Hypoxia preconditioning of adipose stem cell-derived exosomes loaded in gelatin methacryloyl (GelMA) promote type H angiogenesis and osteoporotic fracture repair.

The challenges posed by delayed atrophic healing and nonunion stand as formidable obstacles in osteoporotic fracture treatment. The processes of type H angiogenesis and osteogenesis emerge as pivotal mechanisms during bone regeneration. Notably, the preconditioning of adipose-derived stem cell (ADSC) exosomes under hypoxic conditions has garnered attention for its potential to augment the secretion and functionality of these exosomes. In the present investigation, we embarked upon a comprehensive elucidation of the underlying mechanisms of hypo-ADSC-Exos within the milieu of osteoporotic bone regeneration. Our findings revealed that hypo-ADSC-Exos harboured a preeminent miRNA, namely, miR-21-5p, which emerged as the principal orchestrator of angiogenic effects. Through in vitro experiments, we demonstrated the capacity of hypo-ADSC-Exos to stimulate the proliferation, migration, and angiogenic potential of human umbilical vein endothelial cells (HUVECs) via the mediation of miR-21-5p. The inhibition of miR-21-5p effectively attenuated the proangiogenic effects mediated by hypo-ADSC-Exos. Mechanistically, our investigation revealed that exosomal miR-21-5p emanating from hypo-ADSCs exerts its regulatory influence by targeting sprouly1 (SPRY1) within HUVECs, thereby facilitating the activation of the PI3K/AKT signalling pathway. Notably, knockdown of SPRY1 in HUVECs was found to potentiate PI3K/AKT activation and, concomitantly, HUVEC proliferation, migration, and angiogenesis. The culminating stage of our study involved a compelling in vivo demonstration wherein GelMA loaded with hypo-ADSC-Exos was validated to substantially enhance local type H angiogenesis and concomitant bone regeneration. This enhancement was unequivocally attributed to the exosomal modulation of SPRY1. In summary, our investigation offers a pioneering perspective on the potential utility of hypo-ADSC-Exos as readily available for osteoporotic fracture treatment.

The impact of temperature, humidity and closing school on the mumps epidemic: a case study in the mainland of China.

BACKGROUND: To control resurging infectious diseases like mumps, it is necessary to resort to effective control and preventive measures. These measures include increasing vaccine coverage, providing the community with advice on how to reduce exposure, and closing schools. To justify such intervention, it is important to understand how well each of these measures helps to limit transmission. METHODS: In this paper, we propose a simple SEILR (susceptible-exposed-symptomatically infectious-asymptomatically infectious-recovered) model by using a novel transmission rate function to incorporate temperature, humidity, and closing school factors. This new transmission rate function allows us to verify the impact of each factor either separately or combined. Using reported mumps cases from 2004 to 2018 in the mainland of China, we perform data fitting and parameter estimation to evaluate the basic reproduction number  R 0 . As a wide range of one-dose measles, mumps, and rubella (MMR) vaccine programs in China started only in 2008, we use different vaccination proportions for the first Stage I period (from 2004 to 2008) and the second Stage II period (from 2009 to 2018). This allows us to verify the importance of higher vaccine coverage with a possible second dose of MMR vaccine. RESULTS: We find that the basic reproduction number  R 0  is generally between 1 and 3. We then use the Akaike Information Criteria to assess the extent to which each of the three factors contributed to the spread of mumps. The findings suggest that the impact of all three factors is substantial, with temperature having the most significant impact, followed by school opening and closing, and finally humidity. CONCLUSION: We conclude that the strategy of increasing vaccine coverage, changing micro-climate (temperature and humidity), and closing schools can greatly reduce mumps transmission.

RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss.

Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation and bone remodeling. Nevertheless, the cellular source of RANKL for osteoclastogenesis has not been fully uncovered. Different from peripheral adipose tissue, bone marrow (BM) adipose lineage cells originate from bone marrow mesenchymal stromal cells (BMSCs). Here, we demonstrate that adiponectin promoter-driven Cre expression (AdipoqCre ) can target bone marrow adipose lineage cells. We cross the AdipoqCre mice with ranklfl/fl mice to conditionally delete RANKL from BM adipose lineage cells. Conditional deletion of RANKL increases cancellous bone mass of long bones in mice by reducing the formation of trabecular osteoclasts and inhibiting bone resorption but does not affect cortical bone thickness or resorption of calcified cartilage. AdipoqCre ; ranklfl/fl mice exhibit resistance to estrogen deficiency and rosiglitazone (ROS)-induced trabecular bone loss but show bone loss induced by unloading. BM adipose lineage cells therefore represent an essential source of RANKL for the formation of trabecula osteoclasts and resorption of cancellous bone during remodeling under physiological and pathological conditions. Targeting bone marrow adiposity is a promising way of preventing pathological bone loss.

Development and validation of a predictive model for adverse left ventricular remodeling in NSTEMI patients after primary percutaneous coronary intervention.

INTRODUCTION: To develop and validate clinical evaluators that predict adverse left ventricular remodeling (ALVR) in non-ST-elevation myocardial infarction (NSTEMI) patients after primary percutaneous coronary intervention (PCI). METHODS: The retrospective study analyzed the clinical data of 507 NSTEMI patients who were treated with primary PCI from the Affiliated Hospital of Xuzhou Medical University and the Second Affiliated Hospital of Xuzhou Medical University, between January 1, 2019 and September 31, 2021. The training cohort consisted of patients admitted before June 2020 (n = 287), and the remaining patients (n = 220) were assigned to an external validation cohort. The endpoint event was the occurrence of ALVR, which was described as an increase ≥ 20% in left ventricular end-diastolic volume (LVEDV) at 3-4 months follow-up CMR compared with baseline measurements. The occurrence probability of ALVR stemmed from the final model, which embodied independent predictors recommended by logistic regression analysis. The area under the receiver operating characteristic curve (AUC), Calibration plot, Hosmer-Lemeshow method, and decision curve analysis (DCA) were applied to quantify the performance. RESULTS: Independent predictors for ALVR included age (odds ratio (OR): 1.040; 95% confidence interval (CI): 1.009-1.073), the level of neutrophil to lymphocyte ratio (OR: 4.492; 95% CI: 1.906-10.582), the cardiac microvascular obstruction (OR: 3.416; 95% CI: 1.170-9.970), peak global longitudinal strain (OR: 1.131; 95% CI: 1.026-1.246), infarct size (OR: 1.082; 95% CI: 1.042-1.125) and left ventricular ejection fraction (OR: 0.925; 95% CI: 0.872-0.980), which were screened by regression analysis then merged into the nomogram model. Both internal validation (AUC: 0.805) and external validation (AUC: 0.867) revealed that the prediction model was capable of good discrimination. Calibration plot and Hosmer-Lemeshow method showed high consistency between the probabilities predicted by the nomogram (P = 0.514) and the validation set (P = 0.762) and the probabilities of actual occurrence. DCA corroborated the clinical utility of the nomogram. CONCLUSIONS: In this study, the proposed nomogram model enabled individualized prediction of ALVR in NSTEMI patients after reperfusion and conduced to guide clinical therapeutic schedules.

Diterbutyl phthalate attenuates osteoarthritis in ACLT mice via suppressing ERK/c-fos/NFATc1 pathway, and subsequently inhibiting subchondral osteoclast fusion.

Osteoarthritis (OA) is the most common arthritis with a rapidly increasing prevalence. Disease progression is irreversible, and there is no curative therapy available. During OA onset, abnormal mechanical loading leads to excessive osteoclastogenesis and bone resorption in subchondral bone, causing a rapid subchondral bone turnover, cyst formation, sclerosis, and finally, articular cartilage degeneration. Moreover, osteoclast-mediated angiogenesis and sensory innervation in subchondral bone result in abnormal vascularization and OA pain. The traditional Chinese medicine Panax notoginseng (PN; Sanqi) has long been used in treatment of bone diseases including osteoporosis, bone fracture, and OA. In this study we established two-dimensional/bone marrow mononuclear cell/cell membrane chromatography/time of flight mass spectrometry (2D/BMMC/CMC/TOFMS) technique and discovered that diterbutyl phthalate (DP) was the active constituent in PN inhibiting osteoclastogenesis. Then we explored the therapeutic effect of DP in an OA mouse model with anterior cruciate ligament transaction (ACLT). After ACLT was conducted, the mice received DP (5 mg·kg-1·d-1, ip) for 8 weeks. Whole knee joint tissues of the right limb were harvested at weeks 2, 4, and 8 for analysis. We showed that DP administration impeded overactivated osteoclastogenesis in subchondral bone and ameliorated articular cartilage deterioration. DP administration blunted aberrant H-type vessel formation in subchondral bone marrow and alleviated OA pain assessed in Von Frey test and thermal plantar test. In RANKL-induced RAW264.7 cells in vitro, DP (20 µM) retarded osteoclastogenesis by suppressing osteoclast fusion through inhibition of the ERK/c-fos/NFATc1 pathway. DP treatment also downregulated the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and d2 isoform of the vacuolar (H+) ATPase V0 domain (Atp6v0d2) in the cells. In conclusion, we demonstrate that DP prevents OA progression by inhibiting abnormal osteoclastogenesis and associated angiogenesis and neurogenesis in subchondral bone.

CT-based radiomics to predict development of macrovascular invasion in hepatocellular carcinoma: A multicenter study.

BACKGROUND: Macrovascular invasion (MaVI) occurs in nearly half of hepatocellular carcinoma (HCC) patients at diagnosis or during follow-up, which causes severe disease deterioration, and limits the possibility of surgical approaches. This study aimed to investigate whether computed tomography (CT)-based radiomics analysis could help predict development of MaVI in HCC. METHODS: A cohort of 226 patients diagnosed with HCC was enrolled from 5 hospitals with complete MaVI and prognosis follow-ups. CT-based radiomics signature was built via multi-strategy machine learning methods. Afterwards, MaVI-related clinical factors and radiomics signature were integrated to construct the final prediction model (CRIM, clinical-radiomics integrated model) via random forest modeling. Cox-regression analysis was used to select independent risk factors to predict the time of MaVI development. Kaplan-Meier analysis was conducted to stratify patients according to the time of MaVI development, progression-free survival (PFS), and overall survival (OS) based on the selected risk factors. RESULTS: The radiomics signature showed significant improvement for MaVI prediction compared with conventional clinical/radiological predictors (P < 0.001). CRIM could predict MaVI with satisfactory areas under the curve (AUC) of 0.986 and 0.979 in the training (n = 154) and external validation (n = 72) datasets, respectively. CRIM presented with excellent generalization with AUC of 0.956, 1.000, and 1.000 in each external cohort that accepted disparate CT scanning protocol/manufactory. Peel9_fos_InterquartileRange [hazard ratio (HR) = 1.98; P < 0.001] was selected as the independent risk factor. The cox-regression model successfully stratified patients into the high-risk and low-risk groups regarding the time of MaVI development (P < 0.001), PFS (P < 0.001) and OS (P = 0.002). CONCLUSIONS: The CT-based quantitative radiomics analysis could enable high accuracy prediction of subsequent MaVI development in HCC with prognostic implications.

Triptolide prevents bone loss via suppressing osteoclastogenesis through inhibiting PI3K-AKT-NFATc1 pathway.

Bone loss (osteopenia) is a common complication in human solid tumour. In addition, after surgical treatment of gynaecological tumour, osteoporosis often occurs due to the withdrawal of oestrogen. The major characteristic of osteoporosis is the low bone mass with micro-architectural deteriorated bone tissue. And the main cause is the overactivation of osteoclastogenesis, which is one of the most important therapeutic targets. Inflammation could induce the interaction of RANKL/RANK, which is the promoter of osteoclastogenesis. Triptolide is derived from the traditional Chinese herb lei gong teng, presented multiple biological effects, including anti-cancer, anti-inflammation and immunosuppression. We hypothesized that triptolide could inhibits osteoclastogenesis by suppressing inflammation activation. In this study, we confirmed that triptolide could suppress RANKL-induced osteoclastogenesis in bone marrow mononuclear cells (BMMCs) and RAW264.7 cells and inhibited the osteoclast bone resorption functions. PI3K-AKT-NFATc1 pathway is one of the most important downstream pathways of RANKL-induced osteogenesis. The experiments in vitro indicated that triptolide suppresses the activation of PI3K-AKT-NFATc1 pathway and the target point located at the upstream of AKT because both NFATc1 overexpression and AKT phosphorylation could ameliorate the triptolide suppression effects. The expression of MDM2 was elevated, which demonstrated the MDM-p53-induced cell death might contribute to the osteoclastogenesis suppression. Ovariectomy-induced bone loss and inflammation activation were also found to be ameliorated in the experiments in vivo. In summary, the new effect of anti-cancer drug triptolide was demonstrated to be anti-osteoclastogenesis, and we demonstrated triptolide might be a promising therapy for bone loss caused by tumour.

Guaiacol suppresses osteoclastogenesis by blocking interactions of RANK with TRAF6 and C-Src and inhibiting NF-κB, MAPK and AKT pathways.

Angelica sinensis (AS; Dang Gui), a traditional Chinese herb, has for centuries been used for the treatment of bone diseases, including osteoporosis and osteonecrosis. However, the effective ingredient and underlying mechanisms remain elusive. Here, we identified guaiacol as the active component of AS by two-dimensional cell membrane chromatography/C18 column/time-of-flight mass spectrometry (2D CMC/C18 column/TOFMS). Guaiacol suppressed osteoclastogenesis and osteoclast function in bone marrow monocytes (BMMCs) and RAW264.7 cells in vitro in a dose-dependent manner. Co-immunoprecipitation indicated that guaiacol blocked RANK-TRAF6 association and RANK-C-Src association. Moreover, guaiacol prevented phosphorylation of p65, p50, IκB (NF-κB pathway), ERK, JNK, c-fos, p38 (MAPK pathway) and Akt (AKT pathway), and reduced the expression levels of Cathepsin K, CTR, MMP-9 and TRAP. Guaiacol also suppressed the expression of nuclear factor of activated T-cells cytoplasmic 1(NFATc1) and the RANKL-induced Ca2+ oscillation. In vivo, it ameliorated ovariectomy-induced bone loss by suppressing excessive osteoclastogenesis. Taken together, our findings suggest that guaiacol inhibits RANKL-induced osteoclastogenesis by blocking the interactions of RANK with TRAF6 and C-Src, and by suppressing the NF-κB, MAPK and AKT signalling pathways. Therefore, this compound shows therapeutic potential for osteoclastogenesis-related bone diseases, including postmenopausal osteoporosis.

Neobavaisoflavone inhibits osteoclastogenesis through blocking RANKL signalling-mediated TRAF6 and c-Src recruitment and NF-κB, MAPK and Akt pathways.

Psoralea corylifolia (P corylifolia) has been popularly applied in traditional Chinese medicine decoction for treating osteoporosis and promoting fracture healing since centuries ago. However, the bioactive natural components remain unknown. In this study, applying comprehensive two-dimensional cell membrane chromatographic/C18 column/time-of-flight mass spectrometry (2D CMC/C18 column/TOFMS) system, neobavaisoflavone (NBIF), for the first time, was identified for the bioaffinity with RAW 264.7 cells membranes from the extracts of P corylifolia. Here, we revealed that NBIF inhibited RANKL-mediated osteoclastogenesis in bone marrow monocytes (BMMCs) and RAW264.7 cells dose dependently at the early stage. Moreover, NBIF inhibited osteoclasts function demonstrated by actin ring formation assay and pit-formation assay. With regard to the underlying molecular mechanism, co-immunoprecipitation showed that both the interactions of RANK with TRAF6 and with c-Src were disrupted. In addition, NBIF inhibited the phosphorylation of P50, P65, IκB in NF-κB pathway, ERK, JNK, P38 in MAPKs pathway, AKT in Akt pathway, accompanied with a blockade of calcium oscillation and inactivation of nuclear translocation of nuclear factor of activated T cells cytoplasmic 1 (NFATc1). In vivo, NBIF inhibited osteoclastogenesis, promoted osteogenesis and ameliorated bone loss in ovariectomized mice. In summary, P corylifolia-derived NBIF inhibited RANKL-mediated osteoclastogenesis by suppressing the recruitment of TRAF6 and c-Src to RANK, inactivating NF-κB, MAPKs, and Akt signalling pathways and inhibiting calcium oscillation and NFATc1 translocation. NBIF might serve as a promising candidate for the treatment of osteoclast-associated osteopenic diseases.

l-tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK-TRAF6 interactions and inhibiting NF-κB and MAPK pathways.

Bone homeostasis is delicately orchestrated by osteoblasts and osteoclasts. Various pathological bone loss situations result from the overactivated osteoclastogenesis. Receptor activator of nuclear factor κB ligand (RANKL)-activated NF-κB and MAPK pathways is vital for osteoclastogenesis. Here, we for the first time explored the effects of l-tetrahydropalmatine (l-THP), an active alkaloid derived from corydalis, on the formation and function of osteoclasts in vitro and in vivo. In RAW264.7 cells and bone marrow monocytes cells (BMMCs), l-THP inhibited osteoclastic differentiation at the early stage, down-regulated transcription level of osteoclastogenesis-related genes and impaired osteoclasts functions. Mechanically, Western blot showed that l-THP inhibited the phosphorylation of P50, P65, IκB, ERK, JNK and P38, and the electrophoretic mobility shift assay (EMSA) revealed that DNA binding activity of NF-κB was suppressed, ultimately inhibiting the expression of nuclear factor of activated T cells (NFATc1). Besides, Co-immunoprecipitation indicated that l-THP blocked the interactions of RANK and TNF receptor associated factor 6 (TRAF6) at an upstream site. In vivo, l-THP significantly inhibited ovariectomy-induced bone loss and osteoclastogenesis in mice. Collectively, our study demonstrated that l-THP suppressed osteoclastogenesis by blocking RANK-TRAF6 interactions and inhibiting NF-κB and MAPK pathways. l-THP is a promising agent for treating osteoclastogenesis-related diseases such as post-menopausal osteoporosis.

Reversal of Osteoporotic Activity by Endothelial Cell-Secreted Bone Targeting and Biocompatible Exosomes.

Exosomes, also known as extracellular vesicles, are naturally occurring, biocompatible, and bioacive nanoparticles ranging from 40 to 150 nm in diameter. Bone-secreted exosomes play important roles in bone homeostasis, the interruption of which can lead to diseases such as osteoporosis, rheumatoid arthritis, and osteopetrosis. Though the relationship between vascular and bone homeostasis has been recognized recently, the role of vascular endothelial cell (EC)-secreted exosomes (EC-Exos) in bone homeostasis is not well understood. Herein, we found that EC-Exos show more efficient bone targeting than osteoblast-derived exosomes or bone marrow mesenchymal stem cell-derived exosomes. We also found that EC-Exos can be internalized by bone marrow-derived macrophages (BMMs) to alter their morphology. EC-Exos can inhibit osteoclast activity in vitro and inhibit osteoporosis in an ovariectomized mouse model. Sequencing of exosome miRNA revealed that miR-155 was highly expressed in EC-Exos-treated BMMs. The miR-155 level in EC-Exos was much higher than that in BMMs and ECs, indicating that miR-155 was endogenous cargo of EC-derived vesicles. Blockage of BMMs miR-155 levels reversed the suppression by EC-Exos of osteoclast induction, confirming that exosomal miR-155 may have therapeutic potential against osteoporosis. Taken together, our findings suggest that EC-Exos may be utilized as a bone targeting and nontoxic nanomedicine for the treatment of bone resorption disorders.

Shikimic Acid Inhibits Osteoclastogenesis in Vivo and in Vitro by Blocking RANK/TRAF6 Association and Suppressing NF-κB and MAPK Signaling Pathways.

BACKGROUND/AIMS: Bone homeostasis is associated with the balance between bone-resorbing osteoclasts and bone-forming osteoblasts. Unbalanced bone homeostasis as a result of reduced osteogenesis or excessive osteoclastogenesis can lead to disorders such as osteoporosis, Paget's disease, and rheumatoid arthritis. Shikimic acid is a cyclohexanecarboxylic acid, reported to exhibit pharmacological properties including anti-inflammatory and antioxidant activities. However, its effects on bone homeostasis remain unknown. METHODS: First, the in vitro MTT cell viability assay was performed. Tartrate-resistant acid phosphatase (TRAP) and actin ring formation assays, as well as immunofluorescence staining were then performed to evaluate osteoclastogenesis. Potential signaling pathways were characterized by western blotting and verified in overexpression experiments. Related factors were examined by western blotting, reverse transcription polymerase chain reaction, electrophoretic mobility shift assay, and co-immunoprecipitation. Ovariectomized mice were used for the in vivo study. RESULTS: TRAP staining showed that shikimic acid significantly inhibited osteoclastogenesis and pit resorption in bone marrow monocytes and RAW264.7 cells, and actin ring formation assays showed that shikimic acid suppressed the bone resorption function of osteoclasts. Furthermore, shikimic acid inhibited the receptor activator of nuclear factor-κB RANK/tumor necrosis factor receptor-associated factor 6 (TRAF6) association, suppressed nuclear factor-κB and mitogen-activated protein kinase signaling pathways, and downregulated nuclear factor of activated T-cell cytoplasmic 1. The expression of osteoclastogenesis biomarkers, including TRAF6, calcitonin receptor, TRAP, cathepsin K, and matrix metalloproteinase-9, was inhibited. In vivo, shikimic acid also significantly ameliorated bone loss and prevented osteoclastogenesis in ovariectomized mice. CONCLUSION: Shikimic acid inhibited osteoclastogenesis and osteoclast function by blocking RANK ligand-induced recruitment of TRAF6, as well as downstream signaling pathways in vitro. Shikimic acid also reduced ovariectomy-induced osteoclastogenesis and bone loss in vivo.

The chinese version of achilles tendon total rupture score: cross-cultural adaptation, reliability and validity.

BACKGROUND: The Achilles tendon Total Rupture Score (ATRS), which is originally developed in 2007 in Swedish, is the only patient-reported outcome measure (PROM) for specific outcome assessment of an Achilles tendon rupture.Purpose of this study is to translate and cross-culturally adapt Achilles tendon Total Rupture Score (ATRS) into simplified Chinese, and primarily evaluate the responsiveness, reliability and validity. METHODS: International recognized guideline which was designed by Beaton was followed to make the translation of ATRS from English into simplified Chinese version (CH-ATRS). A prospective cohort study was carried out for the cross-cultural adaptation. There were 112 participants included into the study. Psychometric properties including floor and ceiling effects, Cronbach's alpha, intraclass correlation coefficient, effect size, standard response mean, and construct validity were tested. RESULTS: The mean scores of CH-ATRS are 57.42 ± 13.70. No sign of floor or ceiling effect was found of CH-ATRS. High level of internal consistency was supported by the value of Cronbach's alpha (0.893). ICC (0.979, 95%CI: 0.984-0.993) was high to indicate the high test-retest reliability. Great responsive ness was proved with the high absolute value of ES and SRM (0.84 and 8.98, respectively). The total CH-ATRS score had very good correlation with physical function and body pain subscales of SF-36 (r = -0.758 and r = -0.694, respectively, p < 0.001), while poor correlation with vitality and role physical subscales of SF-36 (r = -0.033 and r = -0.025, respectively, p ≥ 0.05), which supported construct validity of CH-ATRS. CONCLUSION: This Chinese version of Achilles tendon Total Rupture Score (CH-ATRS) can be used as a reliable and valid instrument for Achilles tendon rupture assessing in Chinese-speaking population. Level of evidence II.

The impact of sperm-expressed transcription factors on fate-mapping models.

Genetic lineage tracing has been used extensively in developmental biology. Many transcription factors expressed in sperm may induce Cre-mediated loxP recombination during early zygote development. In this study, we investigated the effect of sperm-expressed Cre on cell type-specific Cre-mediated loxP recombination in fate-mapping models of Tbx18+ progenitor cells. We found the recombination frequency in a reverse mating (RM) lineage was inconsistent with a normal Mendelian distribution. However, the recombination frequency in a positive mating (PM) lineage agreed with a Mendelian distribution. In the PM lineage, LacZ and EYFP were expressed in specific locations, such as the limb buds, heart, and hair follicles. Therefore, the reporter genes accurately and reliably traced cell differentiation in the PM lineage. In contrast, EYFP and LacZ were expressed throughout the embryo in the RM lineage. Thus, the reporter genes did not trace cell differentiation specifically in the RM lineage. Furthermore, Tbx18 mRNA and protein were expressed in the testicles of male mice, but almost no Tbx18 expression was detected in the ovaries of female mice. Similarly, reporter genes and Tbx18 were coexpressed in the seminiferous tubules and sperm cells of testicles. These results revealed that Cre-loxP-mediated pre-recombination in zygotes is due to Tbx18 expressed in testicle sperm cells when Cre is transmitted paternally. Our results indicate that Cre-mediated specific recombination in fate-mapping models of sperm-expressed genes may be influenced by the paternal origin of Cre. Therefore, a careful experimental design is critical when using the Cre-loxP system to trace spatial, temporal or tissue-specific fates.

Development of a machine learning model for predicting pneumothorax risk in coaxial core needle biopsy (≤3 cm).

PURPOSE: The aim is to devise a machine learning algorithm exploiting preoperative clinical data to forecast the hazard of pneumothorax post-coaxial needle lung biopsy (CCNB), thereby informing clinical decision-making and enhancing perioperative care. METHOD: This retrospective analysis aggregated clinical and imaging data from patients with lung nodules (≤3 cm) biopsies. Variable selection was done using univariate analysis and LASSO regression, with the dataset subsequently divided into training (80 %) and validation (20 %) subsets. Various machine learning (ML) classifiers were employed in a consolidated approach to ascertain the paramount model, which was followed by individualized risk profiling showcased through Shapley Additive eXplanations (SHAP). RESULTS: Out of the 325 patients included in the study, 19.6% (64/325) experienced postoperative pneumothorax. High-risk factors determined were Cancer, Lesion_type, GOLD, Size, and Depth. The Gaussian Naive Bayes (GNB) classifier demonstrated superior prediction with an Area Under the Curve (AUC) of 0.82 (95% CI 0.71-0.94), complemented by an accuracy rate of 0.8, sensitivity of 0.71, specificity of 0.84, and an F1 score of 0.61 in the test cohort. CONCLUSION: The formulated prognostic algorithm exhibited commendable efficacy in preoperatively prognosticating CCNB-induced pneumothorax, harboring the potential to refine personalized risk appraisals, steer clinical judgment, and ameliorate perioperative patient stewardship.

Numerical Simulation of the Evaporation Behavior of Fe-Mn Heterogeneous Powder in Selective Laser Melting Process.

Multi-material additive manufacturing using heterogeneous powders as raw materials is one of the important development directions of metal additive manufacturing technology. The evaporation behavior of heterogeneous powders in the selective laser melting (SLM) process has a significant influence on the accuracy of chemical composition control and the quality of the final product. In this paper, the fusion process of Fe20Mn (80 wt.% Fe and 20 wt.% Mn) heterogeneous powder, Fe and Mn elemental powders, and Fe20Mn pre-alloyed powder is numerically simulated using FLOW-3D® software and partially validated through SLM experimental results. The morphology and the characteristics of the flow field and temperature field in the melt pool for four kinds of powder materials are analyzed. The influence of the elemental evaporation behavior of different powders on the mass loss of the Mn element is discussed. The results show that the excessive accumulation of heat increases the maximum temperature of the melt pool, thus increasing mass loss. The Fe20Mn heterogeneous powder has a wider heat-affected zone and a higher peak value of temperature, nearly 400 K higher than that of the Fe20Mn pre-alloyed powders, which exhibits an intensive evaporation behavior. The mass loss of the Mn element obtained from the SLM experiment for Fe20Mn heterogeneous powders forming parts is more than the Fe20Mn pre-alloyed powders' forming parts for different laser powers, up to 17 wt.% at P = 120 W. This tendency is consistent with the numerical analysis of the effect of evaporation behavior of Fe-Mn heterogeneous powder during the SLM process. This study provides the necessary theoretical reference and process guidance for realizing the precise control of the SLM composition of a heterogeneous powder in multi-material additive manufacturing caused by evaporation behavior.

C-arm CT guided percutaneous vertebroplasty for pain release in cancer patient with cervical 1 vertebral metastases: A case report.

OBJECTIVE: To evaluate the efficacy and treatment outcome of C-arm CT percutaneous vertebroplasty in the treatment of cervical 1 (C1) vertebral metastases. METHODS: This report recruited a male patient diagnosed with hepatocellular carcinoma and C1 vertebral metastases, who had suffered from severe neck pain symptoms and the analgesic showed little soothing effect. Under the guidance of C-arm CT, an 18G coaxial needle was used to puncture the left lateral mass of C1 vertebral metastases from lateral space between thyroid cartilage and the left carotid sheath, with 2 ml bone cement injected. RESULTS: Postoperative C-arm CT three-dimensional reconstruction scan showed that the bone cement was well filled and distributed in the left lateral mass of C1 vertebral body, and no leakage of bone cement was observed. The neck pain of the patients was significantly relieved one week after the operation. CONCLUSION: Under the guidance of C-arm CT, cement augmentation using percutaneous vertebroplasty in an anterior cervical direction could serve as a safe and effective pain relief approach for patients with C1 vertebral metastases.

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma.

BACKGROUND: The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated. AIM: To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC. METHODS: We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen. RESULTS: The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs). CONCLUSION: The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion.

Expert consensus on Prospective Precision Diagnosis and Treatment Strategies for Osteoporotic Fractures.

Osteoporotic fractures are the most severe complications of osteoporosis, characterized by poor bone quality, difficult realignment and fixation, slow fracture healing, and a high risk of recurrence. Clinically managing these fractures is relatively challenging, and in the context of rapid aging, they pose significant social hazards. The rapid advancement of disciplines such as biophysics and biochemistry brings new opportunities for future medical diagnosis and treatment. However, there has been limited attention to precision diagnosis and treatment strategies for osteoporotic fractures both domestically and internationally. In response to this, the Chinese Medical Association Orthopaedic Branch Youth Osteoporosis Group, Chinese Geriatrics Society Geriatric Orthopaedics Committee, Chinese Medical Doctor Association Orthopaedic Physicians Branch Youth Committee Osteoporosis Group, and Shanghai Association of Integrated Traditional Chinese and Western Medicine Osteoporosis Professional Committee have collaborated to develop this consensus. It aims to elucidate emerging technologies that may play a pivotal role in both diagnosis and treatment, advocating for clinicians to embrace interdisciplinary approaches and incorporate these new technologies into their practice. Ultimately, the goal is to improve the prognosis and quality of life for elderly patients with osteoporotic fractures.

Bone-Targeted Exosomes: Strategies and Applications.

As the global population ages, bone-related diseases have increasingly become a major social problem threatening human health. Exosomes, as natural cell products, have been used to treat bone-related diseases due to their superior biocompatibility, biological barrier penetration, and therapeutic effects. Moreover, the modified exosomes exhibit strong bone-targeting capabilities that may improve efficacy and avoid systemic side effects, demonstrating promising translational potential. However, a review of bone-targeted exosomes is still lacking. Thus, the recently developed exosomes for bone-targeting applications in this review are focused. The biogenesis and bone-targeting regulatory functions of exosomes, the constructive strategies of modified exosomes to improve bone-targeting, and their therapeutic effects for bone-related diseases are introduced. By summarizing developments and challenges in bone-targeted exosomes, It is striven to shed light on the selection of exosome constructive strategies for different bone diseases and highlight their translational potential for future clinical orthopedics.