Chemotherapy-induced metastasis: molecular mechanisms and clinical therapies.

Chemotherapy, the most widely accepted treatment for malignant tumors, is dependent on cell death induced by various drugs including antimetabolites, alkylating agents, mitotic spindle inhibitors, antitumor antibiotics, and hormonal anticancer drugs. In addition to causing side effects due to non-selective cytotoxicity, chemotherapeutic drugs can initiate and promote metastasis, which greatly reduces their clinical efficacy. The knowledge of how they induce metastasis is essential for developing strategies that improve the outcomes of chemotherapy. Herein, we summarize the recent findings on chemotherapy-induced metastasis and discuss the underlying mechanisms including tumor-initiating cell expansion, the epithelial-mesenchymal transition, extracellular vesicle involvement, and tumor microenvironment alterations. In addition, the use of combination treatments to overcome chemotherapy-induced metastasis is also elaborated.

[Experimental study of proteasome inhibitor MG132 up-regulates Wnt/ß-catenin signaling pathway to improve osteoporosis].

OBJECTIVE: To explore the mechanism of proteasome inhibitor MG132 in improving osteoporosis. METHODS: Total of 32 female SD rats, weighing 220 to 250 g and 8 weeks old, were selected. They were randomly divided into 4 groups(n=8). Rats of group A and group B were cut off ovaris on both sides to make model of osteoporosis, and then they were given proteasome inhibitors MG132 and dimethyl sufoxide (DMSO) respectively. Group C was a sham group and rats were given MG132. Group D was a normal group and rats were given MG132 too. The rats were killed in batches at 6 and 12 weeks after administration, and the femoral neck tissues were obtained. Relevant data were analyzed, such as pathomorphological observation, micro-CT analysis, detection of 20S proteasome activity in tissues, and expression of Wnt and ß-catenin. RESULTS: Morphological observation showed that the trabecular were slightly thinner, reticulated, and occasionally interrupted in group A, while the trabecular were obviously thinner and discontinuous in group B. And the trabecular were intact and arranged reticulated in group C and D. The analysis results of bone mineral density(BMD), bone surface(BS), bone volume/total volume(BV/TV) and trabecular thickness(Tb.Th) showed that group B was worse than other groups in all parameters at different time points(P<0.05), and group A was worse than group C and group D in BS(P<0.05), there was no significant difference in all parameters between group C and group D. RFU value of 20S proteasome in group B was significantly higher than that in other groups(P<0.05). According to the results of Western blot, the gray values of Wnt protein and ß-catenin protein in group A were significantly higher than those in other groups (P<0.05). CONCLUSION: MG-132, a ubiquitin proteasome inhibitor, can regulate Wnt/ß-catenin signaling pathway by inhibiting the degradation of ß-catenin protein, and delaying the occurrence and development of osteoporosis.

Multimedia fate model and risk assessment of typical antibiotics in the integrated demonstration zone of the Yangtze River Delta, China.

Due to the widespread consumption of antibiotics by humans and animals, antibiotic residues from human and animal excrements are released into the environment through domestic sewage and breeding wastewater, which ultimately affect the ecological environment and human health. In this study, the concentrations of 10 antibiotics in the air, water, soil, and sediment from 2013 to 2019 in Qingpu District of the integrated demonstration zone of the Yangtze River Delta were predicated by developing a dynamic Level IV fugacity model. The influence of seasonal environmental factors (e.g., temperature, rainfall) on the distribution and migration of antibiotics in multi-media was also explored. The simulation results show that the 10 antibiotics mainly existed in water and sediment. The concentrations of antibiotics in air, water, soil, and sediment were 0-7.629 × 10-14 ng/L, 1.187 × 10-10-16.793 ng/L, 1.042 × 10-14-3.500 × 10-11 ng/g and 8.015 × 10-12-14.188 ng/g, respectively. It was also found that the increase in temperature and rainfall can reduce the migration rate of some antibiotics into the water and sediment phases. The flux analysis of the cross-media migration and transformation of antibiotics in Qingpu District shows that advection was the prime input and output paths of antibiotics in the water. Moreover, the prime input and output paths of antibiotics in sediment were sedimentation from water to sediment and degradation. Sensitivity analysis shows that the characteristics of antibiotic emission, degradation rate, and Koc were the most influential parameters for target chemicals. The results of risk assessment based on Monte Carlo method reveal that the overall risk level of antibiotics in sediment was relatively risk-free, and the risk of antibiotics in water decreased in the order of tetracyclines > ß-lactams > fluoroquinolones > macrolides > sulfonamides.

Characterization, Antioxidant and Antitumor Activities of Oligosaccharides Isolated from Evodia lepta (Spreng) Merr. by Different Extraction Methods.

Evodia lepta (E. lepta) is a traditional Chinese herbal medicine with various biological activities. One of the active components of this widely used medicinal plant is believed to be an oligosaccharide. The extraction yields, structural characteristics, antioxidant, and antitumor activities of four oligosaccharide extracts obtained by hot water extraction (HEO), ultrasound-assisted extraction (UEO), enzyme-assisted (EEO), and microwave-assisted extraction (MEO) were investigated. Matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS), X-ray diffraction (XRD), and Scanning electron microscopy (SEM) results indicated that the extraction methods had a difference on the molecular mass distribution, structure, and morphology of the EOs. In addition, HEO and MEO showed strong antioxidant activities, which might be related to their uronic acid and protein contents. More interestingly, MEO was more active toward MDA-MB-231 cells compared to other cells, and cell growth inhibition was proposed to occur through apoptosis. Overall, microwave-assisted extraction is a promising technique for the extraction of high quality EO.

Aging alters Hv1-mediated microglial polarization and enhances neuroinflammation after peripheral surgery.

Perioperative neurocognitive disorders have been widely recognized as common adverse events after surgical intervention. Aging is one of the most important independent risk factors for worsened cognitive outcome, and this deterioration is linked to exacerbated microglia-mediated neuroinflammation in the aged brain. Under pathological stimulation, microglia are capable of polarizing toward proinflammatory M1 and anti-inflammatory M2 phenotypes. In the present study, we examined how aging affects microglial responses and neuroinflammation following peripheral surgery. Adult (2-3 months) and aged (18 months old) male C57/BL6 mice were subjected to tibial fracture or sham surgery. Aged mice exhibited higher level of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the hippocampus. The expression of synaptic protein synaptophysin (SYP) was also markedly reduced in the aged brain after the surgery. Both adult and aged mice showed significant increases in M1 microglial polarization (CD16/32). In contrast, tibial fracture surgery induced a decreased M2 microglial polarization (CD206, Ym1/2, Arg1) in aged brain but enhanced M2 microglial polarization in adult brain. Aged mice have upregulated voltage-gated proton channel (Hv1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit expression compared with adult mice. The percentage of CD16/32-positive M1 microglia colabeling with Hv1 was higher in aged mice after tibial fracture surgery. Thus, Hv1/NADPH oxidase upregulation in the aged brain may shift the dynamic equilibrium of microglial activation toward M1 polarization and exaggerate postoperative neuroinflammatory responses after peripheral surgical intervention.

[Clinical effects of suture anchor with V-Y tenoplasty in treating old Achilles tendon rupture].

OBJECTIVE: To explore clinical effects of suture anchor with V-Y tenoplasty for the treatment of old Achilles tendon rupture. METHODS: From May 2014 to March 2018, 26 patients with old Achilles tendon rupture treated by suture anchor with V-Y tenoplasty, including 18 males and 8 females aged from 19 to 56 years old with an average of (36.0±11.7) years old, the courses of disease ranged from 42 to 62 days with an average of (49.0±5.3) days; the distances of Achilles tendon-shortening ranged from 2 to 7 cm with an average of (4.0±1.6) cm. Postoperative complications were observed, preoperative and postoperative American Orthopaedic Foot and Ankle Soviety(AOFAS) score were used to evaluate clinical effects. RESULTS: All patients were followed up from 8 to 18 months with an average of(12.0±2.5) months. No Achilles tendon rupture occurred again. Postoperative AOFAS score at 3 months(93.37 ±3.48) was higher than before operation(57.26±5.06)(t=9.564, P<0.05), and 14 patients got excellent results, 11 moderate and 1 poor. CONCLUSIONS: Suture anchor with V-Y tenoplasty for old Achilles tendon rupture could achieve stable fixation, relieve pain, improve walking ability and quality of life, and also recover good function of ankle joint.

Cell cycle activation contributes to isoflurane-induced neurotoxicity in the developing brain and the protective effect of CR8.

AIMS: It is well established that exposure of common anesthetic isoflurane in early life can induce neuronal apoptosis and long-lasting cognitive deficit, but the underlying mechanisms were not well understood. The cell cycle protein Cyclin B1 plays an important role in the survival of postmitotic neurons. In the present study, we investigated whether cyclin B1-mediated cell cycle activation pathway is a contributing factor in developmental isoflurane neurotoxicity. METHODS: Postnatal day 7 mice were exposed to 1.2% isoflurane for 6 hours. CR8 (a selective inhibitor of cyclin-dependent kinases) was applied before isoflurane treatment. Brain samples were collected 6 hours after discontinuation of isoflurane, for determination of neurodegenerative biomarkers and cell cycle biomarkers. RESULTS: We found that isoflurane exposure leads to upregulated expression of cell cycle-related biomarkers Cyclin B1, Phospho-CDK1(Thr-161), Phospho-n-myc and downregulated Phospho-CDK1 (Tyr-15). In addition, isoflurane induced increase in Bcl-xL phosphorylation, cytochrome c release, and caspase-3 activation that resulted in neuronal cell death. Systemic administration of CR8 attenuated isoflurane-induced cell cycle activation and neurodegeneration. CONCLUSION: These findings suggest the role of cell cycle activation to be a pathophysiological mechanism for isoflurane-induced apoptotic cell death and that treatment with cell cycle inhibitors may provide a possible therapeutic target for prevention of developmental anesthetic neurotoxicity.

C1 Titanium Cables Combined with C2 Pedicle Screw-Rod Fixation for Atlantoaxial Instability Not Suitable for Placement of C1 Screws.

OBJECTIVE: We sought to develop a new posterior fusion technique composed of bilateral C1 titanium cables and C2 pedicle screw-rods for treatment of atlantoaxial instability not suitable for C1 screw placement. METHODS: A study was conducted of 18 patients with atlantoaxial instability who had C1 broken screw trajectory or anatomic anomalies. All patients underwent posterior fixation with bilateral C1 titanium cables and C2 pedicle screws. The follow-up period was a minimum 1 year. Clinical outcomes measurements included visual analog scale score for neck pain assessment, the American Spinal Injury Association Impairment Scale and Japanese Orthopaedic Association score for neurologic status and function. According to preoperative computed tomography (CT) reconstruction and CT angiography, the patients selected in this study were not suitable for C1 screw placement. Postoperative plain radiographs and CT reconstruction were performed to evaluate the reduction, bony fusion, and implant position. All outcomes were evaluated at each follow-up. RESULTS: The average clinical follow-up period was 24 months (range 12-36 months). All patients had complete neck pain relief at postoperative 6 months. Their neurologic symptoms had improved significantly at 1-year follow-up. Radiologic outcomes indicated good bony fusion and construction stability in all patients without implant failure at the last follow-up. No neural or vascular complications related to this technique were observed. CONCLUSIONS: Posterior atlantoaxial fixation using C1 titanium cables and C2 pedicle screw-rod construct appears to be an effective and safe technique for treatment of atlantoaxial instability, which could be an alternative method for cases unsuitable for C1 screw placement when using C1-C2 screw fixation.

Copper-Catalyzed Oxidative Cyclization/1,2-Amino Migration Cascade Reaction.

A novel and efficient copper-catalyzed tandem oxidative cyclization/1,2-amino migration of readily available enamino esters for the synthesis of substituted pyrroles has been developed. In this reaction, one C-N bond was cleaved, and two new C-N bonds and one C(sp2)-C(sp2) bond were constructed in one pot. This catalytic system has the obvious advantages of mild reaction conditions and the use of oxygen as the oxidant. The reaction tolerates a wide range of functional groups and is a reliable method for the straightforward synthesis of valuable aminomethyl-substituted pyrroles in good yields.

[A comparative study between on-endcaps and non-endcaps titanium mesh cage for the treatment of elderly cervical spondylotic myelopathy complicated with osteoporosis approach for anterior cervical spine surgery].

OBJECTIVE: To compare radiographic results and clinical effects of titanium mesh cage with two endcaps(on-endcaps titanium mesh cage) and without endcaps(non-endcaps titanium mesh cage) in anterior cervical corpectomy and fusion(ACCF) for elderly cervical spondylotic myelopathy. METHODS: The clinical data of 60 patients with cervical spondylotic myelopathy underwent ACCF from January 2011 to January 2016 were retrospectively analyzed. There were 26 males and 34 females, aged from 68 to 79 years old with a mean 75.8 years old. The patients were divided into two groups according to the different titanium mesh cage, using on-endcaps titanium mesh cage(group A, 32 cases) or non-endcaps titanium mesh cage (group B, 28 cases). The nerve function was evaluated by JOA score system; the height of intervertebral fusion segments and fusion segmental lordosis angle (Cobb angle) were measured by cervical lateral X-ray films, the bone graft fusion rate of titanium mesh was evaluated by CT. RESULTS: All the patients were followed up from 1 to 2 years with an average of 1.5 years. The preoperative JOA scores of group A were 9.3±1.7, postoperative at 1 week, 3 months, 1 year were 14.2±1.8, 15.7±1.2, 15.4±1.5, respectively; and the preoperative JOA scores of group B were 9.1±1.8, postoperative at 1 week, 3 months, 1 year were 14.5±1.3, 14.9±1.7, 15.2±1.6, respectively. The postoperative JOA scores between two groups were obviously improved than that of preoperative (P<0.05). There was no significant difference in JOA scores of 3 time-point after operation between two groups (P>0.05). In the group A, preoperative intervertebral height were(42.1±2.4) mm, postoperative at 1 week, 3 months, 1 year were (45.3±3.2) mm, (44.7±2.9) mm, (44.5±3.0) mm, respectively; preoperative Cobb angle of fusion segments were (5.3±1.2)°, postoperative at 1 week, 3 months, 1 year were (10.3±1.9) °, (10.1±1.7) °, (9.9±1.3) °, respectively. And in group B, preoperative intervertebral height were (43.4±2.3)mm, postoperative at 1 week, 3 months, 1 year were (45.7±2.8) mm, (44.2±2.7) mm, (41.5±2.1) mm, respectively; preoperative Cobb angle of fusion segments were (5.4±1.0) °, postoperative at 1 week, 3 months, 1 year were (11.2±1.8)°, (10.8±1.6)°, (7.2±1.4) °, respectively. The postoperative intervertebral height, Cobb angle of fusion segments between two groups were obviously improved than that of preoperative (P<0.05). There was no significant difference in intervertebral height and Cobb angle at 1 week, 3 months after operation between two groups(P>0.05). One year after operation, intervertebral height and Cobb angle in group A was better than that of group B(P<0.05). CONCLUSIONS: On-endcaps titanium mesh cage is superior to non-endcaps titanium mesh cage in the maintenance of cervical intervebral height and segmental lordosis angle postoperatively at elderly spondylotic myelopathy complicated with osteoporosis. The usage of on-endcaps titanium mesh cage can effectively reduce postoperative subsidence rate.

Experience with the second-generation Wallis interspinous dynamic stabilization device implanted in degenerative lumbar disease: a case series of 50 patients.

AIM: This study aimed to evaluate the short- to medium-term outcomes of the second-generation Wallis interspinous dynamic stabilization device for treatment of lumbar degenerative disease. MATERIAL AND METHODS: Fifty patients with lumbar degenerative disease treated from August 2007 to September 2009 were included in this retrospective study. The Japanese Orthopedic Association (JOA) score and the Oswestry Disability Index (ODI) were used for therapeutic efficacy evaluation. Odom's criteria were used to evaluate postoperative outcome with regard to symptoms. Anteroposterior X-rays were obtained after surgery. All patients were followed up for 2 years. RESULTS: Based on Odom's criteria, 22, 24 and 4 patients had excellent, good, and fair results respectively. The JOA score at 3, 12, and 24 months after surgery was significantly higher than before surgery (all p < 0.001), and the ODI score at 3, 12, and 24 months after surgery was significantly lower than before surgery (all p < 0.001). The posterior intervertebral disc height and the neural foramina height at 12 and 24 months after surgery was significantly higher than before surgery (both p < 0.001). CONCLUSION: Implantation of the second-generation Wallis interspinous dynamic stabilization device produced satisfactory clinical outcome at short- and medium-term follow-up in patients with lumbar degenerative disease.

A facile BPO-mediated ortho-hydroxylation and benzoylation of N-alkyl anilines for synthesis of 2-benzamidophenols.

A facile benzoyl peroxide (BPO) mediated ortho-hydroxylation and benzoylation of N-alkyl anilines for the synthesis of 2-benzamidophenols has been developed. The reaction tolerates a wide range of functional groups and is a good method for the straightforward synthesis of valuable 2-benzamidophenols in good yields under mild conditions.

[Unilateral pedicle screw fixation and transforaminal lumbar interbody fusion through paraspinal muscle approach for recurrent lumbar disc herniation combined with lumbar instability].

OBJECTIVE: To explore the clinical effects of unilateral pedicle screw fixation and transforaminal lumbar interbody fusion (TLIF) through paraspinal muscle approach for recurrent lumbar disc herniation combined with lumbar instability. METHODS: A total of 35 patients with recurrent lumbar disc herniation combined with lumbar instability were treated between March 2008 and May 2010, including 15 patients managed by the paraspinal muscle approach with unilateral pedicle screw fixation and transforaminal lumbar interbody fusion (TLIF) (unilateral fixation group) and 20 patients by the posterior midline approach with bilateral pedicle screw fixation and posterior lumbar interbody fusion (bilateral fixation group). Operation time and intraoperative blood loss were observed, preoperative and postoperative JOA score and VAS score in low back pain and legs pain, the interbody fusion condition were compared between two groups. RESULTS: All patients were followed up from 6 to 30 months with an average 16.8 months. All clinical symptoms had obviously improved postoperatively. X-rays showed good interbody fusion (only 1 case did not obtain fusion in bilateral fixation group) without cage displacement or settlement and implant loosening or breakage. There was significant difference in operation time and the intraoperative blood loss between two groups (P < 0.05). Postoperative JOA score had obviously decreased than preoperative one (P < 0.05). At 1 week after surgery, there was significant difference in VAS score of low back pain between two groups and there was no significant difference in VAS score of legs pain between two groups (P > 0.05); at final follow-up, there was no significant difference in VAS score of low back pain and legs pain between two groups (P > 0.05). CONCLUSION: Two methods both can obtain satisfactory effect in treating recurrent lumbar disc herniation combined with lumbar instability. Through the paraspinal muscle approach with unilateral pedicle screw fixation and TLIF has advantages of smaller surgical incision, shorter operation time, less intraoperative blood loss, faster relief in low back pain after operation, etc.

Cu(TFA)2-catalyzed oxidative tandem cyclization/1,2-alkyl migration of enamino amides for synthesis of pyrrolin-4-ones.

A novel Cu(TFA)2-catalyzed oxidative tandem cyclization/1,2-alkyl migration of readily available enamino amides for the synthesis of pyrrolin-4-ones has been developed. The reaction tolerates a wide range of functional groups and is a reliable method for the rapid synthesis of substituted pyrrolin-4-ones in high yields under mild conditions.

[Clinical analysis of an interspinous stabilization system (wallis) in treating lumbar degenerative disease].

OBJECTIVE: To evaluate clinical results of an interspinous stabilization system (Wallis) in treating lumbar degenerative disease in the short-term. METHODS: From August 2007 to June 2010,48 patients with lumbar degenerative disease who were treated with interspinous stabilization system, the data of patients were analyzed retrospectively. In all of the 48 cases, there were 30 males and 18 females with an average age of 54.2 years (ranged, 40 to 68 years). Forty-four cases were with single segment and 4 cases with two segments. Of them, 4 cases were in L3, 4, 40 cases were in L4, 5, 4 cases were in L3, 4 and L4, 5. The radiographic data of patients were analyzed. Clinical effects were evaluated by Japanese Orthopedic Association (JOA) score system and low back pain disability questionnaire (Oswestry) and Odom method. RESULTS: All the patients were followed up from 1 to 2 years with an average of 18 months. According to Odom's criteria, 20 cases obtained excellent results, 24 good, 4 fair. JOA score increased from 12.4 +/- 2.7 preoperatively to 26.1 +/- 2.0 postoperatively (P < 0.01). Oswestry score decreased from 14.1 +/- 2.9 preoperatively to 5.5 +/- 1.8 postoperatively (P < 0.01). The posterior height of intervertebral space and height of nerve root canal increased compared with that of preperative height. CONCLUSION: The treatment of lumbar degenerative disease with interspinous stabilization system can obtain satisfactory effects in the near future. It can retain dynamic stable of corresponding segments, expand volume of vertebral canal, and is safe and feasible.

[On the in vitro diagnostic medical equipment industry standard YY 0648-2008].

The paper introduces the scope of application of standard and basic contents of YY0648-2008. It shows part of the standard terms of understanding, especially in the original use of the GB 4793.1-2007 standard provisions based on new knowledge and understanding.