PURPOSE OF REVIEW: Upper tract urothelial carcinoma (UTUC) is a rare malignancy posing significant diagnostic and management challenges. This review provides an overview of the evidence supporting various imaging modalities and offers insights into future innovations in UTUC imaging. RECENT FINDINGS: With the growing use of advancements in computed tomography (CT) technologies for both staging and follow-up of UTUC patients, continuous innovations aim to enhance performance and minimize the risk of excessive exposure to ionizing radiation and iodinated contrast medium. In patients unable to undergo CT, magnetic resonance imaging serves as an alternative imaging modality, though its sensitivity is lower than CT. Positron emission tomography, particularly with innovative radiotracers and theranostics, has the potential to significantly advance precision medicine in UTUC. Endoscopic imaging techniques including advanced modalities seem to be promising in improved visualization and diagnostic accuracy, however, evidence remains scarce. Radiomics and radiogenomics present emerging tools for noninvasive tumor characterization and prognosis. SUMMARY: The landscape of imaging for UTUC is rapidly evolving, with significant advancements across various modalities promising improved diagnostic accuracy, patient outcomes, and safety.

• MeSH
• Carcinoma, Transitional Cell * diagnosis   diagnostic imaging   therapy   pathology   MeSH
• Humans MeSH
• Magnetic Resonance Imaging methods   MeSH
• Kidney Neoplasms diagnostic imaging   therapy   diagnosis   pathology   MeSH
• Ureteral Neoplasms diagnostic imaging   diagnosis   therapy   pathology   MeSH
• Tomography, X-Ray Computed methods   MeSH
• Positron-Emission Tomography methods   MeSH
• Neoplasm Staging MeSH
• Urologic Neoplasms diagnosis   diagnostic imaging   therapy   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

OBJECTIVES: Decision-analytic models assessing the value of emerging Alzheimer's disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD. METHODS: A benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop. RESULTS: Nine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (clinical dementia rating - sum of boxes, clinical dementia rating - global, mini-mental state examination, functional activities questionnaire) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6 to 5.2 years for control strategy and from 0.1 to 1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0 to 0.6 and incremental costs (excluding treatment costs) from -US$66 897 to US$11 896. CONCLUSIONS: Trial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend (1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, (2) a standardized reporting table for model predictions, and (3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health-economic models.

• MeSH
• Alzheimer Disease * economics   drug therapy   MeSH
• Cost-Benefit Analysis * MeSH
• Models, Economic MeSH
• Cognitive Dysfunction * economics   MeSH
• Quality-Adjusted Life Years MeSH
• Humans MeSH
• Decision Support Techniques MeSH
• Disease Progression MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

A series of triterpenoids of the lupane, taraxastane, friedelane and baccharane type were oxidized using selenium dioxide (SeO2) and benzeneseleninic anhydride (BSA) under various conditions. Depending on the reaction conditions, different reaction pathways were observed, including dehydrogenation, allylic oxidation, and 1,2-diketone formation. In this way, derivatives functionalized in the triterpene core (especially in rings A, D, and E), difficult to obtain by other methods, can be easily prepared. In some cases, rarely observed α-phenylseleno-ketones were isolated. An unexpected reaction involving the cleavage of the carbon-carbon double bond was observed in the presence of stoichiometric amounts of osmium tetroxide. Further transformations of selected intermediates facilitated the synthesis of new, functionally enriched derivatives. The key reaction pathways were investigated using density functional theory (DFT), focusing on bond length variations and transition states, revealing energetically favored pathways and critical transition structures, including covalent and noncovalent interactions. Solvent and isomerization equilibrium effects were proposed to explain the experimentally observed discrepancies. Cytotoxic activity of selected derivatives was investigated. Derivatives 4 and 38 showed strongest cytotoxicity in cancer cells and fibroblasts (IC50 2.6-26.4 μM); some compounds were selective for G-361 or HeLa cells. These results suggest that they may find application in pharmaceuticals.

• MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Oxidation-Reduction MeSH
• Pentacyclic Triterpenes MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Drug Screening Assays, Antitumor MeSH
• Selenium * chemistry   MeSH
• Density Functional Theory MeSH
• Triterpenes * chemistry   pharmacology   chemical synthesis   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: The pre-surgical evaluation of epilepsy relies on the electrophysiological recordings of spontaneous seizures. During this period drug dose decreases increase the likelihood of seizures transitioning the brain from a low to high seizure likelihood state, so-called pro-ictal state. This study aimed to identify the dynamic brain changes characteristic of this transition from 386 ten-minute segments of intracranial EEG recordings of 29 patients with drug-refractory temporal lobe epilepsy. METHODS: We studied brain dynamics through mean phase locking value and relative power in gamma band, and autocorrelation function width. We further explored interactions with pro-ictal factors, such as rate of interictal spikes and high frequency oscillations, circadian and multi-day cycles, and clinical outcomes. RESULTS: We observed significant increases in gamma power in the epileptogenic zone, and critical slowing in both the epileptogenic zone and presumably healthy cortex. These changes were linked with increases in spike and high frequency oscillations rate. CONCLUSIONS: Brain dynamics changed on the slow time scale - from the beginning to the end of the multi-day interval - but did not change in the short-term during the pre-ictal interval, thus could reflect pro-ictal changes. SIGNIFICANCE: We highlight gamma power and critical slowing indices as markers of pro-ictal brain states, as well as their potential to track the seizure-related brain mechanisms during the presurgical evaluation of epilepsy patients.

• MeSH
• Adult MeSH
• Electroencephalography methods   MeSH
• Electrocorticography methods   MeSH
• Epilepsy, Temporal Lobe * physiopathology   diagnosis   MeSH
• Gamma Rhythm * physiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Brain * physiopathology   MeSH
• Drug Resistant Epilepsy * physiopathology   MeSH
• Seizures * physiopathology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Epigenetic mechanisms are of pivotal importance in the normal development and maintenance of cell and tissue-specific gene expression patterns, and are fundamental to the genesis of cancer. One significant category of epigenetic modifications is histone methylation. Histone methylation plays a crucial role in the regulation of gene expression, and its dysregulation has been observed in various diseases, including cancer. The maintenance of the histone methylation state is dependent on two classes of enzymes: histone methyltransferases, which add methyl groups to arginine and lysine residues, and lysine demethylases, which remove methyl groups from lysine residues of histones. To date, eight subfamilies have been identified, comprising approximately 30 lysine demethylases. These enzymes are expressed differently across cells and tissues and exert a substantial impact on the development and progression of cancer. The diverse range of lysine demethylases influence a multitude of oncogenic pathways, either by promoting or inhibiting their activity. However, comprehensive data on the full spectrum expression of lysine demethylases in distinct cancer types remain scarce. Lysine demethylases have been demonstrated to play a role in drug resistance in numerous cancers. This is achieved by modulating the metabolic profile of cancer cells, enhancing the ratio of cancer stem cells, and elevating the expression of drug-tolerant genes. Additionally, they facilitate epithelial-mesenchymal transition and metastatic potential. The objective of this review is to synthesize recent data on the relationship between lysine demethylases and cancer, with a particular focus on cancer cell drug resistance.

• MeSH
• Epigenesis, Genetic MeSH
• Epithelial-Mesenchymal Transition MeSH
• Histone Demethylases * metabolism   genetics   MeSH
• Humans MeSH
• Neoplasms * enzymology   genetics   pathology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Epilepsy is a neurological disease characterized by epileptic seizures, which commonly manifest with pronounced frequency and amplitude changes in the EEG signal. In the case of focal seizures, initially localized pathological activity spreads from a so-called "onset zone" to a wider network of brain areas. Chimeras, defined as states of simultaneously occurring coherent and incoherent dynamics in symmetrically coupled networks are increasingly invoked for characterization of seizures. In particular, chimera-like states have been observed during the transition from a normal (asynchronous) to a seizure (synchronous) network state. However, chimeras in epilepsy have only been investigated with respect to the varying phases of oscillators. We propose a novel method to capture the characteristic pronounced changes in the recorded EEG amplitude during seizures by estimating chimera-like states directly from the signals in a frequency- and time-resolved manner. We test the method on a publicly available intracranial EEG dataset of 16 patients with focal epilepsy. We show that the proposed measure, titled Amplitude Entropy, is sensitive to the altered brain dynamics during seizure, demonstrating its significant increases during seizure as compared to before and after seizure. This finding is robust across patients, their seizures, and different frequency bands. In the future, Amplitude Entropy could serve not only as a feature for seizure detection, but also help in characterizing amplitude chimeras in other networked systems with characteristic amplitude dynamics.

• MeSH
• Adult MeSH
• Electroencephalography methods   MeSH
• Entropy MeSH
• Epilepsies, Partial * physiopathology   MeSH
• Humans MeSH
• Brain * physiopathology   MeSH
• Seizures * physiopathology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in Cryptococcus neoformans, a pathogen responsible for life-threatening fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and antifungal properties. Lead compound 25 exhibited a Ki of 180 pM, significant selectivity against host proteases, and potent antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in antifungal therapy but also provided insights into structure-activity relationships that can inform broader applications of macrocyclization in drug discovery.

• MeSH
• Antifungal Agents * pharmacology   chemistry   chemical synthesis   pharmacokinetics   MeSH
• Cryptococcus neoformans * drug effects   enzymology   MeSH
• Protease Inhibitors * pharmacology   chemistry   chemical synthesis   pharmacokinetics   MeSH
• Humans MeSH
• Macrocyclic Compounds * pharmacology   chemistry   chemical synthesis   pharmacokinetics   MeSH
• Microbial Sensitivity Tests MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Expression of acute kidney injury-associated (AKI-associated) transcripts in kidney transplants may reflect recent injury and accumulation of epithelial cells in "failed repair" states. We hypothesized that the phenomenon of failed repair could be associated with deterioration and failure in kidney transplants. METHODS: We defined injury-induced transcriptome states in 4,502 kidney transplant biopsies injury-induced gene sets and classifiers previously developed in transplants. RESULTS: In principal component analysis (PCA), PC1 correlated with both acute and chronic kidney injury and related inflammation and PC2 with time posttransplant. Positive PC3 was a dimension that correlated with epithelial remodeling pathways and anticorrelated with inflammation. Both PC1 and PC3 correlated with reduced survival, with PC1 effects strongly increasing over time whereas PC3 effects were independent of time. In this model, we studied the expression of 12 "new" gene sets annotated in single-nucleus RNA-sequencing studies of epithelial cells with failed repair in native kidneys. The new gene sets reflecting epithelial-mesenchymal transition correlated with injury PC1 and PC3, lower estimated glomerular filtration rate, higher donor age, and future failure as strongly as any gene sets previously derived in transplants and were independent of nephron segment of origin and graft rejection. CONCLUSION: These results suggest 2 dimensions in the kidney transplant response to injury: PC1, AKI-induced changes, failed repair, and inflammation; and PC3, a response involving epithelial remodeling without inflammation. Increasing kidney age amplifies PC1 and PC3. TRIAL REGISTRATION: INTERCOMEX (ClinicalTrials.gov NCT01299168); Trifecta-Kidney (ClinicalTrials.gov NCT04239703). FUNDING: Genome Canada; Natera, Inc.; and Thermo Fisher Scientific.

• MeSH
• Acute Kidney Injury * pathology   genetics   MeSH
• Principal Component Analysis MeSH
• Biopsy MeSH
• Adult MeSH
• Epithelial-Mesenchymal Transition genetics   MeSH
• Epithelial Cells * pathology   metabolism   MeSH
• Kidney pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Cross-Sectional Studies MeSH
• Graft Rejection * pathology   genetics   MeSH
• Aged MeSH
• Transcriptome MeSH
• Kidney Transplantation * adverse effects   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH

Mutations in CACNA1C, the gene encoding Cav1.2 voltage-gated calcium channels, are associated with a spectrum of disorders, including Timothy syndrome and other neurodevelopmental and cardiac conditions. In this study, we report a child with a de novo heterozygous missense variant (c.1973T > C; L658P) in CACNA1C, presenting with refractory epilepsy, global developmental delay, hypotonia, and multiple systemic abnormalities, but without overt cardiac dysfunction. Electrophysiological analysis of the recombinant Cav1.2 L658P variant revealed profound gating alterations, most notably a significant hyperpolarizing shift in the voltage dependence of activation and inactivation. Additionally, molecular modeling suggested that the L658P mutation disrupts interactions within the IIS5 transmembrane segment, reducing the energy barrier for state transitions and facilitating channel opening at more negative voltages. These findings establish L658P as a pathogenic CACNA1C variant primarily associated with severe neurological dysfunction and expands the phenotypic spectrum of CACNA1C-related disorders.

• MeSH
• Child MeSH
• Ion Channel Gating * MeSH
• Humans MeSH
• Mutation, Missense genetics   MeSH
• Models, Molecular MeSH
• Neurodevelopmental Disorders * genetics   MeSH
• Child, Preschool MeSH
• Amino Acid Sequence MeSH
• Calcium Channels, L-Type * genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

For the treatment of bilateral limbal stem cell deficiency (LSCD), cell therapy with transplantation of cultivated oral mucosa epithelial cells (COMET) is a promising alternative. Although not yet established, current protocols on the cultivation of oral mucosal epithelial cell (OMECs) sheets are based mainly on substrates and xenobiotic additives that may lead to variable outcomes and undesirable immune responses by the patient. The aim of this study was to characterize OMECs cultivated in xenobiotic-free media (XF) seeded on fibrin gel, in comparison to conventional complex (COM) medium. Oral mucosal biopsies were retrieved from 31 donors. After cultivation in COM or XF medium, OMECs were compared based on growth kinetics, morphology, cell size and viability. Using immunofluorescence and gene expression analyses, the degree of stemness, proliferation and differentiation was evaluated in OMEC cultures. Our findings showed that although OMECs showed a similar morphology and viability, and comparable growth kinetics, immunofluorescence revealed the preservation of stemness (p63 + p40 positivity in cells ≤11 μm) and proliferation in both COM and XF. Gene expression analyses showed that keratin (K)13 and K15 expression levels were significantly higher in XF (adj. p < 0.001), but otherwise COM and XF-treated OMECs had comparable transcriptional profiles in a panel of stemness, proliferation and differentiation genes. These results demonstrate the feasibility of culturing OMECs on fibrin gel without xenogeneic additives, while maintaining their undifferentiated state and preserving stemness. In conclusion, both in terms of results and methodology, the procedures presented here are suitable for implementation in clinical practice.

• MeSH
• Cell Differentiation MeSH
• Cell Culture Techniques * MeSH
• Limbal Stem Cell Deficiency MeSH
• Adult MeSH
• Epithelial Cells * metabolism   drug effects   MeSH
• Fibrin * MeSH
• Gels MeSH
• Stem Cells * metabolism   cytology   MeSH
• Culture Media MeSH
• Cells, Cultured MeSH
• Middle Aged MeSH
• Humans MeSH
• Limbus Corneae * cytology   pathology   metabolism   MeSH
• Corneal Diseases pathology   drug therapy   metabolism   MeSH
• Cell Proliferation drug effects   MeSH
• Epithelium, Corneal metabolism   cytology   drug effects   pathology   MeSH
• Aged MeSH
• Stem Cell Transplantation methods   MeSH
• Mouth Mucosa * cytology   MeSH
• Cell Survival MeSH
• Xenobiotics pharmacology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH