A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.

The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.

Biomechanical evaluation of Percutaneous endoscopic posterior lumbar interbody fusion and minimally invasive transforaminal lumbar interbody fusion: a biomechanical analysis.

In order to analyze and evaluate the stability of lumbar spine and the risk of cage subsidence after different minimally invasive fusion operations, two finite element models Percutaneous endoscopic posterior lumbar interbody fusion (PE-PLIF) and minimally invasive transforaminal lumbar interbody Fusion (MIS-TLIF) were established. The results showed that compared with MIS-TLIF, PE-PLIF had better segmental stability, lower pedicle screw rod system stress, and lower risk of cage subsidence. The results suggest that the cage with appropriate height should be selected to ensure the segmental stability and avoid the risk of the subsidence caused by the cage with large height.

Construction and validation of a predictive model for postoperative urinary retention after lumbar interbody fusion surgery.

BACKGROUND: Postoperative urine retention (POUR) after lumbar interbody fusion surgery may lead to recatheterization and prolonged hospitalization. In this study, a predictive model was constructed and validated. The objective was to provide a nomogram for estimating the risk of POUR and then reducing the incidence. METHODS: A total of 423 cases of lumbar fusion surgery were included; 65 of these cases developed POUR, an incidence of 15.4%. The dataset is divided into a training set and a validation set according to time. 18 candidate variables were selected. The candidate variables were screened through LASSO regression. The stepwise regression and random forest analysis were then conducted to construct the predictive model and draw a nomogram. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve and the calibration curve were used to evaluate the predictive effect of the model. RESULTS: The best lambda value in LASSO was 0.025082; according to this, five significant variables were screened, including age, smoking history, surgical method, operative time, and visual analog scale (VAS) score of postoperative low back pain. A predictive model containing four variables was constructed by stepwise regression. The variables included age (ß = 0.047, OR = 1.048), smoking history (ß = 1.950, OR = 7.031), operative time (ß = 0.022, OR = 1.022), and postoperative VAS score of low back pain (ß = 2.554, OR = 12.858). A nomogram was drawn based on the results. The AUC of the ROC curve of the training set was 0.891, the validation set was 0.854 in the stepwise regression model. The calibration curves of the training set and validation set are in good agreement with the actual curves, showing that the stepwise regression model has good prediction ability. The AUC of the training set was 0.996, and that of the verification set was 0.856 in the random forest model. CONCLUSION: This study developed and internally validated a new nomogram and a random forest model for predicting the risk of POUR after lumbar interbody fusion surgery. Both of the nomogram and the random forest model have high accuracy in this study.

Percutaneous Endoscopic Posterior Lumbar Interbody Fusion with Unilateral Laminotomy for Bilateral Decompression Vs. Open Posterior Lumbar Interbody Fusion for the Treatment of Lumbar Spondylolisthesis.

Background: Endoscopic lumbar interbody fusion is a new technology that is mostly used for single-segment and unilateral lumbar spine surgery. The purpose of this study is to introduce percutaneous endoscopic posterior lumbar interbody fusion (PE-PLIF) with unilateral laminotomy for bilateral decompression (ULBD) for lumbar spondylolisthesis and evaluate the efficacy by comparing it with open posterior lumbar interbody fusion (PLIF). Methods: Twenty-eight patients were enrolled in PE-PLIF with the ULBD group and the open PLIF group. The perioperative data of the two groups were compared to evaluate the safety of PE-PLIF with ULBD. The visual analog scale (VAS) back pain, VAS leg pain, and Oswestry Disability Index (ODI) scores of the two groups preoperatively and postoperatively were compared to evaluate clinical efficacy. Preoperative and postoperative imaging data were collected to evaluate the effectiveness of the operation. Results: No differences in baseline data were found between the two groups (p > 0.05). The operation time in PE-PLIF with the ULBD group (221.2 ± 32.9 min) was significantly longer than that in the PLIF group (138.4 ± 25.7 min) (p < 0.05), and the estimated blood loss and postoperative hospitalization were lower than those of the PLIF group (p < 0.05). The postoperative VAS and ODI scores were significantly improved in both groups (p < 0.05), but the postoperative VAS back pain score in the PE-PLIF group was significantly lower than that in the PLIF group (p < 0.05). The excellent and good rates in both groups were 96.4% according to MacNab's criteria. The disc height and cross-sectional area of the spinal canal were significantly improved in the two groups after surgery (p < 0.05), with no difference between the groups (p > 0.05). The fusion rates in PE-PLIF with the ULBD group and the PLIF group were 89.3% and 92.9% (p > 0.05), respectively, the cage subsidence rates were 14.3% and 17.9% (p > 0.05), respectively, and the lumbar spondylolisthesis reduction rates were 92.72 ± 6.39% and 93.54 ± 5.21%, respectively (p > 0.05). Conclusion: The results from this study indicate that ULBD can be successfully performed during PE-PLIF, and the combined procedure is a safe and reliable treatment method for lumbar spondylolisthesis.

Aculeaquamide A, cytotoxic paraherquamide from the marine fungus Aspergillus aculeatinus WHUF0198.

A new paraherquamide named aculeaquamide A (1) was isolated from an EtOAc extract of Aspergillus aculeatinus WHF0198 culture media together with five known compounds. The structures of the isolated compounds were elucidated by analysis of NMR and MS data, and the absolute configurations of compound 1 was confirmed by CD spectroscopic methods. All isolated compounds were evaluated for their cytotoxicity against three human cancer cell lines, Bel-7402, A549, and HCT-116. Compounds 1 and 2 showed cytotoxicity against Bel-7402 with IC50 values of 3.3 and 1.9 µM, respectively.

Treatment of cervical spine metastasis with minimally invasive cervical spondylectomy: A case report and literature review.

BACKGROUND: Cervical spondylectomy for the treatment of cervical tumors is traumatic, causes bleeding, and is risky. This study reports on the experience with minimally invasive cervical spondylectomy for a cervical metastasis and reviewed the literature on cervical spondylectomy. The purpose was to reduce the risk and trauma of spondylectomy. CASE SUMMARY: A 60-year-old woman presented with cervical pain and radiating pain in the left upper limb for more than 2 mo. Preoperative diagnosis was C4 metastasis of thyroid cancer. Preoperative visual analogue scale score was 5. American Spinal Cord Injury Association (ASIA) grade was E. Tomita classification was 7. Weinstein-Boriani-Biagini (WBB) classification was A-D, 3-9. Tomita score was 5. Modified Tokuhashi score was 9. Spinal instability neoplastic score (SINS) was 13. The patient underwent minimally invasive cervical spondylectomy on September 28, 2017. The operative time was 200 min; the estimated blood loss was 1200 mL. The operation was successful, without complications. The postoperative visual analogue scale score was 0. The patient remained classified as ASIA grade E at the last follow-up. She accepted regular iodine-131 therapy postoperatively. The serum thyroglobulin (Tg) level of this patient was 299.02 ng/mL at 1 mo after the operation and was 13.57 ng/mL at the last follow-up. There was no local recurrence at the 25-mo follow-up, according to images, single-photon emission computed tomography, and serum Tg levels. Obvious ossification and solid fusion of C3-C5 were found at the last follow-up. CONCLUSION: Minimally invasive cervical spondylectomy with tubular retractor could minimize soft tissue trauma, intraoperative traction injury, and paraspinal muscle injury, accelerating postoperative recovery. This technique requires a rich experience in cervical spine surgery with tubular retractors, so that surgeons can visualize the anatomical structure in a small field.

[C-MYC Gene and Protein Expression in Paraffin Wax of T Lymphoblastic Lymphoma and Leukemia Patients and Its Effect on the Prognosis].

OBJECTIVE: To explore the relevance between the expression of C-MYC gene and protein of patients with T lymphoblastic lymphoma and leukemia(T-LBL/ALL) and its effect on the prognosis. METHODS: Paraffin specimens from 60 cases of T-LBL/ALL with detailed follow-up during May 2005 to May 2016 were selected as study group; at same time 20 cases of reactive hyperplasia (RH) of lymphonuedes were selected as control group. The immunohistochemical EnVision method was used to mark the terminal deoxynucleotidyl transferase (TDT), myeloperoxidase (MPO), Ki-67 and C-MYC immune tissue. RESULTS: C-MYC gene rupture and copy number increase did not occur in 20 cases of RH.The expression of C-MYC protein did not correlate with C-MYC gene copy number increase. The expression rate of C-MYC protein was 66.7% (40/60), and 20 cases of lymph node RH was all negative (0/20), as compared with the positive expression rate of protein C-MYC, the difference was statistically significant (P<0.05). The Ki-67 positive index and mediastinal bloadening had influence on the expression of C-MYC protein (P<0.05), the sex, primary site, symptoms, age, AnnArbor stage and lactate dehydrogenase (LDH) level and bone marrow involvement have no influence on it, there was no statistically significant difference (P>0.05). The 8q24 chromosome breakage occurred in 6 cases (10%), and the number of copies increased in 11 cases (18.3%). C-MYC gene copy number increase and C-MYC gene rupture in a total 20 cases of reactive hyperplasia of lymph nodes did not occur. CONCLUSION: C-MYC gene may play an important role on the development of T-LBL/ALL. It can be an independent prognosis factor.

Tuberculous Spondylitis Following Kyphoplasty: A Case Report and Review of the Literature.

Tuberculous spondylitis of the augmented vertebral column following percutaneous vertebroplasty or kyphoplasty has rarely been described. We report an unusual case of tuberculous spondylitis diagnosed after percutaneous kyphoplasty (PKP). A 61-year-old woman presented to our institution complaining of back pain following a fall 7 days before. Radiologic studies revealed an acute osteoporotic compression L1 fracture. The patient denied history of pulmonary tuberculosis (TB) and there were no signs of infection. The patient was discharged from hospital 4 days after undergoing L1 PKP with a dramatic improvement in her back pain. Two years later, the patient was readmitted with a 1 year history of recurrent back pain. Imaging examinations demonstrated long segmental bony destruction involving L1 vertebra with massive paravertebral abscess formation. The tentative diagnosis of tuberculous spondylitis was made, after a serum T-SPOT. The TB test was found to be positive. Anterior debridement, L1 corpectomy, decompression, and autologous rib graft interposition, and posterior T8-L4 instrumentation were performed. The histologic examination of the resected tissue results confirmed the diagnosis of spinal TB. Anti-TB medications were administered for 12 months and the patient recovered without sequelae. Spinal TB and osteoporotic vertebral compression fractures are similar clinically and radiologically. Spinal surgeons should consider this disease entity to avoid misdiagnosis or complications. Early surgical intervention and anti-TB treatment should be instituted as soon as the diagnosis of spinal TB after vertebral augmentation is made.

Conversion of fibroblasts to neural cells by p53 depletion.

Conversion from fibroblasts to neurons has recently been successfully induced. However, the underlying mechanisms are poorly understood. Here, we find that depletion of p53 alone converts fibroblasts into all three major neural lineages. The induced neuronal cells express multiple neuron-specific proteins and generate action potentials and transmitter-receptor-mediated currents. Surprisingly, depletion does not affect the well-known tumorigenic p53 target, p21. Instead, knockdown of p53 upregulates neurogenic transcription factors, which in turn boosts fibroblast-neuron conversion. p53 binds the promoter of the neurogenic transcription factor Neurod2 and regulates its expression during fibroblast-neuron conversion. Furthermore, our method provides a high efficiency of conversion in late-passage fibroblasts. Genome-wide transcriptional analysis shows that the p53-deficiency-induced neurons exhibit an expression profile different from parental fibroblasts and similar to control-induced neurons. The results may help to understand and improve neural conversion mechanisms to develop robust neuron-replacement therapy strategies.

[Progress on the research of acupuncture for smoking cessation in foreign and domestic].

Up to December of 2011, the domestic and overseas literatures of acupuncture for smoking cessation are searched and collected through Pubmed, CNKI, Wanfang and Chongqing VIP databases, which are analyzed from treatment method, action mechanism, influencing factors of efficacy and efficacy evaluation research and so on. The result shows that (1) acupuncture has positive effect on smoking cessation, and large clinical trials has been carried out. However, most of them are needling methods and the short-term effect observation, which lack of long-term efficacy research of withdrawal symptoms, especially continuous withdrawal symptoms and index of life quality. (2) Because of unified clinical treatment, manipulation standard and curative effect criteria, it is difficult to make comparison among them. (3) The study of mechanism on acupuncture for smoking cessation is not of in-depth. In future, clinical research project of acupuncture on smoking cessation should be optimized and regulated, including the unified treatment, manipulation standard and curative effect criteria, also long-term researches with large-scale samples should be launched to confirm effect ofacupuncture for smoking cessation to further discuss its action mechanism.

[Dynamic changes of serum interleukin-6 and interleukin-8 in patients with acute traumatic brain injury and the clinical significance].

OBJECTIVE: To explore the dynamic changes of serum interleukin-6 (IL-6) and IL-8 in acute traumatic brain injury (TBI) and their correlations to the severity of brain injury and the condition of the patients. METHODS: Thirty-four patients with acute TBI were divided into two groups according to the Glasgow Coma Scale (GCS) score, clinical manifestations and the imaging data, namely patients with GCS score < or = 8 and those with GCS score between 9 and 12. Radioimmunoassay was employed to determine the serum levels of IL-6 and IL-8 at 6 different time points within 15 days after the injury in the two groups. RESULTS: The serum IL-6 reached the peak level on the second day after the injury in patients with GCS score < or = 8 and on the 7th day in patients with GCS score of 9-12, showing significant differences in IL-6 variations between the two groups (P=0.046). The peak serum level of IL-8 occurred on the 7th day in patients with GCS score < or = 8 and on the 3rd day in patients with GCS score of 9-12, also showing significant differences (P=0.045). The peak level of IL-6 on the second day after the injury was significantly higher than the peak level of IL-8 that occurred on the 7th day, demonstrating significant differences in the variations of IL-6 and IL-8 after the injury (P=0.000). CONCLUSION: The changes of serum IL-6 and IL-8 levels show positive correlations to the severity of the condition of the patients sustaining TBI. IL-6 variation is more obvious than that of IL-8 without intimate correlations between them. Clinically, serum IL-6 level can be more informative than serum IL-8 level in evaluating the changes of the condition of the TBI patients in early stage following the injury.