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The limited water solubility of active compounds remains a significant challenge for efficient dermal drug delivery, particularly for BCS class IV drugs such as curcumin. This study aimed to enhance curcumin's dermal penetration using two strategies: extracellular vesicles (EVs) and plantCrystals derived from soybeans. EVs were isolated using classical methods. However, plantCrystals containing extracellular vesicles (PCEVs) were formed during the preparation of plantCrystals through bead milling. Curcumin was either added after PCEVs were formed, resulting in curcumin-added PCEVs, or added to the soybean dispersion before bead milling, forming curcumin-loaded PCEVs. The formulations were characterized for their physicochemical properties and assessed for dermal penetration efficacy using quantitative dermatokinetic and semi-quantitative ex vivo porcine ear models. The results indicated that curcumin-loaded PCEVs achieved higher penetration efficacy compared to curcumin-added PCEVs and curcumin-loaded EVs, with approximately 1.5-fold and 2.7-fold increases in penetration efficacy, respectively. Additionally, curcumin-loaded PCEVs showed superior penetration depth, while curcumin from the curcumin-loaded EVs remained in the stratum corneum. These findings suggest that the plantCrystals strategy via bead milling offers a more effective approach than the classical EVs strategy for improving the topical delivery of class IV drugs like curcumin. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer and stroke are leading causes of global disability and mortality. With improvements in cancer-associated mortality and advancements in treatment of active malignancy, it is more common to encounter patients with ischemic stroke and active malignancy. In this paper, we first review the epidemiology regarding cancer-associated ischemic stroke and management challenges. We then highlight the pathophysiological contributors to the development of hypercoagulability, as well as tumor-associated and treatment-associated contributors to stroke in patients with cancer. The final section addresses acute treatment, secondary prevention, recovery, and future directions regarding management of cancer-associated stroke. Cancer and stroke are leading causes of global disability and mortality. With improvements in cancer-associated mortality and advancements in treatment of active malignancy, it is more common to encounter patients with ischemic stroke and active malignancy. Evidence suggests that cancer-associated ischemic stroke is a unique subtype of stroke; however, there is limited guidance when considering diagnostic workup, secondary prevention, rehabilitation, and future directions within this population. In this narrative review, we aim to describe the epidemiology, pathophysiological mechanisms, management, and future directions regarding understanding of cancer-associated ischemic stroke. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockade has shown remarkable efficacy across various cancers but has failed to improve outcomes in patients with relapsed medulloblastoma (MB). While it is thought that the cold, immunosuppressive tumor microenvironment of MB accounts for this poor efficacy, the precise mechanisms contributing to immune suppression in this context remain unclear. In this study, we explore the immune landscape of MB using a previously unexplored syngeneic mouse model. Our study demonstrates that this model faithfully recapitulates the cold, immunosuppressive tumor microenvironment observed in human disease. Importantly, our research uncovers mechanisms employed by myeloid cells and tumor cells to evade immune detection while highlighting the therapeutic potential of targeting V-domain Ig Suppressor of T-cell Activation (VISTA), a novel inhibitory immune checkpoint, to enhance anti-tumor immunity. Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor–cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA–VSIG axis to enhance anti-tumor responses. [ABSTRACT FROM AUTHOR]

Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.

Simple Summary: Cancer is a leading cause of death worldwide. The costs involved in cancer diagnosis and treatment are extraordinary. Important steps that can be taken that would reduce costs include earlier cancer diagnosis for which significant headway is being made through biomarker identification in bodily fluids and imaging. Other important steps will be to identify treatment approaches that do not 'break the bank' and affect a patient's wellbeing. Herein, we aim to highlight the potential of phytochemicals as a cost-effective approach to aid in the treatment of cancer. We focus on phytochemicals that target ion channels, as molecules that mediate critical communication of a cell with its environment. Ultimately, we posit that phytochemicals targeting ion channels can be employed to aid cancer treatment. Modern chemotherapies offer a broad approach to cancer treatment but eliminate both cancer and non-cancer cells indiscriminately and, thus, are associated with a host of side effects. Advances in precision oncology have brought about new targeted therapeutics, albeit mostly limited to a subset of patients with an actionable mutation. They too come with side effects and, ultimately, 'self-resistance' to the treatment. There is recent interest in the modulation of ion channels, transmembrane proteins that regulate the flow of electrically charged molecules in and out of cells, as an approach to aid treatment of cancer. Phytochemicals have been shown to act on ion channels with high specificity regardless of the tumor's genetic profile. This paper explores the use of phytochemicals in cancer symptom management and treatment. [ABSTRACT FROM AUTHOR]