ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma).

Biosynthesis and health promoting traits of green synthesized cobalt oxide nanoparticles.

Nanomedical applications have increased significantly. This work aimed to fabricate and characterize cobalt oxide nanoparticles (CoOnps) synthesized biologically via aqueous Alhagi maurorum extract and evaluate their cytotoxic and antimicrobial impacts. Green-synthesized CoOnps were prepared and analyzed using UV-Vis spectrophotometer UV-vis, Scanning electron microscopy (SEM), Transmission electron microscopy TEM, Energy dispersive X-ray analysis EDAX, Fourier transform infrared, FTIR, and X-ray diffraction (XRD).

Functional connectivity within sensorimotor cortical and striatal regions is regulated by sepsis in a sex-dependent manner.

Sepsis is a state of systemic immune dysregulation and organ failure that is frequently associated with severe brain disability. Epidemiological studies have indicated that younger females have better prognosis and clinical outcomes relative to males, though the sex-dependent response of the brain to sepsis during post-sepsis recovery remains largely uncharacterized. Using a modified polymicrobial intra-abdominal murine model of surgical sepsis, we characterized the acute effects of intra-abdominal sepsis on peripheral inflammation, brain inflammation and brain functional connectivity in young adult mice of both sexes.

Janus LAAM-loaded electrospun fibrous buccal films for treating opioid use disorder.

The opioid crisis has claimed approximately one million lives in the United States since 1999, underscoring a significant public health concern. This surge in opioid use disorder (OUD) fatalities necessitates improved therapeutic options. Current OUD therapies often require daily clinical visits, leading to poor patient compliance and high costs to the health systems.

Exploration of molecular interactions responsible for anti-inflammatory attributes of GI friendly micro-sized formulation of flurbiprofen and clove oil.

Clove oil obtained from Syzygium aromaticum (L.) is traditionally employed to treat inflammation associated with rheumatism, gastric disorders, and as an analgesic. Chemo-herbal combinations are known to have potent anti-inflammatory and analgesic effects, while mitigating the drug related side effects.

Predicting intermediate-risk prostate cancer using machine learning.

Purposes: Intermediate-risk prostate cancer (IR PCa) is the most common risk group for localized prostate cancer. This study aimed to develop a machine learning (ML) model that utilizes biopsy predictors to estimate the probability of IR PCa and assess its performance compared to the traditional clinical model.

Methods: Between January 2017 and December 2022, patients with prostate-specific antigen (PSA) values of ≤ 20 ng/mL underwent transrectal ultrasonography-guided prostate biopsies.

Dual efficacy of tocilizumab in managing PD-1 inhibitors-induced myocardial inflammatory injury and suppressing tumor growth with PD-1 inhibitors: a preclinical study.

The combined use of tocilizumab (TCZ) and immune checkpoint inhibitors (ICIs) in cancer treatment is gaining attention, but preclinical studies are lacking. Our study aims to investigate the synergistic anti-tumor effect of TCZ combined with ICIs and its role in treating immune-related adverse events (irAEs). The clinical significance of high interleukin-6 (IL-6) expression in tumor patients was analyzed from the Cancer Genome Atlas (TCGA) database.

First-line immune-based combinations or sunitinib in favorable-risk metastatic renal cell carcinoma: a real-world retrospective comparison from the ARON-1 study.

Introduction: Renal cell carcinoma (RCC) is one of the most common types of urogenital cancer. The introduction of immune-based combinations, including dual immune-checkpoint inhibitors (ICI) or ICI plus tyrosine kinase inhibitors (TKIs), has radically changed the treatment landscape for metastatic RCC, showing varying efficacy across different prognostic groups based on the International Metastatic RCC Database Consortium (IMDC) criteria.

Materials And Methods: This retrospective multicenter study, part of the ARON-1 project, aimed to evaluate the outcomes of favorable-risk metastatic RCC patients treated with immune-based combinations or sunitinib.

A novel quantitative angiogenesis assay based on visualized vascular organoid.

Angiogenesis describes the sprouting of blood vessels from existing vasculatures and it plays a pivotal role in disease progress such as diabetes, age-related macular degeneration and cancer. However, the most widely used anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) pathway still lacked of specificity and therapeutic efficacy. To establish a method suitable for high-throughput drug screening and faithfully recapitulate the feature of in vivo angiogenesis, we generated a PECAM1-mRuby3-secNluc; ACTA2-EGFP dual reporter human pluripotent stem cell (hPSC) line and utilizing the cell line to establish a visualized and quantifiable in vitro angiogenesis model with stem cell-derived vascular organoid.

Putative biomarkers of hepatic dysfunction in critically ill sepsis patients.

Sepsis is a major cause of morbidity and mortality worldwide. Among the various types of end-organ damage associated with sepsis, hepatic injury is linked to significantly higher mortality rates compared to dysfunction in other organ systems. This study aimed to investigate potential biomarkers of hepatic injury in sepsis patients through a multi-center, case-control approach.

CircRNA-loaded DC vaccine in combination with low-dose gemcitabine induced potent anti-tumor immunity in pancreatic cancer model.

Although promising, dendritic cell (DC) vaccines may not suffice to fully inhibit tumor progression alone, mainly due to the short expression time of the antigen in DC vaccines, immunosuppressive tumor microenvironment, and tumor antigenic modulation. Overcoming the limitations of DC vaccines is expected to further enhance their anti-tumor effects. In this study, we constructed a circRNA-loaded DC vaccine utilizing the inherent stability of circular RNA to enhance the expression level and duration of the antigen within the DC vaccine.

Long-Term Natural Hydroxyapatite and Synthetic Collagen Hydroxyapatite Enhance Bone Regeneration and Implant Fixation Similar to Allograft in a Sheep Model of Implant Integration.

There is an increasing demand for a suitable bone substitute to replace current clinical gold standard autografts or allografts. Majority of previous studies have focused on the early effects of substitutes on bone formation, while information on their long-term efficacies remains limited. This study investigated the efficacies of natural hydroxyapatite (nHA) derived from oyster shells and synthetic hydroxyapatite mixed with collagen (COL/HA) or chitosan (CS/HA) on bone regeneration and implant fixation in sheep.

High CD38 expression defines a mitochondrial function-adapted CD8 T cell subset with implications for lung cancer immunotherapy.

Despite identifying specific CD8 T cell subsets associated with immunotherapy resistance, the molecular pathways driving this process remain elusive. Given the potential role of CD38 in regulating CD8 T cell function, we aimed to investigate the accumulation of CD38CD8 T cells in lung cancer and explore its role in immunotherapy resistance. Phenotypic analysis of tumoral CD8 T cells from both lung cancer patients and immunotherapy-resistant preclinical models revealed that CD38-expressing CD8 T cells consist of CD38 and CD38 subsets.

IDO1 inhibitor enhances the effectiveness of PD-1 blockade in microsatellite stable colorectal cancer by promoting macrophage pro-inflammatory phenotype polarization.

Microsatellite stable (MSS) colorectal cancer (CRC) is a subtype of CRC that generally exhibits resistance to immunotherapy, particularly immune checkpoint inhibitors such as PD-1 blockade. This study investigates the effects and underlying mechanisms of combining PD-1 blockade with IDO1 inhibition in MSS CRC. Bioinformatics analyses of TCGA-COAD and TCGA-READ cohorts revealed significantly elevated IDO1 expression in CRC tumors, correlating with tumor mutation burden across TCGA datasets.

Basic Science and Pathogenesis.

Background: We aim to investigate efficacies of Ras homolog (Rho)-associated kinases (ROCK) inhibitors on Alzheimer's disease (AD) pathological proteins in human induced pluripotent stem cell (iPSC)-differentiated human neurons and the P301S tau transgenic mouse model (PS19).

Method: Quantitative liquid chromatography-mass spectrometry (LC-MS/MS) and targeted ELISA were implemented to investigate the effect of treatment with fasudil or its derivatives on the human neurons and brains from PS19 mice. We explored the efficacy of these ROCK inhibitors in reducing tau phosphorylation, and the brain proteomic profiles after their administration in mice.

Basic Science and Pathogenesis.

Background: There is growing evidence from laboratory and clinical trials that deep brain stimulation (DBS) at memory associated structures enhances cognitive functions. Best site for memory enhancing-DBS is still unclear. The medial septum (MS), the important modulator of the hippocampal neural network, might be a key target to accomplish therapeutic efficacy in memory impaired patients.

Basic Science and Pathogenesis.

Background: Cardiovascular disease causes vascular dementia and contributes to most clinical dementia. This is embodied in the concept of vascular contributions to cognitive impairment and dementia (VCID). The potent endogenous peptide endothelin-1 (ET1) causes small artery vasoconstriction and fibrosis.

Basic Science and Pathogenesis.

Background: Oxidative stress is formed by a perturbation of redox homeostasis and linked to the development of Alzheimer's disease (AD) [1]. This imbalance results in an abundance of free radicals that exceeds the antioxidant capacity. Xanthine oxidase (XO) is an enzyme responsible for producing uric acid through the metabolism of purine nucleotides, specifically hypoxanthine and xanthine to uric acid [2].

Basic Science and Pathogenesis.

Background: Although pharmacokinetics and pharmacodynamics of biotherapeutics are commonly studied through ELISAs; however, the extremely strong binding of modern antibody-based therapeutics result in background, inability of secondary antibody binding, and nonlinear response curves. The selectivity and specificity imparted through the use of liquid chromatography-targeted mass spectrometry (LC-MS/MS) allows for absolute quantitation of chosen peptides. For MODEL-AD, here we present a high-throughput workflow for absolute quantification of chimeric aducanumab from cortex and plasma of 5XFAD mice.

Basic Science and Pathogenesis.

Background: According to data from the Alzheimer's Association, more than two-thirds of patients living with Alzheimer's disease (AD) in the United States are women. The interplay between aging and hormone depletion during menopause has been proposed as a leading cause, but the molecular underpinnings of this vulnerability are not fully understood. On the one hand, approaches that seek to supplement estrogens to rescue pre-menopausal hormonal levels have had contradictory outcomes in clinical trials.

Basic Science and Pathogenesis.

Background: Despite recent FDA approvement of disease-modifying treatments that reduce Aβ, the identification of novel therapeutic strategies that could delay the Alzheimer's disease (AD) development are needed. We identified and developed novel small molecule compounds that mildly inhibit mitochondrial complex I (MCI). Chronic treatment with a tool compound CP2 in 4 mouse models of familial AD was efficacious protecting against synaptic dysfunction and memory impairment, improving brain energetics and cognitive performance, reducing levels of human pTau and Ab.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the primary cause of dementia, characterized by early amyloid beta accumulation, subsequent tau pathology, and eventually synaptic and neuronal loss. Sleep disturbances, a clinical phenotype in AD, are linked to amyloid beta and impaired protein clearance. However, the influence of tau pathology on sleep is less explored.

Clinical Manifestations.

Background: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer's disease (AD) cognitive continuum. An international working group known as the SCD-initiative recently proposed "SCD plus" features, including report of memory problems, recent SCD relative to conversion, SCD over age 60, and consistent SCD over time, that increase the risk for future objective cognitive decline. These have not been fully assessed in a large community-based setting.

Clinical Manifestations.

Background: Centrally acting muscarinic acetylcholine receptor antagonists like atropine and scopolamine can induce psychosis-like symptoms. Xanomeline, a muscarinic M1/M4 preferring agonist attenuated the effects of amphetamine (animal model for schizophrenia) in the wild-type mice, however, such effects were absent in muscarinic M4 knockout mice. In addition, xanomeline was also found to be effective in attenuating neuropsychiatric symptoms.

Clinical Manifestations.

Sleep disturbances, such as insomnia, are associated with Alzheimer's disease pathology and future risk of cognitive impairment. This raises the exciting possibility of repurposing existing drugs to prevent or delay Alzheimer's disease since there are multiple drug approved by the Food and Drug Administration for the treatment of insomnia. Dual orexin receptor antagonists (DORAs) are one such class of medications.