Senescent cell heterogeneity and responses to senolytic treatment are related to cell cycle status during senescence induction.

Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations.

InO Nanoribbon-Based Field-Effect Transistor Biosensors for Ultrasensitive Detection of Exosomal Circulating microRNA with Peptide Nucleic Acid Probes.

The expression of distinct microRNA (miRNA) species is associated with many major diseases, and thus, stable and reliable detection at low concentrations is crucial for early diagnosis and treatment. Field-effect transistor (FET)-based biosensors have shown significant progress in miRNA detection, but detection at ultralow concentrations remains challenging due to weak signal generation from small, low-charge miRNA molecules. Here, we report an InO nanoribbon-based FET biosensor platform capable of detecting miRNAs at attomolar (aM) concentrations.

Exosomes released from senescent cells and circulatory exosomes isolated from human plasma reveal aging-associated proteomic and lipid signatures.

Senescence emerged as significant mechanism of aging and age-related diseases, offering an attractive target for clinical interventions. Senescent cells release a senescence-associated secretory phenotype (SASP), including exosomes that may act as signal transducers between distal tissues, and propagate secondary senescence. However, the composition of exosomal SASP components remains underexplored.

A Comprehensive Multiomics Signature of Doxorubicin-Induced Cellular Senescence in the Postmenopausal Human Ovary.

A major aging hallmark is the accumulation of cellular senescence burden. Over time, senescent cells contribute to tissue deterioration through chronic inflammation and fibrosis driven by the senescence-associated secretory phenotype (SASP). The human ovary is one of the first organs to age, and prominent age-related fibroinflammation within the ovarian microenvironment is consistent with the presence of senescent cells, but these cells have not been characterized in the human ovary.

Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals.

Active Monitoring With or Without Endocrine Therapy for Low-Risk Ductal Carcinoma In Situ: The COMET Randomized Clinical Trial.

Importance: Active monitoring for low-risk ductal carcinoma in situ (DCIS) of the breast has been proposed as an alternative to guideline-concordant care, but the safety of this approach is unknown.

Objective: To compare rates of invasive cancer in patients with low-risk DCIS receiving active monitoring vs guideline-concordant care.

Design, Setting, And Participants: Prospective, randomized noninferiority trial enrolling 995 women aged 40 years or older with a new diagnosis of hormone receptor-positive grade 1 or grade 2 DCIS without invasive cancer at 100 US Alliance Cancer Cooperative Group clinical trial sites from 2017 to 2023.

Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus .

Replicative errors, inefficient repair, and proximity to sites of reactive oxygen species production make mitochondrial DNA (mtDNA) susceptible to damage with time. We explore allotopic expression (re-engineering mitochondrial genes and expressing them from the nucleus) as an approach to rescue defects arising from mtDNA mutations. We used a mouse strain C57BL/6J(mtFVB) with a natural polymorphism (m.

Quantum chemical package Jaguar: A survey of recent developments and unique features.

This paper is dedicated to the quantum chemical package Jaguar, which is commercial software developed and distributed by Schrödinger, Inc. We discuss Jaguar's scientific features that are relevant to chemical research as well as describe those aspects of the program that are pertinent to the user interface, the organization of the computer code, and its maintenance and testing. Among the scientific topics that feature prominently in this paper are the quantum chemical methods grounded in the pseudospectral approach.

Exosomes Released from Senescent Cells and Circulatory Exosomes Isolated from Human Plasma Reveal Aging-associated Proteomic and Lipid Signatures.

Senescence emerged as significant mechanism of aging and age-related diseases, offering an attractive target for clinical interventions. Senescent cells release a senescence-associated secretory phenotype (SASP), including exosomes that may act as signal transducers between distal tissues, propagating secondary or bystander senescence and signaling throughout the body. However, the composition of exosome SASP remains underexplored, presenting an opportunity for novel unbiased discovery.

Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor-Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination: A Phase 3 Randomized Clinical Trial.

Importance: Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease.

Objective: To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.

Comment on the Definition and Labeling of p.

We propose a more rigorous definition for the recently introduced concept of p. The value of p should be associated not with a "functional group", as originally postulated, but instead with an atom. The proposed clarification is meant to improve the interpretation and labeling of p.

Systemic Alterations in Type-2 Conventional Dendritic Cells Lead to Impaired Tumor Immunity in Pancreatic Cancer.

Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)-mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDAC) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 cDC2 development and function has not been well studied.

Suppression of superoxide/hydrogen peroxide production at mitochondrial site I decreases fat accumulation, improves glucose tolerance and normalizes fasting insulin concentration in mice fed a high-fat diet.

We developed S1QEL1.719, a novel bioavailable S1QEL (suppressor of site I electron leak). S1QEL1.

Automatic detection of circulating tumor cells and cancer associated fibroblasts using deep learning.

Circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs) from whole blood are emerging as important biomarkers that potentially aid in cancer diagnosis and prognosis. The microfilter technology provides an efficient capture platform for them but is confounded by two challenges. First, uneven microfilter surfaces makes it hard for commercial scanners to obtain images with all cells in-focus.

Site IQ in mitochondrial complex I generates S1QEL-sensitive superoxide/hydrogen peroxide in both the reverse and forward reactions.

Superoxide/hydrogen peroxide production by site IQ in complex I of the electron transport chain is conventionally assayed during reverse electron transport (RET) from ubiquinol to NAD. However, S1QELs (specific suppressors of superoxide/hydrogen peroxide production by site IQ) have potent effects in cells and in vivo during presumed forward electron transport (FET). Therefore, we tested whether site IQ generates S1QEL-sensitive superoxide/hydrogen peroxide during FET (site IQf), or alternatively, whether RET and associated S1QEL-sensitive superoxide/hydrogen peroxide production (site IQr) occurs in cells under normal conditions.

Controlled power: how biology manages succinate-driven energy release.

Oxidation of succinate by mitochondria can generate a higher protonmotive force (pmf) than can oxidation of NADH-linked substrates. Fundamentally, this is because of differences in redox potentials and gearing. Biology adds kinetic constraints that tune the oxidation of NADH and succinate to ensure that the resulting mitochondrial pmf is suitable for meeting cellular needs without triggering pathology.

S3QELs protect against diet-induced intestinal barrier dysfunction.

The underlying causes of aging remain elusive, but may include decreased intestinal homeostasis followed by disruption of the intestinal barrier, which can be mimicked by nutrient-rich diets. S3QELs are small-molecule suppressors of site III electron leak; they suppress superoxide generation at complex III of the mitochondrial electron transport chain without inhibiting oxidative phosphorylation. Here we show that feeding different S3QELs to Drosophila on a high-nutrient diet protects against greater intestinal permeability, greater enterocyte apoptotic cell number, and shorter median lifespan.

Cellular and plasma proteomic determinants of COVID-19 and non-COVID-19 pulmonary diseases relative to healthy aging.

We examine the cellular and soluble determinants of coronavirus disease 2019 (COVID-19) relative to aging by performing mass cytometry in parallel with clinical blood testing and plasma proteomic profiling of ~4,700 proteins from 71 individuals with pulmonary disease and 148 healthy donors (25-80 years old). Distinct cell populations were associated with age (GZMKCD8 T cells and CD25 CD4 T cells) and with COVID-19 (TBETEOMES CD4 T cells, HLA-DRCD38 CD8 T cells and CD27CD38 B cells). A unique population of TBETEOMES CD4 T cells was associated with individuals with COVID-19 who experienced moderate, rather than severe or lethal, disease.

A microfluidic-based filtration system to enrich for bone marrow disseminated tumor cells from breast cancer patients.

Disseminated tumors cells (DTCs) present in the bone marrow (BM) are believed to be the progenitors of distant metastatic spread, a major cause of mortality in breast cancer patients. To better understand the behavior and therapeutic vulnerabilities of these rare cell populations, unbiased methods for selective cell enrichment are required. In this study, we have evaluated a microfluidic-based filtration system (ParsortixR, Angle PLC), previously demonstrated for use in circulating tumor cell (CTC) capture, to capture BM DTCs.

Pattern-free generation and quantum mechanical scoring of ring-chain tautomers.

In contrast to the computational generation of conventional tautomers, the analogous operation that would produce ring-chain tautomers is rarely available in cheminformatics codes. This is partly due to the perceived unimportance of ring-chain tautomerism and partly because specialized algorithms are required to realize the non-local proton transfers that occur during ring-chain rearrangement. Nevertheless, for some types of organic compounds, including sugars, warfarin analogs, fluorescein dyes and some drug-like compounds, ring-chain tautomerism cannot be ignored.

Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).

Introduction: Surgical resection is curative for some patients with early lung squamous cell carcinoma. Staging and clinical factors do not adequately predict recurrence risk. We sought to validate the discriminative performance of proposed prognostic gene expression signatures at a level of rigor sufficient to support clinical use.

Long non-coding RNA is associated with lung adenocarcinoma prognosis.

Background: More than half of non-small cell lung cancer (NSCLC) patients present with metastatic disease at initial diagnosis with an estimated five-year survival rate of ~5%. Despite advances in understanding primary lung cancer oncogenesis metastatic disease remains poorly characterized. Recent studies demonstrate important roles of long non-coding RNAs (lncRNAs) in tumor physiology and as prognostic markers.

Oxidised metabolites of the omega-6 fatty acid linoleic acid activate dFOXO.

Obesity-induced inflammation, or meta-inflammation, plays key roles in metabolic syndrome and is a significant risk factor in diabetes and cardiovascular disease. To investigate causal links between obesity, meta-inflammation, and insulin signaling we established a model to determine how elevated dietary fat and changes in the levels and balance of saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) influence inflammation. We observe negligible effect of saturated fatty acid on inflammation but marked enhancement or suppression by omega-6 and omega-3 PUFAs, respectively.

Microscaled proteogenomic methods for precision oncology.

Cancer proteogenomics promises new insights into cancer biology and treatment efficacy by integrating genomics, transcriptomics and protein profiling including modifications by mass spectrometry (MS). A critical limitation is sample input requirements that exceed many sources of clinically important material. Here we report a proteogenomics approach for core biopsies using tissue-sparing specimen processing and microscaled proteomics.

The use of site-specific suppressors to measure the relative contributions of different mitochondrial sites to skeletal muscle superoxide and hydrogen peroxide production.

Reactive oxygen species are important signaling molecules crucial for muscle differentiation and adaptation to exercise. However, their uncontrolled generation is associated with an array of pathological conditions. To identify and quantify the sources of superoxide and hydrogen peroxide in skeletal muscle we used site-specific suppressors (S1QELs, S3QELs and NADPH oxidase inhibitors).