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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.
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Neoplasias Ósseas , Células Endoteliais , Macrófagos , Osteoblastos , Microambiente Tumoral , Via de Sinalização Wnt , Masculino , Microambiente Tumoral/imunologia , Humanos , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Animais , Camundongos , Macrófagos/metabolismo , Macrófagos/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/imunologia , Osteoblastos/metabolismo , Osteoblastos/imunologia , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Linhagem Celular Tumoral , Neoplasias da Próstata/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologiaRESUMO
BACKGROUND: Metastatic prostate cancer in bone is difficult to treat as the tumor cells are relatively resistant to hormonal or chemotherapies when compared to primary prostate cancer. Irreversible electroporation (IRE) is a minimally invasive ablation procedure that has potential applications in the management of prostate cancer in bone. However, a common limitation of IRE is tumor recurrence, which arises from incomplete ablation that allows remaining cancer cells to proliferate. In this study, we combined IRE with radium-223 (Ra-223), a bone-seeking radionuclide that emits short track length alpha particles and thus is associated with reduced damage to the bone marrow and evaluated the impact of the combination treatment on bone-forming prostate cancer tumors. METHODS: The antitumor activity of IRE and Ra-223 as single agents and in combination was tested in vitro against three bone morphogenetic protein 4 (BMP4)-expressing prostate cancer cell lines (C4-2B-BMP4, Myc-CaP-BMP4, and TRAMP-C2-BMP4). Similar evaluation was performed in vivo using a bone-forming C4-2B-BMP4 tumor model in nude mice. RESULTS: IRE and Ra-223 as monotherapy inhibited prostate cancer cell proliferation in vitro, and their combination resulted in significant reduction in cell viability compared to monotherapy. In vivo evaluation revealed that IRE with single-dose administration of Ra-233, compared to IRE alone, reduced the rate of tumor recurrence by 40% following initial apparent complete ablation and decreased the rate of proliferation of incompletely ablated tumor as quantified in Ki-67 staining (53.58 ± 16.0% for IRE vs. 20.12 ± 1.63%; for IRE plus Ra-223; p = 0.004). Histological analysis qualitatively showed the enhanced killing of tumor cells adjacent to bone by Ra-223 compared to those treated with IRE alone. CONCLUSION: IRE in combination with Ra-223, which enhanced the destruction of cancer cells that are adjacent to bone, resulted in reduction of tumor recurrence through improved clearance of proliferative cells in the tumor region.
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Neoplasias da Próstata , Rádio (Elemento) , Animais , Eletroporação , Humanos , Masculino , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia , Neoplasias da Próstata/radioterapia , Rádio (Elemento)/uso terapêuticoRESUMO
In the context of industry 4.0, building data clouds in manufacturing technologies is the fundamental step to approach intelligent automatic process. This new technology has proved to efficiently and effectively monitor five important responses (removal rate, texture, surface accuracy, edge-profiles and mid-spatial frequencies) with more than 95% repeatability in real time. This faster and inexpensive process can serve for the nowadays high-quality segmented telescopes. We illustrate the underlying problem by reference to a case-study - the challenge of an average manufacturing rate of 11.4 segments per month for the 39.3m optical/infrared European Extremely Large Telescope (E-ELT) project.
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Mid-spatial frequency (MSF) errors challenge freeform manufacture, not in the least due to tool-misfit. This can compromise the performance of functional surfaces and is difficult to remove by post-processing. Our previously reported work on an effective process-chain for aluminum polishing demonstrated the ability to remove MSFs by hard-tool grolishing. In this paper, we describe MSF removal on an aluminum mirror, deformed to a saddle-like freeform shape, using power spectral density (PSD) as a diagnostic. CNC Precessions bonnet polishing was optimized to minimize output MSFs, then a non-Newtonian (n-N) tool was used to attenuate the residual MSFs that were present. Our approach was distinct from the approach pioneered by University of Arizona, in that we adopted small-tool polishing on the saddle-like part, with removal rate restored by rotating the n-N tool. In order to define the optimum window of rotation speeds, the dynamic behavior of the n-N material was explored by modelling and experiments. The tool was deployed on an industrial robot, and we describe a novel 'hyper-crossing' tool-path with wide sweeping paths, which is the logical opposite of the unicursal zero-crossing paths we have previously reported. This new path has proved ideally suited to robots, given their high velocity/acceleration capabilities. Detailed results are presented from the PSD viewpoint.
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Development of major optical projects demands great amounts of freeform optics, which requires mass-production technology. The atmospheric pressure plasma processing (APPP) based on chemical etching shows the advantage of high efficiency in form generation. However, the surface texture gets deteriorated with roughness to 60 nm Ra. Bonnet polishing can achieve ultra-smooth surface texture using flexible inflated tool. In this study, a combined processing chain consisting of APPP and bonnet polishing was proposed, in which APPP plays a role in form generation and bonnet polishing plays a role in rapid surface smoothing. Firstly, the form generation using APPP and the surface finishing using bonnet polishing were analyzed. Then the form-preserving ability of bonnet polishing under various conditions, including polishing parameters and surface form characteristics, was investigated experimentally. Consequently, the influence of bonnet polishing on surface form change was analyzed. Two sinusoidal freeform surfaces with 5 mm and 16 mm spatial period were generated using APPP and then smoothed using bonnet polishing. The experimental results show that the polishing induced form change is smaller than 20 nm PV with roughness improved to 2 nm Ra, which verifies the feasibility of the combined processing chain.
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Osteoblasts communicate both with normal cells in the bone marrow and with tumor cells that metastasized to bone. Here we show that osteoblasts release exosomes, we termed osteosomes, which may be a novel mechanism by which osteoblasts communicate with cells in their environment. We have isolated exosomes from undifferentiated/proliferating (D0 osteosomes) and differentiated/mineralizing (D24 osteosomes) primary mouse calvarial osteoblasts. The D0 and D24 osteosomes were found to be vesicles of 130-140 nm by dynamic light scattering analysis. Proteomics profiling using tandem mass spectrometry (LC-MS/MS) identified 206 proteins in D0 osteosomes and 336 in D24 osteosomes. The proteins in osteosomes are mainly derived from the cytoplasm (â¼47%) and plasma membrane (â¼31%). About 69% of proteins in osteosomes are also found in Vesiclepedia, and these canonical exosomal proteins include tetraspanins and Rab family proteins. We found that there are differences in both protein content and levels in exosomes isolated from undifferentiated and differentiated osteoblasts. Among the proteins that are unique to osteosomes, 169 proteins are present in both D0 and D24 osteosomes, 37 are unique to D0, and 167 are unique to D24. Among those 169 proteins present in both D0 and D24 osteosomes, 10 proteins are likely present at higher levels in D24 than D0 osteosomes based on emPAI ratios of >5. These results suggest that osteosomes released from different cellular state of osteoblasts may mediate distinct functions. Using live-cell imaging, we measured the uptake of PKH26-labeled osteosomes into C4-2B4 and PC3-mm2 prostate cancer cells. In addition, we showed that cadherin-11, a cell adhesion molecule, plays a role in the uptake of osteosomes into PC3-mm2 cells as osteosome uptake was delayed by neutralizing antibody against cadherin-11. Together, our studies suggest that osteosomes could have a unique role in the bone microenvironment under both physiological and pathological conditions.
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Calcificação Fisiológica , Proliferação de Células , Exossomos/química , Osteoblastos/patologia , Neoplasias da Próstata/patologia , Proteínas/análise , Animais , Caderinas/fisiologia , Comunicação Celular , Diferenciação Celular , Células Cultivadas , Microambiente Celular/fisiologia , Exossomos/patologia , Humanos , Masculino , Camundongos , Osteoblastos/metabolismo , Neoplasias da Próstata/metabolismo , Proteômica/métodosRESUMO
Loss of E-cadherin and up-regulation of mesenchymal cadherins, a hallmark of the epithelial-mesenchymal transition, contributes to migration and dissemination of cancer cells. Expression of human cadherin-11 (Cad11), also known as osteoblast cadherin, in prostate cancer increases the migration of prostate cancer cells. How Cad11 mediates cell migration is unknown. Using the human Cad11 cytoplasmic domain in pulldown assays, we identified human angiomotin (Amot), known to be involved in cell polarity, migration, and Hippo pathway, as a component of the Cad11 protein complex. Deletion analysis showed that the last C-terminal 10 amino acids in Cad11 cytoplasmic domain are required for Amot binding. Further, Cad11 preferentially interacts with Amot-p80 than Amot-p130 isoform and binds directly to the middle domain of Amot-p80. Cad11-Amot interaction affects Cad11-mediated cell migration, but not homophilic adhesion, as deletion of Amot binding motif of Cad11 (Cad11-ΔAmot) did not abolish Cad11-mediated cell-cell adhesion of mouse L cells, but significantly reduced Cad11-mediated cell migration of human C4-2B4 and PC3-mm2 prostate cancer cells and human HEK293T cells. Together, our studies identified Amot-p80 as a novel component of the Cad11 complex and demonstrated that Amot-p80 is critical for Cad11-mediated cell migration.
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Caderinas/metabolismo , Movimento Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias da Próstata/patologia , beta Catenina/metabolismo , Proteína p120 Ativadora de GTPase/metabolismo , Sequência de Aminoácidos , Angiomotinas , Animais , Western Blotting , Caderinas/genética , Adesão Celular , Proliferação de Células , Células Cultivadas , Imunofluorescência , Células HEK293 , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Proteínas dos Microfilamentos , Dados de Sequência Molecular , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Isoformas de Proteínas , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , beta Catenina/genética , Proteína p120 Ativadora de GTPase/genéticaRESUMO
OBJECTIVE: Lumbar degenerative diseases (LDDs) with huge herniation in the left lateral recess or central canal present challenges for oblique lateral lumbar interbody fusion (OLIF) or endoscope-assisted OLIF procedures. Currently, minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is the primary approach for this issue. This study aims to provide a standardized technical description of the anterior lumbar discectomy and fusion (ALDF) and evaluate the medium-term clinical effectiveness of both ALDF and MIS-TLIF techniques. METHODS: A retrospective review was performed on LDDs who underwent ALDF and MIS-TLIF surgery from January 2018 to January 2020. The evaluation encompassed various clinical outcomes, such as the visual analogue scale (VAS) scores for back pain and leg pain (VAS-back, VAS-leg), the Oswestry disability index (ODI), the 36-item short-form health survey mental component summary (SF-36 MCS), and the physical component summary (SF-36 PCS). Additionally, radiological parameters, including disc height (DH), segmental disk angle (SDA), lumbar lordosis (LL), and cross-sectional area (CSA), were assessed. Data including radiculopathy, estimated blood loss, operation time, time of getting out of bed, fusion rate, and complications were recorded. Student's independent samples t test and Pearson's chi-square test were used to compare the differences between groups. RESULTS: In total, 47 patients were treated by ALDF and 48 patients were treated by MIS-TLIF. The ALDF group exhibited statistically significant lower estimated blood loss and earlier time of getting out of bed compared to the MIS-TLIF group (p < 0.05). The ALDF group demonstrated lower VAS-back scores and a higher remission rate of low back pain 3 years after the surgery (p < 0.05). During the entire follow-up period, the ALDF group exhibited higher increases in DH and SDA compared to the MIS-TLIF group (p < 0.05). At 6 months, the fusion rate in the ALDF group was significantly higher than in the MIS-TLIF group (p < 0.05). The comparison revealed no statistically significant differences in complication rates between the two groups (p > 0.05). CONCLUSION: The ALDF could be considered as a viable surgical alternative for the treatment of LDDs that necessitate ventral neural direct decompression. ALDF exhibited favorable medium-term outcomes in patients with LDDs, displaying advantages in facilitating expedited recovery, enhancing radiographic outcomes, and elevating the remission rate of low back pain. Although ALDF presents slightly higher complication rates compared to MIS-TLIF, it does not adversely affect clinical outcomes.
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Vértebras Lombares , Procedimentos Cirúrgicos Minimamente Invasivos , Fusão Vertebral , Humanos , Fusão Vertebral/métodos , Estudos Retrospectivos , Vértebras Lombares/cirurgia , Pessoa de Meia-Idade , Feminino , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Discotomia/métodos , Idoso , Adulto , Medição da Dor , Avaliação da Deficiência , Degeneração do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/cirurgiaRESUMO
OBJECTIVE: Although the direct anterior approach can reduce muscle damage and ensure accurate prosthesis placement, the steep learning curve and increased risk of complications associated with DAA necessitate careful consideration. Therefore, we describe a technique for a novel percutaneously endoscopic-assisted total hip arthroplasty through mini bikini direct anterior approach (mDAA) and report the learning curve and initial outcomes. METHODS: The first 125 THA performed by a single surgeon between September 2020 and February 2022 using the anterior approach were included, comprising the initial 41 cases of bikini DAA (bDAA) and the subsequent 84 cases of mDAA. Outcome measures included perioperative outcomes and postoperative complications. The cumulative sum analysis (CUSUM) was used to determine the learning curve of anterior approach THA for each patient's ORT. Multivariable analysis was performed to determine risk correlation. RESULTS: A total of 125 anterior approach THA completed between 2020 and 2022 were identified. Among these, 41 were performed via bDAA and 84 via mDAA. No statistically significant differences were observed between the groups in terms of age, gender distribution, BMI or follow-up time. A significant reduction in ORT was noted, from 140 min for bDAA to 130 min for mDAA. Furthermore, there was a consistent decrease in LOI, LOS, and wound-healing problems. There was no statistically significant difference between groups with respect to Harris Hip Scores and other postoperative complications. The curve inflection points of the learning curve for the bDAA and mDAA group were located in the 22nd and 68th cases, respectively. The reduction of hemoglobin indicated a predicted increase in ORT. CONCLUSIONS: In this study, ORT, LOI, LOS, and wound-healing problems decreased overall in mDAA group. After mastering the bDAA technique, approximately 27 mDAA cases are needed to acquire proficiency in this technique. Hence, mDAA is a valuable alternative for those seeking smaller incisions, resolving wound healing problems, and aiming for enhanced recovery after surgery.
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Artroplastia de Quadril , Endoscopia , Curva de Aprendizado , Complicações Pós-Operatórias , Humanos , Artroplastia de Quadril/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Endoscopia/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Estudos de Coortes , Duração da Cirurgia , Idoso de 80 Anos ou mais , AdultoRESUMO
To overcome the high-risk complications and poor alignment of acetabular components in obese patients associated with direct anterior approach (DAA) for total hip arthroplasty (THA), we innovated an endoscopic arthroplasty via mini-open direct anterior approach technique (Endo-DAA). The purpose of this study was to compare the clinical and radiographic outcomes in obese patients subjected to THA between Endo-DAA, Bikini DAA, and conventional DAA. In this retrospective controlled study, a total of 360 consecutive primary THA on obese patients (body mass index greater than 28 kg/m2) via Endo-DAA, Bikini DAA, and conventional DAA performed from October 2017 to October 2022 by different surgeons and in a single center were included. Assessments including perioperative parameters, clinical outcomes, complications, and radiologic measurements were retrieved from patients before the surgery, perioperative period and the latest follow-up. A total of 360 consecutive THA (Endo-DAA = 108, Bikini DAA = 116, Conventional DAA = 136) with complete follow-up data were analyzed. Compared to Bikini DAA or conventional DAA, Endo-DAA significantly shortened the length of incision (5.46 ± 0.53), the duration of operation (64.47 ± 12.38), and postoperative hospital stay (2.15 ± 0.89). Endo-DAA significantly reduces wound related complications compared with conventional DAA. Besides, Endo-DAA achieved a significantly better alignment of acetabular components compared to Bikini DAA or conventional DAA. Furthermore, Endo-DAA improved postoperative pain at the activity at 24 h postoperatively and early functional scores. The Endo-DAA THA technique provides better short-term clinical and radiographic results in obese patients with a low rate of postoperative complications compared to Bikini DAA or conventional DAA.
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Artroplastia de Quadril , Humanos , Artroplastia de Quadril/métodos , Estudos Retrospectivos , Resultado do Tratamento , Obesidade/complicações , Obesidade/cirurgia , Complicações Pós-Operatórias/etiologiaRESUMO
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.
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Edge mis-figure is regarded as one of the most difficult technical issues for manufacturing the segments of extremely large telescopes, which can dominate key aspects of performance. A novel edge-control technique has been developed, based on 'Precessions' polishing technique and for which accurate and stable edge tool influence functions (TIFs) are crucial. In the first paper in this series [D. Walker Opt. Express 20, 19787-19798 (2012)], multiple parameters were experimentally optimized using an extended set of experiments. The first purpose of this new work is to 'short circuit' this procedure through modeling. This also gives the prospect of optimizing local (as distinct from global) polishing for edge mis-figure, now under separate development. This paper presents a model that can predict edge TIFs based on surface-speed profiles and pressure distributions over the polishing spot at the edge of the part, the latter calculated by finite element analysis and verified by direct force measurement. This paper also presents a hybrid-measurement method for edge TIFs to verify the simulation results. Experimental and simulation results show good agreement.
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We present a simulation technique to predict tool influence functions (TIFs) based on the Precessions polishing process, which is driven by addressing mass fabrication of the European Extremely Large Telescope mirror segments. Precessions polishing requires accurate and predictable TIFs to optimize the multiple process parameters, particularly when sequential polishing runs are performed by different polishing tools. In this paper, the static and dynamic TIFs are simulated based on the Preston equation. The velocity distribution is calculated according to the geometry of the precession motion. The pressure distribution at the polishing spot is calculated by means of finite element analysis (FEA). The FEA result is validated by direct force measurement with a simulation error of 4.3%. The simulation results of TIFs are verified by an experiment that shows the residual errors are less than 5% for both static and dynamic TIFs.
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OBJECTIVE: Osteoporosis is a progressive systemic skeletal disorder. Multiple profiling studies have contributed to characterizing biomarkers and therapeutic targets for osteoporosis. However, due to the limitation of the platform of miRNA sequencing, only a part of miRNA can be sequenced based on one platform. MATERIALS AND METHODS: In this study, we performed miRNA sequencing in osteoporosis bone samples based on a novel platform Illumina Hiseq 2500. Bioinformatics analysis was performed to construct osteoporosis-related competing endogenous RNA (ceRNA) networks. Gene interference and osteogenic induction were used to examine the effect of identified ceRNA networks on osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (HBMSCs). RESULTS: miR-1303 was lowly expressed, while cochlin (COCH) and KCNMA1-AS1 were highly expressed in the osteoporosis subjects. COCH knockdown improved the osteogenic differentiation of HBMSCs. Meanwhile, COCH inhibition compensated for the suppression of osteogenic differentiation of HBMSCs by miR-1303 knockdown. Further, KCNMA1-AS1 knockdown promoted osteogenic differentiation of HBMSCs through downregulating COCH by sponging miR-1303. CONCLUSIONS: Our findings suggest that the KCNMA1-AS1/miR-1303/COCH axis is a promising biomarker and therapeutic target for osteoporosis.
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Proteínas da Matriz Extracelular , MicroRNAs , Osteoporose , Humanos , Diferenciação Celular/genética , Células Cultivadas , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta , MicroRNAs/genética , Osteogênese/genética , Osteoporose/genética , Proteínas da Matriz Extracelular/genética , RNA Antissenso/genéticaRESUMO
Background: Previous studies have not provided a consensus on the effect of serum 25-hydroxyvitamin D [25(OH)D] on osteoarthritis (OA). We aimed to evaluate the association using a large, nationally representative sample. Methods: The cross-sectional data were obtained from the 2001 to 2018 National Health and Nutrition Examination Survey (NHANES). Individuals aged ≥40 years who had information of serum 25(OH)D, self-report OA, and related covariates were included. Multivariable logistic regression analysis was employed to assess the association between serum 25(OH)D and osteoarthritis. Results: Among the 21,334 participants included (weighted mean age, 56.9 years; 48.5% men), the proportion of participants with high serum 25(OH)D concentrations (≥100 nmol/L) increased significantly from 4.2% in 2001-2006 to 18.8% in 2013-2018. Higher serum 25(OH)D levels were associated with more osteoarthritis prevalence in fully adjusted model (odd ratio [OR] 1.25 [95% CI: 1.10, 1.43] for the 50-75 nmol/L group; OR 1.62 [95% CI: 1.42, 1.85] for the 75-100 nmol/L group; OR 1.91 [95% CI: 1.59, 2.30] for the ≥100 nmol/L group; with <50 nmol/L group as the reference) (p < 0.001 for trend). The association was consistent across several sensitivity analyses, including propensity score methods and excluding participants who had received vitamin D supplement. In subgroup analysis, the OR for the association increased significantly with body mass index (BMI) (BMI < 25 kg/m2, 1.01 [95% CI: 1.04, 1.08]; BMI 25-30 kg/m2, 1.05 [95% CI: 1.01, 1.08]; BMI ≥ 30 kg/m2, 1.10 [95% CI: 1.06, 1.13]; p = 0.004 for interaction). Conclusion: There was a positive correlation between serum 25(OH)D and osteoarthritis with a possible modification by BMI. Our finding raises concerns about the potential adverse effects of high serum 25(OH)D on osteoarthritis, particularly among obese individuals. More well-designed studies are still needed to validate our findings in future.
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BACKGROUNDS: Ovarian cancer (OC) is the second most common gynecological tumor with the highest mortality rate worldwide. High FAM111B expression has been reported as a predictor of poor prognosis in other cancers, but its correlation with OC has not been reported. METHODS: Immunohistochemistry of tissue microarrays was performed to detect FAM111B expression levels in 141 OC patient tissues. The prognostic value of FAM111B was determined by Kaplan-Meier survival analysis, and correlations between FAM111B expression and clinicopathologic features were investigated by the Clu-square test. The significance of FAM111B expression was verified bioinformatically using the Gene Expression Omnibus database. Protein-protein interaction were performed to explore downstream mechanisms of FAM111B in OC. RESULTS: Among 141 OC patients, FAM111B was positively expressed in 87.23%, 58.16%, and 87.94%; and highly expressed in 8.51%, 17.02%, and 19.86%, as evaluated by cytoplasmic, nuclear, and combined cytoplasmic/nuclear staining. FAM111B expression was positively correlated with the expression of tumor protein markers KI67, EGFR, and PDL-1. Patients with high FAM111B expression had aggressive clinicopathologic features and shorter overall survival (P value 0.0428, 0.0050, 0.0029) and progression-free survival (P value 0.0251, 0.012, 0.0596) compared to the low FAM111B expression group for cytoplasmic, nuclear, and combined cytoplasmic/nuclear groups, respectively. These results were verified using patient data from the Gene Expression Omnibus. Seventeen genes co-expressed with FAM111B were primarily involved in "negative regulation of histone modification", "hippo signaling" and "inner ear receptor cell differentiation". CONCLUSIONS: High FAM111B expression may serve as a novel prognostic predictor and molecular therapeutic target for OC.
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OBJECTIVE: This prospective trial aimed to evaluate the effects of low-dose intravenous norepinephrine (NE) on intraoperative blood loss and bleeding from osteotomy sites during non-tourniquet total knee arthroplasty (TKA) under general anesthesia. METHODS: A total of 120 patients who underwent TKA between December 2020 and May 2022 were enrolled and randomly assigned to the intravenous low-dose NE Group (NE Group) or the control group (C Group). During surgery, NE Group received 0.05-0.1 µg/(kg min) of NE intravenously to raise and maintain the patient's mean arterial pressure (MAP). C Group received the same dose of saline as placebo. Intraoperative blood loss, bleeding score at osteotomy sites, Δlactate levels (Lac), postoperative complications, and transfusion rate during hospitalization were compared between groups. RESULTS: Intraoperative and osteotomy blood loss was significantly lower in the NE Group than in the C Group (P < 0.001). No significant difference was observed in ΔLac between groups (P > 0.05). There was no significant difference in complications between the groups 3 days after surgery (P > 0.05). In addition, there was no significant difference in blood transfusion rates between the two groups during hospitalization (P > 0.05). CONCLUSION: In non-tourniquet TKA under general anesthesia, low-dose intravenous NE safely and effectively reduced intraoperative blood loss and provided a satisfactory osteotomy site while maintaining a higher MAP.
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Antifibrinolíticos , Artroplastia do Joelho , Ácido Tranexâmico , Humanos , Artroplastia do Joelho/efeitos adversos , Perda Sanguínea Cirúrgica/prevenção & controle , Norepinefrina , Estudos Prospectivos , Anestesia Geral , TorniquetesRESUMO
Alkali metal halides have long been used as scintillators for applications as sensors and detectors. Usually, a small amount of impurities are added to these inorganic materials to improve their luminescence efficiencies. We investigate the structures and luminescent properties of un-doped sodium iodide (NaI) and cesium-doped NaI (NaI:Cs) films deposited by thermal vacuum evaporation. Instead of using the toxic element thallium (Tl), we introduced cesium dopant into NaI. This is the first study for the NaI:Cs film excited by UV LED's ultraviolet C (273 nm, 4.54 eV). The luminescence spectra show two main peaks at 3.05 and 4.32/3.955 eV (for fused silica/B270 substrate), originating from the intrinsic defects and/or activator excited states and the intrinsic self-trapped excitons (STEs), respectively. In general, both Cs-doping and post-annealing processes enhance the luminescence performance of NaI films.
RESUMO
Bone is the primary metastasis site for lethal prostate cancer, often resulting in poor prognosis, crippling pain, and diminished functioning that drastically reduce both quality of life and survivability Uniquely, prostate cancer bone metastasis induces aberrant bone overgrowth, due to an increase of osteoblasts induced by tumor-secreted bone morphogenetic protein 4 (BMP4). Conjugating drugs to substances that target the tumor-induced bone area within the metastatic tumor foci would be a promising strategy for drug delivery. To develop such a strategy, we conjugated a near infrared (NIR) fluorescent probe, the dye Cy5.5, to serve as a surrogate for drugs, with alendronate, which targets bone. Characterization, such as infrared spectroscopy, confirmed the synthesis of the Cy5.5-ALN conjugate. The maximum absorbance of free Cy5.5, which was at 675 nm, did not change upon conjugation. Alendronate targeted the bone component hydroxyapatite in a dose-dependent manner up to 2.5 µM, with a maximum of 85% of Cy5.5-ALN bound to hydroxyapatite, while free Cy5.5 alone had 6% binding. In in vitro cell binding studies, Cy5.5-ALN bound specifically with mineralized bone matrix of differentiated MC3T3-E1 cells or 2H11 endothelial cells that were induced to become osteoblasts through endothelial-to-osteoblast transition, the underlying mechanism of prostate-cancer-induced bone formation. Neither Cy5.5-ALN nor free Cy5.5 bound to undifferentiated MC3T3-E1 or 2H11 cells. Bone-targeting efficiency studies in non-tumor-bearing mice revealed accumulation over time in the spine, jaw, knees, and paws injected with Cy5.5-ALN, and quantification showed higher accumulation in femurs than in muscle at up to 28 days, while the free Cy5.5 dye was observed circulating without preferential accumulation and decreased over time. There was a linear relationship with fluorescence when the injected concentration of Cy5.5-ALN was between 0.313 and 1.25 nmol/27 g of mouse, as quantified in mouse femurs both in vivo and ex vivo. Ex vivo evaluation of bone-targeting efficiency in nude mice was 3 times higher for bone-forming C4-2b-BMP4 tumors compared to non-bone-forming C4-2b tumors (p-value <0.001). Fluorescence microscopy imaging of the tumors showed that Cy5.5-ALN co-localized with the bone matrix surrounding tumor-induced bone, but not with the viable tumor cells. Together, these results suggest that a drug-ALN conjugate is a promising approach for targeted delivery of drug to the tumor-induced bone area in the metastatic foci of prostate cancer.
Assuntos
Neoplasias Ósseas , Neoplasias da Próstata , Humanos , Masculino , Camundongos , Animais , Alendronato/farmacologia , Alendronato/química , Linhagem Celular Tumoral , Camundongos Nus , Células Endoteliais , Qualidade de Vida , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , HidroxiapatitasRESUMO
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.