Piezoelectric Drop-on-Demand Inkjet Printing with Ultra-High Droplet Velocity.

Improving droplet velocity as much as possible is considered as the key to improving both printing speed and printing distance of the piezoelectric drop-on-demand inkjet printing technology. There are 3 tough and contradictory issues that need to be addressed simultaneously, namely, the actuation pressure of the piezoelectric printhead, satellite droplets, and the air resistance, which seems almost impossible to achieve with classical methods. Herein, a novel solution is introduced. By modulating the positive crosstalk effect inside and outside the printhead, self-tuning can be achieved, including self-reinforcing of the actuation pressure, self-restraining of satellite droplets, and self-weakening of the air resistance, thereby greatly improving droplet velocity. Based on these mechanisms, waveform design methods for different inks and printheads are investigated. The results demonstrate that monodisperse droplet jetting with a maximum velocity of 27.53 m/s can be achieved, reaching 3 to 5 times that of the classical method (5 to 8 m/s). Correspondingly, the printing speed and distance can be simultaneously increased by almost 10 times, demonstrating an ability of direct printing on irregular surface. Meanwhile, the compatibility of ink materials is expanded, as the Ohnesorge number and the viscosity of printable inks for the printhead used are increased from 0.36-0.72 to 0.03-1.18 and from 10-12 cp to 1-40.3 cp, respectively, even breaking the traditional limitations of the piezoelectric printing technology (Ohnesorge number of 0.1 to 1; viscosity of 1 to 25 cp). All the above provide a new perspective for improving droplet velocity and may even offer a game-changing choice for expanding the boundaries of the piezoelectric drop-on-demand inkjet printing technology.

Electrowetting-assisted printing of 3D-architectured microelectrodes inside flexible piezoelectric films for sensitive, robust responses to bending deformation.

The voltage outputs of flexible piezoelectric films after bending deformation have always been limited by two factors, including the incompatible polarization direction with bending strain and the interfacial fatigue failure between the piezoelectric films and the electrode layers, largely hindering the applications in wearable electronics. Herein, we demonstrate a new piezoelectric film design, where 3D-architectured microelectrodes are fabricated inside a piezoelectric film by electrowetting-assisted printing of conductive nano-ink into the pre-formed meshed microchannels in the piezoelectric film. The 3D architectures increase the piezoelectric output of a typical P(VDF-TrFE) film by more than 7 fold compared with the conventional planar design at the same bending radius, and, more importantly, decrease the output attenuation down to only 5.3% after 10 000 bending cycles, less than one third of that for the conventional design. The dependence of piezoelectric outputs on feature sizes of 3D microelectrodes was investigated numerically and experimentally, providing a route for optimizing the 3D architecture design. Different composite piezoelectric films with internal 3D-architectured microelectrodes were fabricated, exhibiting improved piezoelectric outputs under bending deformations, demonstrating that our printing methods could have broad applications in various fields. The fabricated piezoelectric films, worn on human fingers, are used for remotely controlling the robot hand gestures by human-machine interaction; furthermore, the fabricated piezoelectric patches are used to successfully sense the pressure distribution by integrating with spacer arrays to convert the pressing movement into bending deformation, demonstrating the enormous potential of our piezoelectric films in practical applications.

Preoperative prognostic nutrition index can independently predict the 6-month prognosis of elderly patients undergoing neurosurgical clipping for aneurysmal subarachnoid hemorrhage.

The number of elderly patients with aneurysmal subarachnoid hemorrhage (aSAH) is increasing annually. The prognostic nutritional index (PNI) is used as a novel and valuable prognostic marker for various neoplastic diseases and other critical illnesses. This study aimed to identify the short-term prognostic value of preoperative PNI in elderly patients who underwent neurosurgical clipping for aSAH. This retrospective study included elderly patients with aSAH who underwent neurosurgical clipping from January 2018 to December 2020. Clinical variables and 6-month outcomes were collected and compared. Epidemiological data and effect factors of prognosis were evaluated. Multivariate logistic regression and receiver operating characteristics (ROC) curve analyses were used to evaluate the predictive value of preoperative PNI. Multiple logistic regression was performed to establish a nomogram. A total of 124 elderly patients were enrolled. Multivariate logistic regression analysis showed that preoperative PNI (odds ratio (OR), 0.779; 95% confidence interval (CI), 0.689-0.881; P < 0.001), Hunt-Hess grade (OR, 3.291; 95%CI, 1.816-5.966; P < 0.001), and hydrocephalus (OR, 9.423; 95%CI, 2.696-32.935; P < 0.001) were significant predictors. The area under the ROC curve of PNI was 0.829 (95% CI, 0.755-0.903; P < 0.001) with a sensitivity and specificity of 68.4% and 83.3%, respectively, and the cutoff value was 46.36. Patients with preoperative PNI of < 46.36 had a significantly unfavorable 6-months prognosis (F = 40.768, P < 0.001). Preoperative PNI is independently correlated with the 6-month prognosis in elderly patients who undergo neurosurgical clipping for aSAH.

Associations of striatal dopamine transporter binding with motor and non-motor symptoms in early Parkinson's disease.

Dopamine transporter (DAT) imaging is an in vivo tool to assess presynaptic dopaminergic function in the clinical practices of Parkinson's disease (PD). Current clinical practices focused on qualitatively visual interpretation of DAT imaging, whereas quantitative analyses are potentially more helpful when monitoring the progression of PD. Previous cross-sectional studies indicated certain motor and non-motor features were associated with striatal DAT binding, whereas limited data were reported in terms of the longitudinal correlation between clinical features of PD with striatal DAT binding. The purpose of our study is to clarify current and longitudinal correlations between striatal DAT binding and clinical measures. A total of 352 untreated PD individuals and 167 healthy controls with complete baseline clinical measures and neuroimaging data were identified from the Parkinson's Progression and Markers Initiative (PPMI) database. Patients with PD underwent DAT imaging at the screening visit and following months 12, 24, and 48. Multiple linear regression models and linear mixed-effect models were respectively conducted to investigate the cross-sectional and longitudinal correlation between clinical characteristics and DAT binding. Associations between changes in clinical characteristics and changes in DAT binding were further evaluated and the Spearman rank correlation coefficients were reported. In the cross-sectional analysis, baseline striatal DAT binding was significantly associated with the Hoehn and Yahr scale, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) scores, the rigidity scores, and the axial scores in PD individuals (false discovery rate [FDR]-adjusted p = 0.0017 for all above). Patients who developed freezing of gait had lower striatal DAT binding (FDR-adjusted p = 0.0161). Healthy controls who had higher tremor scores and suffered more severe olfactory dysfunction had lower striatal DAT binding (FDR-adjusted p = 0.0257 for all above). Longitudinal analysis indicated that baseline severity of rapid-eye-movement sleep behavior disorder was significantly associated with longitudinal striatal DAT binding in patients with PD (FDR-adjusted p = 0.0120). Furthermore, changes in MDS-UPDRS scores and the State-Trait Anxiety Inventory (STAI) scores demonstrated significant correlations with changes in striatal DAT binding over 4 years (p = 0.005 and p = 0.032, respectively). Our findings clarified quantitative associations between certain motor and non-motor features with current and future striatal dopamine binding, suggesting the feasibility of using DAT images as a progression predictive marker for PD. Further studies are needed to investigate correlations between different regional dopamine binding with specific clinical features.

Microcrack Arrays in Dense Graphene Films for Fast-Ion-Diffusion Supercapacitors.

Laminated graphene film has great potential in compact high-power capacitive energy storage owing to the high bulk density and opened architecture. However, the high-power capability is usually limited by tortuous cross-layer ion diffusion. Herein, microcrack arrays are fabricated in graphene films as fast ion diffusion channels, converting tortuous diffusion into straightforward diffusion while maintaining a high bulk density of 0.92 g cm-3 . Films with optimized microcrack arrays exhibit sixfold improved ion diffusion coefficient and high volumetric capacitance of 221 F cm-3 (240 F g-1 ), representing a critical breakthrough in optimizing ion diffusion toward compact energy storage. This microcrack design is also efficient for signal filtering. Microcracked graphene-based supercapacitor with 30 µg cm-2  mass loading exhibits characteristic frequency up to 200 Hz with voltage window up to 4 V, showing high promise for compact, high-capacitance alternating current (AC) filtering. Moreover, a renewable energy system is conducted using microcrack-arrayed graphene supercapacitors as filter-capacitor and energy buffer, filtering and storing the 50 Hz AC electricity from a wind generator into the constant direct current, stably powering 74 LEDs, demonstrating enormous potential in practical applications. More importantly, this microcracking approach is roll-to-roll producible, which is cost-effective and highly promising for large-scale manufacture.

Altered large-scale internetwork functional connectivity in patients with vestibular migraine and migraine without aura.

OBJECTIVE: To investigate large-scale internetwork functional connectivity in patients with vestibular migraine (VM) and migraine without aura (MwoA). METHODS: Resting-state functional magnetic resonance imaging data from 34 VM patients, 34 MwoA patients, and 33 healthy controls (HCs) were collected and the results were analyzed using independent component analysis (ICA). We also analyzed the correlations between clinical data and internetwork functional connectivity. RESULTS: In contrast to HCs, MwoA patients showed decreased functional connectivity between the left frontoparietal network (lFPN) and right frontoparietal network (rFPN), with increased functional connectivity between the sensorimotor network (SMN) and lateral visual network (lVN). When compared to MwoA patients, VM patients demonstrated decreased functional network connectivity between the dorsal attention network (DAN) and posterior medial visual network (pmVN), between the SMN and pmVN, and between the SMN and lVN. Meanwhile, increased functional network connectivity was found between the lFPN and rFPN; however, there was no significant difference in functional network connectivity between VM patients and HCs. In addition, associations were found between clinical data and internetwork functional connectivity. CONCLUSION: Functional connectivity between the lFPN and rFPN was reduced in patients with MwoA compared with HCs, which may indicate functional impairment in cognitive control, attention, somatosensory perception, and emotion regulation in patients with MwoA. VM patients showed decreased functional connectivity between the DAN, SMN, pmVN and lVN compared to patients with MwoA, which could account for the multisensory integration abnormalities and be the cause of vestibular symptoms in VM patients. These findings offer fresh perspectives on the pathophysiology of VM and MwoA.

Association of AQP4 single nucleotide polymorphisms (rs335929 and rs2075575) with Parkinson's disease: A case-control study.

OBJECTIVE: The glymphatic system plays an important role in brain waste removal and is functionally and structurally dependent on astrocyte aquaporin-4 (AQP4). Genetic variation in the AQP4 gene has therefore been hypothesized to be associated with genetic susceptibility to neurodegenerative diseases. This study aimed to investigate whether two specific single nucleotide polymorphisms (SNP) in the AQP4 gene, rs335929, and rs2075575, are associated with the risk and clinical features of PD. METHODS: A total of 950 participants, including 475 patients with sporadic PD and 475 independent healthy controls, were included in this case-control study. Two SNPs (rs335929 and rs2075575) of the AQP4 gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Sanger sequencing was used to determine whether the genotyping results were accurate. A chi-square (χ2) test was used to compare the frequencies of alleles and genotypes between patients and controls. Logistic regression was used to calculate dominance ratios (OR) and 95% confidence intervals (CI). RESULTS: The difference between rs2075575 in the dominant model (GG vs GA + AA: P = 0.019) and the overdominant model (GG + AA vs GA: P = 0.013) was statistically significant. Subgroup analysis showed that the frequency of the rs2075575 A allele was significantly higher in female PD patients than in matched female controls (P = 0.017). rs2075575 A allele was significantly more frequent in LOPD patients than in matched elderly controls (P = 0.033). rs335929 polymorphism was not significantly correlated with PD susceptibility in either the overall or subgroup analysis. Haplotype analysis between the two SNPs did not show an association with PD susceptibility. In addition, we found that the rs2075575 G allele was significantly associated with Rapid Eye Movement Behaviour Disorder (RBD) (P = 0.044), and the rs335929 A allele with memory impairment (P = 0.028) in PD. CONCLUSION: The AQP4 gene rs2075575 polymorphism may be associated with PD susceptibility, but not the rs335929 polymorphism. rs2075575 is associated with RBD and rs335929 is associated with memory cognition. Regulation of the glymphatic system by interfering with the genetics of AQP4 and thus influencing the pathology of PD may be a direction worth investigating. Studies in larger sample sizes and across ethnicities are essential for further understanding the potential association between AQP genes and PD pathogenesis.

Knockdown of Brachyury Suppresses Breast Cancer Cell Proliferation and Migration via Targeting E2F3.

Breast cancer is one of the most frequently diagnosed cancer in women and is the major cause of most cancer-related deaths. We previously reported that Brachyury, as a sensitive and specific marker, has been verified to involve in the process of carcinogenesis and progression of breast cancer, but the mechanism by which Brachyury promotes breast cancer cells proliferation and migration still remains less clear. In this study, we identified that Brachyury was markedly increased in breast cancer compared with the adjacent tissues. We have also shown that Brachyury knockdown could decrease the proliferation and migration capability in breast cancer cells both in vitro and in vivo. Finally, we found an important transcriptional factor, E2F3, which is a direct downstream target gene of Brachyury by chromatin immunoprecipitation (ChIP) analysis. Knockdown of E2F3 also decreased breast cancer cell proliferation and migration. Taken together, we reported that Brachyury may act as an oncogenic role in the progression of breast cancer by positively-regulating E2F3 expression.

Association between ABCA7 gene polymorphisms and Parkinson's disease susceptibility in a northern Chinese Han population.

OBJECTIVE: As a typical member of the ABC transporter superfamily, ABCA7 has been shown to play an important role in stalling the pathogenesis of neurodegenerative disorders through maintaining the normal microglial function, regulating cellular responses to inflammation and ER stress, and modulating lipid metabolism. Variants in the ABCA7 locus have been hypothesized to be correlated with the genetic predisposition of several neurodegenerative disorders. The goal of this study was to examine whether there is a link between three specific single nucleotide polymorphisms in the ABCA7 gene, namely, rs3764650, rs4147929, and rs3752246, with the risk of developing Parkinson's disease (PD) in a northern Chinese Han community. METHODS: In this case-control study, we recruited 821 participants, including 411 patients with sporadic PD and 410 independent, healthy controls. A Polymerase Chain Reaction-Restriction Fragment Length Polymorphism genotyping assay was used to identify polymorphisms of the three selected single nucleotide polymorphisms (rs3764650, rs4147929, and rs3752246) of the ABCA7 gene. Sanger sequencing was further applied to identify the accuracy of the genotyping results. The chi-square test was used to compare the frequencies of alleles and genotypes in patients and controls. Odds ratios and 95% confidence intervals were calculated using logistic regression. RESULTS: We found significant between-group differences in the alleles (A vs. G, nominal P = 0.014) and dominant models (AA + GA vs. GG, nominal P = 0.015) of rs4147929. Subgroup analysis showed that the frequency of the rs4147929 A allele in male patients with PD was significantly higher than that in male controls (nominal P = 0.036). For the rs3752246 polymorphism, the frequency of the G allele was significantly higher in patients with PD than in controls, and the dominant model fit the data best when considering the nominal P-values (nominal P = 0.019, nominal P = 0.033, respectively). Differences in G allele and genotypes frequencies between patients and controls remained significant in women (nominal P = 0.032 for allele, nominal P = 0.015 for genotype), as well as in individuals aged more than 50 years (nominal P = 0.044, nominal P = 0.020, respectively). No significant differences were observed in allele or genotype frequencies between patients with PD and healthy controls for rs3764650. The frequency of the TCG (rs3764650-rs3752246-rs4147929) haplotype was significantly lower in the PD group than in the healthy control group (odds ratio = 0.772; 95% confidence interval = 0.634-0.940; P = 0.011). CONCLUSION: The rs4147929 polymorphism was significantly associated with PD susceptibility in the northern Chinese Han population. The A allele of rs4147929 was a risk factor for developing PD. The TCG haplotype presented a protective role in the pathogenesis of PD. Further studies using larger sample sizes, considering different clinical and biochemical parameters such as the cognitive status of subjects at the same time, are warranted to better clarify the effects of these common variants on the pathogenesis and development of PD.

Role of CD36 rs1761667 AA genotype in the expression of inflammatory cytokines and Parkinson's disease progression: A case-control study in a northern Han Chinese population.

OBJECTIVE: This study aimed to investigate the effect of CD36 rs1761667 gene polymorphisms on the expression of CD36 and inflammatory cytokines and the progression of Parkinson's disease (PD). METHODS: A total of 138 patients with PD (60 men and 78 women) and 132 healthy controls (48 men and 84 women) from a northern Han Chinese population were enrolled in this case-control study. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the CD36 rs1761667 genotype. An enzyme-linked immunosorbent assay was used to determine the expression of CD36, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α in the plasma. RESULTS: The frequency of the rs1761667 AA genotype was significantly higher in patients with PD than that in healthy controls, suggesting AA genotype to be a risk factor for PD. When compared with those in healthy controls, CD36 levels were significantly lower in patients with PD, whereas IL-6, IL-1ß, and TNF-α levels were significantly higher in patients with PD. Furthermore, GA and AA carriers with PD showed lower levels of CD36, and GG, GA, and AA carriers showed higher levels of IL-6, IL-1ß, and TNF-α than those in healthy controls. In the PD patient group, AA and GA carriers had lower expression levels of CD36 than GG carriers did, and CD36 levels were lower in AA carriers than in GA carriers. Conversely, AA carriers had elevated expression levels of IL-6 compared with that of GG and GA carriers. Logistic regression analysis revealed that IL-6, IL-1ß, and TNF-α levels were risk factors for PD in a northern Han Chinese population. CONCLUSION: The CD36 rs1761667 AA genotype may increase susceptibility to PD and the expression of inflammatory cytokines.

Poly(ethylene glycol)-sheddable reduction-sensitive polyurethane micelles for triggered intracellular drug delivery for osteosarcoma treatment.

BACKGROUND: The survival rate of osteosarcoma therapy still lags behind overall cancer therapies due to the intrinsic or acquired drug resistance. Developing novel drug delivery systems that may overcome drug resistance would greatly facilitate osteosarcoma therapy. METHODS: Poly(ethylene glycol) (PEG)-sheddable reduction-sensitive polyurethane (SS-PU-SS-PEG) was synthesized using a disulfide-containing polycaprolactone diol as the hydrophobic block and a cystamine-functionalized PEG as the hydrophilic block. SS-PU-SS-PEG micelles were then prepared to load the anti-tumor drug Doxorubicin (DOX) in order to achieve triggered intracellular drug delivery to improve the efficacy of osteosarcoma therapy. RESULTS: When DOX was used as a model drug, the drug-loaded SS-PU-SS-PEG micelles were about 82∼94 nm in diameter and exhibited good stability in phosphate buffer saline (PBS). The micelles could release about 80% DOX in a quantitative fashion within 5 hours under a reductive environment. The intracellular drug release of DOX-loaded SS-PU-SS-PEG micelles increased upon incubation with Saos-2 cells in vitro. The micelles had good biocompatibility. In vitro, DOX-loaded SS-PU-SS-PEG micelles showed significant antitumor activity toward Saos-2 cells, which was close to that of free DOX. In vivo, DOX-loaded SS-PU-SS-PEG micelles exhibited better antitumor activity than free DOX. CONCLUSION: Findings from this study suggest that the SS-PU-SS-PEG micelles could achieve well-controlled triggered drug release in a reduction environment and could therefore improve the antitumor efficacy of osteosarcoma therapies. TRANSLATION POTENTIAL OF THIS ARTICLE: In this study we developed PEG-sheddable reduction-sensitive polyurethane micelles (SS-PU-SS-PEG), which were able to achieve well-controlled triggered release of anti-tumor drug Doxorubicin (DOX) in an intracellular reduction environment. DOX-loaded SS-PU-SS-PEG micelles markedly improved the antitumor efficacy in a Saos-2 cells-bearing xenograft tumor model. Therefore, such micelles might be used as a novel drug delivery system for osteosarcoma treatment.

Zonisamide for the Treatment of Parkinson Disease: A Current Update.

Zonisamide has been used as an add-on treatment in order to overcome the deficiencies of the general therapies currently used to resolve the motor complications and non-motor symptoms of Parkinson disease. Various trials have been designed to investigate the mechanism of action and treatment effects of zonisamide in this condition. Most clinical trials of zonisamide in Parkinson disease were from Japan. The vast majority of studies used changes in the Unified Parkinson's Disease Rating Scale (UPDRS) scores and daily "OFF" time as primary endpoints. Based on adequate randomized controlled trials, zonisamide is considered a safe and efficacious add-on treatment in Parkinson disease. The most convincing proof is available for a dosage of 25-50 mg, which was shown to lead to a significant reduction in the UPDRS III score and daily "OFF" time, without increasing disabling dyskinesia. Furthermore, zonisamide may play a beneficial role in improving non-motor symptoms in PD, including impulsive-compulsive disorder, rapid eye movement sleep behavior disorder, and dementia. Among the various mechanisms reported, inhibition of monoamine oxidase-B, blocking of T-type calcium channels, modulation of the levodopa-dopamine metabolism, modulation of receptor expression, and neuroprotection are the most often cited. The mechanisms underlying neuroprotection, including modulation of dopamine turnover, induction of neurotrophic factor expression, inhibition of oxidative stress and apoptosis, inhibition of neuroinflammation, modulation of synaptic transmission, and modulation of gene expression, have been most extensively studied. This review focuses on structure, pharmacokinetics, mechanisms, therapeutic effectiveness, and safety and tolerability of zonisamide in patients with Parkinson disease.

Molecular Mechanisms Underlying Reciprocal Interactions Between Sleep Disorders and Parkinson's Disease.

Sleep-wake disruptions are among the most prevalent and burdensome non-motor symptoms of Parkinson's disease (PD). Clinical studies have demonstrated that these disturbances can precede the onset of typical motor symptoms by years, indicating that they may play a primary function in the pathogenesis of PD. Animal studies suggest that sleep facilitates the removal of metabolic wastes through the glymphatic system via convective flow from the periarterial space to the perivenous space, upregulates antioxidative defenses, and promotes the maintenance of neuronal protein homeostasis. Therefore, disruptions to the sleep-wake cycle have been associated with inefficient metabolic clearance and increased oxidative stress in the central nervous system (CNS). This leads to excessive accumulation of alpha-synuclein and the induction of neuronal loss, both of which have been proposed to be contributing factors to the pathogenesis and progression of PD. Additionally, recent studies have suggested that PD-related pathophysiological alterations during the prodromal phase disrupt sleep and circadian rhythms. Taken together, these findings indicate potential mechanistic interactions between sleep-wake disorders and PD progression as proposed in this review. Further research into the hypothetical mechanisms underlying these interactions would be valuable, as positive findings may provide promising insights into novel therapeutic interventions for PD.

Expression of PD-L1/PD-L2 is associated with high proliferation index of Ki-67 but not with TP53 overexpression in chondrosarcoma.

PURPOSE: Chondrosarcoma is a malignancy affecting cartilage and is chemo- and radio-resistant. Novel immune checkpoint inhibitors may play a role in treatment; however, expression of programmed cell death ligand 1/2 (PD-L1/PD-L2) in chondrosarcoma is unreported. METHODS: Chondrosarcoma sections were collected and stained immunohistochemically for PD-L1, PD-L2, Ki-67, and TP53. Clinicopathological parameters were collected and analyzed statistically for associations and correlations. PD-L1/PD-L2 positivity was designated using 1% and 5% cutoffs, respectively. RESULTS: A total of 59 chondrosarcoma samples excised between 1997 and 2017 were collected. There were 40 samples assessed as PD-L1-positive and 25 samples as PD-L2-positive. In univariate analysis, PD-L1 positivity was significantly associated with younger age (P = .001), larger tumor (P = .025), advanced tumor grade (P < .001), and recurrence (P < .001). PD-L1 positivity was not associated with gender, location, serum level of lactate dehydrogenase, or serum level of alkaline phosphatase. PD-L2 positivity was solely significantly associated with younger age (P = .015). The associations were however insignificant in multivariate analysis. PD-L1 expression was significantly correlated with Ki-67 (P < .001) and TP53 (P = .02) expressions. PD-L2 expression was not correlated with either Ki-67 or TP53 expression. When grouped as combined expression (both negative vs. either positive), PD-L1/PD-L2 expression was associated with earlier recurrence (P < .001), and was negatively correlated with expression of Ki-67 (P < .001) but not with the expression of TP53. CONCLUSION: PD-L1/PD-L2 is positively expressed in chondrosarcoma and is associated with advanced clinical phenotype. PD-L1/PD-L2 expression is also associated with Ki-67 expression. Our results support the application of immune checkpoint blockade in chondrosarcoma.

Intravenous glucocorticoid for pain control after spinal fusion: A meta-analysis of randomized controlled trials.

OBJECTIVE: Postoperative pain was a common symptom after spinal surgery. This meta-analysis aimed to assess whether intravenous glucocorticoids has a beneficial role in reducing pain in patients following spinal fusion. METHODS: We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and Google databases, from inception to March 2, 2018. Randomized controlled trials (RCTs) that comparing intravenous glucocorticoids with control treatment for spinal fusion were included. A meta-analysis was performed to generate pooled risk ratio (RR) and weighted mean difference with corresponding 95% confidence interval (CI) for discontinuous outcomes (the occurrence of nausea and infection) and continuous outcomes (visual analog scale [VAS] at 12, 24, and 48 h; total morphine consumption; and the length of hospital stay), respectively. RESULTS: Eight clinical trials involving 918 patients (glucocorticoid group = 449, control group = 469) were finally included in this meta-analysis. Compared with control, intravenous glucocorticoids had significantly reduced VAS at 12, 24, and 48 hours with statistically significance (P < .05). Intravenous glucocorticoids can decrease the occurrence of nausea (RR = 0.42, 95% CI 0.29-0.62, P = .000; I = 0.0%) and the length of hospital stay. No difference was noticed in the occurrence of infection between glucocorticoids intravenous and control (P > .05). CONCLUSION: Existing evidence indicated that intravenous glucocorticoids have a beneficial role in decreasing early pain and the occurrence of nausea after spinal fusion surgery. In consideration of the limitation in current meta-analysis, more high-quality RCTs were needed to identify the optimal dose of glucocorticoids in spinal fusion patients.

Genome-wide CRISPR screen reveals SGOL1 as a druggable target of sorafenib-treated hepatocellular carcinoma.

The genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen is a powerful tool used to identify therapeutic targets that can be harnessed for cancer treatment. This study aimed to assess the efficacy of genome-wide CRISPR screening to identify druggable genes associated with sorafenib-treated hepatocellular carcinoma (HCC). A genome-scale CRISPR knockout (GeCKO v2) library containing 123,411 single guide RNAs (sgRNAs) was used to identify loss-of-function mutations conferring sorafenib resistance upon HCC cells. Resistance gene screens identified SGOL1 as an indicator of prognosis of patients treated with sorafenib. Of the 19,050 genes tested, the knockout screen identified inhibition of SGOL1 expression as the most-effective genetic suppressor of sorafenib activity. Analysis of the survival of 210 patients with HCC after hepatic resection revealed that high SGOL1 expression shortened overall survival (P = 0.021). Further, matched pairs analysis of the TCGA database revealed that SGOL1 is differentially expressed. When we used a lentivirus Cas9 vector to determine the effect of targeting SGOL1 with a specific sgRNA in HCC cells, we found that SGOL1 expression was efficiently inhibited and that loss of SGOL1 was associated with sorafenib resistance. Further, loss of SGOL1 from HCC cell decreased the cytotoxicity of sorafenib in vivo. We conclude that the CRISPR screen is a powerful tool for therapeutic target analysis of sorafenib treatment and that SGOL1 serves as a druggable target for HCC treated with sorafenib and an indicator of prognosis.

Inhibition of mTOR and HIF pathways diminishes chondro-osteogenesis and cell proliferation in chondroblastoma.

Chondroblastoma (CBL) is a benign bone tumor occurring mostly in teenagers. Despite this, CBL can recur and metastasize after curettage, which may impede normal epiphysis. In search of a novel targeted therapy for CBL, we aimed at BMP-2, a factor critical for chondro-osteogenesis and chondrocyte proliferation. Two pathways upstream of BMP-2, the mTOR and HIF, were targeted with rapamycin (Rapa) and FM19G11 (FM), respectively. Using immunohistochemistry, we found BMP-2 was highly expressed in CBL tissues. CBL cells explanted and confirmed with higher BMP-2 level than normal cartilage. Protumorigenic effect of Rapa and FM on CBL cells were transduced via BMP-2. Combination of Rapa and FM conferred stronger inhibition of cell proliferation than either monotherapy and inhibited levels of chondro-osteogenic markers (Sox9, aggrecan, and type II collagen). To minimize the adverse effect of Rapa, we performed screening in essential amino acids and found leucine deprivation-sensitized CBL cells to Rapa. Combination treatment of low dose Rapa, FM, and leucine deprivation conferred compatible inhibitory effects on CBL cell proliferation, chondro-osteogenic potential, and tumorigenic capacity. We conclude that targeting BMP-2 using mTOR/HIF inhibition could potently curb the disease. Addition of low-leucine diet could lower the dose of rapamycin in chase for less toxicity.

Expression of bone-morphogenetic protein 2 and tumor necrosis factor α correlates with bone metastases in bladder urothelial carcinoma.

We have investigated the role of bone-morphogenetic protein (BMP) 2 and tumor necrosis factor α (TNF-α) in 33 patients with bladder cancer (BCa) with bone metastasis. Thirty nonmetastatic BCas were included as controls. Immunohistochemical staining with BMP-2 and TNF-α was performed. Expressions of the factors were quantified and studied statistically. As a result, a trend showing higher expression of BMP-2 and TNF-α was associated with advanced disease. Expressions of BMP-2 and TNF-α were significantly higher in BCa with bone metastases (P = .0002 and P = .0172, respectively). The expression of BMP-2 and TNF-α showed a direct correlation in metastatic and muscle-invasive cases (P = .0202 and P = .0004, respectively) but not in nonmetastatic or noninvasive BCa (P = .1834 and P = .9215, respectively). It is postulated that BMP-2 can be responsible for the mechanism involved in triggering bone metastasis in BCa. The correlation with TNF-α indicates that the interaction of the 2 factors may promote local invasion and distant metastasis, especially to bone.

[Retrospective analysis of the clinical outcomes of repeated IVF/ICSI cycles].

OBJECTIVE: To study whether the rates of pregnancy and implantation decline in repeated IVF/ICSI cycles and whether the decline is associated with the availability of embryo cryopreservation. METHODS: We retrospectively analyzed the pregnancy and implantation rates of 1,033 IVF/ICSI cycles accomplished in our center to determine the association of the clinical outcomes with the availability of embryo cryopreservation. RESULTS: The rates of pregnancy and implantation declined slightly in the cycles with embryo cryopreservation (43% vs 43%, P > 0.05; 29% vs 24% , P > 0.05), but significantly in the repeated IVF/ICSI cycles without embryo cryopreservation (43% vs 35%, 43% vs 22% , P < 0.05; 29% vs 23% , 29% vs 16% , P < 0.05). CONCLUSION: The rates of pregnancy and implantation remain similar in the following cycles for those with embryo cryopreservation in the first IVF/ICSI cycles, but decline significantly in the repeated IVF/ICSI cycles for those without.