Low ACADM expression predicts poor prognosis and suppressive tumor microenvironment in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) represents a highly frequent renal cancer subtype. However, medium-chain acyl-CoA dehydrogenase (ACADM) encodes an important enzyme responsible for fatty acid ß-oxidation (FAO) and its association with prognosis and immunity in cancers has rarely been reported. Therefore, the present work focused on exploring ACADM's expression and role among ccRCC cases. We used multiple public databases and showed the hypo levels of ACADM protein and mRNA within ccRCC. Additionally, we found that ACADM down-regulation showed a remarkable relation to the advanced stage, high histological grade, as well as dismal prognostic outcome. As suggested by Kaplan-Meier curve analysis, cases showing low ACADM levels displayed shorter overall survival (OS) as well as disease-free survival (DFS). Moreover, according to univariate/multivariate Cox regression, ACADM-mRNA independently predicted the prognosis of ccRCC. In addition, this work conducted immunohistochemistry for validating ACADM protein expression and its prognostic role in ccRCC samples. KEGG and GO analyses revealed significantly enriched genes related to ACADM expression during fatty acid metabolism. The low-ACADM group with more regulatory T-cell infiltration showed higher expression of immune negative regulation genes and higher TIDE scores, which might contribute to poor response to immunotherapies. In conclusion, our results confirmed that downregulated ACADM predicted a poor prognosis for ccRCC and a poor response to immunotherapy. Our results provide important data for developing immunotherapy for ccRCC.

Self-Expandable Metal Stent as a Bridge to Surgery for Left-Sided Acute Malignant Colorectal Obstruction: Optimal Timing for Elective Surgery.

Objectives: This randomized, single-center, retrospective, comparative cohort study is aimed at investigating the optimal time interval from self-expandable metal stent (SEMS) placement to surgery and potential risk factors for complications in patients with acute malignant colorectal obstruction. Methods: A total of 64 patients with left-sided acute malignant colorectal obstruction treated with SEMS placement and subsequent surgery between January 2013 and September 2020 were enrolled and allocated to a case group (SEMS placing time ≤ 14 days; n = 19 patients) and a control group (SEMS placing time > 14 days; n = 45 patients). The primary outcome was the difference in baseline information, patients' conditions during surgery, and postoperative conditions between the two groups. The secondary outcome included potential risk factors of postoperative complications. The propensity score matching (PSM) and super learner (SL) methods were used to eliminate multiple confounding factors of baseline data. A cohort of 21 samples was used for external validation, comprising 6 cases and 15 controls. Results: A significant difference was observed between the two groups in intraoperative blood loss (P = 0.009), postoperative hospital stay (P = 0.002), postoperative complications (Clavien-Dindo grading ≥ II) (P < 0.001), stoma creation (P < 0.001), and primary anastomosis (P < 0.001). After a 1 : 3 PSM analysis, no statistically significant differences between eight confounding variables of the two groups were observed (P > 0.05). Caliper set as 0.2 multiple logistic regression analysis showed that the potential risk factor for postoperative complications was SEMS placing time (RR = 0.109, 95% confidence interval (CI) = 0.028-0.433; P = 0.002), indicating that SEMS placing time > 14 days was an independent risk factor for postoperative complications in bridge-to-surgery (BTS) setting. The area under the AUC curve was 76.7% and validated using the validation cohort. Conclusions: Long duration of SEMS placement (>14 days) may not influence surgical difficulty but could increase the risk of postoperative complications.

Novel Rim Plating Technique for Treatment of the Inferior Pole Fracture of the Patella.

To aim of the present paper was to introduce a novel fixation technique for the treatment of inferior pole fracture of the patella. We performed a prospective observational study of consecutive cases of inferior pole fracture of the patella that were treated at our institution between January 2018 and June 2019. The patients include three men and one woman, with an average age of 47 years (range: 42-59 years). All patients were treated with the novel rim plating fixation technique for preserving the inferior pole of the patella. During the surgery, a 2.4 mm straight locking compression plate was contoured to adapt to the arc of the lower half of the patella as the rim plate. After reduction of the fracture, the rim plate was fixed to the proximal fragment of the patella through multiple locking screws, against the continuous pull of the patellar tendon. The rim plate encircles and constricts the inferior pole fragments, functioning as a compression and blocking construct. If necessary, an additional anterior tension band or mini locking plate can be used to further prevent anterior displacement of the inferior pole fragments. Under this rigid fixation, motion of the knee and full weight-bearing were encouraged postoperatively. The patients were followed up monthly until 12 months after surgery. The time to achieve 90°pain-free, full range of motion of the knee, and fracture healing, were recorded. Related complications were monitored, including infection, loss of reduction, fixation failure, anterior knee pain, and soft-tissue irritation. The modified Cincinnati knee rating system was used for knee function assessment. The average operative time was 58.8 min (range: 52-63 min). The average blood loss was 59.8 mL (range: 45-71 mL). For all patients, pain-free 90° range of motion was restored in 2-4 weeks, and the full range of motion was restored in 8-11 weeks. All patients achieved bone union in 6-9 weeks with no displacement of the fragments or breakage of the implant. No patient complained of anterior knee pain or soft-tissue irritation. The modified Cincinnati score at 12-month follow up demonstrated excellent outcomes in all four patients. The rim plating technique may be a feasible option for the treatment of the inferior pole fracture of the patella.

Topping-off surgery vs posterior lumbar interbody fusion for degenerative lumbar disease: a finite element analysis.

BACKGROUND: Adjacent segment disease (ASD) is a common complication after posterior lumbar interbody fusion (PLIF). Recently, a topping-off surgery (non-fusion with Coflex) has been developed to reduce the risk of ASD, yet whether and how the topping-off surgery can relieve ASD remains unclear. The purpose of this study was to explore the biomechanical effect of PLIF and Coflex on the adjacent segments via finite element (FE) analysis and discuss the efficacy of Coflex in preventing ASD. METHODS: A FE model of L3-L5 segments was generated based on the CT of a healthy volunteer via three commercially available software. Coflex and PLIF devices were modeled and implanted together with the segment model in the FE software. In the FE model, a pre-compressive load of 500 N, equal to two-thirds of the human body mass, was applied on the top surface of the L3. In addition, four types of moments (anteflexion, rear protraction, bending, and axial rotation) set as 10 Nm were successively applied to the FE model combined with this pre-compressive load. Then, the range of motion (ROM), the torsional rigidity, and the maximum von Mises equivalent stress on the L3-L4 intervertebral disc and the implant were analyzed. RESULTS: Both Coflex and PLIF reduced ROM. However, no significant difference was found in the maximum von Mises equivalent stress of adjacent segment disc between the two devices. Interestingly enough, both systems increased the torsional rigidity at the adjacent lumbar segment, and PLIF had a more significant increase. The Coflex implant had a larger maximum von Mises equivalent stress. CONCLUSIONS: Both Coflex and PLIF reduced ROM at L3-L4, and thus improved the lumbar stability. Under the same load, both devices had almost the same maximum von Mises equivalent stress as the normal model on the adjacent intervertebral disc. But it is worthy to notice the torsional rigidity of PLIF was higher than that of Coflex, indicating that the lumbar treated with PLIF undertook a larger load to reach ROM of Coflex. Therefore, we presumed that ADS was related to a higher torsional rigidity.

Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and osteogenesis in rabbit femoral head osteonecrosis.

PURPOSE: Osteonecrosis of the femoral head may be a disease resulting from abnormal proliferation or differentiation of mesenchymal stem cells. The present investigation explored the novel strategy of hypoxia-preconditioned BMMSCs to reverse the impairment of osteonecrosis BMMSCs and enhance the therapeutic potential of hypoxia-treated BMMSC transplantation. METHODS: BMMSCs from the anterior superior iliac spine region of osteonecrosis rabbit were cultured under 20% O2 or 2% O2 conditions. Normal BMMSCs were cultured under 20% O2 condition as control. Growth factors secreted were examined by enzyme-linked immunosorbent assay. 20% O2 or 2% O2 BMMSCs were injected into the femoral head of rabbits after core decompression. Cell viability and apoptosis were assessed in vitro, and TUNEL staining of the femoral head was analyzed after transplantation. Angiogenesis (capillary-like structure formation, CD31 immunohistochemical staining and ink infusion angiography) and osteogenesis (Alizarin red-S staining, micro-CT scanning and OCN immunohistochemical staining) tests were conducted as well. RESULTS: 2% O2 exposure up-regulated growth factor secretion in BMMSCs. Apoptosis in 2% O2 group was lower when compared with that in 20% O2 osteonecrosis group. Cell viability in 2% O2 was significantly higher when compared with that in 20% O2 osteonecrosis group. Growth factor secretion, cell viability, apoptosis, capillary-like structure formation, Alizarin red-S staining, and ALP staining showed no difference between the 2% O2 BMMSC and normal BMMSC groups. Transplantation of 2% O2 versus 20% O2 mesenchymal stem cells after core decompression resulted in an increase in angiogenesis function and a decrease in local tissue apoptosis. Our study also found that osteogenesis function was improved after hypoxic stem cell transplantation. CONCLUSION: Hypoxic preconditioning of BMMSCs is an effective means of reversing the impairment of osteonecrosis BMMSCs, promoting their regenerative capability and therapeutic potential for the treatment of osteonecrosis.

Lithium chloride attenuates the abnormal osteogenic/adipogenic differentiation of bone marrow-derived mesenchymal stem cells obtained from rats with steroid-related osteonecrosis by activating the ß-catenin pathway.

Steroid-related osteonecrosis of the femoral head (ONFH) may be a disease that results from the abnormal osteogenic/adipogenic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs). In the present study, we examined the possible use of lithium in an aim to reverse the abnormal osteogenic/adipogenic differentiation of BMMSCs isolated from rats with steroid-related ONFH (termed ONFH-BMMSCs). BMMSCs obtained from steroid­related ONFH rat femurs were cultured with or without lithium chloride (LiCl). BMMSCs obtained from normal rat femurs were cultured as controls. LiCl significantly increased the expression of osteocalcin and Runx2 in the ONFH-BMMSCs during osteogenic induction. The mineralization of ONFH-BMMSCs following osteogenic induction was also enhanced. Furthermore, LiCl exerted anti-adipogenic effects on the ONFH-BMMSCs by inhibiting the expression of peroxisome proliferator-activated receptor γ (PPARγ) and fatty acid binding protein 4 (Fabp4) during adipogenic induction, and decreasing lipid droplet formation at the end of adipogenic induction. These effects of LiCl on the ONFH-BMMSCs were associated with an increased expression of ß-catenin and a decreased expression of phosphorylated GSK-3ß at Tyr-216, and these effects were abolished by treatment with quercetin, an antagonist of the ß-catenin pathway. The normal osteogenic/adipogenic activity of BMMSCs may be impaired in steroid-related ONFH. However, as demonstrated by our findings, LiCl reduces abnormal adipogenic activity and simultaneously increases the osteogenic differentiation of ONFH-BMMSCs by activating the ß-catenin pathway.

Circumferential electrocautery of the patella in primary total knee replacement without patellar replacement: a meta-analysis and systematic review.

The purpose of this meta-analysis and systematic review was to identify and assess whether circumferential electrocautery is useful for improving outcomes after primary total knee replacement(TKR). We searched MEDLINE, EMBASE, PubMed, SpringerLink, Web of Knowledge, OVID CINAHL, OVID EBM and Google Scholar and included articles published through January 2014. A total of 6 articles met the inclusion criteria. Of the 776 cases included in the analysis, 388 cases involved patellar denervation, and 388 cases were designated as the control group. The meta-analysis revealed no significant difference in the incidence of anterior knee pain (AKP, p = 0.18) or in the visual analogue scale score (VAS, p = 0.23) between the two groups. In addition, AKSS Function Score indicated no significant difference between the two groups (p = 0.28). However, the OKS (p = 0.02), patellar score (p = 0.01), AKSS-Knee Score (p = 0.004), range of motion (ROM, p < 0.0001) and WOMAC Score (p = 0.0003) indicated that circumpatellarelectrocautery improved clinical outcomes compared with non-electrocautery. The results indicate that circumferential electrocautery of the patella does not significantly improve AKP compared with non-electrocautery techniques but that circumferential electrocautery significantly improves patients' knee function after surgery. Therefore, we believe that circumferential electrocautery is beneficial to the outcome of primary TKR surgery without patellar replacement.

The effect of deferoxamine on angiogenesis and bone repair in steroid-induced osteonecrosis of rabbit femoral heads.

In this study, we examined whether local deferoxamine (DFO) administration can promote angiogenesis and bone repair in steroid-induced osteonecrosis of the femoral head (ONFH). Steroid-induced ONFH was induced in 65 mature male New Zealand white rabbits by methylprednisolone in combination with lipopolysaccharide. Six weeks later, the rabbits received no treatment (model group, N = 15), bilateral core decompression (CD group, N = 20) or CD in combination with local DFO administration (DFO group, N = 20). Six weeks after the surgery, vascularization in the femoral head was evaluated by ink artery infusion angiography and immunohistochemical staining for von Willebrand Factor (vWF). Bone repair was assessed by histologic analysis and micro-computed tomography (micro-CT). Immunohistochemical staining was performed to analyze the expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α), bone morphogenetic protein-2 (BMP-2), and osteocalcin (OCN). Ink artery infusion angiography and microvessel analysis by immuohistochemical staining for vWF showed more blood vessels in the DFO group than other groups. The expression of HIF-1α, VEGF, BMP-2, and OCN, indicated by immunohistochemical staining, was higher in the DFO group compared with other groups. Micro-CT scanning results indicated that the DFO group had larger volume of newly formed bone than the CD group. This work indicated that local DFO administration improved angiogenesis and bone repair of early stage ONFH in rabbit model, and it may offer an efficient, economic, and simple therapy for early stage ONFH.

Hypoxia-inducible factor prolyl hydroxylase inhibitor prevents steroid-associated osteonecrosis of the femoral head in rabbits by promoting angiogenesis and inhibiting apoptosis.

The purpose of this study was to investigate the preventive effect of ethyl 3,4-dihydroxybenzoate(EDHB) on steroid-associated femoral head osteonecrosis(ONFH) in a rabbit model. New Zealand white rabbits were randomly divided into two groups (prevention group and model group), each containing 24 rabbits. Osteonecrosis was induced by lipopolysaccharide(LPS) combined with methylprednisolone(MPS). The prevention group received an intraperitoneal injection of EDHB at 50 mg/kg body weight every other day starting three days before establishing rabbit models of osteonecrosis, for a total of nine doses. Osteonecrosis was verified by haematoxylin-eosin (HE) staining. The expression of HIF-1α and VEGF was analyzed by immunohistochemistry. Angiogenesis, apoptosis and microstructural parameters were also analyzed. The rabbit models of osteonecrosis were successfully established and observed by HE staining. Histopathological observations indicated that EDHB reduced the rate of empty lacunae and the incidence of osteonecrosis. Immunohistochemical staining for HIF-1α and VEGF suggested that EDHB therapy inhibited degradation of HIF-1α and promoted expression of VEGF. Ink artery infusion angiography and microvessel density analysis revealed that there were more microvessels in the prevention group than in the model group. The TUNEL apoptosis assay suggested that EDHB intervention could reduce the number of apoptotic cells in avascular osteonecrosis of the femoral head. Micro-CT scanning indicated that the treatment group had better microstructural parameters than the model group. EDHB prevents steroid-associated osteonecrosis of the femoral head in rabbits by promoting angiogenesis and inhibiting apoptosis of bone cells and hematopoietic tissue.

Immunoregulation effects of bone marrow-derived mesenchymal stem cells in xenogeneic acellular nerve grafts transplant.

This study evaluated whether bone marrow-derived mesenchymal stem cells (BM-MSCs) combined with xenogeneic acellular nerve grafts (xANGs) would reduce the inflammation reaction of xANGs transplantation. BM-MSCs were extracted, separated, purified, and cultured from the bone marrow of rats. Then BM-MSCs were seeded into 5 mm xANGs as experimental group, while xANGs group was chosen as control. Subcutaneous implantation and nerve grafts transplantation were done in this study. Walking-track tests, electrophysiological tests, H&E staining, and immunostaining of CD4, CD8, and CD68 of subcutaneous implantations, cytokine concentrations of IL-2, IL-10, IFN-γ and TNF-α in lymphocytes supernatants and serum of the two groups were evaluated. Walking-track tests and electrophysiological tests suggested the group of BM-MSCs with xANGs obtained better results than xANGs group (P < 0.05). H&E staining and immunostaining of CD4, CD8, and CD68 of subcutaneous implantations showed there were less inflammatory cells in the group of BM-MSCs when compared with the xANGs group. The cytokine concentrations of IL-2, IFN-γ, and TNF-α in BM-MSCs group were lower than xANGs group in lymphocytes supernatants and serum (P < 0.05). However, IL-10 concentrations in BM-MSCs group were higher than xANGs group (P < 0.05). xANG with BM-MSCs showed better nerve repair function when compared with xANG group. Furthermore, xANG with BM-MSCs showed less inflammatory reaction which might indicate the reason of its better nerve regeneration.

The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration.

Hypoxia-inducible factors (HIFs) are oxygen-dependent transcriptional activators that play crucial roles in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions. The group of enzymes that can catalyse the hydroxylation reaction of HIF-1 is prolyl hydroxylase domain proteins (PHDs). PHD inhibitors (PHIs) activate the HIF pathway by preventing degradation of HIF- α via inhibiting PHDs. Osteogenesis and angiogenesis are tightly coupled during bone repair and regeneration. Numerous studies suggest that HIFs and their target gene, vascular endothelial growth factor (VEGF), are critical regulators of angiogenic-osteogenic coupling. In this brief perspective, we review current studies about the HIF pathway and its role in bone repair and regeneration, as well as the cellular and molecular mechanisms involved. Additionally, we briefly discuss the therapeutic manipulation of HIFs and VEGF in bone repair and bone tumours. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours.

Patrilineal background of esophageal cancer and gastric cardia cancer patients in a Chaoshan high-risk area in China.

The Taihang Mountain range of north-central China, the Southern region area of Fujian province, and the Chaoshan plain of Guangdong province are 3 major regions in China well known for their high incidence of esophageal cancer (EC). These areas also exhibit high incidences of gastric cardia cancer (GCC). The ancestors of the Chaoshanese, now the major inhabitants in the Chaoshan plain, were from north-central China. We hypothesized that EC and GCC patients in Chaoshan areas share a common ancestry with Taihang Mountain patients. We analyzed 16 East Asian-specific Y-chromosome biallelic markers (single nucleotide polymorphisms; Y-SNPs) and 6 Y-chromosome short tandem repeat (Y-STR) loci in 72 EC and 48 GCC patients from Chaoshan and 49 EC and 63 GCC patients from the Taihang Mountain range. We also compared data for 32 Chaoshan Hakka people and 24 members of the aboriginal She minority who live near the Chaoshan area. Analysis was by frequency distribution and principal component, correlation and hierarchical cluster analysis of Y-SNP. Chaoshan patients were closely related to Taihang Mountain patients, even though they are geographically distant. Y-STR analysis revealed that the 4 patient groups were more closely related with each other than with other groups. Network analysis of the haplogroup O3a3c1-M117 showed a high degree of patient-specific substructure. We suggest that EC and GCC patients from these 2 areas share a similar patrilineal genetic background, which may play an important role in the genetic factor of EC and GCC in these populations.