Comparison of different fibula procedures in tibiotalocalcaneal arthrodesis with a retrograde intramedullary nail: a mid-term retrospective study.

BACKGROUND: Tibiotalocalcaneal (TTC) arthrodesis with a retrograde intramedullary nail for severe tibiotalar and talocalcaneal arthritis has a high fusion rate; however, no studies have focused on how to handle the fibula intraoperatively to achieve better results. This study aimed to compare the efficacies of various fibular procedures. METHODS: We retrospectively reviewed the cases of severe tibiotalar and talocalcaneal arthritis in adults treated with TTC arthrodesis using a retrograde intramedullary nail between January 2012 and July 2017. The patients were divided into three groups according to different fibular procedures: Fibular osteotomy (FO), fibular strut (FS), and fibular preservation (FP). Functional outcomes and pain were assessed using the American Orthopedic Foot and Ankle Society (AOFAS) ankle and hindfoot score and visual analog scales (VAS), respectively. The operation time, fusion time, radiographic evaluation, and complications were also recorded. RESULTS: Fifty-eight patients with an average age of 53.2 (range, 32-69) years were enrolled in the final analysis. The numbers of patients enrolled in the three groups were 21, 19, and 18 in the FO, FS, and FP groups, respectively. The mean postoperative follow-up time was 66.0 (range, 60-78) months. All groups showed a high fusion rate (90.5% for FO, 94.7% for FS, and 94.4% for FP) and significant improvement in AOFAS ankle and hindfoot scores and VAS scores at the latest follow-up. There were no significant differences in these parameters among the three groups. The mean operation time of FS (131.3 ± 17.1 min) was longer than that of FO (119.3 ± 11.7 min) and FS (112.2 ± 12.6 min), but the fusion time was shorter (15.1 ± 2.8 weeks for FS, 17.2 ± 1.9 weeks for FO, and 16.8 ± 1.9 weeks for FP). Statistically significant differences were observed in these parameters. CONCLUSIONS: TTC arthrodesis using a retrograde intramedullary nail is an effective procedure with a high rate of fusion to treat severe tibiotalar and talocalcaneal arthritis in adults; however, FSs can shorten fusion time when compared with FO and FP. LEVEL OF CLINICAL EVIDENCE: Level 3.

Quantitative Evaluation of the Influence of Posterior Malleolus Fracture and Fixation on the Rotational Stability of the Ankle.

Background: This study aimed to analyze quantitative correlation between the posterior malleolus fracture and fixation and the rotational stability of the ankle and to explore supplementary surgical indications for posterior malleolus fracture. Methods: Twenty fresh frozen cadaver specimens were selected and dissected. Based on the tibial insertion of the ligament complex, the model for the supination external rotation stage 3 ankle fracture with a posterior malleolar fragment and syndesmosis diastasis was created. The area threshold of the posterior tibial insertion of posterior malleolus fracture was biomechanically assessed and the difference of the antirotating ability stiffness of the ankle between simple posterior malleolus fixation and simple syndesmotic fixation was analyzed statistically. Results: The tibial insertion of posterior inferior tibiofibular ligament and inferior transverse tibiofibular ligament complex was relatively broad, and its width decreased as the distance from the joint line increased. Biomechanical analysis showed that: the threshold of posterior area of posterior malleolus fracture was 1/4S; posterior malleolus fixation provided better rotational stability than syndesmotic fixation (P < 0.01). Conclusion: The surgical indications for posterior malleolus fracture should consider simultaneously the restoration of the axial and rotational stability of the ankle. Simple posterior malleolus fracture fixation is recommended when the syndesmosis is unstable and the area ratio of posterior tibial insertion of posterior malleolus fracture is greater than or equal to 1/4. Syndesmotic fixation is proposed to restore and maintain the rotational stability of the ankle when the syndesmosis is unstable and the area ratio is less than 1/4. Regardless of the area ratio, the surgical indication only depends on the impact of the posterior malleolus fracture on the axial stability of tibiotalar joint, the involved articular surface area, and the displacement degree of posterior malleolus fragment, when the syndesmosis is stable.

[Establishment of finite element model of varus-type ankle arthritis and biomechanical analysis of different correction models for tibial anterior surface angle].

Objective: To establish the finite element model of varus-type ankle arthritis and to implement the finite element mechanical analysis of different correction models for tibial anterior surface angle (TAS) in supramalleolar osteotomy. Methods: A female patient with left varus-type ankle arthritis (Takakura stage Ⅱ, TAS 78°) was taken as the study object. Based on the CT data, the three-dimensional model of varus-type ankle arthritis (TAS 78°) and different TAS correction models [normal (TAS 89°), 5° valgus (TAS 94°), and 10° valgus (TAS 99°)] were created by software Mimics 21.0, Geomagic Wrap 2021, Solidworks 2017, and Workbench 17.0. The 290 N vertical downward force was applied to the upper surface of the tibia and 60 N vertical downward force to the upper surface of the fibula. Von Mises stress distribution and stress peak were calculated. Results: The finite element model of normal TAS was basically consistent with biomechanics of the foot. According to biomechanical analysis, the maximum stress of the varus model appeared in the medial tibiotalar joint surface and the medial part of the top tibiotalar joint surface. The stress distribution of talofibular joint surface and the lateral part of the top tibiotalar joint surface were uniform. In the normal model, the stress distributions of the talofibular joint surface and the tibiotalar joint surface were uniform, and no obvious stress concentration was observed. The maximum stress in the 5° valgus model appeared at the posterior part of the talofibular joint surface and the lateral part of the top tibiotalar joint surface. The stress distribution of medial tibiotalar joint surface was uniform. The maximum stress of the 10° valgus model appeared at the posterior part of the talofibular joint surface and the lateral part of the top tibiotalar joint surface. The stress on the medial tibiotalar joint surface increased. Conclusion: With the increase of valgus, the stress of ankle joint gradually shift outwards, and the stress concentration tends to appear. There was no obvious obstruction of fibula with 10° TAS correction. However, when TAS correction exceeds 10° and continues to increase, the obstruction effect of fibula becomes increasingly significant.

Comprehensive analysis of anoikis-related long non-coding RNA immune infiltration in patients with bladder cancer and immunotherapy.

Background: Anoikis is a form of programmed cell death or programmed cell death(PCD) for short. Studies suggest that anoikis involves in the decisive steps of tumor progression and cancer cell metastasis and spread, but what part it plays in bladder cancer remains unclear. We sought to screen for anoikis-correlated long non-coding RNA (lncRNA) so that we can build a risk model to understand its ability to predict bladder cancer prognosis and the immune landscape. Methods: We screened seven anoikis-related lncRNAs (arlncRNAs) from The Cancer Genome Atlas (TCGA) and designed a risk model. It was validated through ROC curves and clinicopathological correlation analysis, and demonstrated to be an independent factor of prognosis prediction by uni- and multi-COX regression. In the meantime, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, immune infiltration, and half-maximal inhibitory concentration prediction (IC50) were implemented with the model. Moreover, we divided bladder cancer patients into three subtypes by consensus clustering analysis to further study the differences in prognosis, immune infiltration level, immune checkpoints, and drug susceptibility. Result: We designed a risk model of seven arlncRNAs, and proved its accuracy using ROC curves. COX regression indicated that the model might be an independent prediction factor of bladder cancer prognosis. KEGG enrichment analysis showed it was enriched in tumors and immune-related pathways among the people at high risk. Immune correlation analysis and drug susceptibility results indicated that it had higher immune infiltration and might have a better immunotherapy efficacy for high-risk groups. Of the three subtypes classified by consensus clustering analysis, cluster 3 revealed a positive prognosis, and cluster 2 showed the highest level of immune infiltration and was sensitive to most chemistries. This is helpful for us to discover more precise immunotherapy for bladder cancer patients. Conclusion: In a nutshell, we found seven arlncRNAs and built a risk model that can identify different bladder cancer subtypes and predict the prognosis of bladder cancer patients. Immune-related and drug sensitivity researches demonstrate it can provide individual therapeutic schedule with greater precision for bladder cancer patients.

Comprehensive analysis of cuproptosis-related long noncoding RNA immune infiltration and prediction of prognosis in patients with bladder cancer.

Background: Bladder cancer (BCa), among the world's most common malignant tumors in the urinary system, has a high morbidity and mortality. Though cuproptosis is a new type of cell death mediated by lipoylated tricarboxylic acid (TCA) cycle proteins, the role of cuproptosis-related long noncoding RNAs (crlncRNAs) in bladder tumors awaits further elucidation. In this paper, we tried to explore how important crlncRNAs are for BCa. Methods: The crlncRNAs were first obtained through Pearson correlation analysis of the RNA-seq data and corresponding clinical data downloaded from The Cancer Genome Atlas (TCGA). Then, three lncRNAs were acquired by Cox regression and Lasso regression to build a prognostic model of crlncRNAs for verification. In the meantime, clinicopathological correlation analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, principal component analysis (PCA), immunoassay, and half-maximal inhibitory concentration prediction (IC50) were carried out. Then, an entire tumor was classified into two clusters by crlncRNA expression to further discuss the differences in prognosis, immune status and drug susceptibility among different subgroups. Results: We obtained a total of 152 crlncRNAs and built a risk model for screened crlncRNAs. We validated the model and found that calibration charts feature a high consistency in verifying nomogram prediction. Receiver operating characteristic (ROC) curve and univariate and multivariate Cox regression suggested that this model can be applied as an independent prognostic factor of bladder cancer due to its high accuracy. According to KEGG analysis, high-risk groups were enriched in cancer and immune-related pathways. During tumor immunoassay, noticeable differences were observed in both immune infiltration and checkpoints between high- and low-risk patients. Of the two subgroups divided among patients by consensus clustering, cluster 2 had a better prognosis, whereas cluster 1 had higher immunoreactivity scores, more immune cell infiltrations and immune checkpoint expressions, and different sensitivities to drugs. Conclusion: The research findings demonstrate that crlncRNAs can be used to predict the prognosis and immune microenvironment of patients suffering from BCa, and differentiate between BCa subgroups to improve the individual therapy of BCa.

Staged surgery for closed Lisfranc injury with dislocation.

Objective: To investigate the clinical efficacy of staged surgery for patients with closed Lisfranc injury and dislocation. Methods: This study included 48 patients with acute closed Lisfranc injury and dislocation admitted between July 2016 and July 2021. The patients were divided into two groups. 23 patients in group A underwent staged surgeries included emergency reduction within 4-8 h after injury, and open reduction and internal fixation of Lisfranc injury and first tarsometatarsal joint fusion after the swelling had subsided. 25 patients in group B underwent open reduction and internal fixation as an elective procedure after the swelling had subsided. American Orthopedic Foot and Ankle Society (AOFAS) midfoot scores and visual analog scale (VAS) scores were used for assessment at the final follow-up. Results: A total of 48 patients with closed Lisfranc injury and dislocation were included. The lengths of hospitalization were 11.52 ± 1.61 day and 19.80 ± 2.37 day in groups A and B, respectively. The total lengths of surgery were 67.34 ± 1.71 min and 104.36 ± 8.31 min in groups A and B, respectively. 48 patients completed the final follow-up (follow-up period range: 12-24 months, mean: 18 months). All fractures had healed at 12-18 weeks after surgery (mean: 14.6 weeks). At the 1-year postoperative follow-up, the AOFAS and VAS score was 86.87 ± 4.24 and 1.91 ± 0.78, respectively, during weight-bearing walking in group A patients and 71.72 ± 5.46 and 3.20 ± 1.17 in group B. By the end of the follow-up period, only 2 patients in group B had developed traumatic arthritis and no patients had joint re-dislocation or required secondary surgery. Conclusion: Staged surgery for closed Lisfranc injury with dislocation reduced the incidence of perioperative complications and achieved good surgical outcomes while shortening the lengths of surgery and hospitalization.

[Comparison of minimally invasive and traditional Chevron osteotomy in treating patients with mild to moderate hallux valgus].

OBJECTIVE: To compare minimally invasive and traditional Chevron osteotomy in treating patients with mild to moderate hallux valgus. METHODS: Clinical data of 36 patients (36 feet) with mild to moderate hallux valgus from January 2019 to February 2021 were retrospectively analyzed, and divided into minimally invasive osteotomy(minimally invasive group) and traditional Chevron osteotomy(traditional group). There were 16 patients in minimally invasive group, including 1 male and 15 females, aged from 36 to 60 years old with an average of(49.0±9.5) years old;9 were mild and 7 were moderate according to Mann classification;treated with minimally invasive osteotomy with hollow screw fixation. There were 20 patients(20 feet) in traditional group, including 2 males and 18 females, aged from 38 to 65 years old with an average of(50.0±9.2) years old;11 were mild and 9 were moderate according to Mann classification;treated with traditional Chevron osteotomy. Hallux valgus angle (HVA), intermetatarsal angle (IMA) before and after operation at 12 months bewteen two groups were observed and compared, and American Orthopedic Foot and Ankle Society (AOFAS) forefoot score and visual analogue scale (VAS) before and after operation at 6 weeks and 12 months between two groups were compared. RESULTS: Thirty-six patiens were followed up from 14 to 30 months with an average of (21.00±5.77) months. All incisions were healed well at stageⅠwithout infection. There were no significant differences in HVA, IMA, AOFAS forefoot scores and VAS before and after operation at 12 months between two groups(P>0.05). However, AOFAS forefoot scores and VAS of minimally invasive group was significantly better than that of traditionl group at 6 weeks after operation (P<0.05). Postoperative HVA, IMA, AOFAS forefoot scores and VAS at 12 months bewteen two groups were improved better than that of preoperation(P<0.05). CONCLUSION: Compared with traditional Chevron osteotomy, minimally invasive osteotomy has less trauma and quicker recovery. Both of them has similar clinical effects, and could receive satisfactory clinical effects, while treatment of minimally invasive osteotomy should pain attention to learning curve.

Classification of avulsion fractures of the fifth metatarsal base using three-dimensional CT mapping and anatomical assessment: a retrospective case series study.

BACKGROUND: To clarify the injury mechanism of the avulsion fracture of the fifth metatarsal combining 3-dimensional (3D) fracture mapping with anatomical measurements. METHODS: Two hundred twenty-two patients with the avulsion fractures of the fifth metatarsal base, who were admitted to our hospital from August 2015 to August 2020. The computed tomography (CT) scans were used to generate the 3-D images of all mapped fracture lines for the avulsion fractures of the fifth metatarsal base were compiled in an overall 3D image. The fifth metatarsal base of 8 unpaired lower limbs of adult Asian frozen cadaveric specimens were also dissected to observe and measure the specific locations of the attachment points of the peroneus brevis, lateral band of the plantar fascia, and peroneus tertius to the fifth metatarsal base. RESULTS: Based on the type of fracture line produced and the specific locations of the attachment points of the tendons or fascia, the avulsion fractures of the fifth metatarsal base can be classified into three types: type I predominantly involves the action of the lateral band of the plantar fascia; type II predominantly involves the action of the peroneus brevis; type IIIA involves the joint action of the peroneus brevis and lateral band of the plantar fascia with one fracture line, and type IIIB involves the joint action of the peroneus brevis and lateral band of the plantar fascia with two fracture lines. CONCLUSION: The lateral band of the plantar fascia and peroneus brevis play a major role, either separately or together, in avulsion fractures of the fifth metatarsal base. With this knowledge, we propose a novel classification based on the injury mechanism, which can serve as a reference for clinical treatment and diagnosis. LEVEL OF EVIDENCE: Level III, retrospective case series.

A Quantitative Method for Intraoperative Evaluation of Distal Fibular Malrotation.

Background: Due to the low sensitivity of commonly used radiographic parameters for the evaluation of rotational malreduction of the distal fibula under intraoperative fluoroscopy, a quantitative method is needed to make up for this defect. Methods: A total of 96 sets of computed tomography images of normal ankles were imported into MIMICS to reconstruct 3D models. The fibula models were rotated along the longitudinal axis from 30 degrees of external rotation to 30 degrees of internal rotation. Virtual X-ray function in MIMICS was used to obtain radiographic images in mortise view. A line was drawn through the tip of the medial malleolus and parallel to the distal tibial plafond, the distances from the medial edge of the fibula to the lateral malleolar fossa cortex and from the medial edge of the fibula to the lateral edge of the fibula were measured on this line, and the ratio of them was calculated and marked as ratio α. Results: The mean ratio α for normal ankles was 0.49 ± 0.06, while the 95% confidence interval was 0.48-0.50. The ratio α decreased when the fibula was externally rotated and increased when the fibula was internally rotated. The effects of different genders or different types on each group of data were compared, and the p values were all greater than 0.05. Conclusions: This is a new method to quantitatively evaluate rotational malreduction of the distal fibula during operation. The ratio α can correspond to the rotation angle of the fibula. The larger the ratio α, the more the internal rotation of the fibula. Contrarily, the smaller the ratio α, the more the external rotation of the fibula. Making the ratio α close to 0.5 may be an intuitive approach that can be used intraoperatively.

RAS protein activator like 2 promotes the proliferation and migration of pulmonary artery smooth muscle cell through AKT/mammalian target of Rapamycin complex 1 pathway in pulmonary hypertension.

RAS protein activator like 2 (Rasal2) exerts pro-proliferative effect in several types of cells. However, whether Rasal2 is involved in the regulation of pulmonary artery smooth muscle cell (PASMC) remains unclear. In the current study, we explored the role of Rasal2 in proliferation and migration of PASMC during the development of pulmonary arterial hypertension (PAH). We found that the protein level of Rasal2 was increased in both pulmonary arteries of chronic hypoxia-induced pulmonary hypertension (CH-PH) mice and hypoxia-challenged PASMC. Overexpression of Rasal2 caused enhanced proliferation and migration of PASMC after hypoxia exposure. Mechanistically, we found elevated phosphorylation of AKT and two downstream effectors of mammalian target of Rapamycin complex 1 (mTORC1), S6 and 4E-Binding Protein 1 (4EBP1) after Rasal2 overexpression in hypoxia-challenged PASMC. Inactivation of mTORC1 abolished Rasal2-mediated enhancement of proliferation and migration of PASMC. Furthermore, we also demonstrated that AKT might act downstream of Rasal2 to enhance the activity of mTORC1. Once AKT was inactivated by MK-2206 application, overexpression of Rasal2 failed to further increase the phosphorylation level of S6 and 4EBP1. Finally, inhibition of AKT also blocked Rasal2-induced proliferation and migration in hypoxia-challenged PASMC. In conclusion, Rasal2 promotes the proliferation and migration of PASMC during the development of PAH via AKT/mTORC1 pathway.

Treatment for Flexible Flatfoot in Children With Subtalar Arthroereisis and Soft Tissue Procedures.

Background: Children with flexible flatfoot is common in clinics and there is no unified conclusion on surgical treatment. And for some patients with severe deformities, the correction of the subtalar joint arthroereisis combine the release of the Achilles tendon or gastrocnemius muscle release is still not satisfactory. The main aim of the present study was to investigate the therapeutic outcomes of subtalar arthroereisis combined with Achilles tendon or gastrocnemius recession and medial soft tissue (spring ligament, talonavicular joint capsule, tibionavicular ligaments and tibiospring ligaments) tightening for treating flexible flatfoot with severe deformities. Methods: Thirty patients (32 feet) with pediatric flexible flatfoot who underwent subtalar arthroereisis and soft tissue procedures during January 2016 to January 2018. There were 18 males (20 feet) and 12 females (12 feet) with an average age of 9.5 years (range, 8-12 years). We used the AOFAS scores and VAS scores combined with angles measure to evaluate the pre-operative and post-operative status. Results: Thirty patients (32 feet) were followed up for 25.3 months on average (range, 18-36 months). There was no infection. Post-operative foot pain, arch collapse, and other symptoms improved. At last follow-up, the Meary angle was decreased from 17.5° ± 4.4° to 4.1° ± 1.2° (P < 0.05), the talar-first metatarsal (AP) was decreased from 15.3° ± 3.1° to 4.8° ± 1.3°(P < 0.05), The mean AOFAS score was rose from 66.6 ± 5.8 to 88.6 ± 7.9 (P < 0.05), the mean VAS score was decreased from 6.6 ± 0.6 to 1.7 ± 0.3 (P < 0.05). Conclusion: The subtalar arthroereisis combined with soft tissue procedures can effectively correct flexible flatfoot in children and it is a significant method for severe forefoot abduction reconstruction. Level of Evidence: IV.

Evaluation of hyperbranched polyglycerol for cold perfusion and storage of donor kidneys in a pig model of kidney autotransplantation.

Hyperbranched polyglycerol (HPG) is a biocompatible polyether polymer that is a potential colloid component in a preservation solution for suppressing interstitial edema during cold storage of a donor organ. This study evaluated the outcomes of kidney transplants after cold perfusion and storage with a HPG-based preservation solution (HPGS) in a pig model of kidney autotransplantation. The left kidneys of farm pigs (weighing 35-45 kg) were perfused with and stored in either cold HPGS or standard UW solution (UWS), followed by transplantation to the right side after right nephrectomy. The survival and function of transplants were determined by the urine output, and serum creatinine (SCr) and blood urea nitrogen (BUN) of recipients. Transplant injury was examined by histological analysis. Here, we showed that there was no significant difference between HPGS and UWS in the prevention of tissue edema, but HPGS was more effective than UWS for initial blood washout of kidney perfusion and for the prevention of cold ischemia injury during cold storage. After autotransplantation, the kidneys preserved with HPGS (HPG group) had better functional recovery than those with UWS (UW group), indicated by significantly more urine output and lower levels of SCr and BUN. The survived grafts in HPG group had less tissue damage than those in UW group. In conclusion, as compared to the UWS the HPGS has less negative impact on kidney cold ischemia during cold storage, resulting in improving immediate functional recovery after transplantation, suggesting that HPG is a promising colloid for donor kidney preservation.

p53 plays a central role in the development of osteoporosis.

Osteoporosis is a metabolic disease affecting 40% of postmenopausal women. It is characterized by decreased bone mass per unit volume and increased risk of fracture. We investigated the molecular mechanism underlying osteoporosis by identifying the genes involved in its development. Osteoporosis-related genes were identified by analyzing RNA microarray data in the GEO database to detect genes differentially expressed in osteoporotic and healthy individuals. Enrichment and protein interaction analyses carried out to identify the hub genes among the deferentially expressed genes revealed TP53, MAPK1, CASP3, CTNNB1, CCND1, NOTCH1, CDK1, IGF1, ERBB2, CYCS to be the top 10 hub genes. In addition, p53 had the highest degree score in the protein-protein interaction network. In vivo and in vitro experiments showed that TP53 gene expression and serum p53 levels were upregulated in osteoporotic patients and a mouse osteoporosis model. The elevated p53 levels were associated with decreases in bone mass, which could be partially reversed by knocking down p53. These findings suggest p53 may play a central role in the development of osteoporosis.

MiR-16-5p regulates postmenopausal osteoporosis by directly targeting VEGFA.

In this study, we used bioinformatics tools, and experiments with patient tissues and human mesenchymal stem cells (hMSCs) to identify differentially regulated genes (DEGs) and microRNAs (miRNAs) that promote postmenopausal osteoporosis. By analyzing the GSE56815 dataset from the NCBI GEO database, we identified 638 DEGs, including 371 upregulated and 267 downregulated genes, in postmenopausal women with low bone density. Enrichment and protein-protein interaction network analyses showed that TP53, RPS27A, and VEGFA were the top three hub genes with the highest degree of betweenness and closeness centrality. TargetScanHuman and DIANA software analyses and dual luciferase reporter assays confirmed that miR-16a-5p directly targets the 3'UTR of VEGFA. Postmenopausal patients with osteoporosis showed higher miR-16-5p and lower VEGFA levels than those without osteoporosis (n=10 each). VEGFA levels were higher in miR-16-5p knockdown hMSCs and were reduced in miR-16-5p-overexpressing hMSCs. mRNA expression of osteogenic markers, ALP, OCN, and RUNX2, as well as calcium deposition based on Alizarin red staining, correlated inversely with miR-16-5p levels and correlated positively with VEGFA levels. These findings suggest that miR-16-5p suppresses osteogenesis by inhibiting VEGFA expression and is a promising target for postmenopausal osteoporosis therapy.

The shared KEGG pathways between icariin-targeted genes and osteoporosis.

Osteoporosis is a common metabolic bone disease that affects about 40% of postmenopausal women. Treatment options for osteoporosis are limited, however. Icariin is an herbal substance that has been shown to improve bone mass, but the mechanisms are largely unknown. Using bioinformatics analysis, we have identified the hub genes and KEGG pathways shared between icariin-targeted genes and osteoporosis. The top five shared KEGG pathways were the Toll-like receptor signaling pathway, adipocytokine pathway, neurotrophin signaling pathway, NOD-like receptor signaling, and B cell receptor signaling pathway; the hub genes were RELA, NFKBIA, and IKBKB, belonging to the NF-κB family. The identified icariin-targeted genes are involved in inflammation, insulin resistance, apoptosis, and immune responses, and regulate the PI3K-Akt, NF-κB, MAPK, and JNK signaling pathways. Our in vitro data show that icariin inhibits apoptosis in human mesenchymal stem cells by suppressing JNK/c-Jun signaling pathway. Together, these findings indicate that icariin exerts its anti-osteoporotic function by inhibiting JNK/c-Jun signaling pathway, and suggest that icariin may be a promising treatment option for osteoporosis.

Resveratrol promotes osteogenesis and alleviates osteoporosis by inhibiting p53.

Although osteoporosis is one of the most common chronic age-related diseases, there is currently no gold standard for treatment. Evidence suggests resveratrol, a natural polyphenolic compound, may be helpful in the treatment of osteoporosis and other diseases. However, the molecular mechanisms underlying the anti-osteoporotic effects of resveratrol remain largely unknown. In the present study, KEGG pathway enrichment analysis of resveratrol-targeted genes identified 33 associated pathways, 12 of which were also involved in osteoporosis. In particular, the MDM2/p53 signaling pathway was identified as a potential key pathway among the shared pathways. In vitro experiments indicated that MDM2-mediated p53 degradation induced osteoblast differentiation, and resveratrol could partially reverse p53-dependent inhibition of osteogenic differentiation. These findings suggest resveratrol may alleviate osteoporosis at least in part by modulating the MDM2/p53 signaling pathway.

Tomatidine Alleviates Osteoporosis by Downregulation of p53.

BACKGROUND As a common metabolic disorder, osteoporosis is characterized by decreasing bone mass density and increased possibility of fragility fracture. The incidence of senile osteoporosis increases year by year. There is no gold standard of treatment for osteoporosis. Tomatidine is the aglycone derivative of tomatine, having the ability to treat various diseases, including osteoporosis. However, the mechanism by which tomatidine improves osteoporosis has not been fully elucidated. Tomatidine is a potential and promising drug for osteoporosis. MATERIAL AND METHODS In this study, the KEGG pathways that tomatidine-targeted genes enriched in were obtained using bioinformatics methods. The KEGG pathways involved in osteoporosis that were also associated with tomatidine-targeted genes were selected. After analysis of these pathways, essential genes that may be involved in this biological process were identified and validated experimentally. RESULTS We found 110 osteoporosis related KEGG pathways and 76 tomatidine-targeted genes-related KEGG pathways were obtained. 39 shared KEGG pathways were identified. The top 5 pathways were: pathway of chronic myeloid leukemia, pathway of B cell receptor signaling, pathway in cancer, bladder cancer pathway, and progesterone-mediated oocyte maturation pathway. MAPK1, MAP2K1, MAPK3, RAF1 were involved in all the 5 pathways. The p53 signaling pathway and the MAPK signaling pathway were involved in the 5 KEGG pathways. In vitro experiments showed that downregulating p53 expression could be potentially protective for osteoporosis. CONCLUSIONS Tomatidine can improve osteoporosis, and one of the mechanisms of its action is achieved by modulating p53. Tomatidine may be a promising drug for osteoporosis.

Role of eotaxin-1/CCL11 in sepsis-induced myocardial injury in elderly patients.

Myocardial injury is a serious complication of sepsis. The present study aimed to identify potential biomarkers of sepsis-induced myocardial injury. Differentially expressed genes (DEGs) in patients and mice with sepsis-induced myocardial injury were identified via bioinformatic analysis. The identified DEG was tested in elderly patients with sepsis-induced myocardial injury. We identified 19 co-expressed DEGs. The most significant DEG was eotaxin-1/CCL11. We enrolled 25 controls without infections and 28 patients with sepsis-induced myocardial injury. Six of patients died within 30 days. Circulating eotaxin-1/CCL11 levels were significantly higher in patients with sepsis-induced myocardial injury than controls and were higher in non-survivors than survivors (both P < 0.01). Eotaxin-1/CCL11 was positively correlated with troponin I (r=0.48, P=0.01), B-type natriuretic peptide (BNP, r=0.44, P=0.02), and white blood cell (WBC) count (r=0.41, P=0.03). For the prediction of 30-day mortality, eotaxin-1/CCL11 had the greatest discriminatory ability (AUC 0.97) compared with troponin I (AUC 0.89), BNP (AUC 0.80), and WBC count (AUC 0.86). Taken together, eotaxin-1/CCL11 was upregulated in sepsis-injured myocardium and circulating eotaxin-1/CCL11 was a biomarker for predicting severity and mortality of elderly patients with sepsis-induced myocardial injury. These results suggest that eotaxin-1/CCL11 may become a useful biomarkers and potential therapeutic target for sepsis-induced myocardial injury.

Circ0001429 regulates progression of bladder cancer through binding miR-205-5p and promoting VEGFA expression.

OBJECTIVE: This study investigates expressions of circ0001429, miR-205-5p and vascular endothelial growth factor (VEGFA) in bladder cancer tissues and their effects on the proliferation, migration and apoptosis. METHODS: Arraystar Human CircRNA chip was applied to analyzing the differential expression of circRNA in four bladder cancer tissues and paired adjacent normal bladder tissues. Real time quantitative PCR was utilized to detect the expression of circ0001429 in tissue specimens. Bioinformatics, RNA immunoprecipitation and luciferase reporter assays were used to verify the relationship among circ0001429, miR-205-5p and VEGFA in bladder cancer. Cell propagation was determined by CCK8 assay and roles of circ0001429 and miR-205-5p in cell migration were verified with transwell migration assay. Flow cytometry and TUNEL staining were conducted to observe the impact on cell apoptosis ability. Xenograft experiment was also performed to validate the influence of circ0001429 on tumor growth in vivo. RESULTS: Expressions of circ0001429 and VEGFA were up-regulated, whereas miR-205-5p expression was down-regulated in bladder cancer tissues in comparison with paired adjacent normal bladder tissues. Circ0001429 enhanced the propagation and metastasis abilities of T24 cells and 5637 cells in vitro, but reduced cell apoptosis. In vivo experiments revealed the inhibitor role of sh-circ0001429 in tumor growth and lung metastasis. Circ0001429 sponged miR-205-5p that targeted VEGFA, thereby modulating the protein level of VEGFA. Meanwhile, miR-205-5p restrained the cell viability and mobility and promoted the apoptosis in bladder cancer. Circ0001429 could accelerate cell propagation, migration and invasiveness through increasing VEGFA expression via miR-205-5p. CONCLUSION: Circ0001429 and VEGFA were highly expressed in bladder cancer, while miR-205-5p were lowly expressed in bladder cancer. The circ0001429 could target at miR-205-5p to regulate VEGFA and promote the development of bladder cancer.

[Long-term outcomes of 125I brachytherapy combined with maximal androgen blockade for metastatic prostate cancer].

OBJECTIVE: To investigate the long-term clinical value of prostate 125I brachytherapy (BT) combined with maximal androgen blockade (MAB) in the treatment of metastatic prostate cancer (mPCa). METHODS: We retrospectively analyzed the clinical data on 173 cases of mPCa treated by MAB (n = 126) or BT+MAB (n = 47) from December 2011 to December 2016 and followed up for 6－76 (44.17 ± 19.73) months. We compared the PSA level, prostate volume, IPSS, progression-free survival, and the rates of 3- and 5-year overall survival between the two groups. RESULTS: After treatment, the minimum PSA level was significantly lower in the BT+MAB than in the MAB group ï¼»3.77 ± 4.14ï¼½ vs ï¼»5.96 ± 7.01ï¼½ ng/ml, P = 0.046) and the time to reach the minimum level was shorter in the former than in the latter (ï¼»5.19 ± 2.83ï¼½ vs ï¼»6.52 ± 3.34ï¼½ mo, P = 0.016). The prostate volume was markedly reduced in both of the groups at 1, 3 and 5 years after treatment as compared with the baseline, even more significantly in the BT+MAB than in the MAB group (P < 0.01), though with no statistically significant difference between the two groups before treatment (P = 0.307). The IPSS was remarkably decreased in both of the groups at 1 and 3 years (P < 0.01) but showed no significant difference at 5 years after treatment as compared with the baseline (P > 0.05) or between the two groups before and after treatment (P > 0.05). The progression-free survival was obviously longer in the BT+MAB than in the MAB group (ï¼»37.29 ± 15.73ï¼½ vs ï¼»29.41 ± 14.37ï¼½ mo, P = 0.011), and the rates of 3- and 5-year overall survival were higher in the former than in the latter (74.60% and 60.70% vs 62.60% and 51.50%, P = 0.227 and P = 0.356). Kaplan-Meier survival curves showed no statistically significant difference in the overall survival between the two groups (P = 0.105). CONCLUSIONS: Both MAB and BT+MAB are effective therapies for mPCa, but the latter can achieve a longer progression-free survival.