatric population. WHAT IS KNOWN: • Autoimmune atrophic gastritis is a chronic immune-mediated inflammatory disease characterised by the destruction of the oxyntic mucosa in the gastric body and fundus, mucosal atrophy, and metaplastic changes. • Autoimmune atrophic gastritis in paediatric patients is important because of the poor outcome and risk of malignancy and possibly underestimated entities primarily reported in single-case reports. WHAT IS NEW: • Upper gastrointestinal inflammatory disorders, independent of H. pylori, have been implicated as potential inducing factors in the development of chronic spontaneous urticaria. • If a paediatric patient presents with symptoms such as anaemia, reduced vitamin B12 levels, recurrent urticaria with no other detectable aetiology, positive anti-parietal cell antibodies, and elevated gastrin levels, autoimmune atrophic gastritis should be considered a possible cause of chronic urticaria.
- MeSH
- Autoimmune Diseases * complications diagnosis MeSH
- Chronic Disease MeSH
- Chronic Urticaria * etiology pathology MeSH
- Child MeSH
- Gastritis, Atrophic * complications pathology MeSH
- Gastritis * complications diagnosis MeSH
- Helicobacter pylori * MeSH
- Histamine MeSH
- Helicobacter Infections * complications MeSH
- Humans MeSH
- Gastric Mucosa pathology MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- MeSH
- Cystectomy MeSH
- Urinary Diversion * MeSH
- Humans MeSH
- Urinary Bladder Neoplasms * surgery MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Germany MeSH
Hyponatremia is a typical side effect of antiseizure drugs from the dibenzazepine family. The study investigated the prevalence of hyponatremia in patients with epilepsy who were treated with eslicarbazepine. We aimed to determine the prevalence of hyponatremia, reveal the factors leading to the discontinuation of treatment, and identify possible risk factors for the development of hyponatremia including the dose dependency. The medical records of 164 patients with epilepsy taking eslicarbazepine in our center were analyzed. The overall prevalence of hyponatremia was 30.5%. The prevalence of mild hyponatremia, seen in 14%-20% of patients, was not dose dependent. The prevalence of moderate and severe hyponatremia was significantly dose dependent. The severity of hyponatremia was significantly dose dependent. Severe hyponatremia was found in 6.1% of patients. Hyponatremia was asymptomatic in the majority of cases, and in 48% did not require any management. Hyponatremia was the reason for discontinuation in 6.2% of patients. The major risk factor for developing hyponatremia was older age. The study shows that eslicarbazepine-induced hyponatremia is usually mild and asymptomatic. It usually does not require any management and seldom leads to treatment discontinuation. Hyponatremia is dose dependent. Another major risk for developing hyponatremia (besides dose) is older age.
OBJECTIVE: The prognostic relevance of hormonal biomarkers in endometrial cancer (EC) has been well-established. A refined three-tiered risk model for estrogen receptor (ER)/progesterone receptor (PR) expression was shown to improve prognostication. This has not been evaluated in relation to the molecular subgroups. This study aimed to evaluate the ER/PR expression within the molecular subgroups in EC. METHODS: A retrospective multicenter cohort study was performed and data from the European Network for Individualized Treatment centers and Vancouver, Canada were used. ER/PR immunohistochemical expression was grouped as: ER/PR 0-10 %, 20-80 % or 90-100 %. Molecular subgroups were determined with full next-generation sequencing or combined with immunohistochemistry: POLEmut, mismatch repair deficient (MMRd), p53mut and no-specific molecular profile (NSMP). RESULTS: A total of 739 patients were included (median follow-up 5.0 years). Tumors were classified as POLEmut in 9.1 %(N = 67), MMRd in 27.6 %(N = 204), p53mut in 20.8 %(N = 154) and NSMP in 42.5 %(N = 314). Among all molecular subgroups, patients with ER/PR 90-100 % expression revealed the best disease-specific survival (DSS). Within p53mut, PR 90-100 % expression showed a 5-year DSS of 100.0 %. ER expression is prognostic more relevant in MMRd and NSMP tumors while PR expression in p53mut and NSMP tumors. Across all molecular subgroups, PR 0-10 %, p53mut, lympho-vascular space invasion and FIGO stage III-IV remained independently prognostic for reduced DSS Whereas PR 90-100 % and POLEmut remained independently prognostic for improved DSS. CONCLUSION: We demonstrated that ER/PR expression remain prognostically relevant within the molecular subgroups, and that a three-tiered cutoff refines prognostication. These data support incorporating routine evaluation of ER/PR expression in clinical practice.
- MeSH
- Adult MeSH
- Immunohistochemistry MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Biomarkers, Tumor * metabolism genetics MeSH
- Tumor Suppressor Protein p53 metabolism genetics MeSH
- Endometrial Neoplasms * metabolism pathology genetics mortality MeSH
- Prognosis MeSH
- Receptors, Estrogen * metabolism biosynthesis MeSH
- Receptors, Progesterone * metabolism biosynthesis MeSH
- Retrospective Studies MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
Sleep is crucial for maintaining brain homeostasis and individuals with insufficient sleep are prone to more pronounced brain atrophy as compared to sufficiently sleeping peers. Moreover, sleep quality deteriorates with ageing and ageing is also associated with cerebral structural and functional changes, pointing to their mutual bidirectional interrelationship. This study aimed at determining whether sleep quality and age, separately, affect brain integrity and subsequently, whether sleep significantly modulates the effect of age on brain structural and functional integrity. 113 healthy volunteers underwent a multi-modal MRI imaging to extract information about the microstructure and function of major nodes of the ascending reticular activating system. Sleep quality was assessed by self-administered Pittsburgh's sleep quality index (PSQI) questionnaire. Subject were divided into good (global PSQI score <5) and poor (global PSQI score ≥5) sleep quality group. Whereas only borderline correlations were found between sleep quality and MRI metrics, age exhibited widespread correlations with both functional and microstructural MRI metrics. The latter effect was significantly modulated by sleep quality in ascending reticular activating system, hypothalamus, thalamus and also hippocampus in MRI metrics associated with iron load, cellularity and connectivity, mainly in the subgroup with poor sleep quality. Ergo, our results indicate sleep quality as a substantial contributor to both microstructural and functional brain changes in ageing and call for further research in this emerging topic.
- Publication type
- Journal Article MeSH
