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BACKGROUND: Primary familial brain calcification (PFBC) is a monogenic disorder characterized by bilateral calcifications in the brain. The genetic basis remains unknown in over half of the PFBC patients, indicating the existence of additional novel causative genes. NAA60 was a recently reported novel causative gene for PFBC. OBJECTIVE: The aim was to identify the probable novel causative gene in an autosomal recessive inherited PFBC family. METHODS: We performed a comprehensive genetic study on a consanguineous Chinese family with 3 siblings diagnosed with PFBC. We evaluated the effect of the variant in a probable novel causative gene on the protein level using Western blot, immunofluorescence, and coimmunoprecipitation. Possible downstream pathogenic mechanisms were further explored in gene knockout (KO) cell lines and animal models. RESULTS: We identified a PFBC co-segregated homozygous variant of c.460_461del (p.D154Lfs*113) in NAA60. Functional assays showed that this variant disrupts NAA60 protein localization to Golgi and accelerated protein degradation. The mutant NAA60 protein alters its interaction with the PFBC-related proteins PiT2 and XPR1, affecting intracellular phosphate homeostasis. Further mass spectrometry analysis in NAA60 KO cell lines revealed decreased expression of multiple brain calcification-associated proteins, including reduced folate carrier (RFC), a folate metabolism-related protein. CONCLUSIONS: Our study replicated the identification of NAA60 as a novel causative gene for autosomal recessive PFBC, demonstrating our causative variant leads to NAA60 loss of function. The NAA60 loss of function disrupts not only PFBC-related proteins (eg, PiT2 and XPR1) but also a wide range of other brain calcification-associated membrane protein substrates (eg, RFC), and provided a novel probable pathogenic mechanism for PFBC. © 2024 International Parkinson and Movement Disorder Society.
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Epimedium is thought to enhance the integrity of tendons and bones, ease joint discomfort and rigidity and enhance kidney function. Although glucocorticoids are commonly used in clinical practice, the mechanism by which the active compound Epimedin C (EC) alleviates glucocorticoid-induced osteoporosis (GIOP) is not well understood. The therapeutic potential of EC in treating GIOP was evaluated using alizarin red S staining, calcein immersion and fluorescence imaging, and bone mineralization, bone mass accumulation and bone density in zebrafish larvae were determined. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the key signalling pathways related to bone development were identified. A protein-protein interaction network (PPIN) was constructed to identify osteoclast characteristic genes and the findings were verified using real-time quantitative PCR (RT-qPCR). The bone tissue damage caused by prednisolone was reduced by EC. It also altered physiological processes, improved bone density, boosted mineralization and increased bone mass and activity. Subsequent empirical investigations showed that EC impacted the major signalling pathways involved in bone development, such as osteoclast differentiation, oestrogen, MAPK, insulin resistance, PPAR and AMPK signalling pathways. It also decreased the expression of genes typical of osteoclasts. The results of our study uncover a previously unknown function of EC in controlling bone formation and emphasize the potential of EC as a therapeutic target. The osteoprotective effect of EC indicates its potential as a cost-effective strategy for treating GIOP.
Subject(s)
Disease Models, Animal , Flavonoids , Glucocorticoids , Osteoclasts , Osteoporosis , Signal Transduction , Zebrafish , Animals , Osteoporosis/chemically induced , Osteoporosis/metabolism , Osteoporosis/genetics , Osteoporosis/pathology , Osteoporosis/drug therapy , Flavonoids/pharmacology , Glucocorticoids/adverse effects , Glucocorticoids/pharmacology , Osteoclasts/metabolism , Osteoclasts/drug effects , Signal Transduction/drug effects , Bone Density/drug effects , Protein Interaction Maps , Osteogenesis/drug effects , Osteogenesis/genetics , Calcification, Physiologic/drug effectsABSTRACT
BACKGROUND: Laparoscopic radical pancreatectomy is safe and beneficial for recectable pancreatic cancer, but the extent of resection for early-stage tumors remains controversial. METHODS: Consecutive patients with left-sided pancreatic cancer who underwent either laparoscopic radical antegrade modular pancreatosplenectomy (LRAMPS, n = 54) or laparoscopic distal pancreatosplecnectomy (LDP, n = 131) between October 2020 and December 2022 were reviewed. The preoperative radiological selection criteria were as follows: (1) tumor diameter ≤ 4 cm; (2) located ≥ 1 cm from the celiac trunk; (3) didn't invade the fascial layer behind the pancreas. RESULTS: After 1:1 propensity score matching (LRAMPS, n = 54; LDP, n = 54), baseline data were well-balanced with no differences. LRAMPS resulted in longer operation time (240.5 vs. 219.0 min, P = 0.020) and higher intraoperative bleeding volume (200 vs. 150 mL, P = 0.001) compared to LDP. Although LRAMPS harvested more lymph nodes (16 vs. 13, P = 0.008), there were no statistically significant differences in lymph node positivity rate (35.2% vs. 33.3%), R0 pancreatic transection margin (94.4% vs. 96.3%), and retroperitoneal margin (83.3% vs. 87.0%) rate. Postoperative complications did not significantly differ between the two groups. However, LRAMPS was associated with increased drainage volume (85.0 vs. 40.0 mL, P = 0.001), longer time to recover semi-liquid diet compared to LDP (5 vs. 4 days, P < 0.001) and increased daily bowel movement frequency. Tumor recurrence pattern and recurrence-free survival were comparable between the two groups, but the adjuvant chemotherapy regimens varied, and the completion rate of the 6-month intravenous chemotherapy was lower in the LRAMPS group compared to the LDP group (51.9% vs. 75.9%, P = 0.016). CONCLUSIONS: LRAMPS did not provide oncological benefits over LDP for left-sided pancreatic cancer within the selection criteria, but it increased operation time, intraoperative bleeding, and postoperative bowel movement frequency. These factors impacted the regimen selection and completion of adjuvant chemotherapy, consequently compromising the potential benefits of LRAMPS in achieving better local control.
Subject(s)
Laparoscopy , Pancreatectomy , Pancreatic Neoplasms , Propensity Score , Splenectomy , Humans , Male , Female , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/pathology , Laparoscopy/methods , Pancreatectomy/methods , Splenectomy/methods , Middle Aged , Aged , Retrospective Studies , Operative Time , Treatment Outcome , Neoplasm Staging , Postoperative Complications/epidemiology , Postoperative Complications/etiologyABSTRACT
Pyroptosis is a programmed cell death, which has garnered increasing attention because it relates to the immune and therapy response. However, few studies focus on the application of pyroptosis-related genes (PRGs) in predicting osteosarcoma (OS) patients' prognoses. In this study, the gene expression and clinical information of OS patients were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Based on these PRGs and unsupervised clustering analysis, all OS samples can be classified into 2 clusters. The 8 key differential expressions for PRGs (LAG3, ITGAM, CCL2, TLR4, IL2RA, PTPRC, FCGR2B, and CD5) were established through the univariate Cox regression and utilized to calculate the risk score of all samples. According to the 8-gene signature, OS samples can be divided into high and low-risk groups and correlation analysis can be performed using immune cell infiltration and immune checkpoints. Finally, we developed a nomogram to improve the PRG-predictive model in clinical application. We verified the predictive performance using receiver operating characteristic (ROC) and calibration curves. There were significant differences in survival, immune cell infiltration and immune checkpoints between the low and high-risk groups. A nomogram was developed with clinical indicators and the risk scores were effective in predicting the prognosis of patients with OS. In this study, a prognostic model was constructed based on 8 PRGs were proved to be independent prognostic factors of OS and associated with tumor immune microenvironment. These 8 prognostic genes were involved in OS development and may serve as new targets for developing therapeutic drugs.
Subject(s)
Bone Neoplasms , Osteosarcoma , Humans , Prognosis , Pyroptosis , Nomograms , Osteosarcoma/genetics , Bone Neoplasms/genetics , Tumor MicroenvironmentABSTRACT
Familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1) is caused by (TTTTA)exp(TTTCA)exp repeat expansions in SAMD12, while pure (TTTTA)exp is polymorphic. Our investigation focused on the origin and evolution of pure (TTTTA)exp and (TTTTA)exp(TTTCA)exp at this locus. We observed a founder effect between them. The phylogenetic analysis suggested that the (TTTTA)exp(TTTCA)exp might be generated from pure (TTTTA)exp through infrequent transformation events. Long-read sequencing revealed somatic generation of (TTTTA)exp(TTTCA)exp from pure (TTTTA)exp, likely via long segment (TTTCA) repeats insertion. Our findings indicate close relationships between the non-pathogenic (TTTTA)exp and the pathogenic (TTTTA)exp(TTTCA)exp, with dynamic interconversions. This sheds light on the genesis of pathogenic repeat expansions from ancestral premutation alleles. Our results may guide future studies in detecting novel repeat expansion disorders and elucidating repeat expansion mutational processes, thereby enhancing our understanding of human genomic variation.
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BACKGROUND: There is no evidence supporting the feasibility of laparoscopic pancreaticoduodenectomy (LPD) compared to open pancreatoduodenectomy (OPD) following neoadjuvant chemotherapy (NACT) for pancreatic ductal adenocarcinoma (PDAC). METHODS: The clinical data of consecutive patients with borderline resectable PDAC who received NACT and underwent either LPD or OPD between January 2020 and December 2022 at Fudan University Shanghai Cancer Center was prospectively collected and retrospectively analyzed. RESULTS: The analysis included 57 patients in the OPD group and 20 in the LPD group. Following NACT, the LPD group exhibited a higher median CA19-9 decrease rate compared to the OPD group (85.3% vs. 66.9%, P = 0.042). Furthermore, 3 anatomically borderline PDACs in the LPD group and 5 in the OPD group were downstaged into resectable status (30.0% vs. 12.3%, P = 0.069). According to RECIST criteria, 51 (66.2%) patients in the entire cohort were evaluated as having stable disease. The median operation time for the LPD group was longer than the OPD group (419 vs. 325 min, P < 0.001), while the venous resection rate was 35.0% vs. 43.9%, respectively (P = 0.489). There was no difference in the number of retrieved lymph nodes, with a median number of 18.5 in the LPD group and 22 in the OPD group, and the R1 margin rate (15.0% vs. 12.3%) was also comparable. The incidence of Clavien-Dindo complications (35.0% vs. 66.7%, P = 0.018) was lower in the LPD group compared to the OPD group. Multivariable regression analysis revealed that a tumor diameter > 3 cm before NACT (HR 2.185) and poor tumor differentiation (HR 1.805) were independent risk factors for recurrence-free survival, and a decrease rate of CA19-9 > 70% (OR 0.309) was a protective factor for early tumor recurrence and overall survival. CONCLUSIONS: LPD for PDAC following NACT is feasible and oncologically equivalent to OPD. Effective control of CA19-9 levels is beneficial in reducing early tumor recurrence and improving overall survival.
Subject(s)
Adenocarcinoma , Carcinoma, Pancreatic Ductal , Laparoscopy , Pancreatic Neoplasms , Humans , Pancreaticoduodenectomy/adverse effects , Retrospective Studies , Neoadjuvant Therapy/adverse effects , Neoplasm Recurrence, Local/etiology , Feasibility Studies , CA-19-9 Antigen , China , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/surgery , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/surgery , Adenocarcinoma/drug therapy , Adenocarcinoma/surgery , Laparoscopy/adverse effects , Postoperative Complications/etiology , Length of StayABSTRACT
BACKGROUND: The incidence of postoperative pancreatic fistula (POPF) following enucleation is high, and prophylactic pancreaticojejunostomy (PPJ) is frequently performed. Minimally invasive enucleation (MEN) has been demonstrated to be safe and feasible, leaving most enucleation wounds exposed. METHODS: The clinical data of 40 patients who underwent open enucleation with PPJ at our center between 2012 and 2021 were compared with those of 80 patients who underwent MEN. RESULTS: The MEN group had better outcomes than the PPJ group in terms of intraoperative bleeding (50.0 versus 100.0 mL), postoperative semi-liquid diet recovery (2.0 versus 5.0 days), and postoperative length of stay (7.7 versus 12.5 days). While the MEN group had higher rates of complex enucleation (60.0% versus 40.0%), main pancreatic duct repair (32.5% versus 10.0%), discharge with drains (48.8% versus 25.0%), and grade B POPFs (47.5% versus 17.5%). Both surgical methods effectively preserved pancreatic function; however, two patients in the PPJ group experienced severe haemorrhaging and died. Additionally, during the follow-up period, gastrointestinal bleeding was found and discomfort in the surgical area was reported. CONCLUSION: Pancreatic enucleation combined with PPJ should be avoided, and although a biochemical or grade B POPF may develop after MEN, it can be compensated for by preserving pancreatic function and ensuring a good long-term quality of life in the patients.
Subject(s)
Pancreatic Neoplasms , Pancreaticojejunostomy , Humans , Pancreaticojejunostomy/adverse effects , Pancreaticojejunostomy/methods , Quality of Life , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/complications , Pancreatic Ducts/surgery , Pancreatectomy/adverse effects , Pancreatectomy/methods , Pancreatic Fistula/epidemiology , Pancreatic Fistula/etiology , Pancreatic Fistula/prevention & control , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control , Postoperative Complications/etiology , Pancreaticoduodenectomy/adverse effects , Risk Assessment , Retrospective StudiesABSTRACT
Miscommunications between air traffic controllers (ATCOs) and pilots in air traffic control (ATC) may lead to catastrophic aviation accidents. Thanks to advances in speech and language processing, automatic speech recognition (ASR) is an appealing approach to prevent misunderstandings. To allow ATCOs and pilots sufficient time to respond instantly and effectively, the ASR systems for ATC must have both superior recognition performance and low transcription latency. However, most existing ASR works for ATC are primarily concerned with recognition performance while paying little attention to recognition speed, which motivates the research in this article. To address this issue, this article introduces knowledge distillation into the ASR for Mandarin ATC communications to enhance the generalization performance of the light model. Specifically, we propose a simple yet effective lightweight strategy, named Target-Swap Knowledge Distillation (TSKD), which swaps the logit output of the teacher and student models for the target class. It can mitigate the potential overconfidence of the teacher model regarding the target class and enable the student model to concentrate on the distillation of knowledge from non-target classes. Extensive experiments are conducted to demonstrate the effectiveness of the proposed TSKD in homogeneous and heterogeneous architectures. The experimental results reveal that the generated lightweight ASR model achieves a balance between recognition accuracy and transcription latency.
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Background: Tumors involving the main pancreatic duct (MPD) used to be a contraindication for enucleation. Methods: Clinical data of consecutive patients with pancreatic tumors who received laparoscopic or robotic enucleation (LEN or REN) between January 2019 and December 2021 at Fudan University Shanghai Cancer Center were analyzed. Results: Ninety-six patients were included in the analysis, with 55 in the LEN group and 41 in the REN group, and no conversion to laparotomy. Most tumors were located in the head of pancreas (71.9 %). The tumor diameter (3.1 vs. 1.9 cm) was larger, and more cystic tumors (92.7 % vs. 56.4 %) and more tumors involving the MPD (34.1 % vs. 3.6 %) were observed in the REN group. MPD support tube insertion was performed in 15 cases, with 11 in the REN group and 4 in the LEN group. The incidence of biochemical and grade B postoperative pancreatic fistula (POPF) was both 46.9 %, and no grade C POPF occurred. Among the 45 patients with grade B POPF, 28 cases (62.2 %) were due to carrying drainage tube >3 weeks without additional treatment, and only 4 cases required invasive treatment. For patients with MPD support tube implantation (n = 15), support tube fall-offs were observed in 12 cases, 2 patients had MPD dilatation, and no MPD stricture, stone formation or pancreatic atrophy was observed during follow-up. Conclusions: The incidence of POPF was high but still controllable without serious complications after minimally invasive enucleation. The MPD is no longer a restricted area, and the robotic system has advantages in handling complex enucleations.
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Although patients with lumbar disc herniation (LDH) can achieve significant relief from lower back and leg pain after lumbar microdiscectomy, a few patients complain of discomfort due to residual leg numbness (RLN). This study aimed to identify potential risk factors for RLN after lumbar microdiscectomy. We prospectively collected and analyzed patients with LDH who underwent microdiscectomy between September 2016 and December 2020. All included patients had preoperative LN symptoms. Patients with RLN were defined as those with LN at the last follow-up. The relationships between RLN and sex, age, body mass index (BMI), current smoking status, diabetes mellitus, revision surgery, preoperative LN Numeric Rating Scale (NRS) score, duration of preoperative LN, RLN at discharge, sagittal range of motion (SROM), Modic change, disc Pfirrmann grade were analyzed. The RLN was observed in 33.5% (112/334) of patients at the last follow-up. No significant differences were observed in age, sex, BMI, current smoking status, or diabetes between the RLN and non-RLN groups. The preoperative LN NRS score, preoperative LN duration, rate of RLN at discharge, and revision surgery were significantly higher in the RLN group than those in the non-RLN group. Multivariate logistic regression analysis identified the preoperative LN NRS score, duration of preoperative LN, RLN at discharge, revision surgery, and SROM as risk factors for RLN in the long-term follow-up. Patients with higher preoperative LN NRS scores and SROM, longer preoperative LN duration, RLN at discharge, and revision surgery were more likely to experience RNL after lumbar microdiscectomy.
Subject(s)
Intervertebral Disc Displacement , Humans , Intervertebral Disc Displacement/surgery , Hypesthesia/epidemiology , Hypesthesia/etiology , Hypesthesia/surgery , Leg/surgery , Diskectomy/adverse effects , Risk Factors , Lumbar Vertebrae/surgery , Treatment Outcome , Retrospective StudiesABSTRACT
Ideal periosteum materials are required to participate in a sequence of bone repair-related physiological events, including the initial immune response, endogenous stem cell recruitment, angiogenesis, and osteogenesis. However, conventional tissue-engineered periosteal materials have difficulty achieving these functions by simply mimicking the periosteum via structural design or by loading exogenous stem cells, cytokines, or growth factors. Herein, we present a novel biomimetic periosteum preparation strategy to comprehensively enhance the bone regeneration effect using functionalized piezoelectric materials. The resulting biomimetic periosteum possessing an excellent piezoelectric effect and improved physicochemical properties was prepared using a biocompatible and biodegradable poly(3-hydroxybutyric acid-co-3-hydrovaleric acid) (PHBV) polymer matrix, antioxidized polydopamine-modified hydroxyapatite (PHA), and barium titanate (PBT), which were further incorporated into the polymer matrix to fabricate a multifunctional piezoelectric periosteum by a simple one-step spin-coating method. The addition of PHA and PBT dramatically enhanced the physicochemical properties and biological functions of the piezoelectric periosteum, resulting in improved surface hydrophilicity and roughness, enhanced mechanical performance, tunable degradation behavior, and stable and desired endogenous electrical stimulations, which is conducive to accelerating bone regeneration. Benefiting from endogenous piezoelectric stimulation and bioactive components, the as-fabricated biomimetic periosteum demonstrated favorable biocompatibility, osteogenic activity, and immunomodulatory functions in vitro, which not only promoted adhesion, proliferation, and spreading as well as osteogenesis of mesenchymal stem cells (MSCs) but also effectively induced M2 macrophage polarization, thereby suppressing reactive oxygen species (ROS)-induced inflammatory reactions. Through in vivo experiments, the biomimetic periosteum with endogenous piezoelectric stimulation synergistically accelerated the formation of new bone in a rat critical-sized cranial defect model. The whole defect was almost completely covered by new bone at 8 weeks post treatment, with a thickness close to that of the host bone. Collectively, with its favorable immunomodulatory and osteogenic properties, the biomimetic periosteum developed here represents a novel method to rapidly regenerate bone tissue using piezoelectric stimulation.
Subject(s)
Osteogenesis , Periosteum , Rats , Animals , Periosteum/physiology , Bone Regeneration , Tissue Engineering , Durapatite/pharmacology , Tissue Scaffolds/chemistryABSTRACT
OBJECTIVE: We compared the clinical outcomes of minimally invasive transforaminal lumbar interbody fusion (Mis-TLIF) and endoscopic transforaminal lumbar interbody fusion (Endo-TLIF). METHODS: We retrospectively analyzed the clinical data of patients who underwent single-segment Mis-TLIF or Endo-TLIF between June 2016 and June 2019 at our hospital. The patients in each treatment group were matched 1:1 for sex, age, and type of lumbar degenerative disease, and their clinical outcomes were compared at discharge and at 1 and 2 years postoperatively. RESULTS: Our study included 64 patients, with 32 patients in each treatment group. Operative time and fluoroscopy time were significantly higher in the Endo-TLIF versus Mis-TLIF groups, whereas estimated blood loss, postoperative drainage volume, and the low back pain visual analog scale score at discharge were significantly lower. Both treatments achieved exact interbody fusion at the final-follow up. There was no significant difference in the visual analog scale score or Oswestry Disability Index between the groups at 1 and 2 years postoperatively. Complication rates were higher in the Endo-TLIF group (21.9%) than in the Mis-TLIF group (6.2%), although the difference was not significant. CONCLUSIONS: Although there was no difference in the long-term outcomes between the treatments, Endo-TLIF had less blood loss and a lower postoperative drainage volume and low back pain visual analog scale score at discharge than Mis-TLIF. However, the longer operative time and potentially higher complication rate of Endo-TLIF suggest that surgeons may need to overcome the steeper learning curve than the procedure of Mis-TLIF.
Subject(s)
Intervertebral Disc Degeneration , Low Back Pain , Spinal Fusion , Humans , Retrospective Studies , Case-Control Studies , Lumbar Vertebrae/surgery , Low Back Pain/etiology , Low Back Pain/surgery , Minimally Invasive Surgical Procedures/methods , Treatment Outcome , Intervertebral Disc Degeneration/surgery , Spinal Fusion/methodsABSTRACT
Osteosarcoma (OS) is a prevalent primary malignant bone tumor that commonly occurs in children and adolescents. Apigenin (4',5,7-trihydroxyflavone) is one of the most researched phenolic compounds that exhibits antitumor effects in several cancers. The aim of the current study was to investigate the effect and underlying mechanisms of apigenin on OS. To address this, OS cells (SOSP-9607) were treated with different concentrations of apigenin. The proliferation, migration, invasion, stem-like properties, and Warburg effect of apigenin-treated OS cells were evaluated. Apigenin was found to suppress the proliferation of SOSP-9607 cells and inhibit epithelial-mesenchymal transition, as indicated by decreased number of migrated and invaded cells, decreased protein expression of vimentin, and increased protein expression of E-cadherin. Additionally, apigenin suppressed tumorsphere formation and reduced the proportion of SOSP-9607 cells with positive expression of the stem cell-related markers Nanog and OCT-4. Apigenin inhibited the Warburg effect in SOSP-9607 cells, as demonstrated by decreased glucose and lactic acid levels, increased citrate and ATP levels, and downregulation of GLUT1, HK1, and LDHA, which are metabolism-related enzymes related to the Warburg effect. Moreover, apigenin inhibited the phosphorylation of PI3K, Akt, and mTOR in SOSP-9607 cells. Collectively, these results indicate that apigenin suppresses the Warburg effect and stem-like properties in SOSP-9607 cells, which may be mediated by PI3K/Akt/mTOR signaling, thus, providing a novel strategy for OS treatment.
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Pancreatic cancer (PC) is one of the most deadly diseases, and its incidence is increasing year by year. The methyltransferase SETD8 has been demonstrated to play an important role in tumor cell proliferation and metastasis. However, little is known about whether SETD8 could affect the invasion and metastasis of PC and the mechanism underlying the regulation. Based on our previous report, here, we further found that SETD8 could promote the invasion and migration of PC cells by inducing the expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 was predominantly upregulated in PC tissues and was correlated with lymph node metastasis and worse prognosis. Mechanistically, SETD8 mediated ROR1 activity and regulated PC cells invasion and migration, although promoting the expression of stemness and epithelial-mesenchymal transition-related molecules. This promotion effect disappeared when the catalytically inactive mutant SETD8 was overexpressed, which could be counteracted by the SETD8-specific methyltransferase inhibitor UNC0379. Collectively, our results demonstrate that SETD8 may be a novel prognostic factor and a therapeutic target of PC.
Subject(s)
Carcinoma, Pancreatic Ductal/metabolism , Epithelial-Mesenchymal Transition/genetics , Histone-Lysine N-Methyltransferase/metabolism , Pancreatic Neoplasms/metabolism , Receptor Tyrosine Kinase-like Orphan Receptors/metabolism , Stem Cells/metabolism , Aged , Biomarkers, Tumor/metabolism , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Cell Movement/genetics , Female , Histone-Lysine N-Methyltransferase/genetics , Humans , Male , Middle Aged , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Prognosis , Receptor Tyrosine Kinase-like Orphan Receptors/genetics , Survival Analysis , Up-Regulation/geneticsABSTRACT
Osteosarcoma is the most common primary orthopedic malignant bone tumor in adolescents. However, the traditional neoadjuvant chemotherapy regimen has reached the bottleneck. TPZ is a hypoxic prodrug that has a powerful anti-tumor effect in the hypoxic microenvironment of tumors. And ferroptosis is a newly discovered cell death in 2012, and ferroptosis inducers have been used in anti-tumor therapy research in recent decades. Though, the role of TPZ and ferroptosis in osteosarcoma remains unclear. The aim of this study was to investigate the role of TPZ in osteosarcoma and the specific mechanism. MTT assay showed the extraordinary inhibition of TPZ on three osteosarcoma cells under hypoxia. And fluorescence of Fe2+ staining was enhanced by TPZ. Western blotting showed decreased expression of SLC7A11 and GPX4. Lipid peroxidation was confirmed by MDA assay and C11 BODIPY 581/591 staining. SLC7A11 overexpression could restored the proliferation and migration abilities inhibited by TPZ. Thus, we for the first time demonstrated that TPZ could inhibit the proliferation and migration of osteosarcoma cells, and induce ferroptosis in part through inhibiting SLC7A11.
Subject(s)
Amino Acid Transport System y+/metabolism , Antineoplastic Agents/pharmacology , Bone Neoplasms/drug therapy , Ferroptosis/drug effects , Osteosarcoma/drug therapy , Tirapazamine/pharmacology , Bone Neoplasms/metabolism , Cell Line, Tumor , Humans , Osteosarcoma/metabolismABSTRACT
Background: Ischemic stroke is a common disease with poor prognosis, which has become one of the leading causes of morbidity and mortality worldwide. Astragaloside IV (AS-IV) is the main bioactive ingredient of Astragali Radix (which has been used for ischemic stroke for thousands of years) and has been found to have multiple bioactivities in the nervous system. In the present study, we aimed to explore the neuroprotective effects of AS-IV in rats with cerebral ischemia/reperfusion (CIR) injury targeting the Sirt1/Mapt pathway. Methods: Sprague-Dawley rats (male, 250-280 g) were randomly divided into the Sham group, middle cerebral artery occlusion/reperfusion (MCAO/R) group, AS-IV group, MCAO/R + EX527 (SIRT1-specific inhibitor) group, and AS-IV + EX527 group. Each group was further assigned into several subgroups according to ischemic time (6 h, 1 d, 3 d, and 7 days). The CIR injury was induced in MCAO/R group, AS-IV group, MCAO/R + EX527 group, and AS-IV + EX527 group by MCAO surgery in accordance with the modified Zea Longa criteria. Modified Neurological Severity Scores (mNSS) were used to evaluate the neurological deficits; TTC (2,3,5-triphenyltetrazolium chloride) staining was used to detect cerebral infarction area; Western Blot was used to assess the protein levels of SIRT1, acetylated MAPT (ac-MAPT), phosphorylated MAPT (p-MAPT), and total MAPT (t-MAPT); Real-time Quantitative Polymerase Chain Reaction (qRT-PCR) was used in the detection of Sirt1 and Mapt transcriptions. Results: Compared with the MCAO/R group, AS-IV can significantly improve the neurological dysfunction (p < 0.05), reduce the infarction area (p < 0.05), raise the expression of SIRT1 (p < 0.05), and alleviate the abnormal hyperacetylation and hyperphosphorylation of MAPT (p < 0.05). While compared with the AS-IV group, AS-IV + EX527 group showed higher mNSS scores (p < 0.05), more severe cerebral infarction (p < 0.05), lower SIRT1 expression (p < 0.01), and higher ac-MAPT and p-MAPT levels (p < 0.05). Conclusion: AS-IV can improve the neurological deficit after CIR injury in rats and reduce the cerebral infarction area, which exerts neuroprotective effects probably through the Sirt1/Mapt pathway.
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Bone marrow stromal cells (MSCs) are a useful source of stem cells for the treatment of various brain injury diseases due to their abundant supply and fewer ethical problems compared with transplant treatment. However, the clinical application of MSCs is limited due to allograft rejection and immunosuppression in the process of MSCs transplantation. According to previous studies, microglial cell autophagy occurs following co-culture with MSCs. In the present study, exosomes were obtained from MSCs and subsequently characterized using transmission electron microscopy, atomic force microscopy and dynamic light scattering particle size analysis. The type of microRNAs (miRs) found in the exosomes was then analyzed via gene chip. The results demonstrated that microglial cell autophagy could be induced by exosomes. This mechanism was therefore investigated further via reverse transcription-quantitative PCR, western blotting and luciferase assays. These results demonstrated that exosomes from MSCs could induce microglial cell autophagy through the miR-32-mediated regulation of disabled homolog 2-interacting protein, thus providing a theoretical basis for the clinical application of miRs in MSCs.
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OBJECTIVE To compare Mesh-plug, Lichtenstein, transabdominal preperitoneal (TAPP), and totally extraperitoneal (TEP) repairs in regards to operation time, seroma, infection, and recurrence of inguinal hernia repair. METHODS Relevant literature was searched in the Cochrane Library, Pubmed, and Embase. Furthermore, the analysis of randomized controlled studies (RCTs) was performed using methods recommended by the Cochrane Collaboration. The main outcomes including operation time, seroma, infection, and recurrence were evaluated. RESULTS A total of 38 RCTs with 3255 patients were included in the meta-analysis. In addition, the comparison between Mesh-plug, Lichtenstein, TAPP, and TEP showed the differences were not significant regarding operation time, seroma, infection, and recurrence. CONCLUSIONS Meta-analysis suggests that Mesh-plug, Lichtenstein, TAPP, and TEP are comparable in the outcomes of hernia repair, such as operation time, seroma, infection, and recurrence.