Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)–like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met–mediated axis that induces β-catenin phosphorylation at Ser⁶⁷⁵ and Wnt signaling activation, inducing multidrug resistance–associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of β-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity–based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/β-catenin–mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.

Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAM). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either protumoral or antitumoral signals to glioma cells. Here, we performed bulk RNA sequencing and single-cell RNA sequencing on samples from patients with GBM, which revealed increased ATP synthase expression and oxidative phosphorylation activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP–P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP–P2X7R signaling axis as a therapeutic strategy in GBM. Significance: Glioblastoma-mediated metabolic reprogramming in tumor-associated microglia increases ATP secretion that supports cancer cell proliferation and invasion by activating P2X7R, which can be inhibited to attenuate tumor growth.

New anabolic medications (abaloparatide and romosozumab) were recently approved for osteoporosis, and data suggest that prescribing antiresorptive medications after a course of anabolic medications offers better outcomes. This study aimed to characterize prescription trends, demographics, geographical distributions, out‐of‐pocket costs, and treatment sequences for anabolic and antiresorptive osteoporosis medications. Using a commercial claims database (Clinformatics Data Mart), adult patients with osteoporosis from 2003 to 2021 were retrospectively reviewed and stratified based on osteoporosis medication class. Patient demographics and socioeconomic variables, provider types, and out‐of‐pocket costs were collected. Multivariable regression analyses were used to identify independent predictors of receiving osteoporosis treatment. A total of 2,988,826 patients with osteoporosis were identified; 616,635 (20.6%) received treatment. Patients who were female, Hispanic or Asian, in the Western US, had higher net worth, or had greater comorbidity burden were more likely to receive osteoporosis medications. Among patients who received medication, 31,112 (5.0%) received anabolic medication; these were more likely to be younger, White patients with higher education level, net worth, and greater comorbidity burden. Providers who prescribed the most anabolic medications were rheumatologists (18.5%), endocrinologists (16.8%), and general internists (15.3%). Osteoporosis medication prescriptions increased fourfold from 2003 to 2020, whereas anabolic medication prescriptions did not increase at this rate. Median out‐of‐pocket costs were $17 higher for anabolic than antiresorptive medications, though costs for anabolic medications decreased significantly from 2003 to 2020 (compound annual growth rate: −0.6%). A total of 8388 (1.4%) patients tried two or more osteoporosis medications, and 0.6% followed the optimal treatment sequence. Prescription of anabolic osteoporosis medications has not kept pace with overall osteoporosis treatment, and there are socioeconomic disparities in anabolic medication prescription, potentially driven by higher median out‐of‐pocket costs. Although prescribing antiresorptive medications after a course of anabolic medications offers better outcomes, this treatment sequence occurred in only 0.6% of the study cohort. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Immunotherapy is a promising therapeutic domain for the treatment of gliomas. However, clinical trials of various immunotherapeutic modalities have not yielded significant improvements in patient survival. Preclinical models for glioma research should faithfully represent clinically observed features regarding glioma behavior, mutational load, tumor interactions with stromal cells, and immunosuppressive mechanisms. In this review, we dive into the common preclinical models used in glioma immunology, discuss their advantages and disadvantages, and highlight examples of their utilization in translational research.

Pregnancy induces substantial anatomical, hormonal, and biomechanical changes in the spine and pelvis to accommodate fetal growth and maintain postural adaptation. This narrative review synthesizes peer-reviewed evidence regarding pregnancy-related spinal biomechanics, with a particular focus on low back pain, spinopelvic alignment, sacroiliac joint dysfunction, and potential contributions to degenerative spinal conditions. A systematic search of PubMed, Embase, and Google Scholar was conducted using Boolean operators and relevant terms, yielding 1050 unique records, with 53 peer-reviewed articles ultimately cited. The review reveals that increased lumbar lordosis, ligamentous laxity, altered gait mechanics, and muscular deconditioning elevate mechanical load on the lumbar spine, predisposing up to 56% of pregnant individuals to low back pain. These changes are often associated with sacroiliac joint laxity, anterior pelvic tilt, and multiparity. Long-term risks may include degenerative disc disease and spondylolisthesis. Conservative interventions such as pelvic floor muscle training, prenatal exercise, and surface topography monitoring offer symptom relief and support early rehabilitation, although standardized protocols and longitudinal outcome data remain limited. Pregnancy-related spinal changes are multifactorial and clinically relevant; an interdisciplinary approach involving spinal biomechanics, physical therapy, and obstetric care is critical for optimizing maternal musculoskeletal health.