Artifacts in spatial transcriptomics data: their detection, importance, prevalence, and prevention.

Data artifacts may induce errors in findings from any spatial transcriptomics platform. To provide protection from these errors, we have developed Border, Location, and edge Artifact DEtection (BLADE). BLADE is a novel collection of automated cross-platform statistical methods for detecting and removing three types of artifacts: (i) border effects, where total gene reads is modified at the border of the capture area; (ii) tissue edge effects, where total gene reads is modified at the edge of the tissue; (iii) location batch malfunctions, where there is a zone in the same location on all slides in a batch with substantially decreased sequencing depth.

NK-Cell-Derived Extracellular Vesicles Engineered to Carry Senolytics Eliminate Chemotherapy-Induced Senescent Osteosarcoma Cells.

Osteosarcoma (OS) is a type of bone tumour characterized by high risk of metastatic progression and recurrence after therapy. Traditional tumour treatment methods such as radiotherapy and chemotherapy can lead to the accumulation of senescent cells in tumours. Treatment-induced senescence (TIS) can lead to incomplete tumour clearance and potential recurrence.

Identification of miR-106b-5p as a senolytic miRNA.

Background: Cellular senescence contributes to ageing and age-related diseases. While miR-106b-5p is elevated in centenarians and GH-deficient models of healthy ageing, its role in senescence was unclear.

Methods: Senolytic effects of miR-106b-5p were evaluated in etoposide-induced senescent IMR90 fibroblasts and HUVECs, and in male naturally aged mice using liposome-mediated delivery.

Adoptive Cell Transfer of Tumor-Infiltrating Lymphocytes for Metastatic Acral Lentiginous Melanoma.

Purpose: Acral lentiginous melanoma is a subtype of cutaneous melanoma arising from palmar, plantar, or subungual skin. These tumors are characterized by aggressive biology, a low tumor mutational burden (TMB), and diminished sensitivity to immune checkpoint blockade. It is unknown whether adoptive cell transfer of tumor-infiltrating lymphocytes (ACT-TIL) has efficacy in patients with acral melanoma.

Targeting DNA damage in ageing: towards supercharging DNA repair.

Ageing is the most important risk factor for many common human diseases, including cancer, diabetes, neurodegeneration and cardiovascular disease. Consequently, combating ageing itself has emerged as a rational strategy for addressing age-related multimorbidity. Over the past three decades, multiple genetic and pharmacologic interventions have led to substantial extension of lifespan and healthspan in model organisms.

Fucoidans are senotherapeutics that enhance SIRT6-dependent DNA repair.

Aging is marked by the accumulation of senescent cells (SnCs), which contribute to tissue dysfunction and age-related diseases. Senotherapeutics, including senolytics which specifically induce lysis of SnCs and senomorphics, which suppress the senescence phenotype, represent promising therapeutic interventions for mitigating age-related pathologies and extending healthspan. Using a phenotypic-based senescent cell screening assay, we identified fucoidans, a class of sulfated polysaccharides derived from brown algae and seaweed, as novel senotherapeutics.

A phase 1 clinical trial shows safe, sustained, AAV-mediated expression of IL-1Ra in the human osteoarthritic knee joint.

Osteoarthritis (OA) is a major global health problem with no disease-modifying therapies. Interleukin-1 (IL-1) is a critical cytokine associated with the pathophysiology of OA and can be inhibited by IL-1 receptor antagonist (IL-1Ra). Here, we tested the delivery of a gene therapeutic encoding the human IL-1Ra to the knee in a phase 1, open-label clinical trial that enrolled nine patients with radiographic knee OA.

Rapid enrichment of progenitor exhausted neoantigen-specific CD8 T cells from peripheral blood.

Neoantigen-reactive peripheral blood lymphocytes (NeoPBL) are tumor-specific T cells found at ultra-low frequencies in the blood. Unlike tumor-infiltrating lymphocytes (TIL), NeoPBL exist in a favorable less dysfunctional phenotypic state , but their rarity has precluded their effective use as cell therapy. Leveraging knowledge of bona fide neoantigens, we combined high-intensity neoantigen stimulation with bead extraction of neoantigen peptide-pulsed target cells to enable the enrichment of NeoPBL to frequencies comparable to cultured TIL over a 28-day period.

Identification of Senomorphic miRNAs in Embryonic Progenitor and Adult Stem Cell-Derived Extracellular Vesicles.

Extracellular vesicles (EVs) are secreted by most cell types, transmitting crucial signaling molecules like proteins, small RNAs, and DNA. We previously demonstrated that EVs from murine and human mesenchymal stem cells (MSCs) functioned as senomorphics to suppress markers of senescence and the inflammatory senescence-associated secretory phenotype (SASP) in cell culture and in aged mice. Here we demonstrate that EVs from additional types of human adult stem cells and embryonic progenitor cells have a senomorphic activity.

Attenuation of Cellular Senescence and Improvement of Osteogenic Differentiation Capacity of Human Liver Stem Cells Using Specific Senomorphic and Senolytic Agents.

Expansion of adult stem cells in culture increases the percent of senescent cells, reduces their differentiation capacity and limits their clinical use. Here, we investigated whether treatment with certain senotherapeutic drugs would reduce the accumulation of senescent cells during expansion of human liver stem cells (HLSCs) while maintaining their differentiation capacity. Our results demonstrate that chronic treatment with the senomorphic XJB-5-131 or the senolytics cocktail D + Q reduced the number of senescent cells and significantly reduced the expression of senescence-associated genes and several inflammatory SASP factors in later passage HLSCs.

Therapeutic application of extracellular vesicles in human diseases.

Extracellular vesicles (EVs) are membrane vesicles released or secreted from almost all cell types. EVs are derived from multivesicular bodies or from the plasma membrane and contain a subset of proteins, lipids, and nucleic acids (e.g.

Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial.

Adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin. In an evolving single-arm phase 2 trial design, TILs were derived from and administered to 91 patients with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers in a schema with lymphodepleting chemotherapy and high-dose interleukin-2 (three cohorts of an ongoing trial). The primary endpoint of this study was the objective response rate as measured using Response Evaluation Criteria in Solid Tumors 1.

Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.

Dysfunctional mitophagy is a key component of Alzheimer's disease (AD) pathology, yet direct evidence and mechanistic insights remain limited. Using a mitophagy reporter in an AD mouse model ( / /mt-Keima), we identified mitochondrial plaques (MPs) composed of accumulated mitochondria within or outside lysosomes in AD, but not normal mouse brains. Similar structures were also found in AD human brains, but not in healthy controls.

Utilization of primary tumor samples for cancer neoantigen discovery.

Background: The use of tumor-infiltrating T lymphocytes (TIL) that recognize cancer neoantigens has led to lasting remissions in metastatic melanoma and certain cases of metastatic epithelial cancer. For the treatment of the latter, selecting cells for therapy typically involves laborious screening of TIL for recognition of autologous tumor-specific mutations, detected through next-generation sequencing of freshly resected metastatic tumors. Our study explored the feasibility of using archived formalin-fixed, paraffin-embedded (FFPE) primary tumor samples for cancer neoantigen discovery, to potentially expedite this process and reduce the need for resections normally required for tumor sequencing.

A machine learning approach identifies cellular senescence on transcriptome data of human cells in vitro.

Although cellular senescence has been recognized as a hallmark of aging, it is challenging to detect senescence cells (SnCs) due to their high level of heterogeneity at the molecular level. Machine learning (ML) is likely an ideal approach to address this challenge because of its ability to recognize complex patterns that cannot be characterized by one or a few features, from high-dimensional data. To test this, we evaluated the performance of four ML algorithms including support vector machines (SVM), random forest (RF), decision tree (DT), and Soft Independent Modelling of Class Analogy (SIMCA), in distinguishing SnCs from controls based on bulk RNA sequencing data.

The Fifth Annual Symposium of the Midwest Aging Consortium.

As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28 to 30, 2024, was hosted by The Ohio State University in Columbus, Ohio, and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms.

The Ercc1 mouse model of XFE progeroid syndrome undergoes accelerated retinal degeneration.

Age-related macular degeneration (AMD) is a major cause of vision loss in older adults. AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage.

Quality of life, religion/spirituality, and dementia risk among Black people in the US.

Objectives: Black people in the United States (US) experience an increased risk of being diagnosed with Alzheimer's disease and related dementias (ADRD). More research is needed on psychosocial factors that may contribute to racial disparities in rates of ADRD. Past work has identified a relationship between quality of life (QoL) and ADRD risk and also found that religion/spirituality (R/S) participation protects against ADRD.

The Fourth Annual Symposium of the Midwest Aging Consortium.

The Midwest Aging Consortium (MAC) has emerged as a critical collaborative initiative aimed at advancing our understanding of aging and developing strategies to combat the rising prevalence of age-related diseases. Founded in 2019, MAC brings together researchers from various disciplines and institutions across the Midwestern United States to foster interdisciplinary geroscience research. This report summarizes the highlights of the Fourth Annual Symposium of MAC, which was held at Iowa State University in May 2023.

Identification of lipid senolytics targeting senescent cells through ferroptosis induction.

Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically α-eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice.

Lipid peroxidation products induce carbonyl stress, mitochondrial dysfunction, and cellular senescence in human and murine cells.

Lipid enals are electrophilic products of lipid peroxidation that induce genotoxic and proteotoxic stress by covalent modification of DNA and proteins, respectively. As lipid enals accumulate to substantial amounts in visceral adipose during obesity and aging, we hypothesized that biogenic lipid enals may represent an endogenously generated, and therefore physiologically relevant, senescence inducers. To that end, we identified that 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE) or 4-oxo-2-nonenal (4-ONE) initiate the cellular senescence program of IMR90 fibroblasts and murine adipose stem cells.