Citations

Abstract Reprogramming of aged donor tissue cells into induced pluripotent stem cells (A-iPSC) preserved the epigenetic memory of aged-donor tissue, defined as genomic instability and poor tissue differentiation in our previous study. The unbalanced expression of RNA exosome subunits affects the RNA degradation complex function and is associated with geriatric diseases including premature aging and cancer progression. We hypothesized that the age-dependent progressive subtle dysregulation of EXOSC2 (exosome component 2) causes the aging traits (abnormal cell cycle and poor tissue differentiation). We used embryonic stem cells as a tool to study EXOSC2 function as the aging trait epigenetic memory determined in A-iPSC because these aging traits could not be studied in senesced aged cells or immortalized cancer cells. We found that the regulatory subunit of PP2A phosphatase, PPP2R5E, is a key target of EXOSC2 and this regulation is preserved in stem cells and cancer.

Breast cancer is the most common malignancy among women worldwide, posing a serious threat to women’s physical and mental health. To address this significant global public health challenge, the Guidelines for the Integrated Diagnosis and Treatment of Breast Cancer with Traditional Chinese and Western Medicine working group, adhering to the principles of evidence-based medicine, has proposed a comprehensive and holistic diagnostic and therapeutic pathway. This pathway integrates the core concepts of traditional Chinese medicine (TCM), such as holistic views and syndrome differentiation and treatment, with the latest advances in breast cancer treatment from both domestic and international perspectives. It objectively evaluates the role of integrated Chinese and western medicine in the all-encompassing and full-cycle management of breast cancer across different phases: the acute phase (perioperative, chemotherapy, and radiotherapy periods), early consolidation phase, late palliative care phase, and follow-up period addressing accompanying symptoms (eg, cancer-related fatigue, bone and joint symptoms). Highlighting the unique features of TCM, the guidelines provide a model for integrated breast cancer treatment for clinicians at various levels of health care institutions. This article offers a detailed interpretation of the guideline’s key highlights and 11 PICO questions concerning TCM management throughout the breast cancer continuum, aiming to enhance the understanding, application, and promotion of the guidelines.

Background/Purpose APS ACTION Registry was created to study the natural course of antiphospholipid syndrome (APS) over 10 years in persistently antiphospholipid antibody (aPL) positive patients with or without systemic autoimmune rheumatic diseases (SARDs). Our primary objective was to compare the characteristics of aPL-positive patients with or without thrombocytopenia (TP) and/or autoimmune hemolytic anemia (AIHA). Methods The registry inclusion criteria are positive aPL based on the Revised Sapporo APS Classification Criteria, tested at least twice within 1 year prior to enrollment. For the primary comparison of demographic, clinical, and serologic characteristics in this retrospective study, we divided patients into two groups: TP/AIHA ever and never. Thrombocytopenia was defined as a platelet count of <100,000 x 10 9 /L tested twice at least 12 weeks apart, and AIHA was defined as anemia with hemolysis and a positive direct antiglobulin test (DAT). For the secondary analysis, we compared patients with TP versus AIHA, and the immunosuppressive use stratified by systemic lupus erythematosus (SLE) classification. Results As of April 2022, of 1,039 patients (primary aPL/APS: 618 [59%]; SLE classification: 334 [31%]) included in the registry, 228 (22%) had baseline (historical or current) TP and/or AIHA (TP only: 176 [17%]; AIHA only: 35 [3%], and both: 17 [2%]). Thrombocytopenia and/or AIHA was significantly associated with Asian race, SLE classification, cardiac valve disease, catastrophic/microvascular APS, triple aPL (lupus anticoagulant, anticardiolipin antibody, and anti-β 2 -glycoprotein-I antibody) positivity, and SLE-related serologic and inflammatory markers. When 101/618 (16%) primary aPL/APS patients and 101/334 (34%) SLE patients with TP and/or AIHA were compared, azathioprine and mycophenolate mofetil were more commonly reported in lupus patients, however corticosteroid, intravenous immunoglobulin, and rituximab use were similar between groups. Conclusion In our large multi-center international cohort of persistently aPL-positive patients, approximately one-fifth had active or historical TP and/or AIHA at registry entry; half of these patients had additional SLE. Cardiac valve disease, catastrophic/microvascular APS, and triple aPL-positivity were aPL-related clinical and laboratory manifestations associated with TP and/or AIHA, suggesting a more severe APS clinical phenotype in aPL-patients with TP and/or AIHA.

Abstract The lung is an inherently mechanosensitive organ, where cells of the airway and parenchyma experience a range of mechanical forces throughout life including shear, stretch, and compression, in both health and disease. In this regard, pediatric and adult lung diseases such as wheezing and asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF) all involve macroscopic and cellular changes to the mechanical properties of the bronchial airways and/or parenchyma to varying extents. Accordingly, understanding how mechanical forces are sensed in the lung, and the responses of cells and tissues in the context of normal development and health versus disease conditions becomes highly relevant. There is increasing recognition that transduction of mechanical forces into cellular responses involves a number of channels, some of which are inherently mechanosensitive. Such channels trigger mechanotransduction pathways that may further mediate cellular remodeling, inflammation, and other pathophysiologic mechanisms in response to stretch, stiffness, and inflammatory cascades. Two particularly important channel families have emerged in pulmonary pathophysiology: the transient receptor potential vanilloid family with focus on member TRPV4 and the recently identified Piezo (PZ) channels. Here, we explore current understanding of the contributions of TRPV4 and PZ channels in lung health and disease states, focusing on the interactions between these mechanosensitive channels and their local environment including immune cells, the extracellular matrix, and cellular cytoskeletal elements. We further discuss potential areas for future research to better understand the impact of mechanical channels on pulmonary health and disease. © 2023 American Physiological Society. Compr Physiol 13:5157‐5178, 2023.

Intensive care units (ICUs) serve patients with life-threatening conditions. However, the availability of ICU resources remains scarce worldwide. Therefore, it is critical to conduct ICU outcome predictions at an early stage and promote efficient use of ICU resources. However, the current ICU outcome prediction methods have limitations such as unsatisfactory accuracy and dependence on resource-demanding laboratory tests or expert domain knowledge. In this research, we design a wavelet transform based additive convolutional neural network (WT-A-CNN) that requires only patients’ vital sign series and information at ICU admission for real-time ICU outcome predictions. The model is evaluated using a large real-world ICU database and outperforms state-of-the-art baselines on both ICU mortality and length-of-stay prediction tasks. Furthermore, the additive structure of the model can be used for model interpretation and analyzing which input signal is more useful for ICU outcome prediction for different patient cohorts. Our work provides an efficient tool for ICU outcome predictions, allowing healthcare providers to act promptly on patients at risk and reduce the negative impacts on patient outcomes.

Abstract Background and aims This post hoc analysis evaluated the corticosteroid-sparing effects of risankizumab (RZB) therapy in patients with moderate-to-severe ulcerative colitis in the phase 3 induction and maintenance studies, INSPIRE and COMMAND. Methods Patients were randomized (2:1) to 12 weeks of intravenous RZB or placebo (PBO) induction therapy; responders to intravenous RZB were randomized (1:1:1) to receive subcutaneous RZB 180 mg, 360 mg, or PBO (RZB withdrawal) maintenance therapy. Baseline corticosteroid doses were maintained during induction, with a mandatory taper beginning at maintenance week 0. Efficacy outcomes were evaluated by baseline corticosteroid use at induction week 12, while corticosteroid-free clinical and endoscopic outcomes were assessed at maintenance week 52 among the overall population and among patients on corticosteroids at baseline. Safety was also assessed. Results At baseline, 35.7% (348/975) of patients were taking corticosteroids. At induction week 12, greater rates were observed for clinical, endoscopic, and patient-reported outcomes in RZB 1200 mg-treated patients compared with PBO, regardless of baseline corticosteroid use. RZB 180 mg and 360 mg treatment resulted in higher corticosteroid discontinuation rates (RZB 180 mg 64.9% [48/74]; RZB 360 mg 54.2% [32/59]; PBO [withdrawal] 36.8% [25/68], P ≤ .01) and corticosteroid-free clinical, endoscopic, and patient-reported outcomes at week 52, compared with PBO (withdrawal). The rates of treatment-emergent adverse events were similar regardless of baseline corticosteroid use during induction and maintenance. Conclusions The efficacy of RZB induction therapy was independent of corticosteroid use, with high rates of corticosteroid-free outcomes observed in the overall population and among patients with baseline corticosteroid use, reaffirming the potential of RZB to serve as a corticosteroid-sparing therapy for patients with ulcerative colitis. Clinicaltrial.gov numbers NCT03398148 and NCT03398135

ABSTRACT The insulin‐like growth factor‐1 (IGF‐1) signaling pathway is known as a potent aging modifier, disruption of which consistently associates with lifespan extension across diverse species. Despite this established association, the mechanisms by which IGF‐1 signaling modulates organ aging remain poorly understood. In this study, we assessed age‐related changes in IGF‐1 expression across multiple organs in mice and identified a more prominent increase in skin IGF‐1 levels with aging—a phenomenon also observed in human skin. To explore the consequences of elevated IGF‐1, we developed transgenic mice ectopically expressing human IGF‐1 in the epidermis, driven by the bovine keratin 5 promoter (IGF‐1 Tg). These mice exhibited premature aging of hair follicles, as evidenced by accelerated hair graying and loss. Single‐cell RNA sequencing analyses of dorsal skin highlighted an upsurge in cellular senescence markers and the senescence‐associated secretory phenotype (SASP) in hair follicle stem cells (HFSCs), alongside a decline in hair growth and HFSC exhaustion. Our findings indicate that excessive IGF‐1 triggers HFSC senescence, thereby disrupting hair follicle homeostasis. Remarkably, interventions in IGF‐1 signaling via downstream mechanisms—specifically blocking Ac‐p53 activation via SIRT1 overexpression or senolytic treatment for senescent cell clearance, or reducing IGF‐1 through dietary restriction—significantly reduced senescence markers, mitigated premature hair follicle aging phenotypes, and restored the stem cell pool. Our findings provide fundamental insights into the biological processes of hair aging and highlight the therapeutic promise of targeted interventions to rejuvenate aged HFSCs and promote hair follicle health.

Abstract Background Impact of BRAF V600E mutations (BRAFV600E), a poor prognostic factor in metastatic colorectal cancer, is lacking in non-CRC gastrointestinal (GI) cancers including pancreatic (PDAC), gastric/gastroesophageal (GEA), hepatocellular carcinoma (HCC), and cholangiocarcinoma (CCA). Due to tumor-agnostic approvals for patients with BRAFV600E, understanding the frequency and impact of BRAF alterations across non-CRC GI cancers is essential for clinical decision-making. Methods Patients with PDAC, GEA, HCC, or CCA who had cell-free DNA detected on Guardant360 (Guardant Health) from 2020 to 2023 were queried. Prevalence of characterized BRAF genomic alterations (GA) was calculated; GAs were grouped by class (Class I/II/III). The Chi-squared test assessed differences between cancer types. A subset of patients had outcomes analysis using GuardantINFORM, a real-world clinicogenomic database, to derive real-world overall survival (rwOS). Results Of 32 480 included patients, BRAF GAs were identified in 4.4%; 19% were BRAFV600E (0.81% prevalence overall). CCA had the highest rate of BRAF GAs and BRAFV600E (P &lt; .01); HCC and GEA had the highest rates of BRAF class II/III alterations. There were no significant differences in rwOS by alteration class or cancer type; numeric differences were observed by alteration class. Few patients were treated with BRAF inhibitors (2.2%). Prevalence of co-occurring alterations was unique by cancer type. Conclusions Frequency of BRAF GAs, including BRAFV600E, in non-CRC GI cancers detected by liquid biopsy is similar to tissue-based rates and can be reliably used to assess BRAF status. BRAF GAs have mixed prognostic implications on survival for patients with non-CRC GI malignancies that warrant further exploration.

Abstract Background Most oncology therapeutics have limited distribution into the brain, and developing strategies to overcome this limitation would be clinically impactful. While therapeutic radiation is often cited as a strategy to accomplish this, there are no published studies demonstrating the effect of radiation on drug distribution into the brain or brain tumors. Methods Mice were treated with brain radiation (6 Gy × 5, 4 Gy × 10; 40 Gy × 1) and dosed with drugs (levetiracetam, cefazolin, nedisertib, brigimadlin, apitolisib, or GNE-317) at times ranging from just prior to months after radiation. Plasma and tissue drug concentrations were measured by LC-MS/MS. Results Radiation did not significantly enhance drug delivery into brain tissue for levetiracetam, cefazolin, GNE-317, apitolisib, or nedisertib at any time post-radiation. Even a single, supra-therapeutic dose of radiation (40 Gy) did not significantly affect brain distribution of GNE-317 or apitolisib (P ≥ .07) from 16 to 160 hours post-radiation. For brigimadlin, radiation (6 Gy × 5) was associated with a modest but significant increase in drug accumulation only at 72 hours post-radiation (brain-to-plasma ratio 0.014 ± 0.006 vs. 0.025 ± 0.010, respectively; P = .04), but not at any other timepoint (24 hours, 15, 28, 94, 133, 183 days; P &gt; .05). Similarly, radiation (6 Gy × 5) of orthotopic tumors did not increase levels of brigimadlin in GBM10 or GBM108 or nedisertib in GBM108 (P &gt; .05). Conclusions Radiation had no meaningful impact on drug delivery into brain or brain tumors for the drugs tested.