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Background Immune checkpoint inhibitors (ICIs) have uncommon associations with cardiotoxicity, yet these cardiotoxic effects are associated with high mortality. An accurate assessment of risk for cardiotoxicity is essential for clinical decision‐making, but data from randomized controlled trials often differ from real‐world observational studies. Methods and Results A systematic search of PubMed, Embase, Cochrane Library, and Scopus was performed, including phase II and III randomized controlled trials (RCTs) and observational studies (OSs) reporting myocarditis or pericardial disease, myocardial infarction, or stroke with an immunotherapy. Odds ratios (ORs) were used to pool results between ICIs and other cancer therapy in RCTs and OSs. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guideline was followed. In total, 54 RCTs (N=38 264) and 24 OSs (N=12 561 455) were included. In RCTs, ICI use resulted in higher risk of myocarditis (OR, 3.55 [95% CI, 2.10–5.98]), pericardial disease (OR, 2.73 [95% CI, 1.57–4.77]), and myocardial infarction (OR, 1.83 [95% CI, 1.03–3.25]), compared with non‐ICI (placebo or chemotherapy). In OSs, ICI use was not associated with myocarditis, pericardial disease, or myocardial infarction compared with controls; however, combination ICIs demonstrated higher risk of myocarditis compared with single ICI use (OR, 3.07 [95% CI, 1.28–7.39]). Stroke risk was not increased with use of ICIs in RCTs. Conclusions We demonstrated increased risk of ICI myocarditis, pericardial disease, and myocardial infarction in RCTs but not OSs. Results of this study suggest there are differences between ICI cardiotoxicity risk, possibly suggesting differences in diagnoses and management, in clinical trials versus the OSs.

Summary: Metastatic prostate cancer (PCa) in bone induces bone-forming lesions. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone EC-to-osteoblast (OSB) transition. Here, we investigated whether EC-to-OSB transition also occurs during normal bone formation. We developed an EC and OSB dual-color reporter mouse (DRM) model that marks EC-OSB hybrid cells with red and green fluorescent proteins. We observed EC-to-OSB transition (RFP and GFP co-expression) in both endochondral and intramembranous bone formation during embryonic development and in adults. Co-expression was confirmed in cells isolated from DRM. Bone marrow– and lung-derived ECs underwent transition to OSBs and mineralization in osteogenic medium. RNA-sequencing revealed GATA family transcription factors were upregulated in EC-OSB hybrid cells and knockdown of GATA3 inhibited BMP4-induced mineralization. Our findings support that EC-to-OSB transition occurs during normal bone development and suggest a new paradigm regarding the endothelial origin of OSBs.

The metabotropic γ-aminobutyric acid type B receptor (GABABR) remains a hotspot in the recent research area. Being an idiosyncratic G-protein coupled receptor family member, the GABABR manifests adaptively tailored functionality under multifarious modulations by a constellation of agents, pointing to cross-talk between receptors and effectors that converge on the domains of mood and memory. This review systematically summarizes the latest achievements in signal transduction mechanisms of the GABABR-effector-regulator complex and probes how the up-and down-regulation of membrane-delimited GABABRs are associated with manifold intrinsic and extrinsic agents in synaptic strength and plasticity. Neuropsychiatric conditions depression and addiction share the similar pathophysiology of synapse inadaptability underlying negative mood-related processes, memory formations, and impairments. In the attempt to emphasize all convergent discoveries, we hope the insights gained on the GABABR system mechanisms of action are conducive to designing more therapeutic candidates so as to refine the prognosis rate of diseases and minimize side effects.

ObjectiveWe aimed to construct and validate machine learning models for endotracheal tube (ETT) size prediction in pediatric patients.MethodsData of 990 pediatric patients underwent endotracheal intubation were retrospectively collected between November 2019 and October 2021, and separated into cuffed and uncuffed endotracheal tube subgroups. Six machine learning algorithms, including support vector regression (SVR), logistic regression (LR), random forest (RF), gradient boosting tree (GBR), decision tree (DTR) and extreme gradient boosting tree (XGBR), were selected to construct and validate models using ten-fold cross validation in training set. The optimal models were selected, and the performance were compared with traditional predictive formulas and clinicians. Furthermore, additional data of 71 pediatric patients were collected to perform external validation.ResultsThe optimal 7 uncuffed and 5 cuffed variables were screened out by feature selecting. The RF models had the best performance with minimizing prediction error for both uncuffed ETT size (MAE = 0.275 mm and RMSE = 0.349 mm) and cuffed ETT size (MAE = 0.243 mm and RMSE = 0.310 mm). The RF models were also superior in predicting power than formulas in both uncuffed and cuffed ETT size prediction. In addition, the RF models performed slightly better than senior clinicians, while they significantly outperformed junior clinicians. Based on SVR models, we proposed 3 novel linear formulas for uncuffed and cuffed ETT size respectively.ConclusionWe have developed machine learning models with excellent performance in predicting optimal ETT size in both cuffed and uncuffed endotracheal intubation in pediatric patients, which provides powerful decision support for clinicians to select proper ETT size. Novel formulas proposed based on machine learning models also have relatively better predictive performance. These models and formulas can serve as important clinical references for clinicians, especially for performers with rare experience or in remote areas.

Background and Aims: We aimed to determine the utility of coronary artery calcium (CAC) for atherosclerotic cardiovascular disease (ASCVD) risk stratification in women with and without early menopause (EM). Methods: To examine the association between CAC and incident ASCVD, we performed Kaplan-Meier survival analysis and multivariable Cox proportional hazards modeling using data from 2,456 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis (MESA) with or without EM, defined as occurring at 50% of middle-aged postmenopausal women with EM had CAC = 0, similar to those without EM. Among women with CAC = 0, those with EM had a low to borderline 10-year risk of ASCVD, but the 15-year risk was significantly higher for women with EM versus those without EM. When CAC ≥ 1, the incidence of ASCVD was similar for women with and without EM. These findings support the use of CAC to help improve ASCVD risk stratification in women with EM. Condensed abstract: This study investigated the association between coronary artery calcium (CAC) and incident atherosclerotic cardiovascular disease (ASCVD) in postmenopausal women with and without early menopause (EM). We found that >50% of women had CAC = 0 and an associated low-to-borderline 10-year cumulative incidence of ASCVD. However, the risk for ASCVD was significantly higher for women with EM after 15-years follow-up. Additional research is needed to better understand the differences in long-term ASCVD risk between women with and without EM who have CAC = 0.

We conducted a search for narrowband radio signals over four observing sessions in 2020–2023 with the L -band receiver (1.15–1.73 GHz) of the 100 m diameter Green Bank Telescope. We pointed the telescope in the directions of 62 TESS Objects of Interest, capturing radio emissions from a total of ∼11,680 stars and planetary systems in the ∼9′ beam of the telescope. All detections were either automatically rejected or visually inspected and confirmed to be of anthropogenic nature. We also quantified the end-to-end efficiency of radio SETI pipelines with a signal injection and recovery analysis. The UCLA SETI pipeline recovers 94.0% of the injected signals over the usable frequency range of the receiver and 98.7% of the injections when regions of dense radio frequency interference are excluded. In another pipeline that uses incoherent sums of 51 consecutive spectra, the recovery rate is ∼15 times smaller at ∼6%. The pipeline efficiency affects calculations of transmitter prevalence and SETI search volume. Accordingly, we developed an improved Drake figure of merit and a formalism to place upper limits on transmitter prevalence that take the pipeline efficiency and transmitter duty cycle into account. Based on our observations, we can state at the 95% confidence level that fewer than 6.6% of stars within 100 pc host a transmitter that is continuously transmitting a narrowband signal with an equivalent isotropic radiated power (EIRP) > 10 ^13 W. For stars within 20,000 ly, the fraction of stars with detectable transmitters (EIRP > 5 × 10 ^16 W) is at most 3 × 10 ^−4 . Finally, we showed that the UCLA SETI pipeline natively detects the signals detected with AI techniques by Ma et al.

Zhiwei Chen,1,* Shengping Shen,1,* Wenbo Shi,1,* Gening Jiang,2 Xin Wang,3 Hong Jian,1 Zhen Zhou,1 Zhengping Ding,1 Shun Lu11Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People’s Republic of China; 2Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, People’s Republic of China; 3Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workObjective: This multicenter, open-label, single-arm, phase II trial evaluated the efficacy and safety of an intercalated combination of erlotinib and gemcitabine/cisplatin or carboplatin in patients with stage IIIA non-small-cell lung cancer (NSCLC).Registration: This trial is registered with ClinicalTrials.gov, number NCT01297101.Methods: The primary endpoint was the objective response rate (ORR), which includes complete response (CR) and partial response (PR), assessed using RECIST version 1.0 in the intention-to-treat population. Adverse events (AEs) were graded by the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Secondary endpoints included the disease control rate, disease-free survival (DFS), overall survival (OS), and safety. Between April 1, 2011, and July 31, 2014, 39 patients with stage IIIA NSCLC received two cycles of intercalated use of erlotinib with gemcitabine/cisplatin or carboplatin.Results: Eighteen patients (46.15%) achieved a PR and no patient achieved a pathologic CR, resulting in an ORR of 46.15% (95% CI 30–63%). Median DFS was 20 months (95% CI 5.26–50.61) and median OS was 25 months (95% CI 15.57–33.39). Patients with EGFR mutations (n=7) had a higher ORR than those with wild-type EGFR (n=9) (85.71% vs 55.56%, P=0.00). Most AEs were CTCAE grade 1 or 2; there were no cases of increased hematologic toxicity or erlotinib-emergent interstitial lung disease observed.Conclusion: Two cycles of intercalated neoadjuvant therapy with erlotinib and gemcitabine/cisplatin or carboplatin were effective and safe for patients with stage IIIA NSCLC. This approach should be further explored in larger randomized controlled trials given the lack of a consensus about the best treatment for stage IIIA NSCLC.Keywords: non-small-cell lung cancer, NSCLC, neoadjuvant, erlotinib, gemcitabine, platinum, objective response rate, progression-free survival, overall survival

Haiyuan Xu,1,2,* Jinge Shen,3,* Jianxing Xiang,4 Haiyan Li,4 Bing Li,4 Tengfei Zhang,4 Lu Zhang,4 Xinru Mao,4 Hong Jian,5 Yongqian Shu11Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 2Department of Oncology, Kunshan First People‘s Hospital affiliated to Jiangsu University, Kunshan 215300, People’s Republic of China; 3Department of Emergency, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200000, People’s Republic of China; 4Burning Rock Biotech, Guangzhou 510000, People’s Republic of China; 5Department of Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200000, People’s Republic of China*These authors contributed equally to this workPurpose: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. The prevalence and characteristics of receptortyrosine–kinase (RTK) fusion as acquired resistance to EGFR tyrosine–kinase inhibitors (TKIs) are rarely investigated.Methods: We retrospectively reviewed genomic profiling data of 3873 EGFR (exons 18–21)-mutant lung cancer patients with more than once next-generation sequencing detection. A total of 16 patients who acquired RTK fusions during EGFR-TKI treatment with paired pre- and post-EGFR-TKI samples were identified. Their treatment history was collected.Results: Newly acquired RTK fusions during EGFR-TKI treatment included RET (n=6, 37.5%), ALK (n=5, 31.3%), NTRK1 (n=4, 25.0%), ROS1 (n=1, 6.3%), and FGFR3 (n=1, 6.3%). All RET and EML4–ALK fusions were uncommon variants of KIF5B-RET and E2:A20 (V5), respectively. Interestingly, RET fusion occurred only after osimertinib treatment, and contributed to drug resistance in 50% (6 of 12) of patients treated with osimertinib, indicating that fusions had different prevalence when functioning as resistance mechanisms to EGFR TKIs. Moreover, we found that in all patients developing drug resistance to EGFR TKIs due to fusion emergence (n=16), those that had a treatment history of third-generation EGFR TKIs accounted for 75% (n=12).Conclusion: We have extended the current knowledge of resistance mechanisms to EGFR TKIs in non-small-celllung cancer. Detection of RTK fusions should be included in genomic profiling panels to uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches, to circumvent tumorigenesis.Keywords: receptor tyrosine kinase fusions, acquired resistance, EGFR tyrosine kinase inhibitors, lung cancer

Summary: Cell type transition occurs during normal development and under pathological conditions. In prostate cancer bone metastasis, prostate cancer-secreted BMP4 induces endothelial cell-to-osteoblast (EC-to-OSB) transition. Such tumor-induced stromal reprogramming supports prostate cancer progression. We delineate signaling pathways mediating EC-to-OSB transition using EC lines 2H11 and SVR. We found that BMP4-activated pSmad1-Notch-Hey1 pathway inhibits EC migration and tube formation. BMP4-activated GSK3β-βcatenin-Slug pathway stimulates Osx expression. In addition, pSmad1-regulated Dlx2 converges with the Smad1 and β-catenin pathways to stimulate osteocalcin expression. By co-expressing Osx, Dlx2, Slug and Hey1, we were able to achieve EC-to-OSB transition, leading to bone matrix mineralization in the absence of BMP4. In human prostate cancer bone metastasis specimens and MDA-PCa-118b and C4-2b-BMP4 osteogenic xenografts, immunohistochemical analysis showed that β-catenin and pSmad1 are detected in activated osteoblasts rimming the tumor-induced bone. Our results elucidated the pathways and key molecules coordinating prostate cancer-induced stromal programming and provide potential targets for therapeutic intervention.

BACKGROUND: Bone metastasis is common in renal cell carcinoma (RCC), and the lesions are mainly osteolytic. The mechanism of bone destruction in RCC bone metastasis is unknown. METHODS: We used a direct intrafemur injection of mice with bone-derived 786-O RCC cells (Bo-786) as an in vivo model to study if inhibition of osteoblast differentiation is involved in osteolytic bone lesions in RCC bone metastasis. RESULTS: We showed that bone-derived Bo-786 cells induced osteolytic bone lesions in the femur of mice. We examined the effect of conditioned medium of Bo-786 cells (Bo-786 CM) on both primary mouse osteoblasts and MC3T3-E1 preosteoblasts and found that Bo-786 CM inhibited osteoblast differentiation. Secretome analysis of Bo-786 CM revealed that BIGH3 (Beta ig h3 protein), also known as TGFBI (transforming growth factor beta-induced protein), is highly expressed. We generated recombinant BIGH3 and found that BIGH3 inhibited osteoblast differentiation in vitro. In addition, CM from Bo-786 BIGH3 knockdown cells (786-BIGH3 KD) reduced the inhibition of osteoblast differentiation compared to CM from vector control. Intrafemural injection of mice with 786-BIGH3 KD cells showed a reduction in osteolytic bone lesions compared to vector control. Immunohistochemical staining of 18 bone metastasis specimens from human RCC showed strong BIGH3 expression in 11/18 (61%) and moderate BIGH3 expression in 7/18 (39%) of the specimens. CONCLUSIONS: These results suggest that suppression of osteoblast differentiation by BIGH3 is one of the mechanisms that enhance osteolytic lesions in RCC bone metastasis, and raise the possibilty that treatments that increase bone formation may improve therapy outcomes.

Cell division cycle 6 (CDC6), an androgen receptor (AR) target gene, is implicated in regulating DNA replication and checkpoint mechanisms. CDC6 expression is increased during prostate cancer (PCa) progression and positively correlates with AR in PCa tissues. AR or CDC6 knockdown, together with AZD7762, a Chk1/2 inhibitor, results in decreased TopBP1-ATR-Chk1 signaling and markedly increased ataxia-telangiectasia-mutated (ATM) phosphorylation, a biomarker of DNA damage, and synergistically increases treatment efficacy. Combination treatment with the AR signaling inhibitor enzalutamide (ENZ) and the Chk1/2 inhibitor AZD7762 demonstrates synergy with regard to inhibition of AR-CDC6-ATR-Chk1 signaling, ATM phosphorylation induction, and apoptosis in VCaP (mutant p53) and LNCaP-C4-2b (wild-type p53) cells. CDC6 overexpression significantly reduced ENZ- and AZD7762-induced apoptosis. Additive or synergistic therapeutic activities are demonstrated in AR-positive animal xenograft models. These findings have important clinical implications, since they introduce a therapeutic strategy for AR-positive, metastatic, castration-resistant PCa, regardless of p53 status, through targeting AR-CDC6-ATR-Chk1 signaling.

Yanrong Cai,1 Lieping Guo,2 Hongxing Shen,2 Xiaofei An,2 Hong Jiang,3 Fang Ji,2 Yunfei Niu21The College of Basic Science of Medicine, Hunan University of Traditional Chinese Medicine, Changsha, 2Department of Orthopaedics, Changhai Hospital, Second Military Medical University, 3School of Materials Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of ChinaAbstract: Biocomposite scaffolds of lithium (Li)-containing mesoporous bioglass and monomethoxy poly(ethylene glycol)-poly(D,L-lactide-co-glycolide)-poly(L-lysine) (mPEG-PLGA-b-PLL) copolymer were fabricated in this study. The results showed that the water absorption and degradability of Li-containing mesoporous bioglass/mPEG-PLGA-b-PLL composite (l-MBPC) scaffolds were obviously higher than Li-containing bioglass/mPEG-PLGA-b-PLL composite (l-BPC) scaffolds. Moreover, the apatite-formation ability of l-MBPC scaffolds was markedly enhanced as compared with l-BPC scaffolds, indicating that l-MBPC scaffolds containing mesoporous bioglass exhibited good bioactivity. The cell experimental results showed that cell attachment, proliferation, and alkaline phosphatase activity of MC3T3-E1 cells on l-MBPC scaffolds were remarkably improved as compared to l-BPC scaffolds. In animal experiments, the histological elevation results revealed that l-MBPC scaffolds significantly promoted new bone formation, indicating good osteogenesis. l-MBPC scaffolds with improved properties would be an excellent candidate for bone tissue repair.Keywords: MBG, copolymer, degradability, bioactivity, osteogenesis, cell proliferation, bone repair

Background and aimsWe aimed to determine the utility of coronary artery calcium (CAC) for atherosclerotic cardiovascular disease (ASCVD) risk stratification in women with and without early menopause (EM).MethodsTo examine the association between CAC and incident ASCVD, we performed Kaplan-Meier survival analysis and multivariable Cox proportional hazards modeling using data from 2,456 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis (MESA) with or without EM, defined as occurring at 50% of middle-aged postmenopausal women with EM had CAC = 0, similar to those without EM. Among women with CAC = 0, those with EM had a low to borderline 10-year risk of ASCVD, but the 15-year risk was significantly higher for women with EM versus those without EM. When CAC ≥ 1, the incidence of ASCVD was similar for women with and without EM. These findings support the use of CAC to help improve ASCVD risk stratification in women with EM.Condensed abstractThis study investigated the association between coronary artery calcium (CAC) and incident atherosclerotic cardiovascular disease (ASCVD) in postmenopausal women with and without early menopause (EM). We found that >50% of women had CAC = 0 and an associated low-to-borderline 10-year cumulative incidence of ASCVD. However, the risk for ASCVD was significantly higher for women with EM after 15-years follow-up. Additional research is needed to better understand the differences in long-term ASCVD risk between women with and without EM who have CAC = 0.

Treatment of metastatic prostate cancer (PCa) with single agents has shown only modest efficacy. We hypothesized dual inhibition of different pathways in PCa results in improved tumor inhibition. The Src family kinases (SFK) and insulin-like growth factor-1 (IGF-1) signaling axes are aberrantly activated in both primary PCa and bone metastases and regulate distinct and overlapping functions in PCa progression. We examined the antitumor effects of combined inhibition of these pathways.Src andIGF-1 receptor (IGF-1R) inhibition was achieved in vitro by short hairpin (sh)RNA and in vitro and in vivo by small molecule inhibitors (dasatinib and BMS-754807, against SFK and IGF-1R/Insulin Receptor(IR), respectively).In vitro, inhibition of IGF-1 signaling affected cell survival and proliferation. SFK blockade alone had modest effects on proliferation, but significantly enhanced the IGF-1R blockade. These findings correlated with a robust inhibition of IGF-1-induced Akt1 phophorylation by dasatinib, whereas Akt2 phosphorylation was SFK independent and only inhibited by BMS-754807. Thus, complete inhibition of both Akt genes, not seen by either drug alone, is likely a major mechanism for the decreased survival of PCa cells. Furthermore, dasatinib and BMS-754807 inhibited in vivo growth of the primary human xenograft MDA PCa 133, with corresponding inhibition of Akt in tumors. Also, both orthotopic and intratibial tumor growth of PC-3 cells were more potently inhibited by dual SFK and IGF-1R/IR blockade compared to either pathway alone, with a corresponding decrease in bone turnover markers.Dual IGF-1R/IR and SFK inhibition may be a rational therapeutic approach in PCa by blocking both independent and complementary processes critical to tumor growth.

Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like gene signature, with activated canonical and noncanonical Wnt pathways, in tumor-associated macrophages isolated from osteogenic tumors (bone-TAMs) than in TAMs isolated from nonosteogenic tumors (ctrl-TAMs). Mechanistic studies showed that endothelial cells (ECs) that had undergone EC-to-osteoblast (EC-to-OSB) transition, the precursors of tumor-induced OSBs, produced paracrine factors, including Wnts, CXCL14, and lysyl oxidase, which induced M2 polarization and recruited M2-like TAMs to the bone-tumor microenvironment (bone-TME). Bone-TAMs suppressed CD8+ T cells' proliferation and cytolytic activity, and these effects were partially reversed by treating bone-TAMs with Wnt inhibitors. Genetic or pharmacological inhibition of Pca-induced EC-to-OSB transition reduced the levels of M2-like macrophages in osteogenic tumors. Our study demonstrates that Pca-induced EC-to-OSB transition drives immunosuppression in the bone-TME, suggesting that therapies that reduce Pca-induced bone formation may improve immunotherapeutic outcomes for bmCRPC. [ABSTRACT FROM AUTHOR]

Background: As an opportunistic pathogenic fungus, Schizophyllum has been rarely reported to infect humans. By reporting a case of definite diagnosis of Schizophyllum infection, we aim to improve clinicians' understanding of this bacterium. Methods: By reporting a case with cough and sputum as the main manifestations, after empirical anti-infective chest CT suggesting a more progressive inflammatory lesion and a mass-like lesion in the paratracheal area of the main airways, a diagnosis of Schizophyllum infection was finally made by bronchoscopy with the delivery of metagenomic next-generation sequencing (mNGS). Results: The patient was finally diagnosed with rare Schizophyllum infection. After antifungal treatment, the symptoms improved, and the patient was discharged. Conclusions: Although Schizophyllum is a rare fungal infection, it should be taken seriously in patients with diabetes or who are immunocompromised. At the same time, mNGS plays a key role in the detection of rare and emerging pathogens, which is worthy of clinical interest. [ABSTRACT FROM AUTHOR]

Simple Summary: Radium 223 (Ra-223) is a radiopharmaceutical that targets tumor-induced osteoblasts (bone-forming cells). Ra-223 reduces bone pain and prolongs overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. The aim of this study was to examine the effects of Ra-223 on resident osteoblasts and normal bone structure in mouse models. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the reduction lasted for at least 18 weeks. Ra-223 reduced the osteoblasts mainly localized in trabecular bone areas. Ra-223 also reduced bone mineral density and altered bone microstructure in the trabecular area of femurs. Furthermore, Ra-223 treatment also significantly reduced tumor-induced osteoblasts. These studies show that Ra-223 affects the structure of bones that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223. Radium 223 (Ra-223) is an α-emitting bone-homing radiopharmaceutical that targets tumor-induced osteoblasts and is used to reduce bone pain and prolong overall survival in men with bone-metastatic, castrate-resistant prostate cancer. However, increased fracture risk in skeletal sites with no bone metastasis has been observed in patients treated with Ra-223. Both luciferase- or green fluorescence protein (GFP)-labeled osteoblast reporter mice were used to monitor the effect of Ra-223 on resident osteoblasts and normal bone structure. Upon Ra-223 treatment, 70% of resident osteoblasts were reduced within 2 days, and the osteoblast reduction lasted for at least 18 weeks without detectable recovery, as measured by in vivo bioluminescent imaging. In GFP-labeled osteoblast reporter mice, Ra-223 mainly reduced osteoblasts localized in the trabecular bone areas; the osteoblasts in the growth plates were less affected. Micro-computed tomography analyses showed that Ra-223 significantly reduced bone mineral density and bone microstructure in the trabecular area of femurs but not in the cortical bone. Tumor-induced bone was generated by inoculating osteogenic TRAMP-BMP4 prostate cancer cells into the mouse femurs; Ra-223 treatment significantly reduced tumor-induced osteoblasts. Our study shows that Ra-223 affects bone structures that are not involved in bone metastasis. Strategies that improve bone health may reduce fracture risk in patients receiving Ra-223. [ABSTRACT FROM AUTHOR]