Circular RNA PDK1 targets miR-4731-5p to enhance TNXB expression in ligamentum flavum hypertrophy.

Hypertrophic ligamentum flavum (LF) is a main factor responsible for lumbar spinal stenosis (LSS); however, the exact mechanisms of the pathogenesis of these processes remain unknown. This study aimed to elucidate whether circular RNAs and microRNAs regulate the pathogenesis of LF and LSS, especially focusing on circPDK1 (hsa_circ_0057105), a circRNA targeting pyruvate dehydrogenase kinase 1 and differentially expressed in LF tissues between lumbar disk herniation and LSS patients. The circPDK1/miR-4731 and miR-4731/TNXB (Tenascin XB) interactions were predicted and validated by luciferase reporter assay. Colony formation, wound-healing, and MTT assays were used for estimating cell proliferation and migration. Protein expression levels were evaluated using Western blotting. TNXB expression was verified using immunohistochemistry (IHC). Overexpressing circPDK1 promoted the proliferation, migration, and expression of fibrosis-related protein (alpha smooth muscle actin (α-SMA), lysyl oxidase like 2 (LOXL2), Collagen I, matrix metalloproteinase-2 (MMP-2) and TNXB) in LF whereas miR-4731-5p showed opposite effects. The expression of TNXB was promoted by circPDK1; contrary results were observed with miR-4731-5p. Co-overexpression of miR-4731-5p partially reversed the proliferative and fibrosis-prompting effects of circPDK1 or TNXB. The circPDK1-miR-4731-TNXB pathway may be proposed as a regulatory axis in LF hypertrophy, which might shed light on in-depth research of LSS, as well as providing a novel therapeutic target for LF hypertrophy-induced LSS.

Using clinical and radiomic feature-based machine learning models to predict pathological complete response in patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiation.

OBJECTIVE: This study aimed to build radiomic feature-based machine learning models to predict pathological clinical response (pCR) of neoadjuvant chemoradiation therapy (nCRT) for esophageal squamous cell carcinoma (ESCC) patients. METHODS: A total of 112 ESCC patients who underwent nCRT followed by surgical treatment from January 2008 to December 2018 were recruited. According to pCR status (no visible cancer cells in primary cancer lesion), patients were categorized into primary cancer lesion pCR (ppCR) group (N = 65) and non-ppCR group (N = 47). Patients were also categorized into total pCR (tpCR) group (N = 48) and non-tpCR group (N = 64) according to tpCR status (no visible cancer cells in primary cancer lesion or lymph nodes). Radiomic features of pretreatment CT images were extracted, feature selection was performed, machine learning models were trained to predict ppCR and tpCR, respectively. RESULTS: A total of 620 radiomic features were extracted. For ppCR prediction models, radiomic model had an area under the curve (AUC) of 0.817 (95% CI: 0.732-0.896) in the testing set; and the combination model that included rad-score and clinical features had a great predicting performance, with an AUC of 0.891 (95% CI: 0.823-0.950) in the testing set. For tpCR prediction models, radiomic model had an AUC of 0.713 (95% CI: 0.613-0.808) in the testing set; and the combination model also had a great predicting performance, with an AUC of 0.814 (95% CI: 0.728-0.881) in the testing set. CONCLUSION: This study built machine learning models for predicting ppCR and tpCR of ESCC patients with favorable predicting performance respectively, which aided treatment plan optimization. CLINICAL RELEVANCE STATEMENT: This study significantly improved the predictive value of machine learning models based on radiomic features to accurately predict response to therapy of esophageal squamous cell carcinoma patients after neoadjuvant chemoradiation therapy, providing guidance for further treatment. KEY POINTS: • Combination model that included rad-score and clinical features had a great predicting performance. • Primary tumor pCR predicting models exhibit better predicting performance compared to corresponding total pCR predicting models.

Using radiomic features of lumbar spine CT images to differentiate osteoporosis from normal bone density.

OBJECTIVE: This study aimed to develop a predictive model to detect osteoporosis using radiomic features from lumbar spine computed tomography (CT) images. METHODS: A total of 133 patients were included in this retrospective study, 41 men and 92 women, with a mean age of 65.45 ± 9.82 years (range: 31-94 years); 53 had normal bone mineral density, 32 osteopenia, and 48 osteoporosis. For each patient, the L1-L4 vertebrae on the CT images were automatically segmented using SenseCare and defined as regions of interest (ROIs). In total, 1,197 radiomic features were extracted from these ROIs using PyRadiomics. The most significant features were selected using logistic regression and Pearson correlation coefficient matrices. Using these features, we constructed three linear classification models based on the random forest (RF), support vector machine (SVM), and K-nearest neighbor (KNN) algorithms, respectively. The training and test sets were repeatedly selected using fivefold cross-validation. The model performance was evaluated using the area under the receiver operator characteristic curve (AUC) and confusion matrix. RESULTS: The classification model based on RF had the highest performance, with an AUC of 0.994 (95% confidence interval [CI]: 0.979-1.00) for differentiating normal BMD and osteoporosis, 0.866 (95% CI: 0.779-0.954) for osteopenia versus osteoporosis, and 0.940 (95% CI: 0.891-0.989) for normal BMD versus osteopenia. CONCLUSIONS: The excellent performance of this radiomic model indicates that lumbar spine CT images can effectively be used to identify osteoporosis and as a tool for opportunistic osteoporosis screening.

A novel circular RNA hsa_circRNA_103809/miR-377-3p/GOT1 pathway regulates cisplatin-resistance in non-small cell lung cancer (NSCLC).

BACKGROUND: Cisplatin is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and emerging evidences suggests that targeting circular RNAs (circRNAs) is an effective strategy to increase cisplatin-sensitivity in NSCLC, but the detailed mechanisms are still not fully delineated. METHODS: Cell proliferation, viability and apoptosis were examined by using the cell counting kit-8 (CCK-8) assay, trypan blue staining assay and Annexin V-FITC/PI double staining assay, respectively. The expression levels of cancer associated genes were measured by using the Real-Time qPCR and Western Blot analysis at transcriptional and translated levels. Dual-luciferase reporter gene system assay was conducted to validated the targeting sites among hsa_circRNA_103809, miR-377-3p and 3' untranslated region (3'UTR) of GOT1 mRNA. The expression status, including expression levels and localization, were determined by immunohistochemistry (IHC) assay in mice tumor tissues. RESULTS: Here we identified a novel hsa_circRNA_103809/miR-377-3p/GOT1 signaling cascade which contributes to cisplatin-resistance in NSCLC in vitro and in vivo. Mechanistically, parental cisplatin-sensitive NSCLC (CS-NSCLC) cells were subjected to continuous low-dose cisplatin treatment to generate cisplatin-resistant NSCLC (CR-NSCLC) cells, and we found that hsa_circRNA_103809 and GOT1 were upregulated, while miR-377-3p was downregulated in CR-NSCLC cells but not in CS-NSCLC cells. In addition, hsa_circRNA_103809 sponged miR-337-3p to upregulate GOT1 in CS-NSCLC cells, and knock-down of hsa_circRNA_103809 enhanced the inhibiting effects of cisplatin on cell proliferation and viability, and induced cell apoptosis in CR-NSCLC cells, which were reversed by downregulating miR-377-3p and overexpressing GOT1. Consistently, overexpression of hsa_circRNA_103809 increased cisplatin-resistance in CS-NSCLC cells by regulating the miR-377-3p/GOT1 axis. Finally, silencing of hsa_circRNA_103809 aggravated the inhibiting effects of cisplatin treatment on NSCLC cell growth in vivo. CONCLUSIONS: Analysis of data suggested that targeting the hsa_circRNA_103809/miR-377-3p/GOT1 pathway increased susceptibility of CR-NSCLC cells to cisplatin, and this study provided novel targets to improve the therapeutic efficacy of cisplatin for NSCLC treatment in clinic.

Glucocorticoids Enhanced Osteoclast Autophagy Through the PI3K/Akt/mTOR Signaling Pathway.

Autophagy is an evolutionarily conserved dynamic process and present in variety of cells at basal levels to maintain homeostasis and to promote cell survival in response to stresses. The early bone loss with excessive glucocorticoids (GCs) was reported to be related with the extension of the life span of osteoclasts. However, the connection between GCs induced bone loss and osteoclast autophagy remains to be elucidated. Autophagy was detected in a Dexamethasone (Dex) induced osteoporotic mice model and primary osteoclast cultures by autophagosome detection kit, and autophagy-related proteins were assayed by Western blotting and Immunostaining. The bone morphology was examined by micro-CT and TRAP staining. The trabecular bone micro-architecture was deteriorated, and the osteoclast number and spread area were increased in the Dex-treated mice compared with the control group (P < 0.01). Meanwhile, autophagy in pre-osteoclasts was increased in mice under Dex administration evidenced by the increased number of autophagosome and up-regulation of autophagy-related protein levels. Further, the enhanced autophagy under Dex treatment was verified in primary cultured osteoclasts, as shown by the increased levels of Beclin 1 and LC3-II/LC3-I and the autophagy complex formation members including Atg1, Atg13, and Atg7. However, the expressions of PI3K, p-Akt and p-mTOR in primary cultured osteoclasts were inhibited under Dex induced autophagy. Using the selective PTEN inhibitor SF1670 to activate the PI3K/Akt/mTOR pathway reversed this osteoclast autophagy under Dex treatment. Our study suggests that osteoclast autophagy was enhanced in glucocorticoids induced bone loss, and the PI3K/Akt/mTOR signaling pathway mediated the increased autophagy in primary cultured osteoclasts under glucocorticoids treatment.

Outcomes of stereotactic body radiotherapy versus lobectomy for stage I non-small cell lung cancer: a propensity score matching analysis.

BACKGROUND: Lobectomy is the standard treatment for patients with stage I non-small cell lung cancer (NSCLC). Recent studies have shown promising results of stereotactic body radiation therapy (SBRT) in these patients. We retrospectively compared the outcomes of lobectomy and SBRT in these patients from our therapeutic center. METHODS: Patients who underwent lobectomy or SBRT for clinical T1-2a (T size≤5 cm), N0 M0, NSCLC between December 2011 and August 2016 were reviewed. Patient characteristics, treatment-related outcomes and toxicities were analyzed. Propensity score matching (PSM) was performed to improve comparability between the two groups. RESULTS: Median follow-up period in the lobectomy (n = 246) and SBRT (n = 70) group was 31.4 months and 24.9 months, respectively. Three-year local recurrence-free survival (LRFS) was comparable in the two groups (97% vs. 91.7%, respectively; P = 0.768). Recurrence-free survival (RFS) at 3-year in the lobectomy and SBRT groups was 85.4 and 69.5%, respectively (P = 0.014). Three-year overall survival (OS) after lobectomy and SBRT was 88.2 and 79.7%, respectively (P = 0.027), while 3-year cancer-specific survival (CSS) was 91.3 and 82.5% (P = 0.022). After PSM (45 matched patients in each group), there was no significant between-group difference with respect to 3-year LRFS (89.6% vs. 87.5%, P = 0.635), RFS (77.6% vs. 67.3%, P = 0.446), OS (78.5% vs. 79.5%, P = 0.915) or CSS (86.4 and 79.5%, P = 0.551). In matched subgroup, 30-day mortality after lobectomy was 2.2%, and no treatment-related death occurred after SBRT. CONCLUSIONS: Treatment-related outcomes of SBRT and lobectomy were comparable. SBRT was well tolerated and had a very low toxicity profile in our study. SBRT is a promising alternative treatment option for stage I NSCLC patients. This study indicates that matching these disparate cohorts of patients is challenging. Clinical trials are essential to define the indications and relative efficacy of lobectomy and SBRT in a selected population.

Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration.

Although mesenchymal stem cells (MSCs) transplantation into the IVD (intervertebral disc) may be beneficial in inhibiting apoptosis of nucleus pulposus cells (NPCs) and alleviating IVD degeneration, the underlying mechanism of this therapeutic process has not been fully explained. The purpose of this study was to explore the protective effect of MSC-derived exosomes (MSC-exosomes) on NPC apoptosis and IVD degeneration and investigate the regulatory effect of miRNAs in MSC-exosomes and associated mechanisms for NPC apoptosis. MSC-exosomes were isolated from MSC medium, and its anti-apoptotic effect was assessed in a cell and rat model. The down-regulated miRNAs in apoptotic NPCs were identified, and their contents in MSC-exosomes were detected. The target genes of eligible miRNAs and possible downstream pathway were investigated. Purified MSC-exosomes were taken up by NPCs and suppressed NPC apoptosis. The levels of miR-21 were down-regulated in apoptotic NPCs while MSC-exosomes were enriched in miR-21. The exosomal miR-21 could be transferred into NPCs and alleviated TNF-α induced NPC apoptosis by targeting phosphatase and tensin homolog (PTEN) through phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Intradiscal injection of MSC-exosomes alleviated the NPC apoptosis and IVD degeneration in the rat model. In conclusion, MSC-derived exosomes prevent NPCs from apoptotic process and alleviate IVD degeneration, at least partly, via miR-21 contained in exosomes. Exosomal miR-21 restrains PTEN and thus activates PI3K/Akt pathway in apoptotic NPCs. Our work confers a promising therapeutic strategy for IVD degeneration.

Circular RNA VMA21 protects against intervertebral disc degeneration through targeting miR-200c and X linked inhibitor-of-apoptosis protein.

OBJECTIVES: Circular RNAs (circRNAs) have been proven to function as competing endogenous RNAs to interact with microRNAs (miRNAs) and influence the expression of miRNA target mRNAs. In this study, we investigated whether circRNAs could act as competing endogenous RNAs to regulate the pathological process of intervertebral disc degeneration (IVDD). METHODS: The role and mechanism of a circRNA, circVMA21, in IVDD were explored in nucleus pulposus (NP) cells and degenerative NP tissues from patients and rat models. The interaction between circVMA21 and miR-200c as well as the target mRNA, X linked inhibitor-of-apoptosis protein (XIAP), was examined. RESULTS: The decreased expression of XIAP in the inflammatory cytokines-treated NP cells and the degenerative NP tissues was directly associated with excessive apoptosis and imbalance between anabolic and catabolic factors of extracellular matrix. miR-200c regulated NP cell viability and functions through inhibiting XIAP. circVMA21 acted as a sponge of miR-200c and functioned in NP cells through targeting miR-200c and XIAP. Intradiscal injection of circVMA21 alleviated IVDD in the rat model. CONCLUSIONS: CircVMA21 could alleviate inflammatory cytokines-induced NP cell apoptosis and imbalance between anabolism and catabolism of extracellular matrix through miR-200c-XIAP pathway. It provides a potentially effective therapeutic strategy for IVDD.

Ischemic Postconditioning Alleviates Cerebral Ischemia-Reperfusion Injury Through Activating Autophagy During Early Reperfusion in Rats.

This study aimed to investigate whether ischemic postconditioning (IpostC) alleviates cerebral ischemia/reperfusion (I/R) injury involved in autophagy. Adult Sprague-Dawley rats were divided into five groups: sham (sham surgery), I/R (middle cerebral artery occlusion [MCAO] for 100 min, then reperfusion), IpostC (MCAO for 100 min, reperfusion for 10 min, MCAO for 10 min, then reperfusion), IpostC+3MA (3-methyladenine, an autophagy inhibitor, administered 30 min before first reperfusion), and IpostC+Veh (vehicle control for IpostC+3MA group). Infarct volume was measured using cresyl violet staining. Autophagy-related proteins were detected by western blot and immunohistochemistry. Autophagosomes, autophagolysosomes, and mitochondrial damage were identified by transmission electron microscopy. Cortical cell apoptosis was detected by the TUNEL assay. Neurologic function was assessed using the modified Neurologic Severity Score. IpostC improved neurological function and reduced infarct volume after I/R (P < 0.05). These effects of IpostC were inhibited by 3MA (P < 0.05). Autophagosome formation was increased in the I/R and IpostC+Veh groups (P < 0.05), but not in the IpostC+3MA group. The I/R group showed enhanced LC3-II/LC3-I ratio, p62, and Cathepsin B levels and decreased LAMP-2 level (all P < 0.05 vs. sham), indicating dysfunction of autophagic clearance. IpostC reduced p62 and Cathepsin B levels and increased the LC3-II/LC3-I ratio, and nuclear translocation of transcription factor EB (all P < 0.05); these effects of IpostC were reversed by 3MA, suggesting IpostC enhanced autophagic flux. Furthermore, IpostC attenuated I/R-induced mitochondrial translocation of Bax and mitochondrial cytochrome-c release (all P < 0.05); 3MA inhibited these effects of IpostC (P < 0.05). In conclusion, IpostC may alleviate cerebral I/R injury by activating autophagy during early reperfusion.

Analysis of single cage position in transforaminal lumbar interbody fusion through digital images.

PURPOSE: The purpose of this study was to investigate the position of single cage inserted using oblique-oriented technique in transforaminal lumbar interbody fusion (TLIF) on digital images of computed tomography (CT). METHODS: From January to August 2015, 44 consecutive patients with degenerative lumbar disease who underwent TLIF in the L4/5 level were retrospectively studied in our department. The single cage was inserted using the oblique-oriented technique; as the main purpose of the study, its position was analyzed using post-operative digital computed tomography images. RESULTS: All cages used in the study had the same length of 36 mm, which were inserted into the discs with a 46.04 ± 3.09-mm horizontal diameter and 34.25 ± 3.59-mm longitudinal diameter. The horizontal and longitudinal diameter of the treated disk established the coordinate. The horizontal and longitudinal coordinate values of the centre of the cage were 0.08 ± 4.12 and 1.20 ± 2.76 mm, respectively. The horizontal distance of the cage centre from the midpoint of the disc negatively correlated with that of the entry point from the midpoint of the disc in the coronal plane. CONCLUSION: A longer single cage can be placed into the L4/5 level disk by inserting it using the oblique-oriented technique. Its center can reach the midpoint of the treated disk in the coronal plane and the anterior position of the disk in the sagittal plane. The entry point of the cage is the further away from the midpoint of the disk; the cage is the more apt to reach the center of the disk in the coronal plane.

The role of cage height on the flexibility and load sharing of lumbar spine after lumbar interbody fusion with unilateral and bilateral instrumentation: a biomechanical study.

BACKGROUND: One- and two-level lumbar interbody fusion with unilateral instrumentation is as effective as that with bilateral instrumentation. The height of the interbody cage influences the operated segment stability and the fusion technique success. The purpose of this research was to determine the effect of the fusion cage height (i.e. long and short) on both the stability (based on flexibility measures) and load sharing of the unilateral and bilateral instrumented transforaminal lumbar interbody fusion (TLIF) technique. METHODS: The flexibility and load sharing tests were performed on seven human lumbar spines. Different configurations combining a long or short cage with a unilateral, bilateral, or no posterior fixation were used to stabilize the operated segment. Two sets of modular cages were designed for each type of test to simulate the long and short cages. During the flexibility test, a pure-moment load of 7.5 Nm was applied. The range of motion (ROM) was recorded for flexion-extension, lateral bending, and axial rotation. During the load sharing test, an axial-compression load of 400 N was applied. The load bearing of the cages was recorded using a cage-embedded load cell. RESULTS: When the fusion cage height decreased 2 mm, the segment flexibility with unilateral fixation showed a significant increase in the ROM for flexion-extension, lateral bending, and axial rotation of 74.9, 83.8, and 175.2% (P < 0.01), respectively. In contrast, for bilateral fixation, the height decrease resulted in no significant change in ROM for flexion-extension (P = 0.686), lateral bending (P = 0.698), and axial rotation (P = 0.133). Using a short fusion cage, the load bearing decreased in 17.1, 21.5, and 54.1% (P < 0.05) for the cage alone, unilateral, and bilateral fixation, respectively. CONCLUSIONS: A cage longer than the intervertebral space should be chosen to increase the stability and intervertebral graft load borne when performing TLIF with unilateral instrumentation.

Femoral head retroposition as a potential compensatory mechanism in patients with a severe mismatch between pelvic incidence and lumbar lordosis.

OBJECTIVE: Severe mismatch between pelvic incidence (PI) and lumbar lordosis (LL) leads to extra anterior displacement of the gravity line. The objective of this study is to investigate whether femoral head retroposition is a separate compensatory mechanism responsible for the extra anterior displacement. SUBJECTS AND METHODS: Based on the values of PI and LL, 94 patients were divided into the PI-LL match group (PI-LL ≤ 0°), the mild PI-LL mismatch group (20°> PI-LL >0°), and the severe PI-LL mismatch group (PI-LL ≥ 20°). A series of parameters including PI, LL, PI-LL, thoracic kyphosis (TK), pelvic tilt (PT), sacral slope (SS), knee flexion angle (KFA), tibial obliquity angle (TOA), sagittal vertical axis (SVA), S1 overhang, femoral head shift (FHS), and pelvic shift (PS) were measured and compared among the three groups. RESULTS: The severe PI-LL mismatch group exhibited significantly greater PI, PI-LL, PT, KFA, SVA, PS, and FHS, and less LL and TK, compared with the control and mild PI-LL mismatch group. The mild PI-LL mismatch group had significantly greater PI-LL, PT, KFA, TOA, and S1 overhang, and less LL and SS than the control group. SS, TOA, and S1 overhang in the severe PI-LL mismatch group differed significantly from that in the control group, but did not differ significantly from that in the mild PI-LL mismatch group. CONCLUSION: Femoral head retroposition is an entirely separate compensatory mechanism and, in this study, participated in the compensation for the anterior displacement of the gravity line induced by extra-sagittal spinal malalignment in patients with severe PI-LL mismatch.

Beta1 integrin inhibits apoptosis induced by cyclic stretch in annulus fibrosus cells via ERK1/2 MAPK pathway.

Low back pain is associated with intervertebral disc degeneration (IVDD) due to cellular loss through apoptosis. Mechanical factors play an important role in maintaining the survival of the annulus fibrosus (AF) cells and the deposition of extracellular matrix. However, the mechanisms that excessive mechanical forces lead to AF cell apoptosis are not clear. The present study was to look for how AF cells sense mechanical changes. In vivo experiments, the involvement of mechanoreceptors in apoptosis was examined by RT-PCR and/or immunoblotting in the lumbar spine of rats subjected to unbalanced dynamic and static forces. In vitro experiments, we investigated apoptotic signaling pathways in untransfected and transfected AF cells with the lentivirus vector for rat ß1 integrin overexpression after cyclic stretch. Apoptosis in AF cells was assessed using flow cytometry, Hoechst 33258 nuclear staining. Western blotting was used to analyze expression of ß1 integrin and caspase-3 and ERK1/2 MAPK signaling molecules. In the rat IVDD model, unbalanced dynamic and static forces induced apoptosis of disc cells, which corresponded to decreased expression of ß1 integrin. Cyclic stretch-induced apoptosis in rat AF cells correlated with the activation of caspase-3 and with decreased levels of ß1 integrin and the phosphorylation levels of ERK1/2 activation level. However, the overexpression of ß1 integrin in AF cells ameliorated cyclic stretch-induced apoptosis and decreased caspase-3 activation. Furthermore, ERK1/2-specific inhibitor promotes apoptosis in vector ß1-infected AF cells. These results suggest that the disruption of ß1 integrin signaling may underlie disc cell apoptosis induced by mechanical stress. Further work is necessary to fully elucidate the pathophysiological mechanisms that underlie IVDD caused by unbalanced dynamic and static forces.

A phase II study of Endostatin in combination with paclitaxel, carboplatin, and radiotherapy in patients with unresectable locally advanced non-small cell lung cancer.

BACKGROUND: Endostatin inhibits the pro-angiogenic action of basic fibroblast growth factor and vascular endothelial growth factor in different human cancers. This study assessed the efficacy of endostatin combined with concurrent chemoradiotherapy of non-small cell lung cancer (NSCLC). METHODS: Nineteen patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-l, and adequate organ function were treated with 60-66 Gy thoracic radiation therapy over 30-33 fractions concurrent with weekly 7.5 mg/m(2) endostatin for 14 days, 50 mg/m(2) paclitaxel, and 2 mg/mL/min carboplatin over 30 min. Patients were then treated with 7.5 mg/m(2) endostatin for 14 days, 150 mg/m(2) paclitaxel, and 5 mg/mL/min carboplatin every 3 weeks for 2 cycles as the consolidation treatment. The objective response rate was recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. RESULTS: Six patients were unable to complete the consolidation treatment (4 pulmonary toxicity, 1 tracheoesophageal fistulae, and 1 progressive disease). Seventeen patients were included for data analysis. Specifically, one (5.9%) patient had a complete response and 12 (70.6%) had a partial response, whereas two patients had stable disease and the other two had disease progression. The overall response rate was 76% (95% confidence interval [CI], 51%-97%). The median progression-free survival was 10 months (95% CI, 7.6-12.3 months), and the median overall survival was 14 months (95% CI, 10.7-17.2 months). Early 10 patients who completed the treatment regimen showed that four patients experienced grade III pulmonary toxicity a few months after chemoradiotherapy, leading to the early closure of the trial according to the study design. CONCLUSIONS: The result of concurrent endostatin treatment with chemoradiotherapy in locally advanced unresectable NSCLC did not meet the goal per study design with unacceptable toxicity. The real impact of endostatin as the first-line treatment combined with chemoradiotherapy on the survival of NSCLC patients remains to be determined. (NCT 01158144).

Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke.

Rapamycin has been demonstrated to exhibit neuroprotective functions via the activation of autophagy in a cerebral ischemia model. However, the involvement of mitophagy in this process and its contribution to the protection of mitochondrial function remains unknown. The present study explored the characteristics of mitophagy after cerebral ischemia and the effect of rapamycin on mitochondrial function. Male Sprague-Dawley rats underwent transient middle cerebral artery occlusion (tMCAO). Neurological deficits scores; infarct volumes; mitophagy morphology; and the levels of malondialdehyde (MDA), adenosine triphosphate (ATP) and mitochondrial membrane potentials (Δψm) were examined. The expression of LC3, Beclin-1 and p62 in the mitochondrial fraction combined with transmission electronic microscopy were used to explore mitophagic activity after ischemia. We also blocked autophagosome formation using 3-methyladenine (3-MA) to check the linkage between the mitochondrial protective effect of rapamycin and enhanced mitophagy. We observed that rapamycin significantly enhanced mitophagy, as evidenced by the increase in LC3-II and Beclin-1 expression in the mitochondria and p62 translocation to the mitochondria. Rapamycin reduced infarct volume, improved neurological outcomes and inhibited mitochondrial dysfunction compared with the control animals (p<0.05). However, these protective effects were reversed by 3-methyladenine treatment after rapamycin. The present study indicates that rapamycin treatment attenuates mitochondrial dysfunction following cerebral ischemia, which is linked to enhanced mitophagy.

Glycogen synthase kinase-3 regulates production of amyloid-ß peptides and tau phosphorylation in diabetic rat brain.

The pathogenesis of diabetic neurological complications is not fully understood. Diabetes mellitus (DM) and Alzheimer's disease (AD) are characterized by amyloid deposits. Glycogen synthase kinase-3 (GSK-3) plays an important role in the pathogenesis of AD and DM. Here we tried to investigate the production of amyloid-ß peptides (A ß) and phosphorylation of microtubule-associated protein tau in DM rats and elucidate the role of GSK-3 and Akt (protein kinase B, PKB) in these processes. Streptozotocin injection-induced DM rats displayed an increased GSK-3 activity, decreased activity and expression of Akt. And A ß 40 and A ß 42 were found overproduced and the microtubule-associated protein tau was hyperphosphorylated in the hippocampus. Furthermore, selective inhibition of GSK-3 by lithium could attenuate the conditions of A ß overproduction and tau hyperphosphorylation. Taken together, our studies suggest that GSK-3 regulates both the production of A ß and the phosphorylation of tau in rat brain and may therefore contribute to DM caused AD-like neurological defects.

Bilateral decompression using a unilateral pedicle construct for lumbar stenosis.

PURPOSE: To determine the effectiveness of bilateral decompression via a unilateral approach using unilateral pedicle screw fixation for two-level lumbar stenosis with instability. METHODS: Between October 2006 and October 2010, 98 patients (61 men and 37 women) who had reached the three-year follow-up interval were treated with unilateral pedicle screw fixation at the authors' institution. All patients underwent two-level transforaminal lumbar interbody fusion (TLIF), and the mean age was 59.6 years (range, 40-72). Visual analog scale (VAS) scores and Oswestry Disability Index (ODI) were used to assess the pre-operative and postoperative clinical results. Fusion status, the disc space height, and the whole lumbar lordotic angle were analysed for the radiological evaluation. RESULTS: The ODI scores decreased significantly in both early and late follow-up evaluations and the visual analog scale (VAS) score demonstrated significant improvement in late follow-up (P < 0.01). The disc space height (P < 0.05) and the whole lumbar lordotic angle (P < 0.05) were increased at the final follow-up. Successful fusion was achieved in all patients. CONCLUSION: Bilateral decompression via a unilateral approach using unilateral pedicle screw fixation for two-level lumbar stenosis with instability, which can maintain the lumbar lordosis and the disc space height, is an effective and less invasive method than with bilateral constructs.

Unilateral versus bilateral instrumented transforaminal lumbar interbody fusion in two-level degenerative lumbar disorders: a prospective randomised study.

PURPOSE: The aim of this study was to analyse the clinical and radiological outcomes of unilateral versus bilateral instrumented TLIF in two-level degenerative lumbar disorders. METHODS: A prospective randomised clinical study was performed from January 2008 to May 2011. Sixty-eight consecutive patients with severe low back pain and radicular pain were divided randomly into the unilateral (n = 33) or bilateral (n = 35) pedicle screw fixation group based on a random number list. Operative time, blood loss, duration of hospital stay, fusion rate, complication rate and implant costs were recorded and analysed statistically. Visual analog scale (VAS) scores, Oswestry Disability Index (ODI), and SF-36 were used to assess the preoperative and postoperative clinical results in the two groups. RESULTS: No differences were observed between the two groups with respect to demographic data. The patients of the two groups had significant improvement in functional outcome compared to preoperatively. There was no significant difference comparing fusion rate, complication rate and duration of hospital stay between the two groups at postoperative follow-up (P > 0.05). However, compared with the bilateral pedicle screw group, a significant decrease occurred in operative time, blood loss and implant costs in the unilateral group. CONCLUSION: Two-level unilateral instrumented TLIF is an effective and safe method with reduced operative time and blood loss for multiple-level lumbar diseases. But it is imperative that the larger cage should be appropriately positioned to support the contralateral part of the anterior column by crossing the midline of the vertebral body.

Favorable cervical extension capacity preventing loss of cervical lordosis after laminoplasty due to spontaneous restoration of initial lordosis.

BACKGROUND CONTEXT: Cervical laminoplasty is a common approach for the treatment of multilevel cervical spondylotic myelopathy (CSM). Postoperative loss of cervical lordosis (LCL) was associated with lower extension motion of the cervical spine before laminoplasty. PURPOSE: To analyze the possible causes of preoperative cervical extension capacity affecting LCL after laminoplasty by evaluating the changes in cervical lordosis (CL) at different stages. STUDY DESIGN/SETTING: Retrospective study. PATIENT SAMPLE: Seventy-two patients undergoing laminoplasty due to multilevel CSM. OUTCOME MEASURES: Radiographic parameters included CL, extension CL (eCL), flexion CL (fCL), range of motion (ROM), extension ROM (eROM), flexion ROM (fROM) and LCL. Clinical outcomes were assessed using the Japanese Orthopedic Association (JOA) and neck disability index (NDI) score. METHODS: The data were recorded before surgery and at 3- and 24-month follow-up. All patients completed a cervical extension test preoperatively. A receiver operating characteristic (ROC) curve of eROM was constructed to discriminate the patients with and without postoperative kyphotic deformity. RESULTS: According to the optimal cut-off value of eROM, the patients were divided into two groups: extension group (eROM≥9.3°) and control group (eROM<9.3°). The radiographic outcomes demonstrated no significant differences in CL, eCL, fCL and ROM between the two groups. Both eROM and fROM were significantly different in the two groups. There was a significant change in CL in the extension group at 3-month follow-up and in the control group at 24-month follow-up. The extension group exhibited significantly lower LCL compared with the control group at follow-up. No significant difference between the two groups was noted in the JOA recovery rate, while the NDI score was significantly different at 24-month follow-up. The positivity ratio of the extension test was significantly greater in the extension group than that in the control group. CONCLUSIONS: eROM in patients with favorable preoperative cervical extension capacity (eROM≥9.3°) consisted of the actual extension capacity and compensatory flexion. The cervical alignment would be spontaneously restored to its initial lordosis in the short term after laminoplasty. These patients had no substantial LCL at 24-month follow-up and would be good candidates for laminoplasty.

Induction immunochemotherapy followed by definitive chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a multi-institutional retrospective cohort study.

This study aimed to evaluate the efficacy and safety of induction immunochemotherapy followed by definitive chemoradiotherapy (CRT) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). We identified unresectable stage III NSCLC patients who received induction immunochemotherapy. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. From February 2019 to August 2022, 158 patients were enrolled. Following the completion of induction immunochemotherapy, the objective response rate (ORR) and disease control rate (DCR) were 52.5% and 83.5%, respectively. The ORR of CRT was 73.5%, representing 68.4% of the total cohort. The median PFS was 17.8 months, and the median OS was 41.9 months, significantly higher than in patients who received CRT alone (p < 0.001). Patients with concurrent CRT demonstrated markedly improved PFS (p = 0.012) and OS (p = 0.017) than those undergoing sequential CRT. Additionally, those with a programmed-death ligand 1 (PD-L1) expression of 50% or higher showed significantly elevated ORRs (72.2% vs. 47.2%, p = 0.011) and superior OS (median 44.8 vs. 28.6 months, p = 0.004) compared to patients with PD-L1 expression below 50%. Hematologic toxicities were the primary severe adverse events (grade ≥ 3) encountered, with no unforeseen treatment-related toxicities. Thus, induction immunochemotherapy followed by definitive CRT demonstrated encouraging efficacy and tolerable toxicities for unresectable LA-NSCLC.