Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents.

BACKGROUND: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority. METHODS: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations. RESULTS: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1st- (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05). CONCLUSION: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents.

Accelerating multipool CEST MRI of Parkinson's disease using deep learning-based Z-spectral compressed sensing.

PURPOSE: To develop a deep learning-based approach to reduce the scan time of multipool CEST MRI for Parkinson's disease (PD) while maintaining sufficient prediction accuracy. METHOD: A deep learning approach based on a modified one-dimensional U-Net, termed Z-spectral compressed sensing (CS), was proposed to recover dense Z-spectra from sparse ones. The neural network was trained using simulated Z-spectra generated by the Bloch equation with various parameter settings. Its feasibility and effectiveness were validated through numerical simulations and in vivo rat brain experiments, compared with commonly used linear, pchip, and Lorentzian interpolation methods. The proposed method was applied to detect metabolism-related changes in the 6-hydroxydopamine PD model with multipool CEST MRI, including APT, CEST@2 ppm, nuclear Overhauser enhancement, direct saturation, and magnetization transfer, and the prediction performance was evaluated by area under the curve. RESULTS: The numerical simulations and in vivo rat-brain experiments demonstrated that the proposed method could yield superior fidelity in retrieving dense Z-spectra compared with existing methods. Significant differences were observed in APT, CEST@2 ppm, nuclear Overhauser enhancement, and direct saturation between the striatum regions of wild-type and PD models, whereas magnetization transfer exhibited no significant difference. Receiver operating characteristic analysis demonstrated that multipool CEST achieved better predictive performance compared with individual pools. Combined with Z-spectral CS, the scan time of multipool CEST MRI can be reduced to 33% without distinctly compromising prediction accuracy. CONCLUSION: The integration of Z-spectral CS with multipool CEST MRI can enhance the prediction accuracy of PD and maintain the scan time within a reasonable range.

PD-1/PD-L1 interaction score and NKT-like cell infiltration predict immunotherapy efficacy in non-small cell lung cancer patients.

OBJECTIVE: The currently available biomarkers are insufficient to accurately predict the immunotherapy response in patients. This work attempted to investigate effects of PD-1/PD-L1 interaction score combined with NKT-like cell infiltration level in tumor microenvironment on predicting immunotherapy efficacy. METHODS: 24 non-small cell lung cancer (NSCLC) patients who underwent immunotherapy were analyzed using multiplex immunofluorescence to quantitatively assess positive cells of target biomarkers and their spatial localization. Correlation between PD-1/PD-L1 interaction score in combination with NKT-like cell infiltration level and immunotherapy response was analyzed. The predictive performance of two individual biomarkers and combined novel biomarkers in immunotherapy efficacy was assessed through receiver operating characteristic curve analysis. Relationships between these factors and patient survival prognosis were analyzed using Kaplan-Meier curves. RESULTS: Among responders, PD-1/PD-L1 interaction score and NKT-like cell infiltration level were significantly higher than nonresponders (P < 0.05), and PD-1/PD-L1 interaction score and NKT-like cell infiltration level could effectively identify the population with immunotherapy response, with area under the curves (AUCs) of 0.7571 and 0.8643, respectively. Combination of the two had the best performance in predicting the efficacy of immunotherapy (AUC = 0.9070). High PD-1/PD-L1 interaction scores and high levels of NKT-like cell infiltration significantly improved progression-free survival (HR = 0.2544, P = 0.0053) and overall survival (HR = 0.2820, P = 0.0053) in patients. CONCLUSIONS: Combination of PD-1/PD-L1 interaction score and NKT-like cell infiltration level had favorable performance in predicting immunotherapy response in NSCLC patients, contributing to accurately identify patients who may benefit from immunotherapy.

Autostereoscopic 3D viewing can change the dimensions of the crystalline lens in myopes.

PURPOSE: Autostereoscopic displays have become increasingly common, but their impact on ocular dimensions remains unknown. We sought to identify changes in the crystalline lens dimensions induced by autostereoscopic three-dimensional (3D) viewing. METHODS: Forty young adults (age: 22.6 ± 2.0 years, male/female: 15/25) were consecutively enrolled and randomly divided into two groups (3D and two-dimensional [2D] viewing groups) to watch a 30-min movie clip displayed in 3D or 2D mode on a tablet computer. The lens thickness (LT), diameter, curvature, decentration and tilt were measured with anterior segment optical coherence tomography under both non-accommodating (static) and accommodating conditions. RESULTS: In the static condition, the LT decreased by 0.03 ± 0.03 mm (p < 0.001) and the anterior radius of curvature (ARC) increased by 0.49 ± 0.59 mm (p = 0.001) post-3D viewing. In contrast, following 2D viewing, the ARC decreased by 0.23 ± 0.25 mm (p = 0.001). Additionally, the increase in the steep ARC post-3D viewing was greater in high-myopic eyes than low to moderate myopic eyes (p = 0.04). When comparing the accommodative with the static (non-accommodative) condition, for 3D viewing the lens decentration decreased (-0.03 ± 0.05 mm, p = 0.02); while for 2D viewing, the posterior curvature radius (-0.14 ± 0.20 mm, p = 0.006) and diameter (-0.13 ± 0.20 mm, p = 0.01) decreased. CONCLUSIONS: Viewing with the autostereoscopic 3D tablet could temporally decrease the thickness and curvature of the lens under non-accommodating conditions. However, its long-term effect requires further exploration.

Construction of Covalent Organic Frameworks via a Visible-Light-Activated Photocatalytic Multicomponent Reaction.

Multicomponent reactions (MCRs), as a powerful one-pot combinatorial synthesis tool, have been recently applied to the synthesis of covalent organic frameworks (COFs). Compared with the thermally driven MCRs, the photocatalytic MCR-based COF synthesis has not yet been investigated. Herein, we first report the construction of COFs by a photocatalytic multicomponent reaction. Upon visible-light irradiation, a series of COFs with excellent crystallinity, stability, and permanent porosity are successfully synthesized via photoredox-catalyzed multicomponent Petasis reaction under ambient conditions. Additionally, the obtained Cy-N3-COF exhibits excellent photoactivity and recyclability for the visible-light-driven oxidative hydroxylation of arylboronic acids. The concept of photocatalytic multicomponent polymerization not only enriches the methodology for COF synthesis but also opens a new avenue for the construction of COFs that might not be possible with the existing synthetic methods based on thermally driven MCRs.

Effects of intrathecal pemetrexed on the survival of patients with leptomeningeal metastasis from lung adenocarcinoma: a propensity score matching analysis.

PURPOSE: To explore the impact of intrathecal pemetrexed (IP) on the survival of lung adenocarcinoma (LUAC) patients with leptomeningeal metastasis (LM). METHODS: We analyzed patients with LUAC and LM who received systemic therapy after LM diagnosis at the Fujian Cancer Hospital between July 2018 and March 2022. Patients who underwent IP were assigned to the IP group; those without IP treatment were designated as the non-IP group. Propensity score matching (PSM) was performed between the two groups. RESULTS: 165 patients were enrolled: 83 and 82 in the IP and non-IP groups, respectively. After 1:1 PSM, we included 114 patients in the matched cohort. Median overall survival (OS) was 13.2 months (95% CI 10.8-15.6 months) in the IP group versus 10.1 months (95% CI 5.3-14.9 months) in the non-IP group (P = 0.488). Only Eastern Cooperative Oncology Group Performance Status (ECOG PS) was confirmed as an independent predictor for OS in the matched cohort (hazard ratio (HR) 2.03; P = 0.023). Multivariate competing-risks analysis showed that IP significantly correlated with central nervous system-related death (HR 0.31; P = 0.046). When stratified by ECOG PS, IP improved survival in patients with poor ECOG PS (PS = 2) (14.3 months vs. 1.6 months; P = 0.003). CONCLUSIONS: Intrathecal pemetrexed did not enhance OS for the entire LUAC patient with LM compared to non-intrathecal chemotherapy. However, it exhibited the potential to reduce the risk of central nervous system-related mortality and improve survival in patients with poor ECOG PS.

Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model.

Inflammation and glutamate (GLU) are widely thought to participate in the pathogenesis of depression, and current evidence suggests that the development of depression is associated with the activation of the kynurenine pathway (KP). However, the exact mechanism of KP among the inflammation, GLU and depression remain poorly understood. In this study, we examined the involvement of KP, inflammation and GLU in depressive phenotype induced by chronic unpredictable mild stress (CUMS) in C57B/6 J mice. Our results showed that CUMS caused depressive like-behavior in the sucrose preference test, tail suspension test and forced swimming test. From a molecular perspective, CUMS upregulated the peripheral and central inflammatory response and activated indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of KP, which converts tryptophan (TRP) into kynurenine (KYN). KYN is a precursor for QA in microglia, which could activate the N-methyl-D-aspartate receptor (NMDAR), increasing the GLU release, mirrored by increased IDO activity, quinolinic acid and GLU levels in the hippocampus, prefrontal cortex and serum. However, intervention with IDO inhibitor 1-methyl-DL-tryptophan (50 mg/kg/s.c.) and 1-methyl-L-tryptophan (15 mg/kg/i.p.) reversed the depressive-like behaviors and adjusted central and peripheral KP's metabolisms levels as well as GLU content, but the inflammation levels were not completely affected. These results provide certain evidence that KP may be a vital pathway mediated by IDO linking inflammation and glutamate, contributing to depression.

Deep Learning-based Trichoscopic Image Analysis and Quantitative Model for Predicting Basic and Specific Classification in Male Androgenetic Alopecia.

Since the results of basic and specific classification in male androgenetic alopecia are subjective, and trichoscopic data, such as hair density and diameter distribution, are potential quantitative indicators, the aim of this study was to develop a deep learning framework for automatic trichoscopic image analysis and a quantitative model for predicting basic and specific classification in male androgenetic alopecia. A total of 2,910 trichoscopic images were collected and a deep learning framework was created on convolutional neural networks. Based on the trichoscopic data provided by the framework, correlations with basic and specific classification were analysed and a quantitative model was developed for predicting basic and specific classification using multiple ordinal logistic regression. A deep learning framework that can accurately analyse hair density and diameter distribution on trichoscopic images and a quantitative model for predicting basic and specific classification in male androgenetic alopecia were established.

Identifying Key Biomarkers and Immune Infiltration in Female Patients with Ischemic Stroke Based on Weighted Gene Co-Expression Network Analysis.

Stroke is one of the leading causes of death and disability worldwide. Evidence shows that ischemic stroke (IS) accounts for nearly 80 percent of all strokes and that the etiology, risk factors, and prognosis of this disease differ by gender. Female patients may bear a greater burden than male patients. The immune system may play an important role in the pathophysiology of females with IS. Therefore, it is critical to investigate the key biomarkers and immune infiltration of female IS patients to develop effective treatment methods. Herein, we used weighted gene co-expression network analysis (WGCNA) to determine the key modules and core genes in female IS patients using the GSE22255, GSE37587, and GSE16561 datasets from the GEO database. Subsequently, we performed functional enrichment analysis and built a protein-protein interaction (PPI) network. Ten genes were selected as the true central genes for further investigation. After that, we explored the specific molecular and biological functions of these hub genes to gain a better understanding of the underlying pathogenesis of female IS patients. Moreover, the "Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT)" was used to examine the distribution pattern of immune subtypes in female patients with IS and normal controls, revealing a new potential target for clinical treatment of the disease.

Identification and validation of hub genes of synovial tissue for patients with osteoarthritis and rheumatoid arthritis.

BACKGROUND: Osteoarthritis (OA) and rheumatoid arthritis (RA) were two major joint diseases with similar clinical phenotypes. This study aimed to determine the mechanistic similarities and differences between OA and RA by integrated analysis of multiple gene expression data sets. METHODS: Microarray data sets of OA and RA were obtained from the Gene Expression Omnibus (GEO). By integrating multiple gene data sets, specific differentially expressed genes (DEGs) were identified. The Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and protein-protein interaction (PPI) network analysis of DEGs were conducted to determine hub genes and pathways. The "Cell Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT)" algorithm was employed to evaluate the immune infiltration cells (IICs) profiles in OA and RA. Moreover, mouse models of RA and OA were established, and selected hub genes were verified in synovial tissues with quantitative polymerase chain reaction (qPCR). RESULTS: A total of 1116 DEGs were identified between OA and RA. GO functional enrichment analysis showed that DEGs were enriched in regulation of cell morphogenesis involved in differentiation, positive regulation of neuron differentiation, nuclear speck, RNA polymerase II transcription factor complex, protein serine/threonine kinase activity and proximal promoter sequence-specific DNA binding. KEGG pathway analysis showed that DEGs were enriched in EGFR tyrosine kinase inhibitor resistance, ubiquitin mediated proteolysis, FoxO signaling pathway and TGF-beta signaling pathway. Immune cell infiltration analysis identified 9 IICs with significantly different distributions between OA and RA samples. qPCR results showed that the expression levels of the hub genes (RPS6, RPS14, RPS25, RPL11, RPL27, SNRPE, EEF2 and RPL19) were significantly increased in OA samples compared to their counterparts in RA samples (P < 0.05). CONCLUSION: This large-scale gene analyses provided new insights for disease-associated genes, molecular mechanisms as well as IICs profiles in OA and RA, which may offer a new direction for distinguishing diagnosis and treatment between OA and RA.

Two-year observation of morphologic and histopathologic changes in the monkey cornea following small incision allogenic lenticule implantation.

PURPOSE: To observe the morphologic and histopathologic changes of femtosecond laser assisted small incision allogenic intrastromal lenticule implantation (AILI) in monkey corneas. METHODS: 6 healthy adult monkeys were included. One eye of two monkeys and both eyes of one monkey received femtosecond lenticule extraction with a -4.0 diopter (D) correction. Each extracted refractive donor lenticule was immediately allogeneically transplanted into a corneal stromal pocket created by a femtosecond laser in another monkey's eye. A postoperative two-year follow-up was performed with slit lamp microscopy, corneal topography, anterior segment optical coherence tomography and in vivo confocal microscopy. All eyes were enucleated for Hematoxylin-Eosin staining and transmission electron microscopy (TEM) observation. RESULTS: No complications were observed in the follow-up period. At postoperative 2 years, the corneas remained clear and the lenticules were integrated with the surrounding tissue under slit lamp microscopy. Nerve fiber regeneration was detected in the lenticule layer as observed through confocal microscopy. Corneal power was increased by 1.83 ± 1.36 D after 2 years, which was less than at 6 months (3.27 ± 1.2 D). Disordered fibers and decreased keratocytes in the implanted lenticules could be detected under light microscopy and TEM, with a clear boundary between the lenticules and the surrounding tissue. CONCLUSIONS: Small incision AILI is feasible and safe for reshaping the cornea. Corneal healing remained stable while refraction showed a moderate regression within postoperative 2 years.

One-year natural course of corneal densitometry in high myopic patients after implantation of an implantable collamer lens (model V4c).

BACKGROUND: Corneal densitometry, which is also known as corneal backscattering, is a surrogate measure of corneal clarity. The purpose of the study was to investigate the changes in corneal densitometry (CD) after implanting an implantable collamer lens (ICL-V4c). METHOD: Twenty-six high myopic patients (aged 29.3 ± 6.6 years, 6 males and 20 females) who underwent ICL-V4c implantation were enrolled. Intraocular pressure (IOP), corneal topography, corneal densitometry, uncorrected distance visual acuity (UCDVA), manifest refraction, and best corrected distance visual acuity (BCDVA) were evaluated pre-operatively and at 1 day, 1 week, and 1, 3, 6, and 12 months post-operatively. Endothelial cell density (ECD) was measured pre-operatively and at 3, 6, and 12 months post-operatively. The efficacy index (mean post-operative UCDVA / mean pre-operative BCDVA) and the safety index (mean post-operative BCDVA / mean pre-operative BCDVA) were evaluated at 1 month, 3 months, 6 months and 12 months post-operatively. RESULTS: Over the annular diameters of 0-2 mm, the pre-operative densitometry values of the anterior layer, central layer, posterior layer, and total layer were 20.1 ± 2.8, 11.8 ± 1.1, 10.5 ± 0.9 and 14.1 ± 1.5, respectively. From pre-operatively to post-operative Month 12, the values changed insignificantly (P = 0.177, P = 0.153, P = 0.543 and P = 0.207, respectively). Over the annular diameters of 2-6 mm, the pre-operative mean densitometry values were 17.9 ± 2.2, 10.5 ± 0.9, and 12.6 ± 1.2, respectively. From pre-operatively to post-operative Month 12, the values decreased to 16.5 ± 2.1, 10.0 ± 0.9, and 11.9 ± 1.2, respectively, which were similar to the pre-operative values (all P > 0.05) but significantly lower than the values obtained at post-operative Day 1 (P = 0.013, P = 0.002 and P = 0.010, respectively). The densitometry value of the posterior layer over the annular diameters of 2 to 6 mm remained unchanged (from 9.4 ± 0.7 to 9.1 ± 0.7) over time (P = 0.372). The efficacy and safety indices assessed at 12 months post-operatively were 1.04 ± 0.27 and 1.19 ± 0.23, respectively. The changes in IOP and ECD values were statistically insignificant (P = 0.896 and P = 0.968, respectively). CONCLUSION: ICL-V4c implantation may be safe and efficient for high ametropia correction. The corneal densitometry values obtained over the annulus of 0-6 mm increased slightly from before the operation to post-operative Day 1 and then decreased gradually, which indicates that ICL-V4c implantation may not compromise corneal clarity.

EA Improves the Motor Function in Rats with Spinal Cord Injury by Inhibiting Signal Transduction of Semaphorin3A and Upregulating of the Peripheral Nerve Networks.

Peripheral nerve networks (PNNs) play a vital role in the neural recovery after spinal cord injury (SCI). Electroacupuncture (EA), as an alternative medicine, has been widely used in SCI and was proven to be effective on neural functional recovery. In this study, the interaction between PNNs and semaphrin3A (Sema3A) in the recovery of the motor function after SCI was observed, and the effect of EA on them was evaluated. After the establishment of the SCI animal model, we found that motor neurons in the ventral horn of the injured spinal cord segment decreased, Nissl bodies were blurry, and PNNs and Sema3A as well as its receptor neuropilin1 (NRP1) aggregated around the central tube of the gray matter of the spinal cord. When we knocked down the expression of Sema3A at the damage site, NRP1 also downregulated, importantly, PNNs concentration decreased, and tenascin-R (TN-R) and aggrecan were also reduced, while the Basso-Beattie-Bresnahan (BBB) motor function score dramatically increased. In addition, when conducting EA stimulation on Jiaji (EX-B2) acupoints, the highly upregulated Sema3A and NRP1 were reversed post-SCI, which can lessen the accumulation of PNNs around the central tube of the spinal cord gray matter, and simultaneously promote the recovery of motor function in rats. These results suggest that EA may further affect the plasticity of PNNs by regulating the Sema3A signal and promoting the recovery of the motor function post-SCI.

Covalent immobilization of recombinant Citrobacter koseri transaminase onto epoxy resins for consecutive asymmetric synthesis of L-phosphinothricin.

Transaminase responsible for alienating prochiral ketone compound is applicable to asymmetric synthesis of herbicide L-phosphinothricin (L-PPT). In this work, the covalent immobilization of recombinant transaminase from Citrobacter koseri (CkTA) was investigated on different epoxy resins. Using optimum ES-105 support, a higher immobilized activity was obtained via optimizing immobilization process in terms of enzyme loading, coupling time and initial PLP concentration. Crucially, due to blocking unreacted epoxy groups on support surface with amino acids, the reaction temperature of blocked immobilized biocatalyst was enhanced from 37 to 57 °C. Its thermostability at 57 °C was also found to be superior to that of free CkTA. The Km value was shifted from 36.75 mM of free CkTA to 39.87 mM of blocked immobilized biocatalyst, demonstrating that the affinity of enzyme to the substrate has not been apparently altered. Accordingly, the biocatalyst performed the consecutive synthesis of L-PPT for 11 cycles (yields>91%) with retaining more than 91.13% of the initial activity. The seemingly the highest reusability demonstrates this biocatalyst has prospective for reducing the costs of consecutive synthesis of L-PPT with high conversion.

Two-year outcome of an eye that underwent hyperopic LASIK following inadvertent myopic SMILE lenticule in situ implantation.

BACKGROUND: This report describes a case in which hyperopic femtosecond laser-assisted in situ keratomileusis (FS-LASIK) was performed following small incision lenticule extraction (SMILE) lenticule in situ implantation. CASE PRESENTATION: The hyperopic left eye of a 46-year-old patient with refraction of + 7.75 diopters sphere (DS)/- 1.25 diopters cylinder (DC) × 5° and corrected distance visual acuity (CDVA) of 20/50 mistakenly underwent the SMILE procedure for myopic astigmatism (- 8.50 DS/- 1.50 DC × 175°) due to medical negligence. The extracted lenticule was subsequently re-implanted in situ. After 8 months, the left eye underwent FS-LASIK to correct hyperopia and astigmatism (+ 5.0 DS/- 0.75 DC × 100°). Two years after FS-LASIK, corneal tomography showed no ectasia and microscopy revealed transparent cornea. The left eye exhibited CDVA of 20/50 with refraction of - 0.75 DS/- 0.25 DC × 165°. CONCLUSIONS: SMILE lenticule in situ implantation offers a solution for corneal volume and thickness restoration. FS-LASIK provides feasible correction of refractive error following lenticule re-implantation. Future studies are needed for determining the effectiveness of the treatment.

Co-expression of NF-κB-p65 and phosphorylated NF-κB-p105 is associated with poor prognosis in surgically resectable non-small cell lung cancer.

Nuclear factor-kappa B (NF-κB) as a prognostic marker remains unclear in non-small cell lung cancer (NSCLC). Here, we studied NF-κB-p65 (p65) expression and phosphorylated NF-κB-p105 (p-p105) expression in NSCLC and correlated the finding with overall survival (OS) and clinicopathological features. A total of 186 archival samples from patients with surgically resectable NSCLC were probed with p65 and p-p105 (Ser 932). The p65-positive expression and p-p105-positive expression were defined as distinct nuclear p65 and cytoplasmic p-p105 labelling in at least 1% of tumour cells, respectively. The positive staining of p65 alone, p-p105 alone and co-expression of p65 and p-p105 were observed in 61 (32.8%), 90 (48.4%) and 35 (18.8%) patients, respectively. Co-expression of p65 and p-p105 but not of either p65 or p-p105 alone was associated with a poor prognosis. Patients with co-expression of p65 and p-p105 had a shorter OS than others, median OS 26.5 months versus 64.1 months, HR 1.85 (95% CI: 1.18-2.91), P = 0.007. There was no statistically significant association between clinicopathological characteristics and either p65 or p-p105 alone or co-expression of p65 and p-p105. This indicates that co-expression of p65 and p-p105 was a poor prognostic factor, and pathologic studies of NF-κB expression could include multiple pathway components in NSCLC.

Two-year topographic and densitometric outcomes of accelerated (45 mW/cm2) transepithelial corneal cross-linking for keratoconus: a case-control study.

BACKGROUND: Conventional corneal cross-linking is effective for retarding the progression of keratoconus. However the long-term efficacy and safety of accelerated (45 mW/cm2) transepithelial corneal cross-linking (ATE-CXL) on progressive keratoconus (KC) treatment is not fully understood. The purpose of this study is to evaluate the 2-year changes in corneal topographic parameters and densitometry values after ATE-CXL for KC. METHODS: Twenty-five progressive eyes of 25 KC patients (KC group) and 25 eyes of 25 myopes without KC (control group) were enrolled. Corneal topography and densitometry values were evaluated pre-operatively and at 6, 12 and 24 months post-operatively in the KC group. RESULTS: The mean values of flat keratometry (K1), steep keratometry (K2), mean keratometry (Km), corneal astigmatism (CA), maximum keratometry (Kmax), central corneal thickness (CCT), thinnest corneal thickness (TCT), anterior corneal elevation (ACE) and posterior corneal elevation (PCE) all remained unchanged over time (all P values > 0.05). The densitometry values of the anterior, central, posterior and total layers over the annular diameters 0 mm to 2 mm (Φ0-2 mm) and Φ2-6 mm all decreased significantly (all P values < 0.05). At post-operative month 24, except for the densitometry value of the posterior layer (Φ0-2 mm), which was significantly lower than that of the control group (post hoc P = 0.010), all densitometry values obtained from the remaining locations of the KC eyes were equal to those of the control group (All post hoc P values > 0.05). Subgroups with Km ≥ 50.30D or ACE ≥35.3 µm progressed significantly when compared with those with Km < 50.30D (F = 8.167, P = 0.004) or ACE< 35.3 µm (F = 5.207, P = 0.022). CONCLUSIONS: K1, K2, Km, CA, Kmax, CCT, TCT, ACE, and PCE values may remain stable but severer KC patients tend to have poorer long-term outcomes. The densitometry values of the full corneal thickness (total layer over Φ0-2 mm and Φ2-6 mm) may decrease to normal levels at 2 years after ATE-CXL for KC.

A pilot study: LASEK with the Triple-A profile of a MEL 90 for mild and moderate myopia.

BACKGROUND: To investigate the visual and refractive outcomes in patients with mild to moderate myopia after laser-assisted subepithelial keratectomy (LASEK) using the 500 Hz pulse rate of the Triple-A profile. METHODS: Thirty-six eyes of 20 patients (mean age, 27.5 ± 4.6 years) were included in this prospective, consecutive study. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), corneal topography, and corneal aberrations were measured preoperatively and 1 day, 1 week, 1, 3 and 6 months post-operation. RESULTS: At 1 week after surgery, UDVA was better than or equal to 20/25 in all eyes. At postoperative 6 months, the efficacy and safety index was 1.05 ± 0.13 and 1.12 ± 0.15, respectively; all eyes had a UDVA of 20/20 or better, and no eyes showed a loss in CDVA; 100% of the eyes were within ±1.00 D of the attempted spherical equivalent (SE) correction. CONCLUSION: The postoperative results indicate that using the Triple-A ablation profile of the MEL 90 excimer laser with a 500 Hz pulse rate is a safe, efficient, and predictable method to correct mild to moderate myopia.

The observation during small incision lenticule extraction for myopia with corneal opacity.

BACKGROUND: To evaluate the feasibility and efficacy of small incision lenticule extraction (SMILE) in the treatment of myopia with corneal opacity. METHODS: To evaluate the treatment of myopia with corneal opacity, 9 patients (4 males, 5 females) who underwent SMILE were enrolled in this prospective clinical study. One eye of each patient was treated. The results of laser scanning and lenticule extraction were observed during the surgery, and the surgical videos were again reviewed after surgery. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and spherical equivalence (SE) were noted at 1 month after surgery. The depth and density of the corneal opacities were measured by anterior segment optical coherence tomography (AS-OCT) and the Pentacam anterior eye segment analyzer. RESULTS: All procedures were uneventful and no intraoperative complications were observed. At 1 month after surgery, the UDVA of all patients was 20/25 or better and no patients lost Snellen lines. The mean safety and efficacy indexes were 1.10 ± 0.24 and 1.08 ± 0.16, respectively, at 1 month postoperatively. The mean postoperative spherical equivalent was 0.27 ± 0.23 diopter (D). All eyes were within ±0.75 D and 8 eyes (88.9%) were within ±0.50 D. There was no eccentric corneal topography or abnormal morphology in the corneal caps. The corneal opacities of all patients were within the optical zone. The mean preoperative depths in the deepest areas of corneal opacity were 152 ± 38 µm (range: 86-217 µm); at 1 month after surgery (P < .01), they were 117 ± 28 µm (range: 86-189 µm). The preoperative maximum density of corneal opacity was 48.5 ± 20.7 (range: 20.4 to 85.8); at 1 month after surgery (P > .05), it was 49.8 ± 26.7 (range: 19.8 to 82.5) at 1 month after surgery. CONCLUSION: Patients with corneal opacity can be successfully treated with the SMILE operation. The short-term outcome was good, however the long-term results need further study. TRIAL REGISTRATION: The trial registration number: ChiCTR-ONRC-13003114 , Date of Last Refreshed on: 2016-01-27, Date of registration on 2013-03-17(retrospectively registered).

Reciprocal activation between STAT3 and miR-181b regulates the proliferation of esophageal cancer stem-like cells via the CYLD pathway.

BACKGROUND: Recent studies have suggested that cancer cells contain subpopulations that can initiate tumor growth, self-renew, and maintain tumor cell growth. However, for esophageal cancer cells, the relationship between STAT3, microRNAs and cancer stem cells remains unclear. METHODS: Serum-free culture was used to enrich esophageal cancer stem-like cells (ECSLC). Flow cytometry determined the proportion of ECSLC. qPCR were performed to examine expression level of stemness factors, mesenchymal markers, ATP-binding cassette (ABC) transporters, STAT3, miR-181b, CYLD. Western blot were performed to analyze the expression of STAT3, p-STAT3 and CYLD (cylindromatosis). BALB/c mice xenograft studies were conducted to evaluate the tumorigenicity of enriched ECSLC. Sphere formation assay and colony formation assays were employed to analyze the relationship between STAT3 and miR-181b. Luciferase assays were used to evaluate activity which CYLD is a target of miR-181b. RESULTS: Sphere formation cells (SFCs) with properties of ECSLC were enriched. Enriched SFCs in serum-free suspension culture exhibited cancer stem-like cell properties and increased single-positive CD44 + CD24-, stemness factor, mesenchymal marker expression ABC transporters and tumorigenicity in vivo compared with the parental cells. Additionally, we found that reciprocal activation between STAT3 and miR-181b regulated SFCs proliferation. Moreover, STAT3 directly activated miR-181b transcription in SFCs and miR-181b then potentiated p-STAT3 activity. Luciferase assays indicated that CYLD was a direct and functional target of miR-181b. CONCLUSION: The mutual regulation between STAT3 and miR-181b in SFCs was required for proliferation and apoptosis resistance. STAT3 and miR-181b control each other's expression in a positive feedback loop that regulates SFCs via CYLD pathway. These findings maybe is helpful for targeting ECSLC and providing approach for esophageal cancer treatments.