Head and neck squamous cell carcinoma (HNSCC), an aggressive malignancy, is characterized by high morbidity and low survival rates with limited therapeutic options outside of regional surgery, ...conventional cytotoxic chemotherapy, and irradiation. Increasing studies have supported the synergistic role of the tumor microenvironment (TME) in cancer advancement. The immune system, in particular, plays a key role in surveillance against the initiation, development, and progression of HNSCC. The understanding of how neoplastic cells evolve and evade the immune system whether through self-immunogenicity manipulation, or expression of immunosuppressive mediators, provides the foundation for the development of advanced therapies. Furthermore, the crosstalk between cancer cells and the host immune system have a detrimental effect on the TME promoting angiogenesis, proliferation, and metastasis. This review provides a recent insight into the role of the key inflammatory cells infiltrating the TME, with a focus on reviewing immunological principles related to HNSCC, as cancer immunosurveillance and immune escape, including a brief overview of current immunotherapeutic strategies and ongoing clinical trials.
Persistent luminescence is a unique optical process where long‐lasting afterglow persists after the cessation of excitation. Nanoscale persistent luminescent materials are getting increased research ...interest from various fields due to their unique optical property. In recent years, inspiring achievements have been made to produce uniform persistent luminescence nanoparticles (PLNPs) in a controllable manner, unleashing their fascinating potential, surpassing other types of luminescent materials in a wide variety of application such as high‐contrast bioimaging and high‐resolution X‐ray detection. In this review, the evolution of uniform PLNPs, from their bulk phosphor counterparts, to the “top‐down” preparation of nanoscale persistent luminescent materials, to the recent “bottom‐up” synthesis of uniform PLNPs is first summarized. The respective milestones of uniform PLNPs prepared by templated synthesis, aqueous synthesis, and colloidal synthesis are highlighted. The key optical properties that can be enhanced in uniform PLNPs, including increasing the persistent luminescence intensity, tuning the excitation irradiance, as well as the emission wavelengths are then analyzed. Detailed strategies to enhance each optical property are also discussed in various sections. Finally, future challenges are highlighted with respect to the perspectives on the development of next‐generation PLNPs with novel applications.
Persistent luminescence nanoparticles (PLNPs) possess long‐lasting afterglow after the excitation ceases, demonstrating merits for various applications. The recent rapid progress of uniform PLNPs boosts their biomedical applications. This review highlights milestones of uniform PLNPs syntheses, analyzes key strategies for enhancing their optical properties, and envisions the challenges and potential future directions of uniform PLNPs for novel applications.
A series of experimental studies, along with DFT calculations, are reported that provide a detailed view into the mechanism of Ullmann coupling of phenols with aryl halides in the presence of ...catalysts generated from Cu(I) and bidentate, anionic ligands. These studies encompass catalysts containing anionic ligands formed by deprotonation of 8-hydroxyquinoline, 2-pyridylmethyl tert-butyl ketone, and 2,2,6,6-tetramethylheptane-3,5-dione. Three-coordinate, heteroleptic species Cu(LX)OAr
were shown by experiment and DFT calculations to be the most stable complexes in catalytic systems containing 8-hydroxyquinoline or 2-pyridylmethyl tert-butyl ketone and to be generated reversibly in the system containing 2,2,6,6-tetramethylheptane-3,5-dione. These heteroleptic complexes were characterized by a combination of
F NMR,
H NMR, and UV-vis spectroscopy, as well as ESI-MS. The heteroleptic complexes generated in situ react with iodoarenes to form biaryl ethers in high yields without evidence for an aryl radical intermediate. Measurements of
C/
C isotope effects showed that oxidative addition of the iodoarene occurs irreversibly. This information, in combination with the kinetic data, shows that oxidative addition occurs to the Cu(LX)OAr
complexes and is turnover-limiting. A Hammett analysis of the effect of phenoxide electronic properties on the rate of the reaction of Cu(LX)OAr
with iodotoluene also is consistent with oxidative addition of the iodoarene to an anionic phenoxide complex. Calculations by DFT suggest that this oxidative addition is followed by dissociation of I
and reductive elimination of the biaryl ether from the resulting neutral Cu(III) complex.
Mechanistic information on a reliable, palladium-catalyzed aminocarbonylation of aryl chlorides with ammonia is reported. The reaction occurs with ethylene complex 1 as catalyst, and mechanistic ...information was gained by isolation of catalytic intermediates and kinetic measurements, including the first mechanistic data on the oxidative addition of aryl chloride to a palladium(0) complex in the presence of CO. Arylpalladium and phenacylpalladium halide intermediates were synthesized, and kinetic measurements of the formation and reactions of these intermediates were undertaken to determine the mechanism of the oxidative addition of aryl bromides and chlorides to a Pd(0) dicarbonyl compound in the presence of CO and the mechanism of the reaction of ammonia with a Pd(II) phenacyl complex to form benzamide. The oxidative addition of aryl chlorides and aryl bromides was determined to occur with rate-limiting reaction of the haloarene with a three-coordinate Pd(0) species bearing a bidentate phosphine and one CO ligand. A primary
C kinetic isotope effect suggested that this step involves cleavage of the carbon-halogen bond. Our data show that the formation of benzamide from the reaction of phenacylpalladium halide complexes with ammonia occurs by a pathway involving reversible displacement of chloride from a phenacylpalladium chloride complex by ammonia, deprotonation of the bound ammonia to form a phenacylpalladium amido complex, and reductive elimination to form the C-N bond. Consistent with this mechanism, the reaction of an aryl palladium amido complex with CO formed the corresponding primary benzamide. A catalyst deactivation pathway involving the formation of a Pd(I) dimer also was elucidated.
Background
Vestibular schwannoma (VS) is the most common tumour of the cerebellopontine angle and poses a significant morbidity for patients. While many exhibit benign behaviour, others have a more ...aggressive nature and pattern of growth. Predicting who will fall into which category consistently remains uncertain. There is a need for a better understanding of the molecular landscape, and important subgroups therein, of this disease.
Methods
We select all vestibular schwannomas from our tumour bank with both methylation and RNA profiling available. Unsupervised clustering methods were used to define two distinct molecular subgroups of VS which were explored using computational techniques including bulk deconvolution analysis, gene pathway enrichment analysis, and drug repurposing analysis. Methylation data from two other cohorts were used to validate our findings, given a paucity of external samples with available multi-omic data.
Results
A total of 75 tumours were analyzed. Consensus clustering and similarity network fusion defined two subgroups (“immunogenic” and “proliferative”) with significant differences in immune, stroma, and tumour cell abundance (p < 0.05). Gene network analysis and computational drug repurposing found critical differences in targets of immune checkpoint inhibition PD-1 and CTLA-4, the MEK pathway, and the epithelial to mesenchymal transition program, suggesting a need for subgroup-specific targeted treatment/trial design in the future.
Conclusions
We leverage computational tools with multi-omic molecular data to define two robust subgroups of vestibular schwannoma with differences in microenvironment and therapeutic vulnerabilities.
Meningiomas are the most common primary intracranial tumour in adults
. Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health ...Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; however, they do not accurately reflect the clinical behaviour of all meningiomas
. Molecular classifications of meningioma that reliably reflect tumour behaviour and inform on therapies are required. Here we introduce four consensus molecular groups of meningioma by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance in a unified analysis. These molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of the newly defined molecular groups and uncovered highly abundant and group-specific protein targets that we validated using immunohistochemistry. Single-cell RNA sequencing revealed inter-individual variations in meningioma as well as variations in intrinsic expression programs in neoplastic cells that mirrored the biology of the molecular groups identified.
Magnetic Resonance Imaging (MRI) evidence of spinal cord compression plays a central role in the diagnosis of degenerative cervical myelopathy (DCM). There is growing recognition that deep learning ...models may assist in addressing the increasing volume of medical imaging data and provide initial interpretation of images gathered in a primary-care setting. We aimed to develop and validate a deep learning model for detection of cervical spinal cord compression in MRI scans. Patients undergoing surgery for DCM as a part of the AO Spine CSM-NA or CSM-I prospective cohort studies were included in our study. Patients were divided into a training/validation or holdout dataset. Images were labelled by two specialist physicians. We trained a deep convolutional neural network using images from the training/validation dataset and assessed model performance on the holdout dataset. The training/validation cohort included 201 patients with 6588 images and the holdout dataset included 88 patients with 2991 images. On the holdout dataset the deep learning model achieved an overall AUC of 0.94, sensitivity of 0.88, specificity of 0.89, and f1-score of 0.82. This model could improve the efficiency and objectivity of the interpretation of cervical spine MRI scans.
BRCA (BReast CAncer gene)-associated protein 1 (BAP1), encoded by the
gene, a tumour suppressor that is lost in several cancers. Importantly, such mutations have been shown to be susceptible to poly ...(ADP-ribose) polymerase (PARP) inhibition in preclinical studies, offering hope for targeted therapy. While rare, BAP1 loss has been observed in a subset of rhabdoid and papillary meningioma and is associated with earlier recurrence. We seek to add to the literature on this rare disease and advocate for more routine BAP1 testing.
We present a report of two cases of BAP1-deficient meningioma and review the available literature on this rare entity.
Both cases present with a distinct trabecular architecture without rhabdoid or papillary features. Interestingly, both also presented with radiographic and histopathological findings unusual for meningioma. While immunohistochemistry and genetic sequencing confirmed BAP1 loss, DNA methylation analysis was required to confirm the final diagnosis.
We suggest that BAP1-deficient meningioma should be considered in the differential diagnosis of extra-axial central nervous system (CNS) tumours with atypical imaging or histopathological features and that BAP1 loss may constitute a clinically important meningioma subtype with opportunities for targeted therapy.
Obesity is frequently complicated by comorbid conditions, yet how excess adipose contributes is poorly understood. Although adipocytes in obese individuals induce systemic inflammation via secreted ...cytokines, another potential mediator has recently been identified (i.e., adipocyte-derived exosomes). We hypothesized that adipocyte-derived exosomes contain mediators capable of activating end-organ inflammatory and fibrotic signaling pathways.
We developed techniques to quantify and characterize exosomes shed by adipocytes from seven obese (age: 12-17.5 y, BMI: 33-50 kg/m(2)) and five lean (age: 11-19 y, BMI: 22-25 kg/m(2)) subjects.
Abundant exosomal miRNAs, but no mRNAs, were detected. Comparison of obese vs. lean visceral adipose donors detected 55 differentially expressed miRNAs (P < 0.05; fold change ≥|1.2|). qRT-PCR confirmed downregulation of miR-148b (ratio = 0.2 (95% confidence interval = 0.1, 0.6)) and miR-4269 (0.3 (0.1, 0.8)), and upregulation of miR-23b (6.2 (2.2, 17.8)) and miR-4429 (3.8 (1.1-13.4)). Pathways analysis identified TGF-β signaling and Wnt/β-catenin signaling among the top canonical pathways expected to be altered with visceral adiposity based on projected mRNA targets for the 55 differentially expressed miRNAs. A select mRNA target was validated in vitro.
These data show that visceral adipocytes shed exosomal-mediators predicted to regulate key end-organ inflammatory and fibrotic signaling pathways.
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